start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260717 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tripartite Interaction Between Penicillium pinophilum-Host Plants and CMV-Y: A Model for Endophyte-Mediated Viral Biocontrol en-subtitle= kn-subtitle= en-abstract= kn-abstract=Plant-fungus-virus tripartite interactions represent complex ecological systems in which mutualistic endophytes can influence host physiology, yet the molecular basis of endophyte-mediated defence remains poorly understood. Here, we demonstrate that the endophytic fungus Penicillium pinophilum EU0013 suppresses the yellow strain of cucumber mosaic virus (CMV-Y) in Solanum lycopersicum and Nicotiana benthamiana. CMV-Y infection induced pronounced oxidative and hormonal perturbations, which were mitigated by P. pinophilum colonisation. Endophyte-associated plants exhibited early accumulation of jasmonate intermediates, consistent with the activation of jasmonate signalling. This response promoted the degradation of jasmonate-ZIM-domain proteins and release of core JA-responsive transcription factors. Virus-induced gene silencing identified MYC2 as a key regulator required for endophyte-mediated antiviral protection, with WRKY17 contributing to defence modulation. In parallel, transcriptome analysis revealed the upregulation of a Dicer-like gene, indicating enhanced engagement of RNA silencing, a primary antiviral mechanism targeting viral RNA. This coordinated activation occurred alongside significant induction of pathogenesis-related proteins, particularly PR9, and improved control of reactive oxygen species. Salicylic acid-responsive defences showed a host-modulated pattern, with PR1 induced by CMV and PR2/PR5 preferentially enhanced in endophyte-associated plants. Collectively, these findings demonstrate that P. pinophilum enhances antiviral immunity through coordinated defence integration pathways, providing a framework for endophyte-based viral disease management. en-copyright= kn-copyright= en-aut-name=IbiangSarah R. en-aut-sei=Ibiang en-aut-mei=Sarah R. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=GalisIvan en-aut-sei=Galis en-aut-mei=Ivan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KondoHideki en-aut-sei=Kondo en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SuzukiNobuhiro en-aut-sei=Suzuki en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Group of Plant-Microbe Interactions, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=Group of Plant-Insect Interactions, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=3 en-affil=Group of Plant-Microbe Interactions, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=4 en-affil=Group of Plant-Microbe Interactions, Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=cucumber mosaic virus kn-keyword=cucumber mosaic virus en-keyword=endophyte‐mediated resistance kn-keyword=endophyte‐mediated resistance en-keyword=jasmonate signalling kn-keyword=jasmonate signalling en-keyword=pathogenesis‐related proteins kn-keyword=pathogenesis‐related proteins en-keyword=solanaceae kn-keyword=solanaceae en-keyword=tripartite interaction kn-keyword=tripartite interaction END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=7 article-no= start-page=e73156 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202607 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Custom‐Made Mouthpiece‐Assisted Oral Cryotherapy During Hematopoietic Stem Cell Transplantation in a Patient With Hemimaxillectomy‐Related Oroantral Communication: A Case Report en-subtitle= kn-subtitle= en-abstract= kn-abstract=A custom-made mouthpiece enabled safe oral cryotherapy in a patient with extensive oroantral communication after hemimaxillectomy and may also be applicable to other patients with communication between the oral cavity and the maxillary sinus or nasal cavity. en-copyright= kn-copyright= en-aut-name=MatsuzakiKumiko en-aut-sei=Matsuzaki en-aut-mei=Kumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyazakiFuminobu en-aut-sei=Miyazaki en-aut-mei=Fuminobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MotoyamaYasuji en-aut-sei=Motoyama en-aut-mei=Yasuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakedaSeiko en-aut-sei=Takeda en-aut-mei=Seiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KubokiTakuo en-aut-sei=Kuboki en-aut-mei=Takuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SogaYoshihiko en-aut-sei=Soga en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Division of Hospital Dentistry, Okayama University Hospital kn-affil= affil-num=2 en-affil=Dental Laboratory Division, Okayama University Hospital kn-affil= affil-num=3 en-affil=Dental Laboratory Division, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Hospital kn-affil= affil-num=5 en-affil=Dental Laboratory Division, Okayama University Hospital kn-affil= affil-num=6 en-affil=Division of Hospital Dentistry, Okayama University Hospital kn-affil= en-keyword=hematopoietic stem cell transplantation kn-keyword=hematopoietic stem cell transplantation en-keyword=hemimaxillectomy kn-keyword=hemimaxillectomy en-keyword=mouthpiece kn-keyword=mouthpiece en-keyword=oral cryotherapy kn-keyword=oral cryotherapy en-keyword=oral mucositis kn-keyword=oral mucositis END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue= article-no= start-page=1875734 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260703 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Quantitative resistance to Rhizoctonia solani AG-4 develops independently in leaves and roots of Brachypodium distachyon en-subtitle= kn-subtitle= en-abstract= kn-abstract=Rhizoctonia solani is a soil-borne phytopathogen with a broad host range, classified into multiple anastomosis groups (AGs). While the rice sheath blight pathogen AG-1 IA is well-studied, defense mechanisms against AG-4, which infects diverse monocots and dicots, remain unclear. Here, we screened 153 Brachypodium distachyon accessions for resistance to AG-4 HG-I+II using both leaf and soil inoculation assays. The accessions exhibited a quantitative resistance spectrum in both assays. Some accessions were resistant to both methods, while others showed resistance in only one, indicating that leaf and root defenses operate independently. Unlike the salicylic acid (SA)-dependent resistance observed in several accessions against AG-1 IA, AG-4 leaf resistance appears to be largely SA-independent. Among 22 resistant accessions, only eight induced the SA marker BdWRKY38, whereas twelve induced the jasmonic acid (JA) marker BdAOS. Additionally, resistance in Bd3–1 was unaffected by expression of the SA hydroxylase NahG. These results are consistent with previous findings that exogenous application of SA, JA, or ethylene fails to confer AG-4 resistance. Instead, most AG-4-resistant accessions showed common upregulation of cell wall biosynthesis-related genes following leaf infection, suggesting that cell wall fortification may contribute to defense against AG-4. These findings establish B. distachyon as a valuable model for dissecting resistance mechanisms against R. solani AG-4. en-copyright= kn-copyright= en-aut-name=FernandaRozi en-aut-sei=Fernanda en-aut-mei=Rozi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MahadevanNiranjan en-aut-sei=Mahadevan en-aut-mei=Niranjan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KohnoNatsuka en-aut-sei=Kohno en-aut-mei=Natsuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NagaoReiko en-aut-sei=Nagao en-aut-mei=Reiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WatanabeMegumi en-aut-sei=Watanabe en-aut-mei=Megumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SakataNanami en-aut-sei=Sakata en-aut-mei=Nanami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MatsuiHidenori en-aut-sei=Matsui en-aut-mei=Hidenori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ToyodaKazuhiro en-aut-sei=Toyoda en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IchinoseYuki en-aut-sei=Ichinose en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KouzaiYusuke en-aut-sei=Kouzai en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MochidaKeiichi en-aut-sei=Mochida en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NoutoshiYoshiteru en-aut-sei=Noutoshi en-aut-mei=Yoshiteru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=School of Agriculture, Okayama University kn-affil= affil-num=4 en-affil=School of Agriculture, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Crop Stress Management Group, Division of Plant Molecular Regulation Research, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization (NARO) kn-affil= affil-num=11 en-affil=RIKEN Center for Sustainable Resource Science kn-affil= affil-num=12 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=Brachypodium distachyon kn-keyword=Brachypodium distachyon en-keyword=cell wall fortification kn-keyword=cell wall fortification en-keyword=phytohormone kn-keyword=phytohormone en-keyword=quantitative resistance kn-keyword=quantitative resistance en-keyword=Rhizoctonia solani kn-keyword=Rhizoctonia solani en-keyword=root infection kn-keyword=root infection END start-ver=1.4 cd-journal=joma no-vol=75 cd-vols= no-issue=3 article-no= start-page=400 end-page=408 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202607 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Outcomes following the discontinuation of biologic therapy in patients with severe asthma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Biologic therapies are pivotal in managing severe asthma. Despite their efficacy, some patients discontinue biologics, with varying outcomes. Predictors of successful versus unsuccessful discontinuation remain poorly defined. This study aimed to identify clinical factors associated with post-discontinuation outcomes in a real-world practice.
Methods: This retrospective cohort included adults with severe asthma who had received biologics for at least 12 months and subsequently discontinued therapy for a minimum of three consecutive months. We assessed the effects of baseline blood eosinophilia (≥300 cells/μL), residual sputum symptoms during biologic therapy, treatment responsiveness, biologic class, and discontinuation reasons on post-discontinuation asthma exacerbation rates using multivariable Cox models.
Results: A total of 118 patients were analyzed. The Kaplan–Meier analysis estimated a 65 % exacerbation-free probability at 12 months after discontinuation. Factors associated with successful discontinuation included a robust clinical response and absence of exacerbations before cessation. Conversely, baseline eosinophilia, residual sputum symptoms during biologics, and discontinuation due to inadequate therapeutic response or financial burden were associated with post-discontinuation exacerbations. In class-stratified restricted models, persistent sputum remained significantly associated with post-discontinuation exacerbations after stopping anti-IL-5 therapies, while baseline eosinophilia was associated with post-discontinuation exacerbations after stopping anti-IgE or anti-IL-4Rα. Among patients with sputum symptoms or poor-response discontinuation, the overall frequency of exacerbations declined after discontinuation.
Conclusions: Baseline eosinophilia, persistent sputum during therapy, and discontinuation prompted by poor response or cost may serve as risk factors for post-discontinuation exacerbations; however, risk is phenotype- and class-dependent. Careful patient selection and monitoring are essential when considering the discontinuation of biologic treatment. en-copyright= kn-copyright= en-aut-name=NagasakiTadao en-aut-sei=Nagasaki en-aut-mei=Tadao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsumotoHisako en-aut-sei=Matsumoto en-aut-mei=Hisako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IwanagaTakashi en-aut-sei=Iwanaga en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsunagaKazuto en-aut-sei=Matsunaga en-aut-mei=Kazuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SekiyaKiyoshi en-aut-sei=Sekiya en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HaradaTomoya en-aut-sei=Harada en-aut-mei=Tomoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SakuraiShogo en-aut-sei=Sakurai en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HaradaNorihiro en-aut-sei=Harada en-aut-mei=Norihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KoyaToshiyuki en-aut-sei=Koya en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FukunagaKoichi en-aut-sei=Fukunaga en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KanekoTakeshi en-aut-sei=Kaneko en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=AsaiKazuhisa en-aut-sei=Asai en-aut-mei=Kazuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KomaseYuko en-aut-sei=Komase en-aut-mei=Yuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=GonYasuhiro en-aut-sei=Gon en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TanakaAkihiko en-aut-sei=Tanaka en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SagaraHironori en-aut-sei=Sagara en-aut-mei=Hironori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=SunadomeHironobu en-aut-sei=Sunadome en-aut-mei=Hironobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NaganoTatsuya en-aut-sei=Nagano en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=NakamuraYoichi en-aut-sei=Nakamura en-aut-mei=Yoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=NiimiAkio en-aut-sei=Niimi en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=HattoriNoboru en-aut-sei=Hattori en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=HajiroTakashi en-aut-sei=Hajiro en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=FujimotoHajime en-aut-sei=Fujimoto en-aut-mei=Hajime kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=HojoMasayuki en-aut-sei=Hojo en-aut-mei=Masayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=MiyaharaNobuaki en-aut-sei=Miyahara en-aut-mei=Nobuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=YamaguchiMasafumi en-aut-sei=Yamaguchi en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=TsujiKimiko en-aut-sei=Tsuji en-aut-mei=Kimiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=SanoAkiko en-aut-sei=Sano en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=HaraguchiRyuta en-aut-sei=Haraguchi en-aut-mei=Ryuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=SanoHiroyuki en-aut-sei=Sano en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=MurakiMasato en-aut-sei=Muraki en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=TohdaYuji en-aut-sei=Tohda en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= affil-num=1 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Nara Hospital kn-affil= affil-num=2 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine kn-affil= affil-num=4 en-affil=Department of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University kn-affil= affil-num=5 en-affil=Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital kn-affil= affil-num=6 en-affil=Department of Multidisciplinary Internal Medicine, Division of Respiratory Medicine and Rheumatology, Faculty of Medicine, Tottori University kn-affil= affil-num=7 en-affil=Department of Respiratory Medicine, Shizuoka General Hospital kn-affil= affil-num=8 en-affil=Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences kn-affil= affil-num=10 en-affil=Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine kn-affil= affil-num=11 en-affil=Department of Pulmonology, Yokohama City University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Respiratory Medicine, Graduate School of Medicine, Osaka Metropolitan University kn-affil= affil-num=13 en-affil=Department of Respiratory Medicine, St.Marianna University School of Medicine, Yokohama Seibu Hospital kn-affil= affil-num=14 en-affil=Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine kn-affil= affil-num=15 en-affil=Department of Medicine, Division of Respiratory Medicine and Allergology, Showa Medical University, School of Medicine kn-affil= affil-num=16 en-affil=Department of Medicine, Division of Respiratory Medicine and Allergology, Showa Medical University, School of Medicine kn-affil= affil-num=17 en-affil=Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University kn-affil= affil-num=18 en-affil=Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine kn-affil= affil-num=19 en-affil=Medical Center for Allergic and Immune Diseases, Yokohama City Minato Red Cross Hospital kn-affil= affil-num=20 en-affil=Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences kn-affil= affil-num=21 en-affil=Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University kn-affil= affil-num=22 en-affil=Department of Respiratory Medicine, Tenri Hospital kn-affil= affil-num=23 en-affil=Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine kn-affil= affil-num=24 en-affil=Division of Respiratory Medicine, National Center for Global Health and Medicine kn-affil= affil-num=25 en-affil=Department of Medical Technology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=26 en-affil=Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science kn-affil= affil-num=27 en-affil=Department of Respiratory Medicine and Allergology, Kochi Medical School, Kochi University kn-affil= affil-num=28 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine kn-affil= affil-num=29 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine kn-affil= affil-num=30 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine kn-affil= affil-num=31 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Nara Hospital kn-affil= affil-num=32 en-affil=Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine kn-affil= en-keyword=Adult asthma kn-keyword=Adult asthma en-keyword=Biologics kn-keyword=Biologics en-keyword=Discontinuation kn-keyword=Discontinuation en-keyword=Exacerbation kn-keyword=Exacerbation en-keyword=Severe asthma kn-keyword=Severe asthma END start-ver=1.4 cd-journal=joma no-vol=32 cd-vols= no-issue=4 article-no= start-page=454 end-page=465 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202604 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Spatial Transcriptomics Analysis of Macrophage-to-Myofibroblast Transition in Bronchiolitis Obliterans Following Hematopoietic Stem Cell Transplantation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Bronchiolitis obliterans (BO) is a severe, fibrotic manifestation of chronic graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Macrophage-derived TGF-β is linked to GVHD-related fibrosis; however, its role in BO remains unclear. Given emerging evidence of macrophage-to-myofibroblast transition (MMT) in fibrosis, this study aimed to investigate whether MMT contributes to BO development. We analyzed lung samples from 3 HSCT recipients with BO who underwent lung transplantation, with tissues from 2 patients with lung cancer as controls. Immunofluorescent staining for CD68, CD206, and α-SMA was used to identify cells undergoing MMT. Spatial transcriptomics was performed to profile gene expression in foamy macrophages across anatomical regions and histological stages, compared to control peribronchiolar regions. Immunostaining showed strong co-expression of CD68, CD206, and α-SMA in foamy macrophages within and surrounding bronchioles in BO samples, with minimal expression in controls, suggesting MMT involvement. In BO, spatial transcriptomics revealed upregulation of macrophage- and TGF-β signaling genes, with distinct stage- and region-specific gene expression patterns. Unsupervised clustering revealed a shift from inflammation to fibrosis. These findings indicate that MMT contributes to fibrosis in BO. Gene expression shifts from inflammation to fibrosis as the disease advances, underscoring the importance of early intervention. en-copyright= kn-copyright= en-aut-name=YamamotoAkira en-aut-sei=Yamamoto en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SeikeKeisuke en-aut-sei=Seike en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SugimotoSeiichiro en-aut-sei=Sugimoto en-aut-mei=Seiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NaoiYusuke en-aut-sei=Naoi en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NaganoTomohiro en-aut-sei=Nagano en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KubotaSaya en-aut-sei=Kubota en-aut-mei=Saya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KambaraYui en-aut-sei=Kambara en-aut-mei=Yui kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiwaraKanako en-aut-sei=Fujiwara en-aut-mei=Kanako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TeraoToshiki en-aut-sei=Terao en-aut-mei=Toshiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OyamaTadashi en-aut-sei=Oyama en-aut-mei=Tadashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KunihiroMari en-aut-sei=Kunihiro en-aut-mei=Mari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KobayashiHiroki en-aut-sei=Kobayashi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KondoTakumi en-aut-sei=Kondo en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FujiwaraHideaki en-aut-sei=Fujiwara en-aut-mei=Hideaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=FujiiKeiko en-aut-sei=Fujii en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of General Thoracic Surgery and Organ Transplant Center, Okayama University Hospital kn-affil= affil-num=5 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine kn-affil= affil-num=9 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=14 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=16 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=17 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=18 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=19 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=20 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=Bronchiolitis obliterans kn-keyword=Bronchiolitis obliterans en-keyword=GeoMx kn-keyword=GeoMx en-keyword=Graft versus host disease kn-keyword=Graft versus host disease en-keyword=Hematopoietic stem cell transplantation kn-keyword=Hematopoietic stem cell transplantation en-keyword=Macrophage kn-keyword=Macrophage en-keyword=Macrophage to myofibroblast transition kn-keyword=Macrophage to myofibroblast transition en-keyword=Myofibroblast kn-keyword=Myofibroblast en-keyword=Spatial transcriptomics kn-keyword=Spatial transcriptomics END start-ver=1.4 cd-journal=joma no-vol=65 cd-vols= no-issue=11 article-no= start-page=1520 end-page=1523 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Endotracheal and Endobronchial Metastases in Epidermal Growth Factor Receptor Exon 19 Deletion Lung Adenocarcinoma: A Case Successfully Managed with Bronchoscopic Therapy and Sequential Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors en-subtitle= kn-subtitle= en-abstract= kn-abstract=Endotracheal and endobronchial metastases from peripheral lung adenocarcinoma are rare, and optimal clinical management remains unclear. We herein report a 60-year-old woman with epidermal growth factor receptor (EGFR) exon 19 deletion-positive early-stage lung adenocarcinoma who underwent surgical resection followed by osimertinib treatment for recurrence. She later developed oligoprogressive disease with airway metastases. Bronchoscopic tumor removal was performed, and next-generation sequencing of the resected specimen revealed an acquired EGFR C797S mutation, along with exon 19 deletion. Gefitinib treatment was initiated, which led to a partial response. This case underscores the utility of repeated molecular profiling and local intervention in managing acquired resistance in EGFR-mutant non-small-cell lung cancer. en-copyright= kn-copyright= en-aut-name=FujiwaraMiho en-aut-sei=Fujiwara en-aut-mei=Miho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=BabaTakahiro en-aut-sei=Baba en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamadaKotaro en-aut-sei=Yamada en-aut-mei=Kotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakamuraEri en-aut-sei=Nakamura en-aut-mei=Eri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakeguchiTetsuya en-aut-sei=Takeguchi en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakigawaYuki en-aut-sei=Takigawa en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MoritaAyako en-aut-sei=Morita en-aut-mei=Ayako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HaraNaofumi en-aut-sei=Hara en-aut-mei=Naofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=WatanabeHiromi en-aut-sei=Watanabe en-aut-mei=Hiromi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=RaiKammei en-aut-sei=Rai en-aut-mei=Kammei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=SatoKen en-aut-sei=Sato en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=MakimotoGo en-aut-sei=Makimoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, NHO Okayama Medical Center kn-affil= affil-num=7 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, NHO Okayama Medical Center kn-affil= affil-num=10 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=11 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=12 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=14 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=15 en-affil=Department of Respiratory Medicine, NHO Okayama Medical Center kn-affil= affil-num=16 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=18 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= en-keyword=EGFR C797S kn-keyword=EGFR C797S en-keyword=EGFR exon 19 deletion kn-keyword=EGFR exon 19 deletion en-keyword=endotracheal metastasis kn-keyword=endotracheal metastasis en-keyword=lung adenocarcinoma kn-keyword=lung adenocarcinoma en-keyword=TBLC kn-keyword=TBLC END start-ver=1.4 cd-journal=joma no-vol=58 cd-vols= no-issue= article-no= start-page=105422 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202604 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pathological features of residual head and neck cancer after near-infrared photoimmunotherapy: implications of an unfavorable tumor immune microenvironment en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose: Near-infrared photoimmunotherapy has been approved in Japan for unresectable locally advanced or recurrent head and neck cancer. While this therapy theoretically induces selective necrosis of epidermal growth factor receptor-expressing tumor cells following administration of cetuximab sarotalocan sodium and irradiation with 690-nm light, residual disease is not uncommon in clinical practice. The mechanisms underlying such persistence remain poorly understood.
Methods: We examined two patients with head and neck squamous cell carcinoma who underwent salvage resection due to residual disease after four cycles of near-infrared photoimmunotherapy. Resected specimens were subjected to histopathological evaluation, including immunohistochemistry for epidermal growth factor receptor, cluster of differentiation 8, programmed cell death protein 1, and forkhead box P3 proteins.
Results: In both cases, residual tumor cells were predominantly localized in the superficial mucosal layers, while deeper layers were replaced by fibrosis. All residual tumors retained expression of epidermal growth factor receptor. Lymphocytic infiltration was sparse, with scattered cluster of differentiation 8-positive cells but few programmed cell death protein 1-positive or forkhead box P3-positive lymphocytes. These findings suggest that the tumor microenvironment surrounding residual tumors may have been unfavorable for the induction of robust antitumor immune responses.
Conclusion: Residual tumors after near-infrared photoimmunotherapy can occur despite adequate laser irradiation and epidermal growth factor receptor expression. Our observations imply that insufficient immune activation within the tumor microenvironment may contribute to treatment resistance. Further characterization of the post-photoimmunotherapy tumor microenvironment will be essential to better understand treatment mechanisms and to optimize therapeutic efficacy. en-copyright= kn-copyright= en-aut-name=MakinoTakuma en-aut-sei=Makino en-aut-mei=Takuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SatoYasuharu en-aut-sei=Sato en-aut-mei=Yasuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NishikoriAsami en-aut-sei=Nishikori en-aut-mei=Asami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NaoiYuto en-aut-sei=Naoi en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AndoMizuo en-aut-sei=Ando en-aut-mei=Mizuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=3 en-affil=Department of Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=4 en-affil=Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=NIR-PIT kn-keyword=NIR-PIT en-keyword=EGFR kn-keyword=EGFR en-keyword=CD8 kn-keyword=CD8 en-keyword=PD-1 kn-keyword=PD-1 en-keyword=FOXP3 kn-keyword=FOXP3 en-keyword=Tumor microenvironment kn-keyword=Tumor microenvironment en-keyword=Photoimmunotherapy kn-keyword=Photoimmunotherapy en-keyword=Head and neck cancer kn-keyword=Head and neck cancer END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=16760 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260409 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Asthma-like bronchodilator responsiveness in patients with neuronal intranuclear inclusion disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative condition characterized by the presence of intranuclear inclusions in neuronal and visceral cells. Patients with NIID can present respiratory symptoms; however, data on pulmonary functions in NIID are lacking. This study investigated the respiratory conditions in NIID patients diagnosed with histopathological and genetic studies. We conducted two spirometries before and after administrating the bronchodilator in NIID patients with asthmatic histories or symptoms. We statistically compared pre- and post-measured values including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and peak expiratory flow (PEF). Before two spirometries, we also measured fractional concentration of exhaled nitric oxide (FeNO), if possible. Of the 51finally enrolled patients, 17 (33.3%, 95% CI 20.8% to 47.9%) patients had asthmatic histories or symptoms, and 14 patients received two spirometries. After administrating the bronchodilator, FEV1 and PEF significantly increased by 150 mL (6.01%, p = 0.002) and 260 mL/s (6.72%, p = 0.017), respectively. The median (interquartile range) of FeNO measured in nine patients was 15 (10–21) ppb. Patients with NIID have airflow reversibility like asthma. This condition appears to be less associated with airway inflammation and may be related to autonomic dysfunction. en-copyright= kn-copyright= en-aut-name=TaharaDaisuke en-aut-sei=Tahara en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TaharaNao en-aut-sei=Tahara en-aut-mei=Nao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TamaiChisato en-aut-sei=Tamai en-aut-mei=Chisato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AkagiAkio en-aut-sei=Akagi en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=RikuYuichi en-aut-sei=Riku en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MiyaharaHiroaki en-aut-sei=Miyahara en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KobayashiRei en-aut-sei=Kobayashi en-aut-mei=Rei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OkadaHisashi en-aut-sei=Okada en-aut-mei=Hisashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KawamotoMichi en-aut-sei=Kawamoto en-aut-mei=Michi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IshiiJunko en-aut-sei=Ishii en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YamazakiHiroki en-aut-sei=Yamazaki en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KurashigeTakashi en-aut-sei=Kurashige en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SugiyamaAtsuhiko en-aut-sei=Sugiyama en-aut-mei=Atsuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NagaishiAkiko en-aut-sei=Nagaishi en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NishidaKatsuya en-aut-sei=Nishida en-aut-mei=Katsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SugieKazuma en-aut-sei=Sugie en-aut-mei=Kazuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=FukudomeTakayasu en-aut-sei=Fukudome en-aut-mei=Takayasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=HasegawaKazuko en-aut-sei=Hasegawa en-aut-mei=Kazuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=IshiuraHiroyuki en-aut-sei=Ishiura en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KoikeHaruki en-aut-sei=Koike en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KasaiTakashi en-aut-sei=Kasai en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=MizunoToshiki en-aut-sei=Mizuno en-aut-mei=Toshiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=AndoMasahiro en-aut-sei=Ando en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=HiguchiYujiro en-aut-sei=Higuchi en-aut-mei=Yujiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=TanakaFumiaki en-aut-sei=Tanaka en-aut-mei=Fumiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=IzumiYuishin en-aut-sei=Izumi en-aut-mei=Yuishin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=SobueGen en-aut-sei=Sobue en-aut-mei=Gen kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=IwasakiYasushi en-aut-sei=Iwasaki en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=ItoSatoru en-aut-sei=Ito en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=SoneJun en-aut-sei=Sone en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= affil-num=1 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= affil-num=2 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= affil-num=3 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= affil-num=4 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= affil-num=5 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= affil-num=6 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= affil-num=7 en-affil=Department of Neurology, NHO Nagoya Medical Center kn-affil= affil-num=8 en-affil=Department of Neurology, NHO Nagoya Medical Center kn-affil= affil-num=9 en-affil=Department of Neurology, Kobe City Medical Center General Hospital kn-affil= affil-num=10 en-affil=Department of Neurology, Kobe City Medical Center General Hospital kn-affil= affil-num=11 en-affil=Department of Neurology, Tokushima University Graduate School of Biomedical Science kn-affil= affil-num=12 en-affil=Department of Neurology, NHO Kure Medical Center and Chugoku Cancer Center kn-affil= affil-num=13 en-affil=Department of Neurology, Chiba University kn-affil= affil-num=14 en-affil=Department of Neurology, NHO Nagasaki Kawatana Medical Center kn-affil= affil-num=15 en-affil=Department of Neurology, NHO Hyogo Chuo National Hospital kn-affil= affil-num=16 en-affil=Department of Neurology, Nara Medical University Hospital kn-affil= affil-num=17 en-affil=Department of Neurology, NHO Nagasaki Kawatana Medical Center kn-affil= affil-num=18 en-affil=Department of Neurology, NHO Sagamihara National Hospital kn-affil= affil-num=19 en-affil=Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=20 en-affil=Department of Neurology, Saga University kn-affil= affil-num=21 en-affil=Department of Neurology, Kyoto Prefectural University of Medicine kn-affil= affil-num=22 en-affil=Department of Neurology, Kyoto Prefectural University of Medicine kn-affil= affil-num=23 en-affil=Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences kn-affil= affil-num=24 en-affil=Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences kn-affil= affil-num=25 en-affil=Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine kn-affil= affil-num=26 en-affil=Department of Neurology, Tokushima University Graduate School of Biomedical Science kn-affil= affil-num=27 en-affil=Aichi Medical University kn-affil= affil-num=28 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= affil-num=29 en-affil=Division of Respiratory Medicine and Allergology, Department of Internal Medicine, School of Medicine, Aichi Medical University kn-affil= affil-num=30 en-affil=Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University kn-affil= en-keyword=Asthma kn-keyword=Asthma en-keyword=Autonomic dysfunction kn-keyword=Autonomic dysfunction en-keyword=Cough kn-keyword=Cough en-keyword=Neuronal intranuclear inclusion disease kn-keyword=Neuronal intranuclear inclusion disease en-keyword=NOTCH2NLC kn-keyword=NOTCH2NLC en-keyword=Pulmonary function kn-keyword=Pulmonary function END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=pcag056 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260428 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=NIMA-related kinases redundantly regulate vegetative and reproductive development in Arabidopsis thaliana en-subtitle= kn-subtitle= en-abstract= kn-abstract=Never-in-mitosis A-related kinases (NEKs) are conserved protein kinases in eukaryotes that regulate cell division and elongation. In Arabidopsis thaliana, NEK6 has been shown to control anisotropic growth through cortical microtubule depolymerization, but the functions of other NEK family members remain largely unknown. Here, we show that Arabidopsis NEKs redundantly regulate organ growth and flowering through phosphorylation-dependent mechanisms. Expression analyses revealed overlapping promoter activities of NEK genes in meristems, vascular tissues, and floral organs. While most single mutants showed no obvious phenotype, multiple mutants exhibited defects in root growth direction, leaf elongation, vascular formation, and floral transition. Biochemical analysis showed that NEK3 and NEK6 phosphorylate both β-tubulin and γ-tubulin, indicating a conserved role in microtubule regulation. In addition, several NEKs interacted with the florigen FLOWERING LOCUS T (FT), and NEK3 phosphorylated FT in vitro and inhibited the FT–FD interaction in transient assays, suggesting a role in flowering regulation. These findings show that Arabidopsis NEKs redundantly coordinate vegetative and reproductive development through phosphorylation-dependent regulation of microtubules and the flowering pathway. en-copyright= kn-copyright= en-aut-name=TakataniShogo en-aut-sei=Takatani en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KanazawaMai en-aut-sei=Kanazawa en-aut-mei=Mai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SakamotoKotaro en-aut-sei=Sakamoto en-aut-mei=Kotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TomitaYuki en-aut-sei=Tomita en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawamotoNozomi en-aut-sei=Kawamoto en-aut-mei=Nozomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SakaiTatsuya en-aut-sei=Sakai en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ArakiTakashi en-aut-sei=Araki en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MotoseHiroyasu en-aut-sei=Motose en-aut-mei=Hiroyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Department of Biology, Faculty of Science, Okayama University kn-affil= affil-num=3 en-affil=Department of Biology, Faculty of Science, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Biostudies, Division of Integrated Life Science, Kyoto University kn-affil= affil-num=5 en-affil=Graduate School of Biostudies, Division of Integrated Life Science, Kyoto University kn-affil= affil-num=6 en-affil=Graduate School of Science and Technology, Niigata University kn-affil= affil-num=7 en-affil=Graduate School of Biostudies, Division of Integrated Life Science, Kyoto University kn-affil= affil-num=8 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=Arabidopsis thaliana kn-keyword=Arabidopsis thaliana en-keyword=flowering kn-keyword=flowering en-keyword=FLOWERING LOCUS T kn-keyword=FLOWERING LOCUS T en-keyword=NIMA-related kinase kn-keyword=NIMA-related kinase en-keyword=organ development kn-keyword=organ development en-keyword=tubulin kn-keyword=tubulin END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue=13 article-no= start-page=4427 end-page=4438 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260714 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Drivers of temporal improvement in CAR T-cell therapy for large B-cell lymphoma: a Japanese nationwide registry analysis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Real-world CD19 chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is characterized by expanded eligibility and evolving management practices. However, the prognostic impact of these changes remains inconsistent, and the specific drivers of outcomes remain unclear. This study analyzed 913 patients with relapsed/refractory (R/R) LBCL from a Japanese registry and compared the outcomes between 2 calendar periods (2019-2021 vs 2022-2024). The 2022-2024 cohort was older, had more adverse baseline features, and was less pretreated. Treatment patterns have shifted toward higher utilization of second-line therapy, a growing preference for axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), and improved disease control before infusion. Accordingly, the 2022-2024 cohort achieved a longer progression-free survival (PFS; 6-month PFS, 63.2% vs 55.2%; P = .005), which persisted after adjusting for baseline characteristics using propensity score matching. Multivariable analysis identified second-line therapy, improved preinfusion disease control, and a shift in product selection from tisagenlecleucel to axi-cel or liso-cel as the primary drivers of this improvement. This benefit was pronounced in high-risk populations, including patients with stable or progressive disease at infusion (6-month PFS, 54.6% vs 43.8%; P = .012) and those who were refractory to first-line therapy (6-month PFS, 51.7% vs 40.3%; P = .013). Despite broader use in higher-risk populations and greater axi-cel exposure, 6-month nonrelapse mortality remained low (2.1% vs 1.5%). Real-world outcomes of CD19 CAR T-cell therapy for R/R LBCL have improved, predominantly driven by second-line therapy, enhanced preinfusion disease control, and increased use of more potent CAR T products. en-copyright= kn-copyright= en-aut-name=YagiYu en-aut-sei=Yagi en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KanemasaYusuke en-aut-sei=Kanemasa en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TeraoToshiki en-aut-sei=Terao en-aut-mei=Toshiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatoMotohiro en-aut-sei=Kato en-aut-mei=Motohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=JoTomoyasu en-aut-sei=Jo en-aut-mei=Tomoyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShimoyamaTatsu en-aut-sei=Shimoyama en-aut-mei=Tatsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KitawakiToshio en-aut-sei=Kitawaki en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HanajiriRyo en-aut-sei=Hanajiri en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=DokiNoriko en-aut-sei=Doki en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YoshiharaSatoshi en-aut-sei=Yoshihara en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IwakiNoriko en-aut-sei=Iwaki en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YamamotoGo en-aut-sei=Yamamoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SakuraiMasatoshi en-aut-sei=Sakurai en-aut-mei=Masatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=MatsukawaToshihiro en-aut-sei=Matsukawa en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SakaidaEmiko en-aut-sei=Sakaida en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=NakashimaYasuhiro en-aut-sei=Nakashima en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=YoshidaAkiyo en-aut-sei=Yoshida en-aut-mei=Akiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=UmezawaYoshihiro en-aut-sei=Umezawa en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KimHaryoon en-aut-sei=Kim en-aut-mei=Haryoon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KataokaKeisuke en-aut-sei=Kataoka en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=GotoHideki en-aut-sei=Goto en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= affil-num=1 en-affil=Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=2 en-affil=Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=3 en-affil=2Department of Hematology, Okayama University Hospital, Okayama, Japan kn-affil= affil-num=4 en-affil=Department of Pediatrics, The University of Tokyo kn-affil= affil-num=5 en-affil=Department of Hematology, Kyoto University Hospital kn-affil= affil-num=6 en-affil=Department of Medical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=7 en-affil=Department of Hematology, Kyoto University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology and Oncology, Nagoya University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=10 en-affil=Department of Hematology, Hyogo Medical University Hospital kn-affil= affil-num=11 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Hematology, National Cancer Center Hospital kn-affil= affil-num=13 en-affil=Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital kn-affil= affil-num=14 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=15 en-affil=Department of Hematology, Hokkaido University Hospital kn-affil= affil-num=16 en-affil=Department of Hematology, Chiba University Hospital kn-affil= affil-num=17 en-affil=Hematology and Hematopoietic Cell Transplantation, Osaka Metropolitan University Hospital kn-affil= affil-num=18 en-affil=Division of Transfusion Medicine, Kanazawa University Hospital kn-affil= affil-num=19 en-affil=Department of Hematology, Institute of Science Tokyo Hospital kn-affil= affil-num=20 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=21 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=22 en-affil=11Department of Hematology, Hokkaido University Hospital, Sapporo, Japan kn-affil= affil-num=23 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=24 en-affil=Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital kn-affil= END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=1 article-no= start-page=5862 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260428 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The role of Pth1r in posterior cranium cartilage regulation and craniosynostosis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Craniosynostosis is a major craniofacial congenital disorder that causes developmental complications. During normal cranial development, intramembranous ossification forms the flat bones and sutures, while cartilage appears transiently in the posterior calvarial region. However, in craniosynostosis, premature suture fusion disturbs normal calvarial morphogenesis. To clarify the role of transient cartilage in this morphogenetic disruption, we investigated its molecular regulation and pathology in mice, focusing on parathyroid hormone 1 receptor (Pth1r) signaling. Conditional deletion of Pth1r in the cranial mesenchyme unexpectedly caused acrocephalic dysmorphology and craniosynostosis, with altered cartilage differentiation. Occipito–interparietal synostosis consistently occurred in Pth1r-ablated Gli1+ and Acan+ lineages, but not after adult Gli1-CreERT2 deletion, indicating a developmental role. Bulk and single-cell RNA-seq analysis revealed nine mesenchymal subsets, with mutant cells showing abnormal chondrocyte differentiation and upregulated Indian hedgehog (Ihh) signaling. These findings indicate that Pth1r maintains proper chondrogenic regulation during calvarial development, and its loss induces craniosynostosis through Ihh overactivation. en-copyright= kn-copyright= en-aut-name=AmanoKatsuhiko en-aut-sei=Amano en-aut-mei=Katsuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OkuzakiDaisuke en-aut-sei=Okuzaki en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FujimotoYuji en-aut-sei=Fujimoto en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=LiuYu-Chen en-aut-sei=Liu en-aut-mei=Yu-Chen kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KogoMikihiko en-aut-sei=Kogo en-aut-mei=Mikihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IidaSeiji en-aut-sei=Iida en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka kn-affil= affil-num=3 en-affil=Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka kn-affil= affil-num=4 en-affil=Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, University of Osaka kn-affil= affil-num=5 en-affil=The First Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry kn-affil= affil-num=6 en-affil=Department of Oral and Maxillofacial Reconstructive Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=1 article-no= start-page=19 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250131 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Performance of the modified 2022 ACR/EULAR giant cell arteritis classification criteria without age restriction for discriminating from Takayasu arteritis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective To evaluate the ability to discriminate giant cell arteritis (GCA) from Takayasu arteritis (TAK) according to the modified 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) GCA classification criteria.
Methods Patients enrolled in the Japanese nationwide retrospective registry were evaluated using the criteria with partial modification; wall thickening of descending thoracic-abdominal aorta were mainly diagnosed by contrast-enhanced computed tomography (CT) or magnetic resonance imaging instead of evaluating with positron emission tomography (PET)-CT. The discriminability of the criteria was evaluated using C-statistic (> 0.7: good ability).
Results Newly diagnosed patients with GCA (n = 139) and TAK (n = 129) were assessed, and 23.3% of TAK were aged 50 years or older at onset. The sensitivity of the modified 2022 ACR/EULAR GCA classification criteria with a score ≥ 6 was 82.0%, 68.5%, and 32.1% in all GCA, GCA with large-vessel involvement, and GCA without cranial arteritis, respectively. The specificity of the modified criteria was 96.1% for the 129 TAK as controls. Five patients with late-onset TAK met the modified criteria, and four had cranial signs and symptoms, two had bilateral axillary artery involvement, and four had descending thoracic-abdominal aorta involvement. The discriminability of the criteria was good (C-statistic: 0.986, 95% confidence interval [CI]: 0.976–0.996) and remained good after excluding age (C-statistic: 0.927, 95% CI: 0.894–0.961). The discriminability of a set of large-vessel lesions (bilateral axillary artery and descending thoracic-abdominal aorta) and inflammatory markers was markedly decreased with poor C-statistic value (C-statistic: 0.598, 95% CI: 0.530–0.667). Discriminability was improved after adding polymyalgia rheumatica (PMR) (C-statistic: 0.757, 95% CI: 0.700–0.813) or age (C-statistic: 0.913, 95%CI: 0.874–0.951) to the set of large-vessel lesions. In GCA patients with a score ≤ 5, 52% had bilateral subclavian and/or axillary artery involvement.
Conclusion The modified 2022 ACR/EULAR GCA classification criteria well performed in classifying GCA and TAK without PET-CT in routine clinical practice. A set of items included in the modified GCA classification criteria had good discriminative ability for GCA and TAK, even when age was excluded. However, age restriction or PMR was required to distinguish GCA without cranial lesions from TAK. en-copyright= kn-copyright= en-aut-name=SugiharaTakahiko en-aut-sei=Sugihara en-aut-mei=Takahiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HarigaiMasayoshi en-aut-sei=Harigai en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UchidaHaruhito A. en-aut-sei=Uchida en-aut-mei=Haruhito A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YoshifujiHajime en-aut-sei=Yoshifuji en-aut-mei=Hajime kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MaejimaYasuhiro en-aut-sei=Maejima en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IshizakiJun en-aut-sei=Ishizaki en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WatanabeYoshiko en-aut-sei=Watanabe en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=DobashiHiroaki en-aut-sei=Dobashi en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KomagataYoshinori en-aut-sei=Komagata en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TamuraNaoto en-aut-sei=Tamura en-aut-mei=Naoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NakaokaYoshikazu en-aut-sei=Nakaoka en-aut-mei=Yoshikazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) en-aut-sei=Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Rheumatology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo kn-affil= affil-num=2 en-affil=Division of Rheumatology, Department of Internal Medicine, Tokyo Women’s Medical University School of Medicine kn-affil= affil-num=3 en-affil=Department of Chronic Kidney Disease and Cardiovascular Disease, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=4 en-affil=Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=5 en-affil=Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo kn-affil= affil-num=6 en-affil=Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of General Medicine, Kawasaki Medical School kn-affil= affil-num=8 en-affil=Division of Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa University kn-affil= affil-num=9 en-affil=Department of Nephrology and Rheumatology, Kyorin University School of Medicine kn-affil= affil-num=10 en-affil=Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine kn-affil= affil-num=11 en-affil=Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute kn-affil= affil-num=12 en-affil= kn-affil= en-keyword=GCA kn-keyword=GCA en-keyword=TAK kn-keyword=TAK en-keyword=Classification criteria kn-keyword=Classification criteria en-keyword=Bilateral axillary artery kn-keyword=Bilateral axillary artery en-keyword=Descending thoracic-abdominal aorta kn-keyword=Descending thoracic-abdominal aorta en-keyword=Bilateral subclavian artery kn-keyword=Bilateral subclavian artery END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=10055 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260220 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Nitric oxide induces p53-mediated cell death in human nasal epithelial cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Nitric oxide (NO) is a key signaling molecule that plays a vital role in maintaining homeostasis of physiological processes such as immune responses and neurotransmission. However, excessive NO production during inflammatory responses to infection can lead to cytotoxicity and tissue damage. The nasal epithelial barrier is a crucial first line of immunological defense against viral infections, and it is likely exposed to excessive NO levels during chronic inflammation. Therefore, clarifying the effects of NO on this barrier is thus critical. In this study, we investigated the biological effects of sustained NO exposure on RPMI2650 human nasal epithelial cells. Post-NO exposure transcriptomic analyses revealed significant upregulation of genes involved in the p53 signaling pathway. RT-qPCR analyses confirmed the temporal upregulation of p53 target genes associated with apoptosis and cell cycle regulation. These gene expression changes downregulated cell proliferation and induced cell death. Our findings suggest that excessive NO exposure induces nasal epithelial cell death via the p53 pathway, which over the long term can result in tissue damage and dysfunction under inflammatory conditions. These results provide new insights into how prolonged NO exposure affects the nasal epithelial cells and may contribute to the progression of chronic infectious diseases. en-copyright= kn-copyright= en-aut-name=KamiuezonoShizuki en-aut-sei=Kamiuezono en-aut-mei=Shizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KubotaSho en-aut-sei=Kubota en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TsuchidaTomoki en-aut-sei=Tsuchida en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakasugiNobumasa en-aut-sei=Takasugi en-aut-mei=Nobumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=UeharaTakashi en-aut-sei=Uehara en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Medicinal Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Nitric oxide kn-keyword=Nitric oxide en-keyword=p53 kn-keyword=p53 en-keyword=Apoptosis kn-keyword=Apoptosis en-keyword=Cell death kn-keyword=Cell death en-keyword=Human nasal epithelial cells kn-keyword=Human nasal epithelial cells END start-ver=1.4 cd-journal=joma no-vol=136 cd-vols= no-issue=10 article-no= start-page=e195021 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260310 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Spatial single-cell proteotyping reveals immunotherapy-resistant features within the complex tumor microenvironment of metastatic NSCLC en-subtitle= kn-subtitle= en-abstract= kn-abstract=BACKGROUND. Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 axis have revolutionized metastatic non–small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood.
METHODS. In this biomarker study involving 103 patients with mNSCLC, including 81 patients who received ICI treatment, we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex IHC platform built for in-depth dissection of the TME.
RESULTS. Among various types of intratumoral lymphocytes, including Th1, Treg, and NK cells, only CD8+ T cells (tumor-infiltrating lymphocytes [TILs]) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8+ TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39/CD103/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8+ TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in EGFR/ALK-oncogene+ NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.
CONCLUSION. Our study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies. en-copyright= kn-copyright= en-aut-name=IsomotoKohsuke en-aut-sei=Isomoto en-aut-mei=Kohsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HarataniKoji en-aut-sei=Haratani en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TsujikawaTakahiro en-aut-sei=Tsujikawa en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TomidaShuta en-aut-sei=Tomida en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MakutaniYusuke en-aut-sei=Makutani en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakedaMasayuki en-aut-sei=Takeda en-aut-mei=Masayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YonesakaKimio en-aut-sei=Yonesaka en-aut-mei=Kimio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanakaKaoru en-aut-sei=Tanaka en-aut-mei=Kaoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IwasaTsutomu en-aut-sei=Iwasa en-aut-mei=Tsutomu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SakaiKazuko en-aut-sei=Sakai en-aut-mei=Kazuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NishioKazuto en-aut-sei=Nishio en-aut-mei=Kazuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ItoAkihiko en-aut-sei=Ito en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=NakagawaKazuhiko en-aut-sei=Nakagawa en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HayashiHidetoshi en-aut-sei=Hayashi en-aut-mei=Hidetoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=2 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=3 en-affil=Department of Otolaryngology–Head and Neck Surgery, Kyoto Prefectural University of Medicine kn-affil= affil-num=4 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Surgery, Kindai University Faculty of Medicine kn-affil= affil-num=6 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=7 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=8 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=9 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=10 en-affil=Department of Genome Biology, Kindai University Faculty of Medicine kn-affil= affil-num=11 en-affil=Department of Genome Biology, Kindai University Faculty of Medicine kn-affil= affil-num=12 en-affil=Department of Pathology, Kindai University Faculty of Medicine kn-affil= affil-num=13 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=14 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=20445 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260503 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Metastatic promoting role of mesenchymal stem cells in oral squamous cell carcinoma revealed by an improved bone marrow chimeric model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Mesenchymal stem cells (MSCs) are essential stromal regulators that coordinate tissue repair, angiogenesis, and immune balance. Within tumours, MSCs remodel the microenvironment and influence disease progression, yet their systemic contribution remains unclear due to the limited recovery of functional MSCs in conventional bone marrow transplantation models. Here, we developed an improved bone marrow collection (iBMC) method using enzymatic digestion, which markedly increases MSC yield while preserving their native phenotype. GFP bone marrow chimeric mice generated by iBMC and conventional transplantation displayed comparable hematopoietic reconstitution but differed in MSC abundance, enabling direct analysis of MSC-specific effects under physiological conditions. In mouse models of oral squamous cell carcinoma (OSCC), MSCs profoundly affected tumour development. MSC-deficient tumours exhibited necrosis and infiltration of immature myeloid-derived suppressor cells (MDSCs), whereas MSC-rich tumours showed enhanced vascularisation, adaptive immune infiltration, and stromal remodelling. Notably, lung metastasis occurred only in MSC-rich mice, accompanied by bone marrow–derived endothelial activation and TNF-α–driven inflammation. Pharmacological inhibition of LepR signalling using SHU9119 unexpectedly increased metastasis, underscoring the dual, context-dependent functions of MSCs. These findings establish iBMC as a reproducible and physiologically relevant model to study MSC-mediated regulation of tumour immunity, angiogenesis, and metastasis. en-copyright= kn-copyright= en-aut-name=EainHtoo Shwe en-aut-sei=Eain en-aut-mei=Htoo Shwe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KawaiHotaka en-aut-sei=Kawai en-aut-mei=Hotaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SanouSho en-aut-sei=Sanou en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SoeYamin en-aut-sei=Soe en-aut-mei=Yamin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OoMay Wathone en-aut-sei=Oo en-aut-mei=May Wathone kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=PiaoTianyan en-aut-sei=Piao en-aut-mei=Tianyan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MinZin Zin en-aut-sei=Min en-aut-mei=Zin Zin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakabatakeKiyofumi en-aut-sei=Takabatake en-aut-mei=Kiyofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NakanoKeisuke en-aut-sei=Nakano en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IbaragiSoichiro en-aut-sei=Ibaragi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NagatsukaHitoshi en-aut-sei=Nagatsuka en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=2 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=3 en-affil=Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=4 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=5 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=6 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=7 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=8 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=9 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=10 en-affil=Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=11 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= en-keyword=Mesenchymal stem cells (MSCs) kn-keyword=Mesenchymal stem cells (MSCs) en-keyword=Oral squamous cell carcinoma (OSCC) kn-keyword=Oral squamous cell carcinoma (OSCC) en-keyword=Bone marrow transplantation kn-keyword=Bone marrow transplantation en-keyword=Chimeric mouse models kn-keyword=Chimeric mouse models en-keyword=Tumour microenvironment (TME) kn-keyword=Tumour microenvironment (TME) END start-ver=1.4 cd-journal=joma no-vol=93 cd-vols= no-issue=1 article-no= start-page=e00346-2 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250131 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A newly developed oral infection mouse model of shigellosis for immunogenicity and protective efficacy studies of a candidate vaccine en-subtitle= kn-subtitle= en-abstract= kn-abstract=Shigella infection poses a significant public health challenge in the developing world. However, lack of a widely available mouse model that replicates human shigellosis creates a major bottleneck to better understanding of disease pathogenesis and development of newer drugs and vaccines. BALB/c mice pre-treated with streptomycin and iron (FeCl3) plus desferrioxamine intraperitoneally followed by oral infection with virulent Shigella flexneri 2a resulted in diarrhea, loss of body weight, bacterial colonization and progressive colitis characterized by disruption of epithelial lining, loss of crypt architecture with goblet cell depletion, increased polymorphonuclear infiltration into the mucosa, submucosal swelling (edema), and raised proinflammatory cytokines and chemokines in the large intestine. To evaluate the usefulness of the model for vaccine efficacy studies, mice were immunized intranasally with a recombinant protein vaccine containing Shigella invasion protein invasion plasmid antigen B (IpaB). Vaccinated mice conferred protection against Shigella, indicating that the model is suitable for testing of vaccine candidates. To protect both Shigella and Salmonella, a chimeric recombinant vaccine (rIpaB–T2544) was developed by fusing IpaB with Salmonella outer membrane protein T2544. Vaccinated mice developed antigen-specific serum IgG and IgA antibodies and a balanced Th1/Th2 response and were protected against oral challenge with Shigella (S. flexneri 2a, Shigella dysenteriae, and Shigella sonnei) using our present mouse model and Salmonella (Salmonella Typhi and Paratyphi) using an iron overload mouse model. We describe here the development of an oral Shigella infection model in wild-type mouse. This model was successfully used to demonstrate the immunogenicity and protective efficacy of a candidate protein subunit vaccine against Shigella. en-copyright= kn-copyright= en-aut-name=HaldarRisha en-aut-sei=Haldar en-aut-mei=Risha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HalderProlay en-aut-sei=Halder en-aut-mei=Prolay kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KoleyHemanta en-aut-sei=Koley en-aut-mei=Hemanta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MiyoshiShin-ichi en-aut-sei=Miyoshi en-aut-mei=Shin-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=DasSantasabuj en-aut-sei=Das en-aut-mei=Santasabuj kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Division of Clinical Medicine, ICMR-National Institute of Cholera and Enteric Diseases kn-affil= affil-num=2 en-affil=Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases kn-affil= affil-num=3 en-affil=Division of Bacteriology, ICMR-National Institute of Cholera and Enteric Diseases kn-affil= affil-num=4 en-affil=Division of Medicine, Dentistry and Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Division of Clinical Medicine, ICMR-National Institute of Cholera and Enteric Diseases kn-affil= en-keyword=oral route kn-keyword=oral route en-keyword=S. flexneri kn-keyword=S. flexneri en-keyword=shigellosis kn-keyword=shigellosis en-keyword=bivalent subunit vaccine (IpaB–T2544) kn-keyword=bivalent subunit vaccine (IpaB–T2544) en-keyword=mouse model kn-keyword=mouse model END start-ver=1.4 cd-journal=joma no-vol=87 cd-vols= no-issue=6 article-no= start-page=680 end-page=684 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=2025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effects of heat stress on gene expression associated with antioxidant capacity of bovine early antral follicles en-subtitle= kn-subtitle= en-abstract= kn-abstract=Heat exposure at the physiological level of oocyte-cumulus-granulosa cell complexes (OCGCs) during in vitro growth (IVG) culture decreases the reduced glutathione (GSH) level of oocytes, an antioxidant, but its mechanism has been unclear. We subjected OCGCs to IVG for 4, 8, or 12 days and investigated the effects of heat exposure on the gene expression of cumulus-granulosa cells associated with antioxidant capacity. Heat exposure did not alter the expression of genes related to GSH synthesis or reuse. Conversely, heat exposure increased mRNA expression of superoxide dismutase 2 and decreased that of glutathione peroxidase 1, which are antioxidant enzymes. Ultimately, heat exposure alters the gene expression of antioxidant enzymes in growing follicles, which may indirectly decrease the GSH level of oocytes. en-copyright= kn-copyright= en-aut-name=KAWANOKohei en-aut-sei=KAWANO en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SAKAGUCHIKenichiro en-aut-sei=SAKAGUCHI en-aut-mei=Kenichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FURUKAWAEri en-aut-sei=FURUKAWA en-aut-mei=Eri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NINPETCHNattapong en-aut-sei=NINPETCH en-aut-mei=Nattapong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YANAGAWAYojiro en-aut-sei=YANAGAWA en-aut-mei=Yojiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KATAGIRISeiji en-aut-sei=KATAGIRI en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Laboratory of Reproductive Physiology, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Laboratory of Veterinary Theriogenology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University kn-affil= affil-num=3 en-affil=National Institute of Animal Health, National Agriculture and Food Research Organization kn-affil= affil-num=4 en-affil=Department of Animal Science, Faculty of Agriculture at Kamphaeng Saen, Kasetsart University kn-affil= affil-num=5 en-affil=Laboratory of Theriogenology, Department of Clinical Sciences, Division of Veterinary Medicine, Faculty of Veterinary Medicine, Hokkaido University kn-affil= affil-num=6 en-affil=Laboratory of Theriogenology, Department of Clinical Sciences, Division of Veterinary Medicine, Faculty of Veterinary Medicine, Hokkaido University kn-affil= en-keyword=antioxidant capacity kn-keyword=antioxidant capacity en-keyword=bovine kn-keyword=bovine en-keyword=early antral follicle kn-keyword=early antral follicle en-keyword=in vitro growth kn-keyword=in vitro growth en-keyword=oxidative stress kn-keyword=oxidative stress END start-ver=1.4 cd-journal=joma no-vol=47 cd-vols= no-issue=12 article-no= start-page=2058 end-page=2064 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20241213 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Staphylococcus aureus δ-Toxin Induces Ca2+ Influx-Independent Degranulation of Murine Cultured Mast Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cutaneous colonization with Staphylococcus aureus (SA) is frequently observed in patients with atopic dermatitis. SA produces a wide variety of bacterial toxins, among which δ-toxin was found to induce degranulation of mast cells. Degranulation of mast cells could enhance bacterial clearance and protection from future SA infection but lead to exacerbation of atopic dermatitis. Because it remains to be determined how δ-toxin triggers degranulation, we investigated δ-toxin-induced changes in murine bone marrow-derived cultured mast cells in this study. We found that δ-toxin-induced degranulation could be classified into two phases, an early Ca2+-independent and a late Ca2+-dependent phase. Recent studies suggest that NOD-like receptor family, pyrin domain containing 3 is involved in the degranulation of mast cells, raising a possibility that leakage of K+ induced by δ-toxin is involved in the Ca2+-independent phase. However, Ca2+-independent degranulation remains unchanged although Ca2+-influx and degranulation induced by δ-toxin were significantly suppressed in the presence of high concentrations of K+. Because actin depolymerization was reported to induce degranulation in the absence of Ca2+ in the permeabilized rat peritoneal mast cells, a slow but steady decrease in the amount of filamentous actin observed here may be involved in Ca2+-independent degranulation induced by δ-toxin. Although Mas-related G protein-coupled receptor (MRGPR) X2 in humans and Mrgprb2 in mice are regarded as the receptors responsible for immunoglobulin E-independent degranulation, δ-toxin-induced degranulation remained unchanged in Mrgprb2−/− mast cells. Our findings pave the way for identification of the target receptors of δ-toxin. en-copyright= kn-copyright= en-aut-name=LiuKang en-aut-sei=Liu en-aut-mei=Kang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatayamaTomoaki en-aut-sei=Katayama en-aut-mei=Tomoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SatoHitomi en-aut-sei=Sato en-aut-mei=Hitomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=Hamaoka-TamuraYuho en-aut-sei=Hamaoka-Tamura en-aut-mei=Yuho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SaitoMichiko en-aut-sei=Saito en-aut-mei=Michiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FurutaKazuyuki en-aut-sei=Furuta en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TanakaSatoshi en-aut-sei=Tanaka en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Laboratory of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University kn-affil= affil-num=2 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Laboratory of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University kn-affil= affil-num=5 en-affil=Bioscience Research Center, Kyoto Pharmaceutical University kn-affil= affil-num=6 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Laboratory of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University kn-affil= en-keyword=mast cell kn-keyword=mast cell en-keyword=δ-toxin kn-keyword=δ-toxin en-keyword=degranulation kn-keyword=degranulation en-keyword=inflammation kn-keyword=inflammation en-keyword=Mas-related G protein-coupled receptor kn-keyword=Mas-related G protein-coupled receptor END start-ver=1.4 cd-journal=joma no-vol=206 cd-vols= no-issue=10 article-no= start-page=e00307-24 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20241024 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Overexpression of diglucosyldiacylglycerol synthase leads to daptomycin resistance in Bacillus subtilis en-subtitle= kn-subtitle= en-abstract= kn-abstract=The lipopeptide antibiotic daptomycin exhibits bactericidal activity against Gram-positive bacteria by forming a complex with phosphatidylglycerol (PG) and lipid II in the cell membrane, causing membrane perforation. With the emergence of daptomycin-resistant bacteria, understanding the mechanisms of bacterial resistance to daptomycin has gained great importance. In this study, we aimed to identify the genetic factors contributing to daptomycin resistance in Bacillus subtilis, a model Gram-positive bacterium. Our findings demonstrated that overexpression of ugtP, which encodes diglucosyldiacylglycerol synthase, induces daptomycin resistance in B. subtilis. Specifically, overexpression of ugtP resulted in increased levels of diglucosyldiacylglycerol (Glc2DAG) and decreased levels of acidic phospholipids cardiolipin and PG, as well as the basic phospholipid lysylphosphatidylglycerol. However, ugtP overexpression did not alter the cell surface charge and the susceptibility to the cationic antimicrobial peptide nisin or the cationic surfactant hexadecyltrimethylammonium bromide. Furthermore, by serial passaging in the presence of daptomycin, we obtained daptomycin-resistant mutants carrying ugtP mutations. These mutants showed increased levels of Glc2DAG and a >4-fold increase in the minimum inhibitory concentration of daptomycin. These results suggest that increased Glc2DAG levels, driven by ugtP overexpression, modify the phospholipid composition and confer daptomycin resistance in B. subtilis without altering the cell surface charge of the bacteria. en-copyright= kn-copyright= en-aut-name=YamamotoRyogo en-aut-sei=Yamamoto en-aut-mei=Ryogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IshikawaKazuya en-aut-sei=Ishikawa en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MiyoshiYusuke en-aut-sei=Miyoshi en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FurutaKazuyuki en-aut-sei=Furuta en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MiyoshiShin-Ichi en-aut-sei=Miyoshi en-aut-mei=Shin-Ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KaitoChikara en-aut-sei=Kaito en-aut-mei=Chikara kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=diglucosyldiacylglycerol kn-keyword=diglucosyldiacylglycerol en-keyword=daptomycin kn-keyword=daptomycin en-keyword=phospholipid kn-keyword=phospholipid END start-ver=1.4 cd-journal=joma no-vol=520 cd-vols= no-issue= article-no= start-page=41 end-page=52 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202504 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tunicate-specific protein Epi-1 is essential for conferring hydrophilicity to the larval tunic in the ascidian Ciona en-subtitle= kn-subtitle= en-abstract= kn-abstract=Animals must avoid adhesion to objects in the environment to maintain their mobility and independence. The marine invertebrate chordate ascidians are characterized by an acellular matrix tunic enveloping their entire body for protection and swimming. The tunic of ascidian larvae consists of a surface cuticle layer and inner matrix layer. Hydrophilic substances coat the cuticle; this modification is thought to be for preventing adhesion. However, the molecule responsible for regulating this modification has not been clarified. We here found that the tunicate-specific protein Epi-1 is responsible for preventing adhesiveness of the tunic in the ascidian Ciona intestinalis Type A. Ciona mutants with homozygous knockouts of Epi-1 exhibited adhesion to plastic plates and to other individuals. The cuticle of the Epi-1 mutants was fragile, and it lost the glycosaminoglycans supplied by test cells, the accessory cells that normally attach to the tunic surface. Although it has an apparent signal peptide for membrane trafficking, we showed that the Epi-1 protein is localized to the cytosol of the epidermal cells. Our study suggests that the emergence of the tunicate-specific protein Epi-1 made the tunic less adhesive, providing a selective advantage for the last common tunicate ancestor. en-copyright= kn-copyright= en-aut-name=KuroiwaKazu en-aut-sei=Kuroiwa en-aut-mei=Kazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Mita-YoshidaKaoru en-aut-sei=Mita-Yoshida en-aut-mei=Kaoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HamadaMayuko en-aut-sei=Hamada en-aut-mei=Mayuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HozumiAkiko en-aut-sei=Hozumi en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NishinoAtsuo S. en-aut-sei=Nishino en-aut-mei=Atsuo S. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SasakuraYasunori en-aut-sei=Sasakura en-aut-mei=Yasunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=2 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=3 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=4 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=5 en-affil=Department of Biology, Faculty of Agriculture and Life Science, Hirosaki University kn-affil= affil-num=6 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= en-keyword=Ascidian kn-keyword=Ascidian en-keyword=Ciona kn-keyword=Ciona en-keyword=Tunic kn-keyword=Tunic en-keyword=Epidermis kn-keyword=Epidermis en-keyword=Cellulose kn-keyword=Cellulose en-keyword=Glycosaminoglycan kn-keyword=Glycosaminoglycan END start-ver=1.4 cd-journal=joma no-vol=88 cd-vols= no-issue=10 article-no= start-page=1199 end-page=1202 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240711 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Evaluation of quercetin as a potential cytoprotector against acetaldehyde using the cultured hepatocyte model with aldehyde dehydrogenase isozyme deficiency en-subtitle= kn-subtitle= en-abstract= kn-abstract=Protective effect of quercetin against acetaldehyde was evaluated using the cultured hepatocyte models with aldehyde dehydrogenase (ALDH) isozyme deficiency (aldh2-kd and aldh1a1-kd). The quercetin-induced cytoprotection against acetaldehyde in the ALDH1A1-deficient mutant (aldh1a1-kd) was weaker than that in the wild type. Furthermore, quercetin did not enhance the ALDH activity in aldh1a1-kd cells, suggesting that ALDH1A1 is involved in quercetin-induced cytoprotection. en-copyright= kn-copyright= en-aut-name=XuYuhang en-aut-sei=Xu en-aut-mei=Yuhang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SawamotoTakeshi en-aut-sei=Sawamoto en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SunRuitong en-aut-sei=Sun en-aut-mei=Ruitong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IshikuraAki en-aut-sei=Ishikura en-aut-mei=Aki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MunemasaShintaro en-aut-sei=Munemasa en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MurataYoshiyuki en-aut-sei=Murata en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SatohAyano en-aut-sei=Satoh en-aut-mei=Ayano kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsumotoAkiko en-aut-sei=Matsumoto en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NakamuraToshiyuki en-aut-sei=Nakamura en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NakamuraYoshimasa en-aut-sei=Nakamura en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Department of Social and Environmental Medicine, Saga University kn-affil= affil-num=9 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=10 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=quercetin kn-keyword=quercetin en-keyword=acetaldehyde kn-keyword=acetaldehyde en-keyword=aldehyde dehydrogenase kn-keyword=aldehyde dehydrogenase en-keyword=cytoprotection kn-keyword=cytoprotection END start-ver=1.4 cd-journal=joma no-vol=88 cd-vols= no-issue=8 article-no= start-page=918 end-page=922 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240522 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Negative regulation of chitosan-induced stomatal closure by glutathione in Arabidopsis thaliana en-subtitle= kn-subtitle= en-abstract= kn-abstract=Chitosan (CHT) is a deacylated derivative of chitin and improves growth and yield performance, activates defensive genes, and also induces stomatal closure in plants. Glutathione (GSH) has significant functions in the growth, development, defense systems, signaling, and gene expression. GSH negatively regulates abscisic acid-, methyl jasmonate-, and salicylic acid-induced stomatal closure. However, the negative regulation by GSH of CHT-induced stomatal closure is still unknown. Regulation of CHT-induced stomatal closure by GSH in guard cells was investigated using two GSH-deficient mutants, cad2-1 and chlorina 1-1 (ch1-1), and a GSH-decreasing chemical, 1-chloro-2,4-dinitrobenzene (CDNB). The cad2-1 and ch1-1 mutations and CDNB treatment enhanced CHT-induced stomatal closure. Treatment with glutathione monoethyl ester restored the GSH level in the guard cells of cad2-1 and ch1-1 and complemented the stomatal phenotype of the mutants. These results indicate that GSH negatively regulates CHT-induced stomatal closure in Arabidopsis thaliana. en-copyright= kn-copyright= en-aut-name=JahanIsrat en-aut-sei=Jahan en-aut-mei=Israt kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MunemasaShintaro en-aut-sei=Munemasa en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakamuraToshiyuki en-aut-sei=Nakamura en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakamuraYoshimasa en-aut-sei=Nakamura en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MurataYoshiyuki en-aut-sei=Murata en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=Arabidopsis thaliana kn-keyword=Arabidopsis thaliana en-keyword=chitosan kn-keyword=chitosan en-keyword=glutathione kn-keyword=glutathione en-keyword=stomatal closure kn-keyword=stomatal closure END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=7 article-no= start-page=e112232 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260707 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Reappraisal of the Entity of Pediatric Uveitis: Bilateral Iridocyclitis With Retinal Capillaritis (BIRC) in Juveniles in 18 Additional Cases en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objectives: Bilateral iridocyclitis with retinal capillaritis (BIRC) in juveniles is a newly recognized ​​​​​entity of juvenile chronic uveitis with no systemic involvement. In this study, 18 additional consecutive patients with BIRC were reported to show that the entity would be useful in the differential diagnosis.
Methods: Clinical features were retrospectively reviewed in 18 consecutive patients diagnosed with BIRC in juveniles at Okayama University Hospital, Okayama, Japan, between 1996 and 2025.
Results: The 18 patients comprised 6 males and 12 females, with an age at onset ranging from 9 to 16 years (median, 13 years). All patients presented with aqueous cells and mutton-fat keratic precipitates in both eyes, and fluorescein angiography revealed varying degrees of optic disc leakage and retinal capillary leakage in the midperipheral to peripheral fundus of both eyes. None had systemic symptoms, including skin rashes, joint pain, or fever, and no abnormalities were detected on blood examinations, urinalysis, or plain chest x-rays. Oral prednisolone, tapered from 30 mg daily, together with topical 0.1% betamethasone four times daily, was administered to five patients: two with optic disc edema and three with macular edema in both eyes or the unilateral eye. The remaining 13 patients were treated with topical 0.1% betamethasone eye drops alone. In patients who developed elevated intraocular pressure, often due to a steroid response, the instillation of topical 0.1% betamethasone was reduced to twice daily, or intraocular pressure-lowering eye drops were used in combination. In two patients who showed relapse of unilateral macular edema after oral prednisolone was tapered or discontinued, oral colchicine (1 mg daily) was introduced, resulting in the subsidence of macular edema. Bilateral uveitis in all 18 patients subsided within 6 months to a few years until 19 years of age, and all topical medications were discontinued, with relapse occurring in only one patient.
Conclusions: BIRC in juveniles should be included in the differential diagnosis for school-age children and young adolescents. BIRC follows a chronic course of a few years and subsides completely with a good prognosis. In cases of macular edema or optic disc edema that affects vision, oral corticosteroid treatment is recommended, whereas patients with no sight-threatening signs can be treated with topical corticosteroid eye drops alone. The entity of BIRC may be distinct from juvenile chronic iridocyclitis in young girls with onset at preschool age, which shares common features with juvenile idiopathic arthritis-associated uveitis. en-copyright= kn-copyright= en-aut-name=MatsuoToshihiko en-aut-sei=Matsuo en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Ophthalmology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=bilateral iridocyclitis with retinal capillaritis (birc) kn-keyword=bilateral iridocyclitis with retinal capillaritis (birc) en-keyword=colchicine kn-keyword=colchicine en-keyword=corticosteroid kn-keyword=corticosteroid en-keyword=fluorescein angiography kn-keyword=fluorescein angiography en-keyword=juvenile kn-keyword=juvenile en-keyword=juvenile chronic iridocyclitis (jci) kn-keyword=juvenile chronic iridocyclitis (jci) en-keyword=juvenile idiopathic arthritis (jia) kn-keyword=juvenile idiopathic arthritis (jia) en-keyword=macular edema kn-keyword=macular edema en-keyword=optical coherence tomography kn-keyword=optical coherence tomography en-keyword=optic disc edema kn-keyword=optic disc edema END start-ver=1.4 cd-journal=joma no-vol=43 cd-vols= no-issue=16 article-no= start-page=1886 end-page=1897 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202506 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Methotrexate, Doxorubicin, and Cisplatin Versus Methotrexate, Doxorubicin, and Cisplatin + Ifosfamide in Poor Responders to Preoperative Chemotherapy for Newly Diagnosed High-Grade Osteosarcoma (JCOG0905): A Multicenter, Open-Label, Randomized Trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose Our previous NECO phase II studies on high-grade osteosarcoma suggested that administering ifosfamide (IF; 16 g/m2 [4g/m2 once on day 1, then 2g/m2 once on days 2-7] × six) to patients showing a poor response (PrRsp) to preoperative chemotherapy with methotrexate, doxorubicin, and cisplatin (MAP) improves their prognoses. In this Japan Clinical Oncology Group (JCOG) study, JCOG0905, we aimed to investigate the efficacy and safety of IF in patients with PrRsp.
Methods JCOG0905 is a multicenter, open-label, multi-institutional, randomized trial. Eligible patients (50 years and younger) had resectable, high-grade osteosarcoma (stage II or III, Union for International Cancer Control TNM) of the extremities, limb girdles, and thoracic wall. After two MAP cycles and tumor resection, patients with PrRsp were randomly assigned to either the MAP or MAP plus 15 g/m2 (3g/m2 once daily on days 1-5) × six IF (MAP + IF [MAPIF]) group. The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The planned sample size was 100 patients with a one-sided α of .1 and a power of 0.7, assuming a 3-year DFS of 50% and 65% for MAP and MAPIF, respectively. This trial is registered with the Japan Registry of Clinical Trials (jRCT; jRCTs031180126).
Results Of the 287 patients registered between February 2010 and August 2020, 51 and 52 patients with PrRsp were assigned to the MAP and MAPIF groups, respectively. As of March 2022, DFS did not differ between groups (hazard ratio [HR], 1.05 [95% CI, 0.55 to 1.98]) and OS was numerically inferior in the MAPIF group (HR, 1.48 [95% CI, 0.68 to 3.22]). Nine and zero patients in the MAPIF and MAP groups discontinued treatment because of adverse events, respectively.
Conclusion Evidence from JCOG0905 does not support the addition of IF for patients with PrRsp. en-copyright= kn-copyright= en-aut-name=HiragaHiroaki en-aut-sei=Hiraga en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MachidaRyunosuke en-aut-sei=Machida en-aut-mei=Ryunosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KawaiAkira en-aut-sei=Kawai en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KunisadaToshiyuki en-aut-sei=Kunisada en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YonemotoTsukasa en-aut-sei=Yonemoto en-aut-mei=Tsukasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=EndoMakoto en-aut-sei=Endo en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishidaYoshihiro en-aut-sei=Nishida en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NaganoAkihito en-aut-sei=Nagano en-aut-mei=Akihito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AeKeisuke en-aut-sei=Ae en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YoshidaShinichirou en-aut-sei=Yoshida en-aut-mei=Shinichirou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AsanumaKunihiro en-aut-sei=Asanuma en-aut-mei=Kunihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ToguchidaJunya en-aut-sei=Toguchida en-aut-mei=Junya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=FurutaTaisuke en-aut-sei=Furuta en-aut-mei=Taisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NakayamaRobert en-aut-sei=Nakayama en-aut-mei=Robert kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=AkisueToshihiro en-aut-sei=Akisue en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=HirumaToru en-aut-sei=Hiruma en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=MoriiTakeshi en-aut-sei=Morii en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NishimuraHideki en-aut-sei=Nishimura en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=HiraokaKoji en-aut-sei=Hiraoka en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=TakeyamaMasanobu en-aut-sei=Takeyama en-aut-mei=Masanobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=EmoriMakoto en-aut-sei=Emori en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=TsukushiSatoshi en-aut-sei=Tsukushi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=HatanoHiroshi en-aut-sei=Hatano en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=KawashimaHiroyuki en-aut-sei=Kawashima en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=IsuKazuo en-aut-sei=Isu en-aut-mei=Kazuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=TanakaKazuhiro en-aut-sei=Tanaka en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=KataokaTomoko en-aut-sei=Kataoka en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=FukudaHaruhiko en-aut-sei=Fukuda en-aut-mei=Haruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=IwamotoYukihide en-aut-sei=Iwamoto en-aut-mei=Yukihide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= affil-num=1 en-affil=Musculoskeletal Oncology, NHO Hokkaido Cancer Center kn-affil= affil-num=2 en-affil=Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital kn-affil= affil-num=3 en-affil=Musculoskeletal Oncology, National Cancer Center Hospital kn-affil= affil-num=4 en-affil=Orthopaedic Surgery, Faculty of Medicine, Okayama University kn-affil= affil-num=5 en-affil=Orthopaedic Surgery, Chiba Cancer Center kn-affil= affil-num=6 en-affil=Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=7 en-affil=Department of Rehabilitation Medicine, Nagoya University Hospital kn-affil= affil-num=8 en-affil=Orthopaedic Surgery, Gifu University School of Medicine kn-affil= affil-num=9 en-affil=Orthopaedic Surgery, Cancer Institute Hospital kn-affil= affil-num=10 en-affil=Orthopaedic Surgery, Tohoku University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Orthopaedic Surgery, Mie University kn-affil= affil-num=12 en-affil=Department of Tissue Regeneration, Center for Induced Pluripotent Stem Cell Research and Application, Institute for Frontier Medical Sciences, Kyoto University kn-affil= affil-num=13 en-affil=Orthopaedic Surgery, Hiroshima University kn-affil= affil-num=14 en-affil=Department of Orthopaedic Surgery, Keio University School of Medicine kn-affil= affil-num=15 en-affil=Orthopaedic Surgery, Kobe University kn-affil= affil-num=16 en-affil=Bone and Soft Tissue Tumour Surgery, Kanagawa Cancer Center kn-affil= affil-num=17 en-affil=Orthopaedic Surgery, Kyorin University kn-affil= affil-num=18 en-affil=Orthopaedic Surgery, Kagawa University Hospital kn-affil= affil-num=19 en-affil=Orthopaedic Surgery, Kurume University Hospital kn-affil= affil-num=20 en-affil=Orthopaedic Surgery, Yokohama City University Hospital kn-affil= affil-num=21 en-affil=Orthopaedic Surgery, Sapporo Medical University Hospital kn-affil= affil-num=22 en-affil=Orthopaedic Surgery, Aichi Cancer Center kn-affil= affil-num=23 en-affil=Musculoskeletal Oncology, Niigata Cancer Center Hospital kn-affil= affil-num=24 en-affil=Orthopaedic Surgery, Niigata University Medical & Dental Hospital kn-affil= affil-num=25 en-affil=Orthopaedic Surgery, Higashi Sapporo Hospital kn-affil= affil-num=26 en-affil=Advanced Medical Sciences, Oita University Faculty of Medicine kn-affil= affil-num=27 en-affil=Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital kn-affil= affil-num=28 en-affil=Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital kn-affil= affil-num=29 en-affil=Orthopaedic Surgery, Kyushu Rosai Hospital kn-affil= affil-num=30 en-affil=Orthopaedic Surgery, Faculty of Medicine, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=40 cd-vols= no-issue=4 article-no= start-page=561 end-page=568 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240705 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Central dentinogenic ghost cell tumor of the maxilla: a case report with new imaging findings and review of the literature en-subtitle= kn-subtitle= en-abstract= kn-abstract=A dentinogenic ghost cell tumor (DGCT) is a rare benign odontogenic tumor that commonly shows characteristics of solid proliferation and has a relatively high risk of recurrence after surgical treatment. We herein report a case of a central DGCT that occurred in the maxilla and resulted in bone expansion. This study highlights new imaging findings (particularly magnetic resonance imaging) along with histopathological observations. In addition, we conducted a review of the existing literature on this rare tumor. A 37-year-old man developed swelling around the right cheek. A benign odontogenic tumor such as ameloblastoma was suspected based on the imaging examination findings (including bone expansion and the internal characteristics of the tumor) on panoramic imaging, computed tomography, and magnetic resonance imaging. The lesion was surgically excised from the right maxilla. Postoperative histopathological examination led to a definitive diagnosis of central DGCT. The tumor comprised epithelial neoplastic islands, resembling ameloblastoma, inside tight fibroconnective tissue; masses of ghost cells and formation of dentin were also observed. We had suspected that the minute high-density region around the molars on the imaging examinations represented alveolar bone change; however, it represented dentin formation. This led to difficulty diagnosing the lesion. Although DGCT may present characteristic findings on imaging examinations, its occurrence is infrequent, and in some cases, the findings may include the presence or absence of an impacted tooth without obvious calcification. The present case suggests that we should consider the possibility of an odontogenic tumor with calcification when high-density structures are observed inside the lesion. en-copyright= kn-copyright= en-aut-name=YoshidaSuzuka en-aut-sei=Yoshida en-aut-mei=Suzuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakeshitaYohei en-aut-sei=Takeshita en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KawazuToshiyuki en-aut-sei=Kawazu en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HisatomiMiki en-aut-sei=Hisatomi en-aut-mei=Miki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OkadaShunsuke en-aut-sei=Okada en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujikuraMamiko en-aut-sei=Fujikura en-aut-mei=Mamiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ObataKyoichi en-aut-sei=Obata en-aut-mei=Kyoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakabatakeKiyofumi en-aut-sei=Takabatake en-aut-mei=Kiyofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YoshidaSaori en-aut-sei=Yoshida en-aut-mei=Saori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AsaumiJunichi en-aut-sei=Asaumi en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Oral and Maxillofacial Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Oral and Maxillofacial Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Oral and Maxillofacial Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Oral and Maxillofacial Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Oral and Maxillofacial Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Oral and Maxillofacial Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Oral and Maxillofacial Surgery, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Preliminary Examination Room, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Oral and Maxillofacial Radiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Dentinogenic ghost cell tumor kn-keyword=Dentinogenic ghost cell tumor en-keyword=Benign odontogenic tumor kn-keyword=Benign odontogenic tumor en-keyword=Maxilla kn-keyword=Maxilla en-keyword=Calcification kn-keyword=Calcification en-keyword=Computed tomography kn-keyword=Computed tomography en-keyword=Magnetic resonance imaging kn-keyword=Magnetic resonance imaging END start-ver=1.4 cd-journal=joma no-vol=100 cd-vols= no-issue=1 article-no= start-page=66 end-page=77 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20241120 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Different impacts of granulocyte colony‐stimulating factor administration on allogeneic hematopoietic cell transplant outcomes for adult acute myeloid leukemia according to graft type en-subtitle= kn-subtitle= en-abstract= kn-abstract=We retrospectively evaluated the impacts of using granulocyte colony-stimulating factor (G-CSF) and its timing on posttransplant outcomes for 9766 adults with acute myeloid leukemia (AML) between 2013 and 2022 using a Japanese database. We separately evaluated three distinct cohorts based on graft type: 3248 received bone marrow transplantation (BMT), 3066 received peripheral blood stem cell transplantation (PBSCT), and 3452 received single-unit cord blood transplantation (CBT). Multivariate analysis showed that G-CSF administration significantly accelerated neutrophil recovery after BMT, PBSCT, and CBT. However, it was associated with a higher risk of grades II–IV acute graft-versus-host disease (GVHD) across all graft types. Moreover, an increased incidence of overall chronic GVHD was observed with G-CSF administration in BMT and CBT patients, but not in PBSCT patients. G-CSF administration significantly improved overall survival (OS) and leukemia-free survival (LFS) only following CBT. Regarding the timing of G-CSF, in comparison with late initiation of G-CSF (Days 5–10), early initiation (Days 0–4) did not provide benefits for hematopoietic recovery regardless of graft type. In contrast, late initiation was significantly associated with a lower risk of grades II–IV acute GVHD and better OS and LFS in CBT patients. These data demonstrated that G-CSF administration accelerated neutrophil recovery and increased the risk of grades II–IV acute GVHD across all graft types, but significantly improved survival outcomes but only following CBT. Therefore, routine use of G-CSF should be considered for CBT in adult patients with AML. en-copyright= kn-copyright= en-aut-name=KonumaTakaaki en-aut-sei=Konuma en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KamedaKazuaki en-aut-sei=Kameda en-aut-mei=Kazuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MoritaKaoru en-aut-sei=Morita en-aut-mei=Kaoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KondoTadakazu en-aut-sei=Kondo en-aut-mei=Tadakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KimuraFumihiko en-aut-sei=Kimura en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakasoneHideki en-aut-sei=Nakasone en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OuchiFumihiko en-aut-sei=Ouchi en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UchidaNaoyuki en-aut-sei=Uchida en-aut-mei=Naoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaMasatsugu en-aut-sei=Tanaka en-aut-mei=Masatsugu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NishidaTetsuya en-aut-sei=Nishida en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FukudaTakahiro en-aut-sei=Fukuda en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HasegawaYuta en-aut-sei=Hasegawa en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=Sakata‐YanagimotoMamiko en-aut-sei=Sakata‐Yanagimoto en-aut-mei=Mamiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OnizukaMakoto en-aut-sei=Onizuka en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=SawaMasashi en-aut-sei=Sawa en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=OtaShuichi en-aut-sei=Ota en-aut-mei=Shuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=FujiwaraShin‐Ichiro en-aut-sei=Fujiwara en-aut-mei=Shin‐Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=YoshiharaSatoshi en-aut-sei=Yoshihara en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=IshimaruFumihiko en-aut-sei=Ishimaru en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=YoshimitsuMakoto en-aut-sei=Yoshimitsu en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=KandaYoshinobu en-aut-sei=Kanda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=OhbikiMarie en-aut-sei=Ohbiki en-aut-mei=Marie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=YanadaMasamitsu en-aut-sei=Yanada en-aut-mei=Masamitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= affil-num=1 en-affil=Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo kn-affil= affil-num=2 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= affil-num=3 en-affil=Division of Hematology, Jichi Medical University kn-affil= affil-num=4 en-affil=Department of Hematology, Kobe City Medical Center General Hospital kn-affil= affil-num=5 en-affil=Division of Hematology, Department of Internal Medicine, National Defense Medical College kn-affil= affil-num=6 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= affil-num=7 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=8 en-affil=Department of Hematology, Toranomon Hospital kn-affil= affil-num=9 en-affil=Department of Hematology, Kanagawa Cancer Center kn-affil= affil-num=10 en-affil=Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital kn-affil= affil-num=11 en-affil=Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital kn-affil= affil-num=12 en-affil=Department of Hematology, Hokkaido University Hospital kn-affil= affil-num=13 en-affil=Department of Hematology, University of Tsukuba Hospital kn-affil= affil-num=14 en-affil=Department of Hematology and Oncology, Tokai University School of Medicine kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Anjo Kosei Hospital kn-affil= affil-num=16 en-affil=Department of Hematology, Sapporo Hokuyu Hospital kn-affil= affil-num=17 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=18 en-affil=Division of Hematology, Jichi Medical University kn-affil= affil-num=19 en-affil=Department of Hematology, Hyogo Medical University Hospital kn-affil= affil-num=20 en-affil=Technical Department, Japanese Red Cross Society Blood Service Headquarters kn-affil= affil-num=21 en-affil=Department of Hematology and Rheumatology, Kagoshima University Hospital kn-affil= affil-num=22 en-affil=Division of Hematology, Jichi Medical University kn-affil= affil-num=23 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=24 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=25 en-affil=Department of Hematology and Oncology, Nagoya City University East Medical Center kn-affil= END start-ver=1.4 cd-journal=joma no-vol=361 cd-vols= no-issue= article-no= start-page=107331 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202504 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effect of chemistry on the compressibility and high-pressure structural evolution of the CaFe2O4-type aluminous silicate phase en-subtitle= kn-subtitle= en-abstract= kn-abstract=Approximately 22–26 vol% of a basaltic phase assemblage at lower mantle conditions is comprised of a (Na,Mg,Fe2+)(Al,Si,Fe3+)2O4 phase with CaFe2O4-type (CF-type) structure. Previous experimental studies attempted to determine the equation of state of the CF-type phase but reported contrasting compressibility values, even for samples with the same composition. Therefore, the elastic properties of the CF-type phase remain, to date, largely unconstrained. Here, we conducted single-crystal X-ray diffraction (SCXRD) measurements in the diamond anvil cell (DAC) at high pressure and room temperature on three samples of CF-type phase with compositions Na0.90(1)Al1.03(2)Si1.00(2)O4 (NaCF), Na0.66(4)Mg0.28(4)Al1.22(3)Si0.78(3)O4 (MgCF) and Na0.62(2)Mg0.19(1)Fe2+0.17(1)Fe3+0.080(4)Al1.20(3)Si0.70(1)O4 (FeCF). A multi-sample loading approach was employed for most DAC runs, where two samples were loaded in the same sample chamber to reduce possible systematic deviations between datasets, thus enhancing internal consistency and corroborating data reproducibility. Experiments on the NaCF and MgCF samples were conducted up to ∼50 GPa, while the FeCF sample was compressed to ∼72 GPa to better characterize the effect of the spin crossover of octahedrally coordinated Fe3+. We found the isothermal bulk modulus (KT0) to increase with decreasing NaAlSiO4 content, accompanied by only a slight decrease in its pressure derivative (K'T0). Analysis of the crystal structures of the three samples at high pressure allowed compositional trends to be determined also for the interatomic bonds and polyhedral compressibility, as well as the distortion indices. These suggest an overall stiffening of the A site with increasing Mg2+ and Fe2+ content, as well of the two B sites with increasing Al3+ and Fe3+ content. Enhanced compressibility of the unit cell and octahedral B sites was observed between ∼26–42 GPa in the FeCF sample, suggesting a pressure-induced spin crossover of Fe3+, in agreement with some previous observations. Finally, trends in the elastic properties from experimental studies conducted along the NaAlSiO4-MgAl2O4 join are discussed and used as a proxy to evaluate the reliability of end-member properties for the CF-type phase employed in most recent mineral physical and thermodynamic databases. Our analysis suggests current mineral physical models might underestimate densities and overestimate bulk sound velocities of NaAlSiO4-rich CF-type phases with basaltic composition. en-copyright= kn-copyright= en-aut-name=CrinitiGiacomo en-aut-sei=Criniti en-aut-mei=Giacomo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Boffa BallaranTiziana en-aut-sei=Boffa Ballaran en-aut-mei=Tiziana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KurnosovAlexander en-aut-sei=Kurnosov en-aut-mei=Alexander kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IshiiTakayuki en-aut-sei=Ishii en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=RogmannElena-Marie en-aut-sei=Rogmann en-aut-mei=Elena-Marie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=GlazyrinKonstantin en-aut-sei=Glazyrin en-aut-mei=Konstantin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FedotenkoTimofey en-aut-sei=Fedotenko en-aut-mei=Timofey kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FrostDaniel J. en-aut-sei=Frost en-aut-mei=Daniel J. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Bayerisches Geoinstitut, University of Bayreuth kn-affil= affil-num=2 en-affil=Bayerisches Geoinstitut, University of Bayreuth kn-affil= affil-num=3 en-affil=Bayerisches Geoinstitut, University of Bayreuth kn-affil= affil-num=4 en-affil=Institute for Planetary Materials, Okayama University kn-affil= affil-num=5 en-affil=Bayerisches Geoinstitut, University of Bayreuth kn-affil= affil-num=6 en-affil=Deutsches Elektronen-Synchrotron DESY kn-affil= affil-num=7 en-affil=Deutsches Elektronen-Synchrotron DESY kn-affil= affil-num=8 en-affil=Bayerisches Geoinstitut, University of Bayreuth kn-affil= en-keyword=CaFe2O4-type phase kn-keyword=CaFe2O4-type phase en-keyword=Lower mantle kn-keyword=Lower mantle en-keyword=Equations of state kn-keyword=Equations of state en-keyword=Structural refinements kn-keyword=Structural refinements en-keyword=Crystal chemistry kn-keyword=Crystal chemistry en-keyword=Fe3+ spin-crossover kn-keyword=Fe3+ spin-crossover END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=3 article-no= start-page=497 end-page=503 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250205 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Five-year outcomes with gefitinib induction and chemoradiotherapy in EGFR-mutant stage III non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background We previously showed the 2-year OS rate, the primary endpoint, of 90% in a phase II trial of gefitinib induction followed by chemoradiotherapy (CRT) in unresectable, stage III, EGFR-mutant, non-small-cell lung cancer (NSCLC). However, neither long-term survival data nor late-phase adverse event profiles have been presented.
Patients and methods Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy for 8 weeks. After confirming no disease progression during induction therapy, cisplatin and docetaxel on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy were subsequently administered.
Results In the enrolled twenty patients, the 5-year OS rate and median survival time were 70.0% [95% confidence interval: 45.1–85.3] and 5.5 years [4.91-NE], respectively, whereas 5-year PFS rate and median PFS time were 15.0% (3.7–33.5) and 1.4 years [0.69–2.29], respectively. Efficacy did not seem influenced even if radiation field was re-planed in response to the effect of gefitinib induction. As for late adverse events, pulmonary fibrosis occurred in 7 patients (35%). The median time from completion of CRT to the occurrence of the event was 245 days. All were grade 1, and there was no evidence of cavitation of the lesions or chronic infections such as Aspergillus infection during the course of the disease. One case of small cell lung cancer occurred during the period.
Conclusions With longer follow-up time, we demonstrated favorable efficacy with tolerable toxicity profiles in the EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III, NSCLC.
Trial registration numbers UMIN00005086. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000006047&type=summary&language=EjRCTs071180036. https://jrct.niph.go.jp/latest-detail/jRCTs071180036 en-copyright= kn-copyright= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SaekiSho en-aut-sei=Saeki en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SakataShinya en-aut-sei=Sakata en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamaguchiMasafumi en-aut-sei=Yamaguchi en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HaradaDaijiro en-aut-sei=Harada en-aut-mei=Daijiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=BesshoAkihiro en-aut-sei=Bessho en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TanakaKentaro en-aut-sei=Tanaka en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=InoueKoji en-aut-sei=Inoue en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=InoueKoji en-aut-sei=Inoue en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=GembaKenichi en-aut-sei=Gemba en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KuboToshio en-aut-sei=Kubo en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SatoAkiko en-aut-sei=Sato en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=WatanabeHiromi en-aut-sei=Watanabe en-aut-mei=Hiromi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KishimotoJunji en-aut-sei=Kishimoto en-aut-mei=Junji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=ShioyamaYoshiyuki en-aut-sei=Shioyama en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KatsuiKuniaki en-aut-sei=Katsui en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SugioKenji en-aut-sei=Sugio en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Respiratory Medicine, Kumamoto University Hospital kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Kumamoto University Hospital kn-affil= affil-num=4 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=5 en-affil=Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital kn-affil= affil-num=7 en-affil=Department of Respiratory Medicine, Kyushu University Hospital kn-affil= affil-num=8 en-affil=Department of Respiratory Medicine, Kitakyushu Municipal Medical Center kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Ehime Prefectural Central Hospital kn-affil= affil-num=10 en-affil=Department of Respiratory Medicine, Chugoku Central Hospital kn-affil= affil-num=11 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=13 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=15 en-affil=Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=16 en-affil=Radiation Oncology, Ion Beam Therapy Center, SAGA HIMAT Foundation kn-affil= affil-num=17 en-affil=Department of Radiology, Kawasaki Medical School kn-affil= affil-num=18 en-affil=Division of Radiation Oncology, Department of Thoracic and Breast Surgery, Oita University kn-affil= affil-num=19 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= en-keyword=Non-small-cell lung cancer kn-keyword=Non-small-cell lung cancer en-keyword=Locally advanced setting kn-keyword=Locally advanced setting en-keyword=Chemoradiation kn-keyword=Chemoradiation en-keyword=Epidermal growth factor receptor kn-keyword=Epidermal growth factor receptor END start-ver=1.4 cd-journal=joma no-vol=5 cd-vols= no-issue=1 article-no= start-page=12 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250320 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Early Response After Radiation Therapy on Three-Dimensional Oral Cancer Model Using Patient-Derived Cancer-Associated Fibroblasts en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Objectives: Cancer-associated fibroblasts (CAFs), which are an important component of the tumor microenvironment, have been reported to have an adverse effect on conventional radiotherapy. This study aims to elucidate the effects of CAFs in boron neutron capture therapy (BNCT) using a three-dimensional (3D) oral cancer model. Methods: Three-dimensional cancer models were fabricated using patient-derived CAFs or patient-derived normal oral fibroblasts (NOFs) and a human oral squamous cell carcinoma cell line. Each 3D cancer model was performed with either a conventional X-ray treatment or BNCT and additionally analyzed histomorphologically. Results: The 3D oral cancer-CAFs model demonstrated a greater depth of cancer cell invasion than the 3D oral cancer-NOFs model. Radiation therapy for the 3D oral cancer models indicated a trend for decreasing cancer cell invasion and cell number with dose dependence in both X-ray and BNCT. In comparison with X-rays, BNCT showed a consistent increase in the number of NOFs and a significant reduction in the number of CAFs. Conclusions: BNCT for the 3D oral cancer model was shown to be effective against cancer cells and CAFs but not against NOFs, indicating its usefulness as a minimally invasive treatment for advanced cancer. Furthermore, it is indicated that the 3D oral cancer-CAFs model is a valuable tool to evaluate cancer treatment and research, particularly in high-grade malignant tumors with invasion. en-copyright= kn-copyright= en-aut-name=YamamotoIzumi en-aut-sei=Yamamoto en-aut-mei=Izumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IgawaKazuyo en-aut-sei=Igawa en-aut-mei=Kazuyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KondoNatsuko en-aut-sei=Kondo en-aut-mei=Natsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakuraiYoshinori en-aut-sei=Sakurai en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=FujimuraAtsushi en-aut-sei=Fujimura en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakabatakeKiyofumi en-aut-sei=Takabatake en-aut-mei=Kiyofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HuangPeng en-aut-sei=Huang en-aut-mei=Peng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MichiueHiroyuki en-aut-sei=Michiue en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IbaragiSoichiro en-aut-sei=Ibaragi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IzumiKenji en-aut-sei=Izumi en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= affil-num=2 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= affil-num=3 en-affil=Particle Radiation Oncology Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=4 en-affil=Particle Radiation Oncology Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=5 en-affil=Department of Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= affil-num=8 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= affil-num=9 en-affil=Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Division of Biomimetics, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University kn-affil= en-keyword=3D model kn-keyword=3D model en-keyword=oral cancer kn-keyword=oral cancer en-keyword=patient-derived cells kn-keyword=patient-derived cells en-keyword=cancer-associated fibroblasts kn-keyword=cancer-associated fibroblasts en-keyword=radiation treatment kn-keyword=radiation treatment en-keyword=boron neutron capture therapy kn-keyword=boron neutron capture therapy en-keyword=malignant tumors kn-keyword=malignant tumors END start-ver=1.4 cd-journal=joma no-vol=301 cd-vols= no-issue=3 article-no= start-page=108273 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202503 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Taste receptor type 1 member 3 in osteoclasts regulates osteoclastogenesis via detection of glucose en-subtitle= kn-subtitle= en-abstract= kn-abstract=The taste system extends beyond the oral cavity, with various taste receptors found in extraoral organs. Mice deficient in the taste receptor type 1 (TAS1R) family member, TAS1R3, and fed a high-fat, high-sugar diet showed high bone mass without altering food consumption. However, the underlying mechanisms, including the cell types responsible for TAS1R3 expression, remain unclear. Here, we demonstrate the expression and function of TAS1R3 in osteoclasts, which are responsible for bone resorption. The expression of Tas1r3, but not Tas1r1 or Tas1r2, is evoked during osteoclast differentiation. Osteoclastogenesis-related genes were downregulated in TAS1R3-deficient mice, whereas the opposite phenotypes were elicited by TAS1R3 overexpression. Contrary to the common heterodimerization with TAS1R1 or TAS1R2, TAS1R3 formed a homodimer that functioned to detect glucose, enhance p38 phosphorylation, and induce osteoclastogenesis. These results provide novel insights into the role of TAS1R3 in bone metabolism and suggest that TAS1R3 may be a viable target for therapeutic agents in bone metabolic diseases. en-copyright= kn-copyright= en-aut-name=YoshimuraAnna en-aut-sei=Yoshimura en-aut-mei=Anna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsubaraTakuma en-aut-sei=Matsubara en-aut-mei=Takuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KodamaNao en-aut-sei=Kodama en-aut-mei=Nao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KakutaYoshimitsu en-aut-sei=Kakuta en-aut-mei=Yoshimitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YasudaKazuma en-aut-sei=Yasuda en-aut-mei=Kazuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YoshidaRyusuke en-aut-sei=Yoshida en-aut-mei=Ryusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KaminumaOsamu en-aut-sei=Kaminuma en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HosomiShuhei en-aut-sei=Hosomi en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ShinkawaHiroji en-aut-sei=Shinkawa en-aut-mei=Hiroji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YuanQuan en-aut-sei=Yuan en-aut-mei=Quan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KawamotoTatsuo en-aut-sei=Kawamoto en-aut-mei=Tatsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KokabuShoichiro en-aut-sei=Kokabu en-aut-mei=Shoichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Division of Molecular Signaling and Biochemistry, Kyushu Dental University kn-affil= affil-num=2 en-affil=Division of Molecular Signaling and Biochemistry, Kyushu Dental University kn-affil= affil-num=3 en-affil=Division of Molecular Signaling and Biochemistry, Kyushu Dental University kn-affil= affil-num=4 en-affil=Laboratory of Structural Biology, Graduate School of Systems Life Sciences, Kyushu University kn-affil= affil-num=5 en-affil=Division of Molecular Signaling and Biochemistry, Kyushu Dental University kn-affil= affil-num=6 en-affil=Department of Oral Physiology, Graduate School of Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University kn-affil= affil-num=8 en-affil=Department of Gastroenterology, Graduate School of Medicine, Osaka Metropolitan University kn-affil= affil-num=9 en-affil=Department of Hepatobiliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University kn-affil= affil-num=10 en-affil=State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University kn-affil= affil-num=11 en-affil=Division of Orofacial Functions and Orthodontics, Kyushu Dental University kn-affil= affil-num=12 en-affil=Division of Molecular Signaling and Biochemistry, Kyushu Dental University kn-affil= en-keyword=glucose kn-keyword=glucose en-keyword=osteoclasts kn-keyword=osteoclasts en-keyword=p38 kn-keyword=p38 en-keyword=TAS1R3 kn-keyword=TAS1R3 en-keyword=taste receptor kn-keyword=taste receptor END start-ver=1.4 cd-journal=joma no-vol=126 cd-vols= no-issue= article-no= start-page=106710 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202503 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Proteome analysis reveals the molecular mechanisms of fucoxanthin-induced apoptosis in glial cells PC12 after nanoencapsulation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Fucoxanthin (FX) is a natural pigment belonging to the xanthophyll carotenoid, which has been proven to have inhibitory effects on glioblastoma. In our previous study, nano-FX was fabricated through whey protein and flaxseed gum co-encapsulated for improved stability and glial cell (PC12) inhibitory activity of FX. To investigate the molecular mechanisms of FX-induced apoptosis in PC12 after nanoencapsulation, proteomics analysis based on TMT technology was performed. Protein profiles in PC12 were determined after 0 (Control), 8 (L_Treat), and 24 (H_Treat) μg/mL nano-FX intervention. Results indicated 78 differential abundant proteins (DAPs) linked to the cytotoxicity of nano-FX could be potential biomarkers. GO and KEGG analysis revealed altered proteasome and NF-kappa B/MAPK/TNF. Proteins involved in cell proliferation were downregulated, while proteins response to autophagy and apoptosis were upregulated. The multiple mechanisms involved in the anti-tumor activity of nano-FX will provide a reference for the development of FX high value-added functional foods. en-copyright= kn-copyright= en-aut-name=WangChunyan en-aut-sei=Wang en-aut-mei=Chunyan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MaXinxin en-aut-sei=Ma en-aut-mei=Xinxin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakamuraYoshimasa en-aut-sei=Nakamura en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=QiHang en-aut-sei=Qi en-aut-mei=Hang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=School of Food Science, Henan Institute of Science and Technology kn-affil= affil-num=2 en-affil=School of Food Science, Henan Institute of Science and Technology kn-affil= affil-num=3 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=4 en-affil=SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, School of Food Science and Technology, Dalian Polytechnic University kn-affil= en-keyword=Fucoxanthin kn-keyword=Fucoxanthin en-keyword=Nanoencapsulation kn-keyword=Nanoencapsulation en-keyword=Apoptosis kn-keyword=Apoptosis en-keyword=Proteome analysis kn-keyword=Proteome analysis en-keyword=Molecular mechanisms kn-keyword=Molecular mechanisms END start-ver=1.4 cd-journal=joma no-vol=111 cd-vols= no-issue=5 article-no= start-page=1705 end-page=1715 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250911 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by systemic inflammation and lymphadenopathy. Two major clinical subtypes, idiopathic plasmacytic lymphadenopathy (iMCD-IPL) and iMCD with thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly (iMCD-TAFRO), have distinct pathophysiological mechanisms. While interleukin-6 (IL-6) is known to be elevated in iMCD, differences in the sources of IL-6 production between subtypes remain unclear. We examined the source of IL-6 production and its transcriptional regulation across iMCD subtypes using immunohistochemistry, in situ hybridization, and gene expression profiling. Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO. Plasma cells exhibited stronger IL-6 protein expression in iMCD-IPL than in iMCD-TAFRO. Gene expression analysis revealed upregulation of XBP1, MZB1, DERL3, SSR4, FKBP11, FKBP2, PIM2, RABAC1, and SDF2L1 in iMCD-IPL, implicating endoplasmic reticulum stress and plasma cell differentiation in IL-6 dysregulation. Our findings suggest that XBP1-mediated IL-6 production may contribute to the pathogenesis of iMCD-IPL, potentially explaining its favorable responses to IL-6 blockade therapy. In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype. Future studies should clarify how proteomics and gene expression profiling could inform subtype-specific therapeutic strategies in iMCD. en-copyright= kn-copyright= en-aut-name=NishikoriAsami en-aut-sei=Nishikori en-aut-mei=Asami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishimuraMidori Filiz en-aut-sei=Nishimura en-aut-mei=Midori Filiz kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NishimuraYoshito en-aut-sei=Nishimura en-aut-mei=Yoshito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamadaRio en-aut-sei=Yamada en-aut-mei=Rio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HaratakeTomoka en-aut-sei=Haratake en-aut-mei=Tomoka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ChijimatsuRyota en-aut-sei=Chijimatsu en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ItoToshihiro en-aut-sei=Ito en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KogaTomohiro en-aut-sei=Koga en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OchiSayaka en-aut-sei=Ochi en-aut-mei=Sayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KawaharaYuri en-aut-sei=Kawahara en-aut-mei=Yuri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=UetaHimawari en-aut-sei=Ueta en-aut-mei=Himawari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=TakedaYudai en-aut-sei=Takeda en-aut-mei=Yudai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=GonzalezMichael V. en-aut-sei=Gonzalez en-aut-mei=Michael V. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FajgenbaumDavid C. en-aut-sei=Fajgenbaum en-aut-mei=David C. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=Van RheeFrits en-aut-sei=Van Rhee en-aut-mei=Frits kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=MomoseShuji en-aut-sei=Momose en-aut-mei=Shuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SatoYasuharu en-aut-sei=Sato en-aut-mei=Yasuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=2 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=3 en-affil=Division of Hematology/Oncology, Mayo Clinic kn-affil= affil-num=4 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=5 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=6 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan; Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan; Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Immunology, Nara Medical University kn-affil= affil-num=9 en-affil=Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences kn-affil= affil-num=10 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=11 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=12 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=13 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=14 en-affil=Center for Cytokine Storm Treatment and Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania kn-affil= affil-num=15 en-affil=Center for Cytokine Storm Treatment and Laboratory, Department of Medicine, Perelman School of Medicine, University of Pennsylvania kn-affil= affil-num=16 en-affil=University of Arkansas for Medical Sciences kn-affil= affil-num=17 en-affil=Department of Pathology, Saitama Medical Center, Saitama Medical University kn-affil= affil-num=18 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=295 cd-vols= no-issue= article-no= start-page=51 end-page=64 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202609 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A novel spontaneous rat model of chronic kidney disease with mitochondrial dysfunction driven by thioredoxin insufficiency en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Chronic kidney disease (CKD) is a global health burden with high prevalence and poor prognosis. Although oxidative stress and mitochondrial dysfunction have been implicated in its pathogenesis, in vivo causal evidence remains limited. Thioredoxin (Trx), encoded by Txn1, is a redox-active protein that plays a central role in controlling oxidative stress and maintaining intracellular redox homeostasis.
Methods: To address this gap, we investigated the lifelong phenotypes of Txn1-F54L mutant rats harboring approximately one-third of the normal Trx activity. These rats were generated via N-ethyl-N-nitrosourea mutagenesis and validated by clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 genome editing. Comprehensive analyses included biochemical testing, histopathology, immunohistochemistry, transmission electron microscopy, RNA-sequencing, western blotting, and cytokine profiling.
Results: Txn1-F54L mutant rats spontaneously developed progressive CKD, with median survival times of 110–119 days for homozygotes and 303–346 days for heterozygotes. Their clinical features—elevated blood urea nitrogen, hypoalbuminemia, hypercholesterolemia, hypertension, and arterial medial sclerosis—closely resembled those of human CKD. Histopathological evaluation revealed extensive tubular injury, interstitial fibrosis, and glomerulosclerosis. Transcriptomic profiling identified 3,418 differentially expressed genes significantly enriched in immune activation and fibrosis pathways. Mitochondrial dysfunction was prominent in proximal tubules, accompanied by oxidative stress accumulation and concurrent activation of regulated cell death pathways (apoptosis, necroptosis, and pyroptosis). Elevated serum levels of interleukin-1β, interleukin-6, and interferon-γ indicated systemic inflammation.
Conclusions: Our findings demonstrate that lifelong Trx deficiency induces oxidative stress–mediated mitochondrial dysfunction and regulated cell death, leading to inflammation and progressive CKD. This study establishes the Txn1 mutant rat as a valuable spontaneous CKD model, providing translational insights and a platform for developing therapeutic strategies targeting oxidative stress–induced pathways. en-copyright= kn-copyright= en-aut-name=OhmoriIori K. en-aut-sei=Ohmori en-aut-mei=Iori K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OuchidaMamoru en-aut-sei=Ouchida en-aut-mei=Mamoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HadaYoshiko en-aut-sei=Hada en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UchidaHaruhito A. en-aut-sei=Uchida en-aut-mei=Haruhito A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ToyokuniShinya en-aut-sei=Toyokuni en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MashimoTomoji en-aut-sei=Mashimo en-aut-mei=Tomoji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Section of Developmental Physiology and Pathology, Faculty of Education, Okayama University kn-affil= affil-num=2 en-affil=Department of Molecular Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo kn-affil= en-keyword=Chronic kidney disease kn-keyword=Chronic kidney disease en-keyword=Mitochondria kn-keyword=Mitochondria en-keyword=Thioredoxin kn-keyword=Thioredoxin en-keyword=Trx kn-keyword=Trx en-keyword=Txn1 kn-keyword=Txn1 en-keyword=Regulated cell death kn-keyword=Regulated cell death END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=5705 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260119 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Variations in the perceived value of anti-SARS-CoV-2 therapeutics based on physicians’ clinical backgrounds en-subtitle= kn-subtitle= en-abstract= kn-abstract=Although the global emergency phase of the coronavirus disease 2019 (COVID-19) pandemic has ended, antiviral therapy remains crucial for patients at high risk of severe illness. In Japan, the out-of-pocket costs for antiviral drugs shifted from full public coverage to partial patient payment in April 2024. However, the impact of physicians’ background characteristics on antiviral cost perceptions and prescribing behavior remains underexplored. This study involved a secondary analysis of a nationwide, web-based interventional survey of 1,500 physicians treating COVID-19. Participants reported whether they avoided prescribing antivirals owing to drug costs and identified what they considered an appropriate cost per treatment course. Associations between physicians’ characteristics and their cost perceptions were analyzed. Among 1,500 physicians surveyed, 1,193 (79.5%) reported avoiding antiviral prescriptions owing to drug costs. The most commonly selected appropriate cost was ≤ 33 USD (65.0%). Generalists, pulmonologists, ear, nose, and throat specialists, and clinic-based physicians were more likely to refrain from prescribing antivirals and favor lower treatment costs compared with physicians in other specialties or hospital settings. A multivariate analysis revealed workplace setting as the only factor independently associated with cost-related prescribing behavior. High antiviral drug costs in Japan may contribute to underprescription, particularly among clinic-based physicians, and this underprescription could hypothetically lead to delays in treatment, which might increase the risk of severe outcomes in high-risk patients. As high-risk patients with mild COVID-19 often first seek care in clinics, promoting appropriate antiviral use in these settings is essential. Strengthening communication and sharing clinical experiences between hospitals and clinics may help reduce prescribing disparities driven by drug costs. en-copyright= kn-copyright= en-aut-name=HagiwaraAkihiko en-aut-sei=Hagiwara en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KomiyaKosaku en-aut-sei=Komiya en-aut-mei=Kosaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShindoYuichiro en-aut-sei=Shindo en-aut-mei=Yuichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakamatsuKazufumi en-aut-sei=Takamatsu en-aut-mei=Kazufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NishimuraNaoki en-aut-sei=Nishimura en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakechiYukako en-aut-sei=Takechi en-aut-mei=Yukako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakazonoTakahiro en-aut-sei=Takazono en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IzumiShinyu en-aut-sei=Izumi en-aut-mei=Shinyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=GotohShimpei en-aut-sei=Gotoh en-aut-mei=Shimpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=SakaoSeiichiro en-aut-sei=Sakao en-aut-mei=Seiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IzumoTakehiro en-aut-sei=Izumo en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YamamotoKazuko en-aut-sei=Yamamoto en-aut-mei=Kazuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YateraKazuhiro en-aut-sei=Yatera en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KakeyaHiroshi en-aut-sei=Kakeya en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=ShibataYoko en-aut-sei=Shibata en-aut-mei=Yoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TomiiKeisuke en-aut-sei=Tomii en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SagaraHironori en-aut-sei=Sagara en-aut-mei=Hironori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=SasakiYuka en-aut-sei=Sasaki en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=HiraiToyohiro en-aut-sei=Hirai en-aut-mei=Toyohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=YokoyamaAkihito en-aut-sei=Yokoyama en-aut-mei=Akihito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=MukaeHiroshi en-aut-sei=Mukae en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=OguraTakashi en-aut-sei=Ogura en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= affil-num=1 en-affil=Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine kn-affil= affil-num=2 en-affil=Respiratory Medicine and Infectious Diseases, Oita University Faculty of Medicine kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Nagoya University Graduate School of Medicine kn-affil= affil-num=4 en-affil=Department of Respiratory Medicine and Allergology, Kochi Medical School, Kochi University kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, National Center for Global Health and Medicine kn-affil= affil-num=6 en-affil=Iki-iki Clinic kn-affil= affil-num=7 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, National Center for Global Health and Medicine kn-affil= affil-num=10 en-affil=Department of Clinical Application, Center for iPS Cell, Research and Application, Kyoto University kn-affil= affil-num=11 en-affil=Department of Pulmonary Medicine, School of Medicine, International University of Health and Welfare kn-affil= affil-num=12 en-affil=Department of Respiratory Medicine, Japanese Red Cross Medical Center kn-affil= affil-num=13 en-affil=Division of Infectious, Respiratory, and Digestive Medicine, First Department of Internal Medicine, University of the Ryukyus Graduate School of Medicine kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, School of Medicine, University of Occupational and Environmental Health kn-affil= affil-num=15 en-affil=Department of Infection Control Science, Osaka Metropolitan University Graduate School of Medicine kn-affil= affil-num=16 en-affil=Department of Pulmonary Medicine, Fukushima Medical University School of Medicine kn-affil= affil-num=17 en-affil=Department of Respiratory Medicine, Kobe City Medical Center General Hospital kn-affil= affil-num=18 en-affil=Department of Medicine, Division of Respiratory Medicine and Allergology, Showa Medical University School of Medicine kn-affil= affil-num=19 en-affil=Center for Pulmonary Disease, National Hospital Organization Tokyo National Hospital kn-affil= affil-num=20 en-affil=Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University kn-affil= affil-num=21 en-affil=Department of Respiratory Medicine and Allergology, Kochi Medical School, Kochi University kn-affil= affil-num=22 en-affil=Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences kn-affil= affil-num=23 en-affil=Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center kn-affil= en-keyword=Antiviral kn-keyword=Antiviral en-keyword=COVID-19 kn-keyword=COVID-19 en-keyword=Prescription kn-keyword=Prescription en-keyword=Workplace kn-keyword=Workplace END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=3 article-no= start-page=169 end-page=178 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202606 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Peripheral Blood T-Cell Receptor Repertoire and Host Immune Background in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=The association between peripheral blood T-cell receptor (TCR) repertoire and chemotherapy response remains unclear. We evaluated peripheral blood TCR repertoire and gut microbiota in 21 breast cancer patients receiving neoadjuvant chemotherapy (NAC) who were enrolled in the SBP-14 prospective cohort study between October 2019 and March 2022. We analyzed stool samples obtained pre-NAC and peripheral blood samples obtained pre- and post-NAC. The primary endpoint was the association between baseline peripheral blood TCR repertoire and treatment response. Eleven patients (52%) had hormone receptor-positive breast cancer. All patients received anthracyclines and taxanes, with anti-HER2 therapy for HER2-positive disease. TCR diversity (TCR alpha chain [TRA], p=0.095; TCR beta chain [TRB], p=0.051) and clonality (TRA, p=0.271; TRB, p=0.500) were not significantly associated with treatment response. Gut microbiota diversity was not correlated with TCR diversity (TRA: ρ=0.046, p=0.845; TRB: ρ=0.021, p=0.929); however, three bacterial orders (Erysipelotrichales, Bacillales, and Pasteurellales) were significantly associated with TCR repertoire. Baseline TCR repertoire was not associated with treatment response in this cohort of breast cancer patients. en-copyright= kn-copyright= en-aut-name=NakamuraYuki en-aut-sei=Nakamura en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IwamotoTakayuki en-aut-sei=Iwamoto en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KajiwaraYukiko en-aut-sei=Kajiwara en-aut-mei=Yukiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HidaAkira en-aut-sei=Hida en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakamotoShogo en-aut-sei=Nakamoto en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MiyoshiYuichiro en-aut-sei=Miyoshi en-aut-mei=Yuichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ShienTadahiko en-aut-sei=Shien en-aut-mei=Tadahiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IkedaMasahiko en-aut-sei=Ikeda en-aut-mei=Masahiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=DoiharaHiroyoshi en-aut-sei=Doihara en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OgataRyohei en-aut-sei=Ogata en-aut-mei=Ryohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KoikeYoshikazu en-aut-sei=Koike en-aut-mei=Yoshikazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NomuraTsunehisa en-aut-sei=Nomura en-aut-mei=Tsunehisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=TanakaKatsuhiro en-aut-sei=Tanaka en-aut-mei=Katsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NakashimaKazutaka en-aut-sei=Nakashima en-aut-mei=Kazutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=YamatsujiTomoki en-aut-sei=Yamatsuji en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TairaNaruto en-aut-sei=Taira en-aut-mei=Naruto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital kn-affil= affil-num=2 en-affil=Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital kn-affil= affil-num=3 en-affil=Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital kn-affil= affil-num=4 en-affil=Department of Pathology, Matsuyama Shimin Hospital kn-affil= affil-num=5 en-affil=Department of Breast and Endocrine Surgery, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Breast Endocrine Surgery, Kagawa Prefectural Center Hospital kn-affil= affil-num=7 en-affil=Department of Breast and Endocrine Surgery, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Breast and Thyroid Surgery, Fukuyama City Hospital kn-affil= affil-num=9 en-affil=Department of General Surgery, Kawasaki Medical School General Medical Center kn-affil= affil-num=10 en-affil=Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital kn-affil= affil-num=11 en-affil=Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital kn-affil= affil-num=12 en-affil=Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital kn-affil= affil-num=13 en-affil=Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital kn-affil= affil-num=14 en-affil=Department of General Surgery, Kawasaki Medical School General Medical Center kn-affil= affil-num=15 en-affil=Department of General Surgery, Kawasaki Medical School General Medical Center kn-affil= affil-num=16 en-affil=Department of Breast and Thyroid Surgery, Kawasaki Medical School Hospital kn-affil= en-keyword=TCR repertoire kn-keyword=TCR repertoire en-keyword=gut microbiota kn-keyword=gut microbiota en-keyword=neoadjuvant chemotherapy kn-keyword=neoadjuvant chemotherapy en-keyword=breast cancer kn-keyword=breast cancer END start-ver=1.4 cd-journal=joma no-vol=330 cd-vols= no-issue=5 article-no= start-page=L593 end-page=L609 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The role of S100A8/A9 in the pathogenesis of acute exacerbations of pulmonary fibrosis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Acute exacerbation of idiopathic pulmonary fibrosis is a life-threatening condition characterized by neutrophilic inflammation. S100A8/A9, an alarmin released by activated neutrophils and monocytes/macrophages, plays a pivotal role in regulating inflammatory responses. However, its specific involvement in acute exacerbations of pulmonary fibrosis remains unclear. This study evaluated the role of S100A8/A9 in the pathogenesis of acute exacerbations of pulmonary fibrosis. S100A8/A9 levels were measured in bronchoalveolar lavage fluid and serum from patients with idiopathic interstitial pneumonia, with and without acute exacerbations. To model acute exacerbations of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Subsequently, inflammatory cell infiltration, cytokine levels, morphological changes, and fibrosis marker levels in lung tissue and airways were analyzed. S100A8/A9 levels were significantly higher in the bronchoalveolar lavage fluid and serum of patients with idiopathic interstitial pneumonia experiencing acute exacerbations relative to those without; these levels were correlated with patient prognosis. In an experimental mouse model, intratracheal administration of bleomycin followed by lipopolysaccharide resulted in a significant increase in airway S100A8/A9 levels compared with bleomycin alone and control mice. Anti-S100A8/A9 neutralizing antibody Ab45 mitigated airway inflammation and lung fibrosis in mice with acute exacerbations of pulmonary fibrosis, reducing S100A8/A9 levels and neutrophil extracellular traps. In vitro, recombinant S100A8/A9 or lipopolysaccharide and neutrophils activated and differentiated fibroblasts; these effects were inhibited by anti-S100A8/A9 neutralizing antibody Ab45 and the humanized form of Ab45 (HuAb45). These findings highlight S100A8/A9 as a potential prognostic biomarker and therapeutic target for acute exacerbations of pulmonary fibrosis. en-copyright= kn-copyright= en-aut-name=NakamuraNaoki en-aut-sei=Nakamura en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HigoHisao en-aut-sei=Higo en-aut-mei=Hisao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SenooSatoru en-aut-sei=Senoo en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TaniguchiAkihiko en-aut-sei=Taniguchi en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OzekiTaichi en-aut-sei=Ozeki en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SunamiRyota en-aut-sei=Sunami en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=InukaiYumi en-aut-sei=Inukai en-aut-mei=Yumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamamotoShusei en-aut-sei=Yamamoto en-aut-mei=Shusei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ItanoJunko en-aut-sei=Itano en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TanakaAyaka en-aut-sei=Tanaka en-aut-mei=Ayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TomonobuNahoko en-aut-sei=Tomonobu en-aut-mei=Nahoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KinoshitaRie en-aut-sei=Kinoshita en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SakaguchiMasakiyo en-aut-sei=Sakaguchi en-aut-mei=Masakiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=MiyaharaNobuaki en-aut-sei=Miyahara en-aut-mei=Nobuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Respiratory Medicine, National Hospital Organization Fukuyama Medical Center kn-affil= affil-num=5 en-affil=Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Medical Laboratory Science, Okayama University Faculty of Health Sciences kn-affil= affil-num=9 en-affil=Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Respiratory Medicine, Kurashiki Central Hospital kn-affil= affil-num=11 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= en-keyword=anti-S100A8/A9 neutralizing antibody kn-keyword=anti-S100A8/A9 neutralizing antibody en-keyword=calprotectin kn-keyword=calprotectin en-keyword=idiopathic pulmonary fibrosis kn-keyword=idiopathic pulmonary fibrosis en-keyword=lipopolysaccharide kn-keyword=lipopolysaccharide en-keyword=neutrophil extracellular traps kn-keyword=neutrophil extracellular traps END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260521 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Stimulator of interferon genes agonist augmented antitumor immunity of osimertinib in Egfr ‐mutated lung cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers (NSCLCs) lack effective immunotherapy due to a noninflamed tumor microenvironment (TME). We previously reported that EGFR tyrosine-kinase-inhibitor (TKI) induced CD8+ T-cell immunity, which was insufficient for tumor eradication. We evaluated the potential of combining EGFR-TKI with stimulator of interferon genes (STING) agonists in activating a systemic antitumor response. Using a syngeneic mouse model of genetically engineered Egfr-mutant NSCLC, we evaluated the antitumor effects of STING agonist ADU-S100, alone and combined with osimertinib. Immunohistochemistry and flow cytometry were used to assess the TME. Osimertinib alone enhanced CD8+ T-cell infiltration but not Natural Killer (NK) cell infiltration. ADU-S100 injection alone modestly suppressed tumor growth with increasing CD8+/NK cell infiltration in the TME, but lacked an abscopal effect. Combining ADU-S100 with osimertinib significantly enhanced the antitumor effects and CD8+/NK cell infiltration. Depletion of either CD8+ or NK cells reduced the combination effect. Crucially, the combination induced an abscopal effect accompanied by PD-1+/CD8+ cell infiltration. Combining osimertinib with a STING agonist augmented innate and adaptive immunity, inducing systemic antitumor responses in EGFR-mutant NSCLC. en-copyright= kn-copyright= en-aut-name=NishimuraJun en-aut-sei=Nishimura en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KuribayashiTadahiro en-aut-sei=Kuribayashi en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=BrägelmannJohannes en-aut-sei=Brägelmann en-aut-mei=Johannes kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OkawaSachi en-aut-sei=Okawa en-aut-mei=Sachi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TaokaMasataka en-aut-sei=Taoka en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MoriShunta en-aut-sei=Mori en-aut-mei=Shunta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishimuraTomoka en-aut-sei=Nishimura en-aut-mei=Tomoka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanakaTakaaki en-aut-sei=Tanaka en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MakimotoGo en-aut-sei=Makimoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=RaiKammei en-aut-sei=Rai en-aut-mei=Kammei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KatayamaRyohei en-aut-sei=Katayama en-aut-mei=Ryohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TabataMasahiro en-aut-sei=Tabata en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SosMartin L. en-aut-sei=Sos en-aut-mei=Martin L. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Translational Genomics Faculty of Medicine and University Hospital Cologne, University of Cologne Germany kn-affil= affil-num=4 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=10 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=11 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=12 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=13 en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Centre, Japanese Foundation for Cancer Research kn-affil= affil-num=14 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=15 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=16 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=17 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=18 en-affil=Department of Translational Genomics Faculty of Medicine and University Hospital Cologne, University of Cologne Germany kn-affil= affil-num=19 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=20 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= en-keyword=abscopal effect kn-keyword=abscopal effect en-keyword=CD8+ T cells kn-keyword=CD8+ T cells en-keyword=EGFR mutation kn-keyword=EGFR mutation en-keyword=EGFR tyrosine kinase inhibitor kn-keyword=EGFR tyrosine kinase inhibitor en-keyword=NK cells kn-keyword=NK cells en-keyword=stimulator of interferon genes kn-keyword=stimulator of interferon genes END start-ver=1.4 cd-journal=joma no-vol=45 cd-vols= no-issue=18 article-no= start-page=1675 end-page=1687 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260404 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Trisomy 8 alters chromatin conformations and activates Y chromosome genes in stem cells to drive a pre-leukemic state en-subtitle= kn-subtitle= en-abstract= kn-abstract=The mechanistic role of trisomy 8 in the development of myelodysplastic syndrome (MDS) remains poorly defined. Here, we generated a trisomy 8 mouse model by transferring a human chromosome 8 into murine embryonic stem cells and prospectively examined the effects on hematopoietic stem cells (HSC) by trisomy 8. The expression of inflammatory genes was enhanced, and hematopoietic programs mediated by transcription factors and polycomb repressive complex 2 (PRC2) were dysregulated in trisomy 8 HSC, which impaired their self-renewal and balanced differentiation. Trisomy 8 HSC altered the chromatin accessibility and conformations and activated Y chromosome genes, such as Uty/Kdm6c epigenetic modifier, which is known to demethylate histone H3K27me3 modification. The Uty gene facilitated the activation of PRC2-target and Runx1-target genes in leukemogenesis and drove the proliferation of human trisomy 8 leukemic cells. Since the RUNX1 gene is frequently mutated in patients with trisomy 8 MDS, its deletion attenuated the enhanced expression of inflammatory genes and mitigated the impaired self-renewal of trisomy 8 HSC in mice. Our findings reveal that trisomy 8 altered the transcriptional programs and chromatin conformations in HSC and drove a pre-malignant state through activating the expression of Uty, suggesting a route for the development of trisomy 8 MDS. en-copyright= kn-copyright= en-aut-name=BaiJie en-aut-sei=Bai en-aut-mei=Jie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ArakiKimi en-aut-sei=Araki en-aut-mei=Kimi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KurotakiDaisuke en-aut-sei=Kurotaki en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=Eerdunduleng en-aut-sei=Eerdunduleng en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SorinSupannika en-aut-sei=Sorin en-aut-mei=Supannika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HiramatsuKei en-aut-sei=Hiramatsu en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UnoNarumi en-aut-sei=Uno en-aut-mei=Narumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HamashimaAi en-aut-sei=Hamashima en-aut-mei=Ai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IimoriMihoko en-aut-sei=Iimori en-aut-mei=Mihoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KikuchiKenta en-aut-sei=Kikuchi en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TerashimaMinoru en-aut-sei=Terashima en-aut-mei=Minoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KubotaSho en-aut-sei=Kubota en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KohrogiKensaku en-aut-sei=Kohrogi en-aut-mei=Kensaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HuangGang en-aut-sei=Huang en-aut-mei=Gang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=OgawaMinetaro en-aut-sei=Ogawa en-aut-mei=Minetaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=OshimuraMitsuo en-aut-sei=Oshimura en-aut-mei=Mitsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KazukiYasuhiro en-aut-sei=Kazuki en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SashidaGoro en-aut-sei=Sashida en-aut-mei=Goro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=2 en-affil=Institute of Resource Development and Analysis, Kumamoto University kn-affil= affil-num=3 en-affil=Laboratory of Chromatin Organization in Immune Cell Development, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=4 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=5 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=6 en-affil=Department of Chromosome Biomedical Engineering, Integrated Medical Sciences, Graduate School of Medical Sciences, Tottori University kn-affil= affil-num=7 en-affil=Laboratory of Bioengineering, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences kn-affil= affil-num=8 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=9 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=10 en-affil=Laboratory of Chromatin Organization in Immune Cell Development, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=11 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= affil-num=12 en-affil=Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=13 en-affil=Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University kn-affil= affil-num=14 en-affil=Department of Cell Systems & Anatomy, Department of Pathology & Laboratory Medicine, UT Health San Antonio, Joe R. and Teresa Lozano Long School of Medicine, Mays Cancer Center at UT Health San Antonio kn-affil= affil-num=15 en-affil=Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University kn-affil= affil-num=16 en-affil=Chromosome Engineering Research Center, Tottori University kn-affil= affil-num=17 en-affil=Department of Chromosome Biomedical Engineering, Integrated Medical Sciences, Graduate School of Medical Sciences, Tottori University kn-affil= affil-num=18 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=52 cd-vols= no-issue=3 article-no= start-page=e70104 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260429 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=VGLL3 Regulates DAPK2-Mediated Autophagy During Osteoblast Differentiation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Vestigial-like family member 3 (VGLL3), a transcriptional cofactor of the TEA domain family, has been previously identified as a regulator of osteoblast differentiation. Building upon our previous findings, we investigated VGLL3 function in MC3T3-E1 osteoblasts using an integrated approach combining transcriptomic analysis and functional assays to identify its downstream effectors and explore associated autophagy mechanisms. RNA-seq analysis of Vgll3-knockdown (shVgll3) cells identified death-associated protein kinase 2 (DAPK2), a regulator of autophagy, as a downstream effector. Autophagic activity was examined using transmission electron microscopy and western blot analysis of LC3-II and p62 proteins. The effects of Dapk2 knockdown (shDapk2) on osteoblast differentiation were evaluated using qPCR, western blotting, alkaline phosphatase staining, and Alizarin Red staining. Rapamycin treatment was used to determine whether pharmacologic activation of autophagy could restore osteoblast function. Vgll3 knockdown significantly suppressed autophagic flux, as evidenced by fewer autophagic vacuoles, decreased LC3-II accumulation, and increased p62 expression. A comparable reduction in autophagic activity was observed in shDapk2 cells and was accompanied by impaired osteoblast differentiation. Rapamycin treatment partially restored autophagy and osteogenic differentiation in Vgll3-deficient cells. Finally, overexpression of DAPK2 partially rescued autophagic activity and osteogenic differentiation in shVgll3 cells, supporting its role as a key downstream functional effector. FOXM1 was further implicated as a potential transcriptional regulator contributing to DAPK2 expression. Collectively, our findings suggest that VGLL3 may influence osteogenic differentiation in osteoblasts, potentially involving DAPK2-associated autophagy. en-copyright= kn-copyright= en-aut-name=HeYuhan en-aut-sei=He en-aut-mei=Yuhan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WengYao en-aut-sei=Weng en-aut-mei=Yao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SitosariHeriati en-aut-sei=Sitosari en-aut-mei=Heriati kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZhengYilin en-aut-sei=Zheng en-aut-mei=Yilin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=QuYaxin en-aut-sei=Qu en-aut-mei=Yaxin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IkegameMika en-aut-sei=Ikegame en-aut-mei=Mika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OkamuraHirohiko en-aut-sei=Okamura en-aut-mei=Hirohiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Oral Biology, Faculty of Dentistry, Universitas Gadjah Mada kn-affil= affil-num=5 en-affil=Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=autophagy kn-keyword=autophagy en-keyword=bone metabolism kn-keyword=bone metabolism en-keyword=death-associated protein kinase 2 kn-keyword=death-associated protein kinase 2 en-keyword=osteoblast differentiation kn-keyword=osteoblast differentiation en-keyword=vestigial-like 3 kn-keyword=vestigial-like 3 END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=3 article-no= start-page=419 end-page=427 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Predictors for Recurrences Within One Year Following Radical Nephrectomy for Non-metastatic Renal Cell Carcinomas en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: This study aimed to identify predictors of rapid recurrence following radical nephrectomy for non-metastatic renal cell carcinomas.
Patients and Methods: Patients with non-metastatic renal cell carcinoma who underwent radical nephrectomy between 2014 and 2024 at Okayama University Hospital were included. Rapid recurrence was defined as local or distant metastasis occurring within one year after radical nephrectomy, whereas recurrences occurring beyond one year were classified as non-rapid.
Results: Among a total of 194 patients, 37 (19%) experienced recurrence during a median follow-up of 37 months, with 16 (43%) being classified as experiencing rapid recurrence. The multivariate Cox hazard model revealed that microscopic venous invasion and a size of 60 mm or larger were predictors of rapid recurrence (hazard ratio=4.1, 95% confidence interval=1.5-11.4, p=0.006, and hazard ratio=8.0, 95% confidence interval=2.6-25.0, p<0.001, respectively). Dividing the entire cohort into four groups based on the presence of the two risk factors (0, 1: venous invasion, 1: tumor size, and 2), the median PFS was not estimable, 87, 67, and 7 months, respectively (p<0.001).
Conclusion: Microscopic venous invasion and tumor size of 60 mm or larger were identified as independent predictors of rapid recurrence following radical nephrectomy for non-metastatic renal cell carcinoma. en-copyright= kn-copyright= en-aut-name=BEKKUKENSUKE en-aut-sei=BEKKU en-aut-mei=KENSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YAMANOITOMOAKI en-aut-sei=YAMANOI en-aut-mei=TOMOAKI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KAWADATATSUSHI en-aut-sei=KAWADA en-aut-mei=TATSUSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TOMINAGAYUSUKE en-aut-sei=TOMINAGA en-aut-mei=YUSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SADAHIRATAKUYA en-aut-sei=SADAHIRA en-aut-mei=TAKUYA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KATAYAMASATOSHI en-aut-sei=KATAYAMA en-aut-mei=SATOSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IWATATAKEHIRO en-aut-sei=IWATA en-aut-mei=TAKEHIRO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NISHIMURASHINGO en-aut-sei=NISHIMURA en-aut-mei=SHINGO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ARAKIMOTOO en-aut-sei=ARAKI en-aut-mei=MOTOO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Renal cell carcinoma kn-keyword=Renal cell carcinoma en-keyword=adjuvant therapy kn-keyword=adjuvant therapy en-keyword=radical nephrectomy kn-keyword=radical nephrectomy en-keyword=early recurrence kn-keyword=early recurrence en-keyword=metastases kn-keyword=metastases END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=1 end-page=17 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Afatinib Overcomes Osimertinib Resistance via Egfr V804F Mutation in a Syngeneic Egfr-Mutant Lung Cancer Mouse Model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Osimertinib is the standard first-line treatment for advanced EGFR-mutant non-small cell lung cancer. However, acquired resistance invariably develops, and identifying novel resistance pathways is clinically important as a substantial portion remains undefined. We used an immunocompetent syngeneic lung cancer mouse model harboring an Egfr exon 19 deletion (mDEL tumors) to establish acquired resistance. Osimertinib-resistant tumors were generated in vivo using a drug-holiday/re-challenge protocol. The resistance mechanism was identified using Sanger sequencing, receptor tyrosine kinase arrays, and western blotting. Egfr V804F knock-in cells were generated using CRISPR/Cas9, and their sensitivity to osimertinib and afatinib was assessed in vitro and in vivo. We established two distinct osimertinib-resistant tumor lines in a syngeneic lung cancer mouse model (mDEL OsiR #1/#3). The analysis revealed an on-target secondary Egfr V804F mutation (corresponding to human EGFR V802F) in both tumor lines. Importantly, Egfr V804F knock-in cells demonstrated significant osimertinib resistance, with a 5.7–10.5-fold increase in in vitro IC50 (mean, 8.2-fold), but remained highly sensitive to afatinib. Furthermore, afatinib effectively overcame osimertinib resistance in the V804F knock-in cell-derived mouse model. Consistently, afatinib treatment resulted in marked tumor shrinkage and suppression of EGFR signaling in the established mDEL OsiR #1/#3 in vivo. These findings establish secondary Egfr V804F/EGFR V802F as an on-target osimertinib resistance mechanism, providing a preclinical rationale for evaluating afatinib in biomarker-selected patients harboring this alteration. en-copyright= kn-copyright= en-aut-name=TanakaTakaaki en-aut-sei=Tanaka en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FujitaniMasato en-aut-sei=Fujitani en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TaokaMasataka en-aut-sei=Taoka en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ShimomuraIwao en-aut-sei=Shimomura en-aut-mei=Iwao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OkawaSachi en-aut-sei=Okawa en-aut-mei=Sachi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MoriShunta en-aut-sei=Mori en-aut-mei=Shunta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KuribayashiTadahiro en-aut-sei=Kuribayashi en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NishimuraJun en-aut-sei=Nishimura en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NishimuraTomoka en-aut-sei=Nishimura en-aut-mei=Tomoka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MoritaAyako en-aut-sei=Morita en-aut-mei=Ayako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HaraNaofumi en-aut-sei=Hara en-aut-mei=Naofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MakimotoGo en-aut-sei=Makimoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HigoHisao en-aut-sei=Higo en-aut-mei=Hisao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=RaiKammei en-aut-sei=Rai en-aut-mei=Kammei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TomidaShuta en-aut-sei=Tomida en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=KatayamaRyohei en-aut-sei=Katayama en-aut-mei=Ryohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research kn-affil= affil-num=3 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research kn-affil= affil-num=5 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=11 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=12 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=14 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=15 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=16 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=17 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=18 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=19 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=20 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=21 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= affil-num=22 en-affil=Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research kn-affil= affil-num=23 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University kn-affil= en-keyword=afatinib kn-keyword=afatinib en-keyword=EGFR-mutant NSCLC kn-keyword=EGFR-mutant NSCLC en-keyword=exon 19 deletion kn-keyword=exon 19 deletion en-keyword=osimertinib resistance kn-keyword=osimertinib resistance en-keyword=V802F (human EGFR)/V804F (murine Egfr) kn-keyword=V802F (human EGFR)/V804F (murine Egfr) END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=11 article-no= start-page=4730 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260524 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Genomic Basis of Lifestyle Divergence in Rice-Associated Burkholderia: From Pathogenesis to Plant Growth Promotion en-subtitle= kn-subtitle= en-abstract= kn-abstract=The genus Burkholderia encompasses both plant pathogenic and beneficial species, yet the genomic determinants underlying this lifestyle divergence remain poorly understood. Using 16S rRNA sequencing of 100 rice cultivars, our companion study demonstrated that resistant varieties are enriched in beneficial Burkholderiaceae, leading to the isolation of three phenotypically contrasting strains. Here, we present comparative genomic analyses of non-pathogenic biocontrol strain Burkholderia vietnamiensis J14EpLeaf2 and pathogenic strains Burkholderia gladioli A1EpSeed5 and Burkholderia cepacia J14Eple. Pathogenic strains possess significantly larger genomes (8.36–8.46 Mb) enriched in mobile genetic elements compared to the streamlined 6.95 Mb genome of B. vietnamiensis. CAZyme analysis revealed broader repertoires of glycoside hydrolases and polysaccharide lyases in pathogens, consistent with enhanced plant cell wall degradation. B. gladioli possesses a complete T3SS and expanded T6SS with 301 predicted effectors, while B. cepacia lacks structural T3SS genes but harbors 271 candidate effectors predicted to be secreted via alternative secretion pathways, compared to 180 in B. vietnamiensis. Notably, B. cepacia harbors cystic fibrosis-associated markers (cable pili, ZmpA/ZmpB), raising significant biosafety concerns that preclude its agricultural application. LC-MS validated IAA, ornibactin, and AHL production in B. vietnamiensis, supporting its plant growth-promoting and biocontrol functions. Computational PPI networks predicted distinct interaction landscapes requiring experimental validation. This study provides a genomic framework for distinguishing pathogenic from beneficial Burkholderia and supports B. vietnamiensis as a safe biocontrol agent while cautioning against B. cepacia J14Eple. en-copyright= kn-copyright= en-aut-name=OforiAndrews Danso en-aut-sei=Ofori en-aut-mei=Andrews Danso kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NasimiZohreh en-aut-sei=Nasimi en-aut-mei=Zohreh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AckahFrank Kwekucher en-aut-sei=Ackah en-aut-mei=Frank Kwekucher kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AhmedMuhammad Irfan en-aut-sei=Ahmed en-aut-mei=Muhammad Irfan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YanYaoting en-aut-sei=Yan en-aut-mei=Yaoting kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=LiWang en-aut-sei=Li en-aut-mei=Wang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KandroAbdul Ghani en-aut-sei=Kandro en-aut-mei=Abdul Ghani kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OkadaKazunori en-aut-sei=Okada en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MochidaKeiichi en-aut-sei=Mochida en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NoutoshiYoshiteru en-aut-sei=Noutoshi en-aut-mei=Yoshiteru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ZhengAiping en-aut-sei=Zheng en-aut-mei=Aiping kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University kn-affil= affil-num=2 en-affil=State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University kn-affil= affil-num=3 en-affil=Department of Crop Science, School of Agriculture and Natural Sciences, University of Cape Coast kn-affil= affil-num=4 en-affil=State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University kn-affil= affil-num=5 en-affil=State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University kn-affil= affil-num=6 en-affil=State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University kn-affil= affil-num=7 en-affil=State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University kn-affil= affil-num=8 en-affil=Agro-Biotechnology Research Center, The University of Tokyo kn-affil= affil-num=9 en-affil=Bioproductivity Informatics Research Team, RIKEN Center for Sustainable Resource Science kn-affil= affil-num=10 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=11 en-affil=State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Sichuan Agricultural University kn-affil= en-keyword=Burkholderia kn-keyword=Burkholderia en-keyword=comparative genomics kn-keyword=comparative genomics en-keyword=virulence factors kn-keyword=virulence factors en-keyword=secretion systems kn-keyword=secretion systems en-keyword=CAZymes kn-keyword=CAZymes en-keyword=plant-microbe interactions kn-keyword=plant-microbe interactions en-keyword=biocontrol kn-keyword=biocontrol en-keyword=pathogenicity kn-keyword=pathogenicity en-keyword=protein–protein interaction networks kn-keyword=protein–protein interaction networks en-keyword=rice sheath blight kn-keyword=rice sheath blight END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=1 end-page=13 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260514 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Atezolizumab + Chemotherapy in Older Patients With Lung Cancer in Japan en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pivotal phase 3 trials leading to the approvals of atezolizumab─chemotherapy combinations for non-small cell and extensive-stage small cell lung cancer (NSCLC and ES-SCLC) had strict eligibility criteria. J-TAIL-2 was a prospective, observational study in Japan that evaluated atezolizumab regimens for advanced NSCLC/ES-SCLC, including patients ineligible for global trials. The primary endpoint was 12-month overall survival (OS); safety and efficacy in subgroups defined by age, ECOG PS and/or G8 score, and creatinine clearance were key secondary endpoints. As of February 3, 2023, 1217 patients were treated in clinical practice based on Japanese labeling/treatment guidelines. Patients received atezolizumab with either carboplatin and nab-paclitaxel (atezo + CnP), carboplatin/cisplatin and pemetrexed (atezo + PP), or bevacizumab and carboplatin and paclitaxel (atezo + bev + CP) in the NSCLC cohort (n = 814) or with carboplatin and etoposide (atezo + CE) in the ES-SCLC cohort (n = 403). Overall, 53.5% were ≥ 70 years old, and 11.8% had ECOG PS ≥ 2; median G8 scores were 13 (NSCLC cohort) and 12 (ES-SCLC). Patients < 70 and ≥ 70 years had similar median (m)OS and progression-free survival (mPFS) across treatment regimens. Patients with ECOG PS < 2 and G8 score ≥ median had the highest mOS/PFS vs. patients with ECOG PS ≥ 2 and G8 score 0.5 log2 fold change) and linked to clinical outcomes reported in J-TAIL-2. IL-6, MUC-16, and KRT-19 were associated with shorter progression-free survival across multiple regimens. Granzyme A and B, immune activation markers, were elevated in responders who received atezolizumab + CnP and atezolizumab + bev + CP. High levels of baseline immune stimulation proteins were associated with irAEs across regimens. Protein expression changes were varied and regimen-dependent in subgroup analyses including older patients and those with EGFR-mutant tumors. These data warrant further investigation across different cancer types and atezolizumab-containing regimens to determine their relevance to efficacy and irAE occurrence of atezolizumab combination therapy. en-copyright= kn-copyright= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishioMakoto en-aut-sei=Nishio en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OsoegawaAtsushi en-aut-sei=Osoegawa en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KikuchiEiki en-aut-sei=Kikuchi en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KimuraHideharu en-aut-sei=Kimura en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MiyauchiEisaku en-aut-sei=Miyauchi en-aut-mei=Eisaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YoshiokaHiroshige en-aut-sei=Yoshioka en-aut-mei=Hiroshige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YoshinoIchiro en-aut-sei=Yoshino en-aut-mei=Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MisumiToshihiro en-aut-sei=Misumi en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=WatanabeYasutaka en-aut-sei=Watanabe en-aut-mei=Yasutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KatakamiNobuyuki en-aut-sei=Katakami en-aut-mei=Nobuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KisoharaAkira en-aut-sei=Kisohara en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=YamaguchiMasafumi en-aut-sei=Yamaguchi en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KurokiHirotaka en-aut-sei=Kuroki en-aut-mei=Hirotaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=SugimotoMasamichi en-aut-sei=Sugimoto en-aut-mei=Masamichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=AshimuraHisao en-aut-sei=Ashimura en-aut-mei=Hisao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=TanakaMisa en-aut-sei=Tanaka en-aut-mei=Misa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=GemmaAkihiko en-aut-sei=Gemma en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=2 en-affil=Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Kanazawa University Hospital kn-affil= affil-num=7 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=8 en-affil=Department of Respiratory Medicine, Tohoku University Hospital kn-affil= affil-num=9 en-affil=Department of Thoracic Oncology, Kansai Medical University kn-affil= affil-num=10 en-affil=Department of Thoracic Surgery, International University of Health and Welfare Narita Hospital kn-affil= affil-num=11 en-affil=Department of Data Science, National Cancer Center Hospital East kn-affil= affil-num=12 en-affil=Department of Thoracic Oncology, Saitama Cancer Center kn-affil= affil-num=13 en-affil=Department of Pulmonary Medicine and Medical Oncology Takarazuka City Hospital Takarazuka Japan kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, Kasukabe Medical Center kn-affil= affil-num=15 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=16 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=17 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=18 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=19 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=20 en-affil=Nippon Medical School kn-affil= en-keyword=atezolizumab kn-keyword=atezolizumab en-keyword=biomarker kn-keyword=biomarker en-keyword=non-small cell lung cancer kn-keyword=non-small cell lung cancer en-keyword=plasma protein kn-keyword=plasma protein en-keyword=small cell lung cancer kn-keyword=small cell lung cancer END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue= article-no= start-page=1774957 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260430 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Hochuekkito attenuates anxiety-like behavior associated with pulmonary inflammation induced by intratracheal lipopolysaccharides in mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: We have previously demonstrated that intratracheal lipopolysaccharide (LPS) injection induces significant pulmonary inflammation accompanied by hippocampal microglial activation, indicative of neuroinflammation. Hochuekkito (HET) is a traditional Japanese herbal medicine used to treat various conditions, including mental disorders and physical weakness. We have previously reported that HET ameliorates anxiety-like behaviors induced by intraperitoneal LPS injections in mice. However, its anxiolytic effects on anxiety-like behaviors due to pulmonary inflammation remain poorly understood. Therefore, in the present study, we aimed to investigate the effects of HET on anxiety-like behaviors induced by intratracheal LPS injection in mice.
Methods: Mice received HET (1.0 g/kg) once daily for 2 weeks through oral gavage prior to LPS treatment. The light-dark box test was conducted 24 h following LPS injection to assess anxiety-like behaviors. Diazepam, a clinically used anxiolytic, served as a positive control. The lung wet-to-dry weight ratio was determined, and the concentrations of interleukin-6 (IL-6) in the lungs and serum were assessed.
Results: Repeated administration of HET prevented the development of anxiety-like behaviors and reduced serum IL-6 concentrations and hippocampal Il6 mRNA expression levels in LPS-treated mice. Diazepam failed to exert significant effects in LPS-treated mice, whereas HET remained effective under inflammatory conditions. Moreover, LPS injections significantly increased the number of Iba-1-immunoreactive microglial cells in the CA1 region of the hippocampus, whereas this effect was suppressed by treatment with HET. In the bronchoalveolar lavage fluid (BALF), the LPS-induced increase in white blood cell count was significantly reduced by treatment with HET. Furthermore, HET alleviated LPS-induced pulmonary inflammation, as evidenced by decreased lung wet-to-dry weight ratios.
Conclusion: This study suggests that inflammation induced by intratracheal LPS injection contributes to anxiety-like behaviors in mice and that IL-6 may play a key role in linking peripheral inflammation to neuroinflammatory responses. The anxiolytic effects of HET appear to be associated, at least in part, with the suppression of IL-6 elevation in both the periphery and the hippocampus, along with attenuation of microglial activation. Our findings suggest that HET may serve as a potential therapeutic agent for anxiety-like behaviors associated with pulmonary inflammation. en-copyright= kn-copyright= en-aut-name=IzushiYasuhisa en-aut-sei=Izushi en-aut-mei=Yasuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=UshioSoichiro en-aut-sei=Ushio en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UedaTeppei en-aut-sei=Ueda en-aut-mei=Teppei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TasakaYuichi en-aut-sei=Tasaka en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AsanumaMasato en-aut-sei=Asanuma en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KitamuraYoshihisa en-aut-sei=Kitamura en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Pharmacotherapy, Graduate School of Pharmacy, Shujitsu University kn-affil= affil-num=2 en-affil=Department of Pharmaceutical Sciences for Health Crisis Management, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=3 en-affil=Department of Pharmacotherapy, Graduate School of Pharmacy, Shujitsu University kn-affil= affil-num=4 en-affil=Laboratory of Clinical Pharmacy, School of Pharmacy, Shujitsu University kn-affil= affil-num=5 en-affil=Department of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Medical Neurobiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pharmacotherapy, Graduate School of Pharmacy, Shujitsu University kn-affil= en-keyword=anxiety kn-keyword=anxiety en-keyword=hochuekkito kn-keyword=hochuekkito en-keyword=inflammation kn-keyword=inflammation en-keyword=interleukin-6 kn-keyword=interleukin-6 en-keyword=lipopolysaccharide kn-keyword=lipopolysaccharide en-keyword=lung kn-keyword=lung en-keyword=traditional Japanese herbal medicine kn-keyword=traditional Japanese herbal medicine END start-ver=1.4 cd-journal=joma no-vol=195 cd-vols= no-issue= article-no= start-page=110231 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202607 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Biliverdin supplementation in perfusate and preservation solution attenuates ischemia-reperfusion injury in a rat donation-after-circulatory-death heart transplantation model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Heart transplantation faces a persistent donor shortage; therefore, hearts from donation after circulatory death have become a feasible option despite unavoidable warm ischemia and subsequent ischemia-reperfusion injury. Biliverdin, an endogenous bile pigment with strong antioxidant and anti-inflammatory properties, has shown protective effects against ischemia-reperfusion injury in several organ transplantation models. Whether biliverdin attenuates warm ischemic injury in donation after circulatory death heart transplantation remains unclear. This study evaluated biliverdin supplementation in the perfusate and preservation solution in a rat donation after circulatory death model.
Methods: Circulatory death was induced under deep anesthesia, and warm ischemia was maintained for 18 minutes, including the mandatory 5-minute stand-off period. Donor hearts were then flushed and subsequently cold-stored in the same biliverdin-supplemented extracellular-type trehalose–containing Kyoto solution, whereas control grafts received extracellular-type trehalose–containing Kyoto without biliverdin at both stages before heterotopic transplantation. Grafts were assessed at 3 and 24 hours after reperfusion (n = 6 per group). Evaluations included early graft recovery, myocardial injury markers, histological and ultrastructural changes, and inflammatory and stress-response gene expression.
Results: Biliverdin significantly improved early graft recovery, shortening reanimation time and increasing left ventricular fractional shortening at 24 hours. Serum troponin I levels were lower in biliverdin-treated grafts. Biliverdin also reduced histological injury and inflammatory cell infiltration. Ultrastructural analysis showed preserved mitochondrial architecture and ultrastructural integrity. Early proinflammatory gene expression was suppressed.
Conclusion: Biliverdin supplementation in the perfusate and preservation solution attenuates ischemia-reperfusion injury in the experimental rat donation after circulatory death heart transplantation model. These findings provide proof of concept for further mechanistic and translational evaluation of biliverdin for myocardial protection in donation after circulatory death. en-copyright= kn-copyright= en-aut-name=TokiokaKohei en-aut-sei=Tokioka en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NojimaTsuyoshi en-aut-sei=Nojima en-aut-mei=Tsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HirayamaTakahiro en-aut-sei=Hirayama en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HongoTakashi en-aut-sei=Hongo en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ObaraTakafumi en-aut-sei=Obara en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AgetaKohei en-aut-sei=Ageta en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IgawaTakuro en-aut-sei=Igawa en-aut-mei=Takuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AokageToshiyuki en-aut-sei=Aokage en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TsukaharaKohei en-aut-sei=Tsukahara en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YumotoTetsuya en-aut-sei=Yumoto en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NaitoHiromichi en-aut-sei=Naito en-aut-mei=Hiromichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NakaoAtsunori en-aut-sei=Nakao en-aut-mei=Atsunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Biological Process of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology kn-affil= affil-num=9 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=33 cd-vols= no-issue=5 article-no= start-page=e70494 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202605 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparative Efficacy of First-Line Immune Checkpoint Inhibitor-Based Combination Therapies in Patients With Sarcomatoid Renal Cell Carcinoma: A Japanese Multicenter Cohort Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objectives: Sarcomatoid renal cell carcinoma (sRCC) is an aggressive histological variant associated with a poor prognosis. While immune checkpoint inhibitor (ICI)-based combinations have become the standard of care, the optimal first-line regimen, specifically dual immunotherapy (IO-IO) vs. IO plus tyrosine kinase inhibitor (IO-TKI), remains controversial. We herein examined the real-world clinical outcomes of Japanese patients with sRCC.
Methods: We conducted a retrospective multicenter study on 46 patients with advanced or metastatic sRCC receiving first-line ICI-based combination therapy between January 2018 and December 2024 (IO-IO: n = 18; IO-TKI: n = 28). In a comparative survival analysis, three favorable-risk patients in the IO-TKI group were excluded to align risk profiles, focusing on intermediate/poor-risk groups (n = 43). The primary endpoint was overall survival (OS).
Results: In the entire cohort (n = 46), the objective response rate was numerically higher in the IO-TKI group (64.3%) than in the IO-IO group (50.0%) (p = 0.37). In the comparative analysis of intermediate/poor-risk patients (n = 43), progression-free survival (PFS) was slightly longer (p = 0.071), and OS was significantly longer (p = 0.016) in the IO-TKI group than in the IO-IO group. A multivariable analysis adjusted for IMDC risk categories showed favorable survival with the IO-TKI regimen (HR 0.37, p = 0.061).
Conclusions: The present study indicates that first-line IO-TKI combination therapy represents a promising treatment option with a potential survival advantage over IO-IO therapy for Japanese patients with sRCC. However, due to the retrospective design and small sample size, reliably determining the comparative efficacy of these regimens remains challenging, and further validation is warranted. en-copyright= kn-copyright= en-aut-name=TamuraKeita en-aut-sei=Tamura en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsushitaYuto en-aut-sei=Matsushita en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeHiromitsu en-aut-sei=Watanabe en-aut-mei=Hiromitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YanagisawaTakafumi en-aut-sei=Yanagisawa en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MoriKeiichiro en-aut-sei=Mori en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MorinakaHirofumi en-aut-sei=Morinaka en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=BekkuKensuke en-aut-sei=Bekku en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ToyodaShingo en-aut-sei=Toyoda en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NukayaTakuhisa en-aut-sei=Nukaya en-aut-mei=Takuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MaenosonoRyoichi en-aut-sei=Maenosono en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KomuraKazumasa en-aut-sei=Komura en-aut-mei=Kazumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ArakiMotoo en-aut-sei=Araki en-aut-mei=Motoo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=FujitaKazutoshi en-aut-sei=Fujita en-aut-mei=Kazutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TakaharaKiyoshi en-aut-sei=Takahara en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=AzumaHaruhito en-aut-sei=Azuma en-aut-mei=Haruhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=InamotoTeruo en-aut-sei=Inamoto en-aut-mei=Teruo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Urology, Hamamatsu University School of Medicine kn-affil= affil-num=2 en-affil=Department of Urology, Hamamatsu University School of Medicine kn-affil= affil-num=3 en-affil=Department of Urology, Hamamatsu University School of Medicine kn-affil= affil-num=4 en-affil=Department of Urology, Jikei University School of Medicine kn-affil= affil-num=5 en-affil=Department of Urology, Jikei University School of Medicine kn-affil= affil-num=6 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=7 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Urology, Kindai University Faculty of Medicine kn-affil= affil-num=9 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=10 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=11 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=12 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Urology, Kindai University Faculty of Medicine kn-affil= affil-num=14 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=15 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=16 en-affil=Department of Urology, Hamamatsu University School of Medicine kn-affil= en-keyword=dual immunotherapy kn-keyword=dual immunotherapy en-keyword=immune checkpoint inhibitor kn-keyword=immune checkpoint inhibitor en-keyword=immunotherapy plus tyrosine kinase inhibitor kn-keyword=immunotherapy plus tyrosine kinase inhibitor en-keyword=sarcomatoid renal cell carcinoma kn-keyword=sarcomatoid renal cell carcinoma END start-ver=1.4 cd-journal=joma no-vol=46 cd-vols= no-issue=6 article-no= start-page=BSR20260010 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202606 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tubulogenesis of bovine uterine glands by epidermal growth factor and collagen I in 3D culture systems en-subtitle= kn-subtitle= en-abstract= kn-abstract=Uterine glands are endometrial exocrine epithelia that support early embryo development. Their secretions are particularly essential for conceptus elongation in cattle. Uterine glands develop from the luminal epithelium and elongate into the stromal layer toward the myometrium. This process is regulated by growth factors, WNT proteins, and the surrounding extracellular matrix (ECM); however, the precise mechanisms that govern bovine uterine gland morphogenesis remain unclear. In this study, we determined how these signaling factors and ECM components affect the tubular formation of bovine uterine gland fragments in 3D culture systems. Uterine gland fragments were enzymatically isolated from bovine endometria and 3D-cultured in Matrigel with or without growth factors (EGF, FGF1, FGF2, FGF7, FGF10, and IGF-1) and WNT (WNT3A, WNT5A, and WNT7A) proteins. Of these, only EGF stimulated the elongation of uterine gland fragments and eventually induced the formation of uterine gland-like structures. EGF-induced tubulogenesis was accompanied by a rapid increase in cell proliferation and alterations in cell–ECM interactions. The supplementation of collagen I with Matrigel further promoted the elongation of the tubular structures. Although the addition of collagen I did not alter the gene expression profiles of the uterine gland-like structures, the integrin-ROCK pathway contributed to the collagen-induced enhancement of elongation. Our findings clarified that EGF and collagen I, but not FGFs, IGF-1, or WNTs, are key regulators for the tubular formation of 3D-cultured bovine uterine gland fragments. This 3D culture system provides a new platform to examine the cellular and molecular mechanisms underlying bovine uterine gland morphogenesis. en-copyright= kn-copyright= en-aut-name=SuginoYosuke en-aut-sei=Sugino en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IchikawaRei en-aut-sei=Ichikawa en-aut-mei=Rei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MatsuyamaShuichi en-aut-sei=Matsuyama en-aut-mei=Shuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamotoYuki en-aut-sei=Yamamoto en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawanoKohei en-aut-sei=Kawano en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KimuraKoji en-aut-sei=Kimura en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Bioagricultural Sciences, Nagoya University kn-affil= affil-num=3 en-affil=Graduate School of Bioagricultural Sciences, Nagoya University kn-affil= affil-num=4 en-affil=Department of Veterinary Medicine, Tokyo University of Agriculture and Technology kn-affil= affil-num=5 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=3D cell culture kn-keyword=3D cell culture en-keyword=bovine, collagen I kn-keyword=bovine, collagen I en-keyword=epidermal growth factor kn-keyword=epidermal growth factor en-keyword=tubular structure kn-keyword=tubular structure en-keyword=uterine gland kn-keyword=uterine gland END start-ver=1.4 cd-journal=joma no-vol=194 cd-vols= no-issue= article-no= start-page=118923 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Elucidation of mechanisms underlying the therapeutic effects of cordycepin on pulmonary hypertension, with a focus on cell senescence and gut microbiota en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by excessive pulmonary vascular remodeling and aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs). Emerging evidence suggests that gut microbiota dysbiosis contributes to PH development. Cordycepin, a natural adenosine analogue derived from Cordyceps militaris, has demonstrated antiproliferative and microbiota-modulating properties; however, its mechanism of action in PH remains unclear.
Objective: Elucidate the mechanisms underlying the therapeutic effects of cordycepin on PH, focusing on cellular senescence and gut microbiota.
Methods: The effects of cordycepin on PH pathology were investigated by transcriptome analysis of PASMCs from patients, and metagenomic analysis of rodent PH models. Cellular senescence was analyzed in lung tissue from p16Ink4a-CreERT2 reporter mice and in rat bone marrow-derived macrophages (BMDMs).
Results: RNA sequencing analysis revealed activation of p53 signaling by cordycepin in PASMCs. Cordycepin suppressed CDK1 expression and TERT phosphorylation at threonine 249. It ameliorated vascular and cardiac remodeling in PH rat and mouse models. Cordycepin induced M1-like macrophage senescence in p16 Ink4a reporter mice lungs and rat BMDMs. Cordycepin significantly reshaped the gut microbiota, increasing beneficial genera (e.g. Alistipes and Acetatifactor) and reducing proinflammatory taxa (e.g., Ruminococcus), with modulating key metabolic pathways, including short-chain fatty acid, tryptophan, and vitamin K2 metabolism.
Conclusion: Cordycepin exerts multi-target therapeutic effects in PH by inhibiting PASMC proliferation via the p53–CDK1/pTERT axis, modulating gut microbiota-linked immunometabolism and induces proinflammatory macrophage senescence. These findings support cordycepin as a promising candidate for PH therapies targeting the vascular, immune, and gut–lung axes. en-copyright= kn-copyright= en-aut-name=LiGaopeng en-aut-sei=Li en-aut-mei=Gaopeng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ZhaoZhixin en-aut-sei=Zhao en-aut-mei=Zhixin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MachitaniMitsuhiro en-aut-sei=Machitani en-aut-mei=Mitsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IshikawaRyou en-aut-sei=Ishikawa en-aut-mei=Ryou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IshikawaKaori en-aut-sei=Ishikawa en-aut-mei=Kaori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YokotaNaoya en-aut-sei=Yokota en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HabaReiji en-aut-sei=Haba en-aut-mei=Reiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakamuraKazufumi en-aut-sei=Nakamura en-aut-mei=Kazufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SunZhihong en-aut-sei=Sun en-aut-mei=Zhihong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KuraharaLin-Hai en-aut-sei=Kurahara en-aut-mei=Lin-Hai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HiranoKatsuya en-aut-sei=Hirano en-aut-mei=Katsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University kn-affil= affil-num=2 en-affil=Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University kn-affil= affil-num=3 en-affil=Division of Cancer Stem Cell, National Cancer Center Research Institute kn-affil= affil-num=4 en-affil=Department of Diagnostic Pathology, Kagawa University Hospital kn-affil= affil-num=5 en-affil=Department of General Medicine, Kagawa University Hospital kn-affil= affil-num=6 en-affil=Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University kn-affil= affil-num=7 en-affil=Department of Diagnostic Pathology, Kagawa University Hospital kn-affil= affil-num=8 en-affil=Center for Advanced Heart Failure, Okayama University Hospital kn-affil= affil-num=9 en-affil=Inner Mongolia Key Laboratory of Dairy Biotechnology and Engineering, Key Laboratory of Dairy Products Processing, Ministry of Agriculture and Rural Affairs, Key Laboratory of Dairy Biotechnology and Engineering, Ministry of Education, Inner Mongolia Agricultural University kn-affil= affil-num=10 en-affil=Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University kn-affil= affil-num=11 en-affil=Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University kn-affil= en-keyword=Pulmonary hypertension kn-keyword=Pulmonary hypertension en-keyword=p53 kn-keyword=p53 en-keyword=CDK1 kn-keyword=CDK1 en-keyword=TERT kn-keyword=TERT en-keyword=p16 kn-keyword=p16 en-keyword=Microbiota kn-keyword=Microbiota END start-ver=1.4 cd-journal=joma no-vol=68 cd-vols= no-issue=1 article-no= start-page=100726 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Roles of the aryl hydrocarbon receptor and its ligands in osteoclast differentiation and temporomandibular joint osteoarthritis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays an essential role in skeletal homeostasis. Increasing evidence indicates that AhR critically regulates osteoclast differentiation and activity, thereby influencing bone mass, bone resorption, and susceptibility to skeletal diseases. Although AhR has also been implicated in osteoblast-lineage cells, its regulatory roles in osteoclasts and immune cells are less well understood but are increasingly recognized as central to bone remodeling. In particular, AhR signaling modulates immune cell subsets relevant to bone metabolism and governs the differentiation of bone marrow-derived macrophages into osteoclasts.
Highlight: This review summarizes the recent findings regarding the regulation of osteoclast differentiation by AhR and its ligands under both physiological and pathological conditions. Special emphasis is placed on the interaction between AhR and the RANKL signaling axis in osteoclasts, as well as on how exogenous and endogenous ligands, including benzo[a]pyrene (B[a]P) and 6-formylindolo[3,2-b]carbazole (FICZ), modulate bone resorption and subchondral bone remodeling in temporomandibular joint osteoarthritis. Furthermore, the role of macrophages as osteoclast progenitors and immunomodulators has been highlighted, positioning AhR as a critical intermediary that links environmental exposure, inflammation, and skeletal metabolism.
Conclusion: In this review, we outlined the diverse functions of AhR signaling and its ligands in oral and temporomandibular joint osteoarthritis. AhR plays a central role in bone remodeling. The harmful exogenous ligand B[a]P generally promotes bone loss, whereas the endogenous ligand FICZ exerts protective actions. These insights highlight AhR as a key regulatory switch linking the skeletal and immune systems and as a promising therapeutic target for bone-destructive disorders. en-copyright= kn-copyright= en-aut-name=IzawaTakashi en-aut-sei=Izawa en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HutamiIslamy Rahma en-aut-sei=Hutami en-aut-mei=Islamy Rahma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshikawaYuri en-aut-sei=Yoshikawa en-aut-mei=Yuri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KozakiGohji en-aut-sei=Kozaki en-aut-mei=Gohji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HamadaYusaku en-aut-sei=Hamada en-aut-mei=Yusaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NambaYuki en-aut-sei=Namba en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TaguchiMisa en-aut-sei=Taguchi en-aut-mei=Misa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ChenJiamin en-aut-sei=Chen en-aut-mei=Jiamin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HabumugishaJanvier en-aut-sei=Habumugisha en-aut-mei=Janvier kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Orthodontics, Universitas Islam Sultan Agung kn-affil= affil-num=3 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Aryl hydrocarbon receptor (AhR) kn-keyword=Aryl hydrocarbon receptor (AhR) en-keyword=AhR ligands kn-keyword=AhR ligands en-keyword=Osteoclasts kn-keyword=Osteoclasts en-keyword=Arthritis kn-keyword=Arthritis en-keyword=Temporomandibular joint osteoarthritis kn-keyword=Temporomandibular joint osteoarthritis END start-ver=1.4 cd-journal=joma no-vol=208 cd-vols= no-issue=6 article-no= start-page=2124 end-page=2133 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260415 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Decreased renal function predicts severe cytokine release syndrome after CAR-T-cell therapy for large B-cell lymphoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cytokine release syndrome (CRS) remains a major toxicity of chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL), and robust pre-infusion predictors are needed for risk-adapted management. We retrospectively analysed LBCL patients in the Japanese nationwide registry who underwent CD19 CAR-T-cell therapy between 2019 and 2024. Among 900 patients (median age 62 years), cumulative incidences of CRS within 30 days after infusion were 75.0% for any grade, 20.8% for grade ≥ 2 and 14.0% for grade ≥ 3. In multivariable analysis, lower estimated glomerular filtration rate (eGFR) (adjusted hazard ratio [aHR] 1.108 per 10 mL/min per 1.73 m2 decrease; 95% confidence interval [CI] 1.015–1.209; p = 0.022), higher ferritin (aHR 1.006 per 100 ng/mL; 95% CI 1.001–1.010; p = 0.016), C-reactive protein (CRP) (aHR 1.142 per mg/dL; 95% CI 1.091–1.195; p < 0.001) and lactate dehydrogenase (LDH) (aHR 1.073 per 100 U/L; 95% CI 1.008–1.142; p = 0.028) independently predicted grade ≥ 2 CRS. We then built a four-factor CRS pre-infusion risk evaluation model, cytokine release syndrome-pre-infusion risk evaluation (CRS-PRE), that stratified grade ≥ 2 CRS risk into low, intermediate and high groups with incidences of 2.8%, 26.0% and 50.0% respectively. Decreased eGFR, a surrogate of host renal reserve, with elevated ferritin, CRP and LDH emerged as predictors of high-grade CRS. The CRS-PRE may facilitate risk-adapted monitoring and intervention in clinical practice. en-copyright= kn-copyright= en-aut-name=AraiYasuyuki en-aut-sei=Arai en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=JoTomoyasu en-aut-sei=Jo en-aut-mei=Tomoyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SatoTakayuki en-aut-sei=Sato en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakuraiMasatoshi en-aut-sei=Sakurai en-aut-mei=Masatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KajiDaisuke en-aut-sei=Kaji en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KitawakiToshio en-aut-sei=Kitawaki en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ShimadaKazuyuki en-aut-sei=Shimada en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShimoyamaTatsu en-aut-sei=Shimoyama en-aut-mei=Tatsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YoshiharaSatoshi en-aut-sei=Yoshihara en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MakitaShinichi en-aut-sei=Makita en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=YamamotoGo en-aut-sei=Yamamoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KataokaKeisuke en-aut-sei=Kataoka en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SakaidaEmiko en-aut-sei=Sakaida en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=GotoHideki en-aut-sei=Goto en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=NakashimaYasuhiro en-aut-sei=Nakashima en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=YoshidaAkiyo en-aut-sei=Yoshida en-aut-mei=Akiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=UmezawaYoshihiro en-aut-sei=Umezawa en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KimHaryoon en-aut-sei=Kim en-aut-mei=Haryoon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KatoMotohiro en-aut-sei=Kato en-aut-mei=Motohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=2 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=3 en-affil=Department of Hematology and Oncology, Kurashiki Central Hospital kn-affil= affil-num=4 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=5 en-affil=Department of Hematology, Toranomon Hospital kn-affil= affil-num=6 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Nagoya University Graduate School of Medicine kn-affil= affil-num=8 en-affil=Division of Clinical Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital kn-affil= affil-num=9 en-affil=Department of Hematology, Hyogo Medical University Hospital kn-affil= affil-num=10 en-affil=Department of Hematology, National Cancer Center Hospital kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Hematology, Toranomon Hospital kn-affil= affil-num=13 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=14 en-affil=Department of Hematology, Chiba University Hospital kn-affil= affil-num=15 en-affil=Department of Hematology, Hokkaido University Hospital kn-affil= affil-num=16 en-affil=Department of Hematology, Osaka Metropolitan University Hospital kn-affil= affil-num=17 en-affil=Department of Hematology, Kanazawa University Hospital kn-affil= affil-num=18 en-affil=Department of Hematology, Institute of Science Tokyo Hospital kn-affil= affil-num=19 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=20 en-affil=Department of Pediatrics, The University of Tokyo kn-affil= affil-num=21 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=22 en-affil=Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital kn-affil= en-keyword=chimeric antigen receptor T-cell therapy kn-keyword=chimeric antigen receptor T-cell therapy en-keyword=cytokine release syndrome kn-keyword=cytokine release syndrome en-keyword=estimated glomerular filtration rate kn-keyword=estimated glomerular filtration rate en-keyword=large B-cell lymphoma kn-keyword=large B-cell lymphoma END start-ver=1.4 cd-journal=joma no-vol=827 cd-vols= no-issue= article-no= start-page=154001 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202608 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Staphylococcus aureus activates dendrite elongation in dendritic cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Dendritic cells (DCs) are thought to extend dendrites to enhance the efficiency of antigen uptake and presentation. We previously reported that short-chain fatty acids (SCFAs), such as butyrate and valerate, promote dendrite extension in DCs. In this study, we found that the human pathogen Staphylococcus aureus also induces dendrite extension in DCs and investigated the underlying mechanisms. Dendrite extension in DC2.4 cells was induced not only by live S. aureus but also by heat-killed bacteria and purified peptidoglycan (PGN). DC2.4 cells lacking TLR2 or its adaptor protein MyD88 extend dendrites in response to SCFAs, but failed to extend dendrites in response to S. aureus. Furthermore, inhibitors of ERK, PI3K, and Cdc42 suppressed dendrite extension triggered by S. aureus. Co-stimulation with S. aureus and butyrate enhanced dendrite extension beyond either stimulus alone. DC2.4 cells co-stimulated with S. aureus and butyrate also showed increased uptake of insoluble beads and, upon co-culture with T cells, induced elevated production of IL-17 and IL-10 by T cells. Collectively, these findings suggest that S. aureus activates ERK/PI3K/Cdc42 signaling through TLR2 recognition of PGN to drive dendrite extension in DCs. In addition, S. aureus promotes dendrite extension in DCs via a pathway distinct from that of SCFAs, thereby acting cooperatively with SCFAs to enhance immune responses. en-copyright= kn-copyright= en-aut-name=KobataKai en-aut-sei=Kobata en-aut-mei=Kai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FurutaKazuyuki en-aut-sei=Furuta en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IkeyaYuki en-aut-sei=Ikeya en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ChishakiYohei en-aut-sei=Chishaki en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IshikawaKazuya en-aut-sei=Ishikawa en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KaitoChikara en-aut-sei=Kaito en-aut-mei=Chikara kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Staphylococcus aureus kn-keyword=Staphylococcus aureus en-keyword=Dendritic cells kn-keyword=Dendritic cells en-keyword=Dendrite elongation kn-keyword=Dendrite elongation en-keyword=Peptidoglycan: TLR2/MyD88 signaling kn-keyword=Peptidoglycan: TLR2/MyD88 signaling en-keyword=ERK/PI3K/Cdc42 pathway kn-keyword=ERK/PI3K/Cdc42 pathway en-keyword=Short-chain fatty acids (SCFAs) kn-keyword=Short-chain fatty acids (SCFAs) en-keyword=Butyrate kn-keyword=Butyrate en-keyword=Host–microbe interactions kn-keyword=Host–microbe interactions en-keyword=Antigen presentation kn-keyword=Antigen presentation en-keyword=T-cell activation kn-keyword=T-cell activation en-keyword=IL-17 kn-keyword=IL-17 en-keyword=IL-10 kn-keyword=IL-10 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=pcag052 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260612 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cytokinin receptor AHK3 influences leaf size by modulating trans-zeatin-type cytokinin levels in xylem en-subtitle= kn-subtitle= en-abstract= kn-abstract=Trans-zeatin (tZ)-type cytokinins (CKs) are predominantly synthesized in roots, transported to the shoot via the xylem, and coordinate diverse physiological processes in aerial organs. Within this process, the regulation of CK biosynthesis by nitrate signaling via nodule inception-like protein 7, as well as the loading of tZ-type CKs into the xylem by ATP-binding cassette transporter G14, have been well studied. However, the roles of other components remain unclear. Here, we show that CK perception and degradation in roots, as mediated by Arabidopsis histidine kinase 3 (AHK3) and CK oxidase/dehydrogenase 4 (CKX4), modulate root-to-shoot tZ-type cytokinin transport in response to nitrate. Grafting experiments demonstrate that root-specific AHK3 deficiency systemically increases the leaf blade area through long-distance signals of root-derived tZ-type CKs, perceived by shoot-expressed AHK3. Transcriptome and hormonome analyses reveal that root-specific AHK3 deficiency reduces CKX4 expression in roots, elevating tZ-type CK levels in roots and xylem sap and thereby enhancing the leaf CK response. Transfer experiments manipulating root nitrate levels show that root-specific AHK3 deficiency promotes the leaf blade area in a manner dependent on both nitrate and root-derived tZ-type CK signaling. Moreover, both nitrate signals and root-expressed AHK3 are required for maximal CKX4 induction in roots, and root-specific CKX4 deficiency enhances the leaf blade area in a nitrate-dependent manner. These findings reveal a novel mechanism in which an AHK3–CKX4 module governs xylem transport of tZ-type CKs, fine-tuning leaf size according to root nitrate status. en-copyright= kn-copyright= en-aut-name=MondenKota en-aut-sei=Monden en-aut-mei=Kota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SuzukiTakamasa en-aut-sei=Suzuki en-aut-mei=Takamasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KojimaMikiko en-aut-sei=Kojima en-aut-mei=Mikiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakebayashiYumiko en-aut-sei=Takebayashi en-aut-mei=Yumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KamiyaTakehiro en-aut-sei=Kamiya en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KibaTakatoshi en-aut-sei=Kiba en-aut-mei=Takatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SakakibaraHitoshi en-aut-sei=Sakakibara en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakagawaTsuyoshi en-aut-sei=Nakagawa en-aut-mei=Tsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HachiyaTakushi en-aut-sei=Hachiya en-aut-mei=Takushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=College of Bioscience and Biotechnology, Chubu University kn-affil= affil-num=3 en-affil=RIKEN Center for Sustainable Resource Science kn-affil= affil-num=4 en-affil=RIKEN Center for Sustainable Resource Science kn-affil= affil-num=5 en-affil=Graduate School of Agricultural and Life Sciences, Tokyo University kn-affil= affil-num=6 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=7 en-affil=RIKEN Center for Sustainable Resource Science kn-affil= affil-num=8 en-affil=Department of Molecular and Functional Genomics, Interdisciplinary Centerfor Science Research, Shimane University kn-affil= affil-num=9 en-affil=Department of Molecular and Functional Genomics, Interdisciplinary Centerfor Science Research, Shimane University kn-affil= en-keyword=Arabidopsis thaliana kn-keyword=Arabidopsis thaliana en-keyword=cytokinin kn-keyword=cytokinin en-keyword=micrografting kn-keyword=micrografting en-keyword=nitrate signal kn-keyword=nitrate signal en-keyword=trans-zeatin kn-keyword=trans-zeatin END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=10 article-no= start-page=1527 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260509 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Activation of TAS2R Signaling by Diphenidol Suppresses Tumor Growth and Remodels the Tumor Immune Microenvironment in Oral Squamous Cell Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP3-dependent intracellular Ca2+ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4+CD25+Foxp3+ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy. en-copyright= kn-copyright= en-aut-name=NasrunNisrina Ekayani en-aut-sei=Nasrun en-aut-mei=Nisrina Ekayani kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanimuraAkihiko en-aut-sei=Tanimura en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshidaKoki en-aut-sei=Yoshida en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UeharaOsamu en-aut-sei=Uehara en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KunisadaYuki en-aut-sei=Kunisada en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakabatakeKiyofumi en-aut-sei=Takabatake en-aut-mei=Kiyofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HosoyaAkihiro en-aut-sei=Hosoya en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakebeHiroaki en-aut-sei=Takebe en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NagatsukaHitoshi en-aut-sei=Nagatsuka en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AbikoYoshihiro en-aut-sei=Abiko en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=RuslinMuhammad en-aut-sei=Ruslin en-aut-mei=Muhammad kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ShimoTsuyoshi en-aut-sei=Shimo en-aut-mei=Tsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido kn-affil= affil-num=2 en-affil=Division of Pharmacology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido kn-affil= affil-num=3 en-affil=Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido kn-affil= affil-num=4 en-affil=Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido kn-affil= affil-num=5 en-affil=Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Division of Craniofacial Development and Tissue Biology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=8 en-affil=Division of Histology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido kn-affil= affil-num=9 en-affil=Department of Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido kn-affil= affil-num=11 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Hasanuddin University kn-affil= affil-num=12 en-affil=Division of Reconstructive Surgery for Oral and Maxillofacial Region, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido kn-affil= en-keyword=bitter taste receptor kn-keyword=bitter taste receptor en-keyword=diphenidol kn-keyword=diphenidol en-keyword=immunometabolism kn-keyword=immunometabolism en-keyword=oral squamous cellcarcinoma kn-keyword=oral squamous cellcarcinoma en-keyword=TAS2R signaling kn-keyword=TAS2R signaling en-keyword=tumor immune microenvironment kn-keyword=tumor immune microenvironment END start-ver=1.4 cd-journal=joma no-vol=49 cd-vols= no-issue=3 article-no= start-page=496 end-page=502 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260314 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Bortezomib Induces Apoptosis via Upregulation of Abhd4 in Peripheral Nerve Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Bortezomib, a first-in-class proteasome inhibitor, is widely used to treat multiple myeloma and other hematological malignancies. Despite its therapeutic efficacy, bortezomib causes peripheral neuropathy (PN) in approximately 20–30% of patients, often leading to dose reduction or discontinuation. Preventive or therapeutic approaches to bortezomib-induced PN are currently unavailable, as its precise mechanism remains unclear. In this study, we compared the effects of bortezomib and the second-generation proteasome inhibitor carfilzomib on peripheral nerve cells to identify candidate molecules involved in PN development. Transcriptome profiling of differentiated F11 cells, a hybridoma of a rat embryonic dorsal root ganglion and mouse neuroblastoma cell line N18TG2, revealed that bortezomib selectively upregulated α/β-hydrolase containing domain 4 (Abhd4), whereas carfilzomib did not. This finding was confirmed by quantitative RT-PCR and immunoblotting, which demonstrated consistent increases in Abhd4 mRNA and protein levels following bortezomib treatment. Functional analysis further revealed that Abhd4 overexpression promoted early apoptosis, suggesting a mechanistic link between bortezomib-induced Abhd4 elevation and neuronal vulnerability. Therefore, these results suggest that Abhd4 represents a candidate molecular signature associated with bortezomib-induced PN. Although further in vivo validation is needed, these findings warrant further investigation of Abhd4 as a potential contributor to bortezomib-induced PN. en-copyright= kn-copyright= en-aut-name=KonishiYusuke en-aut-sei=Konishi en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OmuraTomohiro en-aut-sei=Omura en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IjichiTakeshi en-aut-sei=Ijichi en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishiguchiHiroki en-aut-sei=Nishiguchi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HayakawaRyunosuke en-aut-sei=Hayakawa en-aut-mei=Ryunosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KitahiroYumi en-aut-sei=Kitahiro en-aut-mei=Yumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ItoharaKotaro en-aut-sei=Itohara en-aut-mei=Kotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamamotoKazuhiro en-aut-sei=Yamamoto en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YanoIkuko en-aut-sei=Yano en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Pharmacy, Kobe University Hospital kn-affil= affil-num=2 en-affil=Department of Pharmacy, Kobe University Hospital kn-affil= affil-num=3 en-affil=Department of Pharmacy, Kobe University Hospital kn-affil= affil-num=4 en-affil=Department of Pharmacy, Kobe University Hospital kn-affil= affil-num=5 en-affil=Education and Research Center for Clinical Pharmacy, Kobe Pharmaceutical University kn-affil= affil-num=6 en-affil=Department of Pharmacy, Kobe University Hospital kn-affil= affil-num=7 en-affil=Department of Pharmacy, Kobe University Hospital kn-affil= affil-num=8 en-affil=Department of Integrated Clinical and Basic Pharmaceutical Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Pharmacy, Kobe University Hospital kn-affil= en-keyword=bortezomib kn-keyword=bortezomib en-keyword=carfilzomib kn-keyword=carfilzomib en-keyword=peripheral neuropathy kn-keyword=peripheral neuropathy en-keyword=multiple myeloma kn-keyword=multiple myeloma en-keyword=proteasome inhibitor kn-keyword=proteasome inhibitor END start-ver=1.4 cd-journal=joma no-vol=117 cd-vols= no-issue=4 article-no= start-page=896 end-page=903 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260127 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Roles of TIF1β in Leukemic Stem Cell Through SETDB1-Dependent and Independent Mechanisms en-subtitle= kn-subtitle= en-abstract= kn-abstract=TIF1β/TRIM28/KAP1 has been recognized as a scaffold protein that partners with KRAB-ZFPs and heterochromatin complexes to enforce gene silencing. In embryonic and pluripotent stem cells, it maintains self-renewal by silencing endogenous retroelements through the establishment of heterochromatin. While these canonical functions have been extensively examined in embryonic stem (ES) cells, accumulating evidence also highlights its diverse contributions to cancer biology. We herein focused on the oncogenic role of TIF1β in leukemic progression, contrasting this with its physiological roles in hematopoietic stem cell maintenance, differentiation, and immune regulation, thereby providing a comparative perspective on H3K9 methyltransferase SETDB1-dependent and -independent mechanisms. TIF1β-mediated epigenetic plasticity was recently shown to establish a leukemic chromatin environment for promoting oncogenic transcriptional programs while repressing lineage-differentiation regulators, which drives leukemic progression in a context-dependent manner. This review summarizes the dual role of TIF1β as a chromatin modulator, functioning both as a canonical transcriptional co-repressor and as a context-dependent co-activator, and also discusses how these modalities cooperate to sustain leukemic stem cell programs. en-copyright= kn-copyright= en-aut-name=MoriiMariko en-aut-sei=Morii en-aut-mei=Mariko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KubotaSho en-aut-sei=Kubota en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SashidaGoro en-aut-sei=Sashida en-aut-mei=Goro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University kn-affil= en-keyword=BCR::ABL1 kn-keyword=BCR::ABL1 en-keyword=hematopoiesis kn-keyword=hematopoiesis en-keyword=heterochromatin kn-keyword=heterochromatin en-keyword=leukemia kn-keyword=leukemia en-keyword=transcription kn-keyword=transcription END start-ver=1.4 cd-journal=joma no-vol=75 cd-vols= no-issue=4 article-no= start-page=121 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260324 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Immunological effects of amivantamab in EGFR or MET-expressing non-small cell lung cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Epidermal growth factor receptor (EGFR) mutations represent one of the most frequent oncogenic driver in non-small cell lung cancer (NSCLC). Amivantamab, a bispecific antibody targeting EGFR and MET proto-oncogene, receptor tyrosine kinase (MET), has demonstrated clinical benefit in EGFR-mutant NSCLC through dual blockade, but its immunological role in human clinical specimens, especially tumor-infiltrating lymphocytes (TILs), has not been directly evaluated.
Methods We analyzed surgically resected tumor samples from 40 patients with NSCLC to investigate immune responses and their associations with EGFR and MET expression. TILs were characterized by flow cytometry (FCM) and immunohistochemistry (IHC). To assess the immunomodulatory potential of amivantamab, fresh tumor digests containing live tumor cells and TILs were cultured ex vivo with CD3 and CD28 stimulation in the absence or presence of amivantamab, followed by FCM. EGFR and MET expression were also evaluated by IHC.
Results EGFR mutations and high EGFR protein expression were associated with a trend toward reduced CD8⁺ T-cell and dendritic cell (DC) infiltration. In ex vivo TIL assays, exposure to amivantamab significantly activated CD8⁺ T cells, such as programmed cell death-1 expression and cytokine production, and promoted DC maturation. These effects were most pronounced in tumors with high EGFR or MET protein expression rather than EGFR mutations.
Conclusions This study provides the first direct evidence from ex vivo fresh TIL assays using human NSCLC clinical specimens that amivantamab can activate immune responses. EGFR and MET expression may serve as potential biomarkers for amivantamab-induced immune responses. en-copyright= kn-copyright= en-aut-name=YoshichikaRyo en-aut-sei=Yoshichika en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MukoharaFumiaki en-aut-sei=Mukohara en-aut-mei=Fumiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamadaKotaro en-aut-sei=Yamada en-aut-mei=Kotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NagasakiJoji en-aut-sei=Nagasaki en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WatanabeHiroko en-aut-sei=Watanabe en-aut-mei=Hiroko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UedaYouki en-aut-sei=Ueda en-aut-mei=Youki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SuzawaKen en-aut-sei=Suzawa en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShienKazuhiko en-aut-sei=Shien en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IshinoTakamasa en-aut-sei=Ishino en-aut-mei=Takamasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University kn-affil= affil-num=8 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University kn-affil= affil-num=9 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama University kn-affil= affil-num=10 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=11 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Non-small cell lung cancer kn-keyword=Non-small cell lung cancer en-keyword=Amivantamab kn-keyword=Amivantamab en-keyword=Antitumor immunity kn-keyword=Antitumor immunity en-keyword=EGFR kn-keyword=EGFR en-keyword=MET kn-keyword=MET END start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue=3 article-no= start-page=100926 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Potential Immune Microenvironment Biomarkers in SCLC: J-TAIL-2 Observational Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Effective predictors of response to atezolizumab plus carboplatin/etoposide (CE) therapy in extensive-stage SCLC (ES-SCLC) remain limited. This exploratory analysis from J-TAIL-2 aimed to identify markers of survival benefit with atezolizumab plus CE therapy in ES-SCLC.
Methods: J-TAIL-2 (ClinicalTrials.gov ID, NCT04501497) was a multicenter observational study that enrolled patients receiving atezolizumab plus CE (ES-SCLC cohort) in clinical practice in Japan per local label and treatment guidelines. In this exploratory analysis, the association of CD8+ tumor-infiltrating lymphocyte (TIL) density and SCLC subtypes (SCLC-A [ASCL1 dominant], SCLC-N [NEUROD1 dominant], SCLC-P [ASCL1/NEUROD1 double-negative with POU2F3 expression], and SCLC-O [ASCL1/NEUROD1 double-negative not otherwise specified]) with overall survival (OS) and progression-free survival (PFS) was evaluated. SCLC subtyping was performed by immunohistochemistry.
Results: SCLC samples (n = 100; data cutoff, February 3, 2023) were categorized as SCLC-A (73%), SCLC-N (16%), SCLC-P (8%), and SCLC-O (3%). Among 96 patients who received first-line atezolizumab plus CE, median age was 72 (range, 39–87) years and 81% were male. Furthermore, 56 patients were classified into the CD8+ TIL-high subgroup and 40 into the TIL-low subgroup. Median (m)PFS with atezolizumab plus CE was 6.1 months (95% confidence interval [CI]: 4.5–7.5) in the TIL-high versus 4.4 months (95% CI: 4.0–5.1) in the TIL-low subgroup (p = 0.01); mOS was 18.4 (95% CI: 11.8–not estimable) versus 10.8 months (95% CI: 7.7–16.2; p = 0.04). mOS and mPFS were not significantly different between SCLC subtypes but were numerically shorter in the SCLC-N group.
Conclusions: CD8+ TIL density is a potential biomarker of clinical benefit in ES-SCLC and may facilitate patient selection for atezolizumab combination therapy. en-copyright= kn-copyright= en-aut-name=ShirasawaMasayuki en-aut-sei=Shirasawa en-aut-mei=Masayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishioMakoto en-aut-sei=Nishio en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OsoegawaAtsushi en-aut-sei=Osoegawa en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KikuchiEiki en-aut-sei=Kikuchi en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KimuraHideharu en-aut-sei=Kimura en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MiyauchiEisaku en-aut-sei=Miyauchi en-aut-mei=Eisaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YoshiokaHiroshige en-aut-sei=Yoshioka en-aut-mei=Hiroshige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YoshinoIchiro en-aut-sei=Yoshino en-aut-mei=Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MisumiToshihiro en-aut-sei=Misumi en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YatabeYasushi en-aut-sei=Yatabe en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YoshidaTatsuya en-aut-sei=Yoshida en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KashimaJumpei en-aut-sei=Kashima en-aut-mei=Jumpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=OkiMasahide en-aut-sei=Oki en-aut-mei=Masahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AshimuraHisao en-aut-sei=Ashimura en-aut-mei=Hisao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KobayashiYuki en-aut-sei=Kobayashi en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=TanakaMisa en-aut-sei=Tanaka en-aut-mei=Misa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=GemmaAkihiko en-aut-sei=Gemma en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=2 en-affil=Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Kanazawa University Hospital kn-affil= affil-num=7 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Tohoku University Hospital kn-affil= affil-num=10 en-affil=Department of Thoracic Oncology, Kansai Medical University kn-affil= affil-num=11 en-affil=International University of Health and Welfare Narita Hospital kn-affil= affil-num=12 en-affil=Department of Data Science, National Cancer Center Hospital East kn-affil= affil-num=13 en-affil=Department of Diagnostic Pathology, National Cancer Center Hospital kn-affil= affil-num=14 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=15 en-affil=Department of Diagnostic Pathology, National Cancer Center Hospital kn-affil= affil-num=16 en-affil=Department of Respiratory Medicine, NHO Nagoya Medical Center kn-affil= affil-num=17 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=18 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=19 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=20 en-affil=Nippon Medical School kn-affil= en-keyword=Small cell kn-keyword=Small cell en-keyword=Lung cancer kn-keyword=Lung cancer en-keyword=Atezolizumab kn-keyword=Atezolizumab en-keyword=Chemotherapy kn-keyword=Chemotherapy en-keyword=Immune microenvironment kn-keyword=Immune microenvironment END start-ver=1.4 cd-journal=joma no-vol=117 cd-vols= no-issue=5 article-no= start-page=1260 end-page=1272 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260227 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=TGF-β Inhibitor Potentiates Osimertinib-Induced Anti-Tumor Immunity in Egfr-Mutant Lung Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Immunotherapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) remains challenging. We previously found that EGFR-tyrosine kinase inhibitors induced antitumor immunity but also triggered immunosuppressive cytokines, including transforming growth factor-β (TGF-β), in Egfr-mutant lung cancer. Here, we investigate whether TGF-β inhibition potentiates osimertinib-induced antitumor immunity using a syngeneic mouse model of Egfr-mutated lung cancer, with cancer cells subcutaneously transplanted into wild-type C57BL/6J mice. We evaluated the antitumor effect of the combination therapy with osimertinib and either nintedanib (an indirect TGF-β inhibitor) or vactosertib (a specific TGF-β type I receptor kinase inhibitor). Changes in the tumor microenvironment during treatment were assessed using immunohistochemical staining, western blot analysis, and flow cytometry. We found that TGF-β expression was upregulated in the tumor treated with osimertinib. Nintedanib monotherapy showed no significant antitumor effect, whereas osimertinib combined with nintedanib significantly potentiates the antitumor effect compared with osimertinib monotherapy in vivo. Crucially, no additive effect of nintedanib on osimertinib monotherapy was observed in vitro. Combination therapy with osimertinib and nintedanib significantly increased effector T cells (CD8+CD44+CD62L−) and Granzyme B+ areas and decreased CD206+ cells, while significantly decreasing TGF-β and SMAD2/3 expression. Similar effects were observed with vactosertib but not with a vascular endothelial growth factor receptor 2 inhibitor. In conclusion, combination therapy with osimertinib and TGF-β inhibitors potentiates osimertinib-induced antitumor immunity. These findings highlight a novel therapeutic strategy for EGFR-mutated NSCLC and warrant further clinical investigation. en-copyright= kn-copyright= en-aut-name=KuribayashiTadahiro en-aut-sei=Kuribayashi en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishimuraJun en-aut-sei=Nishimura en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OkawaSachi en-aut-sei=Okawa en-aut-mei=Sachi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TaokaMasataka en-aut-sei=Taoka en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MoriShunta en-aut-sei=Mori en-aut-mei=Shunta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TanakaTakaaki en-aut-sei=Tanaka en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishimuraTomoka en-aut-sei=Nishimura en-aut-mei=Tomoka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MoritaAyako en-aut-sei=Morita en-aut-mei=Ayako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HaraNaofumi en-aut-sei=Hara en-aut-mei=Naofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MakimotoGo en-aut-sei=Makimoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=RaiKammei en-aut-sei=Rai en-aut-mei=Kammei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=10 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=12 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=13 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=14 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=15 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=16 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=18 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= en-keyword=EGFR kn-keyword=EGFR en-keyword=lung cancer kn-keyword=lung cancer en-keyword=nintedanib kn-keyword=nintedanib en-keyword=osimertinib kn-keyword=osimertinib en-keyword=TGF-β kn-keyword=TGF-β END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=1 article-no= start-page=329 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260131 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=High-risk soft-tissue sarcomas in elderly patients: does perioperative radiotherapy improve local control and prognosis? en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aims Accumulating evidence suggests that advanced age is associated with poor local control and prognosis in patients with soft-tissue sarcomas (STSs), highlighting the need to optimise treatment for this age group. However, real-world data on treatment details and outcomes in elderly patients are limited. This study aimed to clarify the role of perioperative radiotherapy (RT) for treating high-risk STSs in elderly patients.
Methods Patients aged ≥ 70 years who underwent surgery for localised, high-grade, deep-seated non-small round cell STSs measuring ≥ 5 cm were included in the Bone and Soft Tissue Tumour Registry in Japan. Patients with small-round cell STSs or myxoid liposarcomas, or those who received perioperative chemotherapy or intraoperative RT, were excluded.
Results Among the 1,214 patients who met the criteria, 47 (4%), 219 (18%), and 2 (0.2%) received neoadjuvant, adjuvant, and both neoadjuvant and adjuvant RT, respectively. The 5- and 10-year disease-specific survival (DSS) rates were 72.7% and 64.7%, respectively. Tumour size ≥ 10 cm, intralesional margin, and local recurrence were associated with poorer DSS; however, perioperative RT did not affect DSS. The 5- and 10-year cumulative probabilities of local recurrence (LR) were 14.6% and 19.5%, respectively. Trunk wall tumours, dedifferentiated liposarcomas, marginal margins, and intralesional margins were associated with a higher probability of LR. Adjuvant RT was associated with a reduced LR probability in patients with intralesional (p = 0.005) or marginal margins (p = 0.044); however, no such benefit was observed in patients with wide margins, who constituted the majority of the cohort, resulting in no significant association between perioperative RT and LR in overall analyses. In the propensity score-matched cohort, no significant differences in DSS or cumulative probability of LR were observed between patients with and without perioperative RT.
Conclusion Adjuvant RT was associated with reduced LR rates in elderly patients with high-risk STSs who had intralesional or marginal margins. However, because most patients achieved wide margins and no benefit of perioperative RT was observed in this group, RT was not associated with reduced LR or improved survival in the overall or propensity score–matched analyses. Prospective trials are warranted to define the role of perioperative RT in elderly patients with high-risk STSs. en-copyright= kn-copyright= en-aut-name=FujiwaraTomohiro en-aut-sei=Fujiwara en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MitsuhashiToshiharu en-aut-sei=Mitsuhashi en-aut-mei=Toshiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NezuYutaka en-aut-sei=Nezu en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TajimaTakashi en-aut-sei=Tajima en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MiwaShinji en-aut-sei=Miwa en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KojimaToshio en-aut-sei=Kojima en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FujiwaraShuichi en-aut-sei=Fujiwara en-aut-mei=Shuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawaiAkira en-aut-sei=Kawai en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaKazuhiro en-aut-sei=Tanaka en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Centre for Innovative Clinical Medicine, Medical Development Field, Okayama University kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Yokohama City University kn-affil= affil-num=4 en-affil=Department of Orthopaedic Surgery, Kyorin University Faculty of Medicine kn-affil= affil-num=5 en-affil=Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery, Nihon University School of Medicine kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine kn-affil= affil-num=8 en-affil=Department of Musculoskeletal Oncology, National Cancer Centre Hospital kn-affil= affil-num=9 en-affil=Department of Advanced Medical Sciences, Oita University Faculty of Medicine kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Soft-tissue sarcoma kn-keyword=Soft-tissue sarcoma en-keyword=High-risk kn-keyword=High-risk en-keyword=Surgery kn-keyword=Surgery en-keyword=Perioperative radiotherapy kn-keyword=Perioperative radiotherapy en-keyword=Elderly patients kn-keyword=Elderly patients END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=4 article-no= start-page=728 end-page=741 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202604 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Constitutive EGFR Activation Induced by PTPRR Downregulation Confers Resistance to KRAS Inhibitors en-subtitle= kn-subtitle= en-abstract= kn-abstract=KRASG12C inhibitors, such as sotorasib, show clinical efficacy for non–small cell lung cancer (NSCLC) positive for the G12C mutations of KRAS, but primary and acquired resistance to these drugs remains a clinical problem. In this study, we show that the development of resistance to sotorasib in KRASG12C-positive NSCLC cells was mediated by constitutive activation of EGFR resulting from downregulation of the protein tyrosine phosphatase receptor type R (PTPRR). PTPRR has been identified as a physiologic regulator of ERK signaling in several cancer types. In our study, PTPRR was demonstrated to bind directly to EGFR, facilitating its dephosphorylation on tyrosine residues. Resumption of PTPRR expression in the resistant cells attenuated EGFR phosphorylation and restored sotorasib sensitivity. PTPRR downregulation was associated with gene promoter hypermethylation in the sotorasib-resistant cells and NSCLC tissue samples. Furthermore, low PTPRR expression in tumor specimens was associated with shorter progression-free and overall survival for patients with NSCLC treated with sotorasib. In contrast to sotorasib, high PTPRR expression was associated with a poor response to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC, suggesting that PTPRR may broadly regulate EGFR dependence in NSCLC. Finally, dual blockade of KRASG12C and EGFR showed a substantial antitumor effect in a xenograft model of sotorasib-resistant NSCLC. This approach is therefore a rational therapeutic strategy for KRASG12C-positive NSCLC, especially for tumors showing PTPRR downregulation.
Significance: The current study shows that downregulation of PTPRR induces EGFR activation and resistance to KRASG12C inhibitors in NSCLC, suggesting dual KRAS-EGFR blockade as a rational therapy. PTPRR may help identify patient subgroups that would benefit from the addition of EGFR inhibitors to KRASG12C-targeted therapies. en-copyright= kn-copyright= en-aut-name=KanemuraHiroaki en-aut-sei=Kanemura en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakeharaToshiyuki en-aut-sei=Takehara en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MaenishiOsamu en-aut-sei=Maenishi en-aut-mei=Osamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TomidaShuta en-aut-sei=Tomida en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IwawakiNatsumi en-aut-sei=Iwawaki en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KunimasaKei en-aut-sei=Kunimasa en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakayamaTomohiro en-aut-sei=Nakayama en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=WatanabeSatomi en-aut-sei=Watanabe en-aut-mei=Satomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SuzukiShinichiro en-aut-sei=Suzuki en-aut-mei=Shinichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SakaiKazuko en-aut-sei=Sakai en-aut-mei=Kazuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AzumaKoichi en-aut-sei=Azuma en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KudoKeita en-aut-sei=Kudo en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=NishioKazuto en-aut-sei=Nishio en-aut-mei=Kazuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NakagawaKazuhiko en-aut-sei=Nakagawa en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=HayashiHidetoshi en-aut-sei=Hayashi en-aut-mei=Hidetoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TeramuraTakeshi en-aut-sei=Teramura en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=YonesakaKimio en-aut-sei=Yonesaka en-aut-mei=Kimio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= affil-num=1 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=2 en-affil=Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine kn-affil= affil-num=3 en-affil=Department of Pathology, Kindai University Faculty of Medicine kn-affil= affil-num=4 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine kn-affil= affil-num=6 en-affil=Department of Thoracic Oncology, Osaka International Cancer Institute kn-affil= affil-num=7 en-affil=Department of Medical Oncology, Kishiwada City Hospital kn-affil= affil-num=8 en-affil=Department of Medical Oncology, Kishiwada City Hospital kn-affil= affil-num=9 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=10 en-affil=Department of Genome Biology, Kindai University Faculty of Medicine kn-affil= affil-num=11 en-affil=Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine kn-affil= affil-num=12 en-affil=Department of Medical Oncology, National Hospital Organization Osaka Minami Medical Center kn-affil= affil-num=13 en-affil=Department of Genome Biology, Kindai University Faculty of Medicine kn-affil= affil-num=14 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=15 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=16 en-affil=Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine kn-affil= affil-num=17 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= END start-ver=1.4 cd-journal=joma no-vol=51 cd-vols= no-issue= article-no= start-page=100972 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Highly sensitive detection of cancer cells using a voltage-tuned terahertz chemical microscope en-subtitle= kn-subtitle= en-abstract= kn-abstract=Terahertz chemical microscopy (TCM) is a promising label-free technique for detecting biochemical interactions by monitoring changes in terahertz (THz) wave emission from semiconductor sensing plates. However, quantitative biological detection has been hindered by large plate-to-plate variations originating from uncontrolled depletion-layer electric fields formed during fabrication. These variations shift the response curve of THz amplitude and reduce reproducibility and sensitivity. Here, we introduce a voltage-tuned sensing plate that allows direct control of the depletion-layer electric field by applying a bias voltage to the Si layer of the sensing plate. This enables deliberate adjustment of surface potential and alignment of the THz response curve to the region of highest gain. Using lung adenocarcinoma cells (PC9) captured via AE1/AE3 antibodies targeting specific cell-surface antigens, we demonstrate that voltage tuning enhances detection sensitivity by up to 50-fold and restores linearity between THz amplitude and the logarithm of cell concentration, even in plates with negligible response at 0 V. These findings establish voltage control as a simple, universally applicable strategy to stabilize TCM performance, reduce fabrication-induced variability, and improve analytical sensitivity for biosensing and materials-analysis applications. en-copyright= kn-copyright= en-aut-name=DingXue en-aut-sei=Ding en-aut-mei=Xue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OhmiYuto en-aut-sei=Ohmi en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WangJin en-aut-sei=Wang en-aut-mei=Jin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=InoueHirofumi en-aut-sei=Inoue en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KiwaToshihiko en-aut-sei=Kiwa en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Medical Support, Okayama University Hospital kn-affil= affil-num=5 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=Terahertz chemical microscopy kn-keyword=Terahertz chemical microscopy en-keyword=Voltage tuning kn-keyword=Voltage tuning en-keyword=Cancer cells kn-keyword=Cancer cells en-keyword=Surface potential kn-keyword=Surface potential END start-ver=1.4 cd-journal=joma no-vol=76 cd-vols= no-issue=2 article-no= start-page=100082 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202607 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pharmaceutical agents targeting KATP channel modulate sweet taste sensitivity in mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sweet detection involves at least two mechanisms: a G-protein coupled sweet taste receptor (Tas1r2/Tas1r3) and glucose transporters. As in pancreatic β-cells, glucose transport may lead to closure of ATP-sensitive potassium (KATP) channels. Since expression of KATP channels in sweet taste cells has been reported, modulation of KATP channel activity would affect sweet taste sensitivity. Here, we examined the effect of glibenclamide (a KATP channel closer) and diazoxide (an opener) on mouse taste behavior. Glibenclamide selectively reduced taste sensitivity to glucose without affecting responses to sucrose or sucralose compared to insulin, suggesting selective impairment of the transporter-dependent pathway. In contrast, diazoxide broadly suppressed responses to all tested sweeteners, indicating a generalized effect on sweet detection. Neither drug altered responses to non-sweet taste. These findings suggest that pharmacological modulation of KATP channel differently influences sweet taste; closers reduce glucose sensitivity whereas openers attenuate response to multiple sweeteners. en-copyright= kn-copyright= en-aut-name=SawaiChika en-aut-sei=Sawai en-aut-mei=Chika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WangKuanyu en-aut-sei=Wang en-aut-mei=Kuanyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HorieKengo en-aut-sei=Horie en-aut-mei=Kengo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MitohYoshihiro en-aut-sei=Mitoh en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=UedaHirotaka en-aut-sei=Ueda en-aut-mei=Hirotaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshidaRyusuke en-aut-sei=Yoshida en-aut-mei=Ryusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Oral Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Sweet taste receptor kn-keyword=Sweet taste receptor en-keyword=Glucose transporter kn-keyword=Glucose transporter en-keyword=Diabetes kn-keyword=Diabetes en-keyword=Taste disorder kn-keyword=Taste disorder en-keyword=Cephalic phase insulin release kn-keyword=Cephalic phase insulin release END start-ver=1.4 cd-journal=joma no-vol=370 cd-vols= no-issue= article-no= start-page=199761 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202608 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Toward in planta studies of persistent fungal viruses in a model plant en-subtitle= kn-subtitle= en-abstract= kn-abstract=A model plant, Nicotiana benthamiana, was examined as a host for persistent fungal viruses capable of crossing organismal kingdoms. Protoplasts of N. benthamiana were transfected with a mixture of virions of a betapartitivirus, Rosellinia necatrix partitivirus 18 (RnPV18), and an alphapartitivirus, RnPV19, and were then subjected to plantlet regeneration. Primary RT-PCR-based screening showed that nearly 100% of the resulting calli tested positive for RnPV18, whereas approximately 90% were positive for RnPV19. However, secondary screening performed at a later stage of tissue culture revealed that only 6% of the calli retained RnPV19, whereas approximately 33% retained RnPV18. These results suggest that the calli were chimeric, consisting of virus-infected and virus-free sectors, and that the partitiviruses were progressively lost during callus maintenance. It is also possible that these fungal partitiviruses were unable to fully adapt to, or counteract, host defense responses sufficiently to establish stable infection. We succeeded in obtaining RnPV18-positive calli and suspension cultures that maintained the virus at detectable levels, as shown by northern blotting, after prolonged subculture for at least 9 months. High-throughput small RNA analyses revealed both similarities and differences in virus-derived small RNA profiles among protoplasts, calli, and suspension cultures. Viral genome analyses further revealed developmental stage-specific and stage-independent substitutions compared with the RnPV18 genomic sequence maintained in the original fungal host. Interestingly, a C-to-U mutation in the RNA-dependent RNA polymerase-encoding region of RnPV18 was detected much more frequently in a particular line, designated B21, than in another stably RnPV18-infected line, P8, irrespective of whether the virus was maintained in suspension cultures or calli. This may explain why virus accumulation in B21 calli and suspension cultures was much lower than that in P8 cell cultures, as RNA-seq analyses showed 159 K counts per million for P8 versus 44 K counts per million for B21. Taken together, this study provides a platform for investigating partitiviruses and other ubiquitous persistent viruses, which are generally difficult to inoculate experimentally. en-copyright= kn-copyright= en-aut-name=TelengechPaul en-aut-sei=Telengech en-aut-mei=Paul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HisanoSakae en-aut-sei=Hisano en-aut-mei=Sakae kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FavarettoFrancesco en-aut-sei=Favaretto en-aut-mei=Francesco kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IchikawaHiroaki en-aut-sei=Ichikawa en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MaruyamaKazuyuki en-aut-sei=Maruyama en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HyodoKiwamu en-aut-sei=Hyodo en-aut-mei=Kiwamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KondoHideki en-aut-sei=Kondo en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SuzukiNobuhiro en-aut-sei=Suzuki en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=3 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=4 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=5 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=6 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=7 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=8 en-affil=Agrivirology Laboratory, Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=Cross-kingdom infection kn-keyword=Cross-kingdom infection en-keyword=Tissue culture kn-keyword=Tissue culture en-keyword=Partitivirus kn-keyword=Partitivirus en-keyword=dsRNA virus kn-keyword=dsRNA virus en-keyword=Nicotiana, benthamiana kn-keyword=Nicotiana, benthamiana en-keyword=Callus kn-keyword=Callus en-keyword=Suspension culture kn-keyword=Suspension culture en-keyword=Model plant kn-keyword=Model plant END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=pcag055 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260428 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Involvement of tRNA thiolation in uORF-mediated translational regulation during Xylogenesis in Arabidopsis thaliana en-subtitle= kn-subtitle= en-abstract= kn-abstract=Post-transcriptional modification of tRNAs is an important mechanism for regulating translation efficiency and cellular homeostasis, yet its contribution to upstream open reading frame (uORF)-mediated translational control remains largely unexplored. In this study, we investigated the role of tRNA thiolation in thermospermine-dependent regulation of xylem development in Arabidopsis thaliana. Using a suppressor screen of the thermospermine-deficient mutant acaulis5 (acl5), which exhibits dwarfism and excessive xylem differentiation, we identified suppressor-of-acl502 (sac502) as a recessive loss-of-function allele of CTU2, a gene encoding a key enzyme in the biosynthesis of the wobble uridine modification 5-methoxycarbonylmethyl-2-thiouridine. Mutations in other components of the same modification pathway, including ROL5 and TRM9, similarly suppressed the acl5 phenotype. Translational analyses using 5′ leader-GUS reporter constructs revealed that the ctu2 mutation did not enhance translation of the mRNA containing a thermospermine-responsive uORF of SAC51, but instead significantly reduced translation of that of SACL3, a member of the SAC51 family, and that of LONESOME HIGHWAY (LHW), which contains another conserved uORF in the 5′ leader region. Polysome profiling further demonstrated decreased association of SACL3 and LHW mRNAs with actively translating ribosomes in ctu2. Genetic interaction analyses supported the conclusion that the suppression of excessive xylem formation in acl5 by ctu2 is attributable to reduced LHW activity. In addition, ctu2 mutants displayed increased sensitivity to exogenous thermospermine, resembling the response of lhw mutants. Together, our results reveal that tRNA thiolation contributes to uORF-mediated translational regulation of key developmental regulators and identify tRNA modification as an important regulatory layer controlling vascular development. en-copyright= kn-copyright= en-aut-name=NishiiYuichi en-aut-sei=Nishii en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ArakiDaichi en-aut-sei=Araki en-aut-mei=Daichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SaraumiMitsuru en-aut-sei=Saraumi en-aut-mei=Mitsuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakahashiTaku en-aut-sei=Takahashi en-aut-mei=Taku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=Arabidopsis kn-keyword=Arabidopsis en-keyword=mRNA translation kn-keyword=mRNA translation en-keyword=thermospermine kn-keyword=thermospermine en-keyword=tRNA thiolation kn-keyword=tRNA thiolation en-keyword=uOR kn-keyword=uOR END start-ver=1.4 cd-journal=joma no-vol=105 cd-vols= no-issue=5 article-no= start-page=255 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260420 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=HLA-matched versus haploidentical donor transplantation with post-transplant cyclophosphamide: a study on behalf of the donor/source working group of the Japanese society for transplantation and cellular therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Post-transplant cyclophosphamide (PTCy) is now being increasingly applied to HLA-matched donor (MD) transplantation. Prior studies in Western countries have demonstrated that allogeneic hematopoietic cell transplantation (allo-HCT) employing PTCy yields better outcomes with HLA-matched donors (MDs) than with haploidentical donors (HIDs). However, the effect of HLA mismatch may differ among racial groups. We retrospectively analyzed adult patients with hematological malignancies who underwent their first allo-HCT with PTCy from MDs or HIDs registered to the Japanese registry database between 2013 and 2021. Among 63 (related, n = 33; unrelated, n = 30) and 1261 patients who received MD and HID allo-HCT with PTCy, 50 (related, n = 30; unrelated, n = 20) and 100 patients were assigned to MD and HID groups by 1:2 propensity score matching (PSM). The results showed that MD recipients had better neutrophil recovery (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.04–2.10; P = 0.031) and lower risk of non-relapse mortality (NRM) (HR, 0.19; 95% CI, 0.05–0.81; P = 0.024) than HID recipients. Multivariable analyses in the entire cohort before PSM confirmed these findings. Fatal infection was the primary cause of NRM in the HID group. This study is the first to demonstrate that, within a homogeneous Asian cohort, MD may have an advantage over HID in PTCy-based allo-HCT in facilitating neutrophil engraftment and reducing the risk of NRM. en-copyright= kn-copyright= en-aut-name=NakayaYosuke en-aut-sei=Nakaya en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakamaeHirohisa en-aut-sei=Nakamae en-aut-mei=Hirohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SugitaJunichi en-aut-sei=Sugita en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KandaJunya en-aut-sei=Kanda en-aut-mei=Junya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HasegawaYuta en-aut-sei=Hasegawa en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=EtoTetsuya en-aut-sei=Eto en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FukudaTakahiro en-aut-sei=Fukuda en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KuritaNaoki en-aut-sei=Kurita en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HiramotoNobuhiro en-aut-sei=Hiramoto en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NagafujiKoji en-aut-sei=Nagafuji en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OtaShuichi en-aut-sei=Ota en-aut-mei=Shuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=AndoToshihiko en-aut-sei=Ando en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KawakitaToshiro en-aut-sei=Kawakita en-aut-mei=Toshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=AkasakaTakashi en-aut-sei=Akasaka en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=MoriYasuo en-aut-sei=Mori en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KamimuraTomohiko en-aut-sei=Kamimura en-aut-mei=Tomohiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=OnizukaMakoto en-aut-sei=Onizuka en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=NakasoneHideki en-aut-sei=Nakasone en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Hematology, Osaka Metropolitan University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Hematology, Osaka Metropolitan University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Hematology, Sapporo Hokuyu Hospital kn-affil= affil-num=4 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=5 en-affil=Department of Hematology, Hokkaido University Hospital kn-affil= affil-num=6 en-affil=Department of Hematology, Hamanomachi Hospital kn-affil= affil-num=7 en-affil=Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital kn-affil= affil-num=8 en-affil=Department of Hematology, University of Tsukuba Hospital kn-affil= affil-num=9 en-affil=Department of Hematology, Kobe City Medical Center General Hospital kn-affil= affil-num=10 en-affil=Division of Hematology and Oncology, Department of Medicine, Kurume University HospitalDepartment of Hematology, Sapporo Hokuyu Hospital kn-affil= affil-num=11 en-affil=Department of Hematology, Sapporo Hokuyu Hospital kn-affil= affil-num=12 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=13 en-affil=Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University kn-affil= affil-num=14 en-affil=Department of Hematology, NHO Kumamoto Medical Center kn-affil= affil-num=15 en-affil=Department of Hematology, Tenri Hospital kn-affil= affil-num=16 en-affil=Hematology, Oncology & Cardiovascular medicine, Kyushu University Hospital kn-affil= affil-num=17 en-affil=Department of Hematology, Harasanshin Hospital kn-affil= affil-num=18 en-affil=Department of Hematology/Oncology, Tokai University School of Medicine kn-affil= affil-num=19 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=20 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= en-keyword=Post-transplant cyclophosphamide kn-keyword=Post-transplant cyclophosphamide en-keyword=Matched donor kn-keyword=Matched donor en-keyword=Haploidentical donor kn-keyword=Haploidentical donor en-keyword=Graft-versus-host disease kn-keyword=Graft-versus-host disease en-keyword=Hematological malignancies. kn-keyword=Hematological malignancies. END start-ver=1.4 cd-journal=joma no-vol=105 cd-vols= no-issue=5 article-no= start-page=244 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260414 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Donor selection for patients with HLA-homozygous haplotypes in allogeneic hematopoietic stem cell transplantation en-subtitle= kn-subtitle= en-abstract= kn-abstract=HLA homozygous haplotypes occur worldwide, but outcomes after allogeneic hematopoietic stem cell transplantation using alternative donor sources remain uncertain. We retrospectively analyzed the Japanese national transplantation registry to compare outcomes after first allogeneic hematopoietic stem cell transplantation in patients with HLA homozygous haplotypes. Donors were classified as homo-to-homo, defined as HLA-matched, or hetero-to-homo, defined as allele-level mismatches at HLA-A, -B, -C, and/or -DRB1 restricted to the host-versus-graft direction. The unrelated donor homo-to-homo group served as the reference. We included 691 patients: related donor homo-to-homo (n = 121), related donor hetero-to-homo (n = 76), unrelated donor homo-to-homo (n = 374), unrelated donor hetero-to-homo (n = 22), cord blood homo-to-homo (n = 40), and cord blood hetero-to-homo (n = 58). Compared with the unrelated donor homo-to-homo group, overall survival was inferior in the cord blood homo-to-homo group (adjusted hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.11–2.64; P = 0.015), whereas the unrelated donor hetero-to-homo group showed a nonsignificant trend toward inferior overall survival (adjusted HR, 1.77; 95% CI, 0.97–3.22; P = 0.061). In this Japanese cohort, cord blood homo-to-homo transplantation was associated with inferior overall survival, whereas related donor hetero-to-homo and cord blood hetero-to-homo transplantation were not. These findings should be interpreted cautiously given the retrospective design and long study period, and require validation in contemporary, ethnically diverse cohorts. en-copyright= kn-copyright= en-aut-name=YoshinagaNoriyoshi en-aut-sei=Yoshinaga en-aut-mei=Noriyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IwasakiMakoto en-aut-sei=Iwasaki en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KimuraFumihiko en-aut-sei=Kimura en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HirayamaMasahiro en-aut-sei=Hirayama en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KanayaMinoru en-aut-sei=Kanaya en-aut-mei=Minoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MorishimaSatoko en-aut-sei=Morishima en-aut-mei=Satoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UchidaNaoyuki en-aut-sei=Uchida en-aut-mei=Naoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=DokiNoriko en-aut-sei=Doki en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FukudaTakahiro en-aut-sei=Fukuda en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KandaYoshinobu en-aut-sei=Kanda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NishidaTetsuya en-aut-sei=Nishida en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=HasegawaYuta en-aut-sei=Hasegawa en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KakoShinichi en-aut-sei=Kako en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TanakaMasatsugu en-aut-sei=Tanaka en-aut-mei=Masatsugu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KurokawaMineo en-aut-sei=Kurokawa en-aut-mei=Mineo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KawakitaToshiro en-aut-sei=Kawakita en-aut-mei=Toshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KataokaKeisuke en-aut-sei=Kataoka en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KondoYukio en-aut-sei=Kondo en-aut-mei=Yukio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=ImadaKazunori en-aut-sei=Imada en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=IchinoheTatsuo en-aut-sei=Ichinohe en-aut-mei=Tatsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=OnizukaMakoto en-aut-sei=Onizuka en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=KandaJunya en-aut-sei=Kanda en-aut-mei=Junya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= affil-num=1 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=2 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=3 en-affil=Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences kn-affil= affil-num=4 en-affil=Division of Hematology, Department of Internal Medicine, National Defense Medical College kn-affil= affil-num=5 en-affil=Department of Pediatrics, Mie University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Blood Disorders Center, Aiiku Hospital kn-affil= affil-num=7 en-affil=Central Japan Cord Blood Bank kn-affil= affil-num=8 en-affil=Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital kn-affil= affil-num=9 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=10 en-affil=Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital kn-affil= affil-num=11 en-affil=Division of Hematology, Jichi Medical University kn-affil= affil-num=12 en-affil=Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital kn-affil= affil-num=13 en-affil=Department of Hematology, Hokkaido University Hospital kn-affil= affil-num=14 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= affil-num=15 en-affil=Department of Hematology, Kanagawa Cancer Center kn-affil= affil-num=16 en-affil=Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital kn-affil= affil-num=17 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=18 en-affil=Department of Hematology, NHO Kumamoto Medical Center kn-affil= affil-num=19 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=20 en-affil=Department of Hematology, Toyama Prefectural Central Hospital kn-affil= affil-num=21 en-affil=Department of Hematology, Japanese Red Cross Osaka Hospital kn-affil= affil-num=22 en-affil=Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University kn-affil= affil-num=23 en-affil=Department of Hematology/Oncology, Tokai University School of Medicine kn-affil= affil-num=24 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=25 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= en-keyword=HLA-homozygous haplotypes kn-keyword=HLA-homozygous haplotypes en-keyword=Hematopoietic stem cell transplantation kn-keyword=Hematopoietic stem cell transplantation en-keyword=Donor source kn-keyword=Donor source en-keyword=Host-versus-graft direction mismatch kn-keyword=Host-versus-graft direction mismatch END start-ver=1.4 cd-journal=joma no-vol=2026 cd-vols= no-issue=1 article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Case of Peripheral Odontogenic Myxofibroma Arising in the Palatal Gingiva of the Maxillary Second Premolar Region: A Case Report en-subtitle= kn-subtitle= en-abstract= kn-abstract=Odontogenic myxofibroma (OMF) is a rare benign mesenchymal odontogenic tumor characterized by myxoid stroma with a prominent fibrous component. Although it usually arises intraosseously within the jaws, the peripheral variant, peripheral odontogenic myxofibroma (POMF), which occurs in extraosseous soft tissues, is uncommon and may be clinically misdiagnosed as a reactive gingival lesion. We report a case of POMF in a 68-year-old man who was referred for evaluation of a painless, slowly enlarging swelling of the palatal gingiva in the left maxillary second premolar region, which had initially been diagnosed as chronic periodontitis at a local clinic. An intraoral examination revealed an elastic, firm mass with partial erythema on the palatal marginal gingiva. Panoramic radiography showed mild generalized horizontal bone loss without lesion-specific changes, and computed tomography revealed no bone resorption associated with the lesion. Exfoliative cytology was negative for intraepithelial lesions or malignancy. The lesion was excised with a 5-mm clinical margin, including periosteum, and superficial peripheral ostectomy of the adjacent cortical bone was performed. Histopathological examination revealed a myxoid stroma rich in mucinous matrix and collagen fibers, containing sparsely distributed spindle-shaped cells and scattered nests of odontogenic epithelium. Alcian blue staining revealed diffuse positivity, supporting the diagnosis of POMF. No recurrence was observed during a 2-year follow-up period. This case highlights a diagnostic pitfall in the tooth-bearing gingiva and underscores the importance of histopathological confirmation of persistent gingival masses. When imaging shows no apparent bone involvement, and clinical suspicion of malignancy is low, complete excision with an adequate soft-tissue margin and selective, limited bone removal may achieve local control while preserving the adjacent teeth; long-term follow-up remains advisable. en-copyright= kn-copyright= en-aut-name=MasuiMasanori en-aut-sei=Masui en-aut-mei=Masanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YutoriHirokazu en-aut-sei=Yutori en-aut-mei=Hirokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FujimuraAi en-aut-sei=Fujimura en-aut-mei=Ai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IbaragiSoichiro en-aut-sei=Ibaragi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Oral and Maxillofacial Surgery , Faculty of Medicine , Dentistry and Pharmaceutical Sciences Okayama University kn-affil= affil-num=2 en-affil=Department of Oral and Maxillofacial Surgery , Kagawa Prefectural Central Hospital kn-affil= affil-num=3 en-affil=Department of Oral and Maxillofacial Surgery , Kagawa Prefectural Central Hospital kn-affil= affil-num=4 en-affil=Department of Oral and Maxillofacial Surgery , Faculty of Medicine , Dentistry and Pharmaceutical Sciences Okayama University kn-affil= en-keyword=case report kn-keyword=case report en-keyword=excisional biopsy kn-keyword=excisional biopsy en-keyword=palatal gingiva kn-keyword=palatal gingiva en-keyword=peripheral odontogenic myxofibroma kn-keyword=peripheral odontogenic myxofibroma en-keyword=peripheral odontogenic myxoma kn-keyword=peripheral odontogenic myxoma END start-ver=1.4 cd-journal=joma no-vol=40 cd-vols= no-issue=6 article-no= start-page=e70582 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260528 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Risk Factors for Waiting List Mortality in Lung Transplant Candidates With Post‐Hematopoietic Stem Cell Transplantation Non‐Infectious Pulmonary Complications en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Late-onset non-infectious pulmonary complications (LONIPCs) following hematopoietic stem cell transplantation (HSCT) are a known indication for need of lung transplantation. This study aimed to clarify the clinical characteristics of patients with LONIPCs after HSCT who were registered for lung transplantation and reveal the risk factors for waiting list mortality.
Methods: We retrospectively reviewed the clinical data of patients with LONIPCs after allogeneic HSCT who were referred to Okayama University Hospital and registered in the Japan Organ Transplant Network for deceased-donor lung transplantation between 2005 and 2023. Pediatric patients aged <18 years at the time of registration were excluded.
Results: Thirty-four patients were included in this study. Notably, two distinct phenotypic groups were identified: One with a bronchiolitis obliterans pattern on high-resolution computed tomography and a mixed ventilatory defect, and the other with a pleuroparenchymal fibroelastosis pattern and a restrictive ventilatory defect. The median waiting duration for a deceased-donor lung transplant was 662 days, and 16 patients died during the waiting period. The cumulative incidence of waiting list mortality was 20.6% (95% confidence interval [CI], 8.9%–35.6%) at 1 year and 46.1% (95% CI, 27.8%–62.7%) at 3 years. A history of pneumothorax, greater dyspnea on exertion, and higher serum Krebs von den Lungen-6 levels were associated with an increased risk of waiting list mortality.
Conclusion: In patients with LONIPCs after HSCT, a history of pneumothorax may be a marker of a poor prognosis and could serve as a criterion for referral of lung transplantation. en-copyright= kn-copyright= en-aut-name=HigoHisao en-aut-sei=Higo en-aut-mei=Hisao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SenooSatoru en-aut-sei=Senoo en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MakimotoSatoko en-aut-sei=Makimoto en-aut-mei=Satoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NaganoTomohiro en-aut-sei=Nagano en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KondoTakumi en-aut-sei=Kondo en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YamamotoHaruchika en-aut-sei=Yamamoto en-aut-mei=Haruchika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TanakaShin en-aut-sei=Tanaka en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MiyoshiKentaroh en-aut-sei=Miyoshi en-aut-mei=Kentaroh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SugimotoSeiichiro en-aut-sei=Sugimoto en-aut-mei=Seiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MiyaharaNobuaki en-aut-sei=Miyahara en-aut-mei=Nobuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Radiology, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= en-keyword=hematopoietic stem cell transplantation kn-keyword=hematopoietic stem cell transplantation en-keyword=late-onset non-infectious pulmonary complications kn-keyword=late-onset non-infectious pulmonary complications en-keyword=lung transplantation kn-keyword=lung transplantation en-keyword=pneumothorax kn-keyword=pneumothorax END start-ver=1.4 cd-journal=joma no-vol=53 cd-vols= no-issue=10 article-no= start-page=e2025GL121007 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Spin Transition of Fe3+ in δ-(Al,Fe)OOH and Implication for Mid-Lower Mantle Seismic Heterogeneities en-subtitle= kn-subtitle= en-abstract= kn-abstract=δ-(Al,Fe)OOH is an important water carrier and plays a critical role on Earth's deep water cycle. Lattice parameters of δ-(Al0.89Fe0.11)OOH were measured by synchrotron single-crystal X-ray diffraction at simultaneously high temperature and pressure up to 65 GPa and 800 K in diamond anvil cells. The results reveal that the spin crossover increases from 30 to 37 GPa at 300 K to 36–48 GPa at 700 K. Moreover, at the spin crossover, the KT and VΦ of δ-(Al0.89Fe0.11)OOH occur significant elastic softening, with maximum reductions of 50% on KT and 29% on VΦ at 33 GPa and 300 K to 37% on KT and 23% on VΦ at 41 GPa and 700 K. The anomalous elastic properties of δ-(Al,Fe)OOH at the spin crossover enhance our understanding of local seismic observations anomalies and help identify potential water-rich regions in the mid-lower mantle. en-copyright= kn-copyright= en-aut-name=ZhaoChaoshuai en-aut-sei=Zhao en-aut-mei=Chaoshuai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MaoZhu en-aut-sei=Mao en-aut-mei=Zhu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ZhangXinyue en-aut-sei=Zhang en-aut-mei=Xinyue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YuYingxin en-aut-sei=Yu en-aut-mei=Yingxin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SunNingyu en-aut-sei=Sun en-aut-mei=Ningyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ZhangJianbo en-aut-sei=Zhang en-aut-mei=Jianbo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WangYuzhu en-aut-sei=Wang en-aut-mei=Yuzhu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IshiiTakayuki en-aut-sei=Ishii en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=State Key Laboratory of Precision Geodesy, University of Science and Technology of China kn-affil= affil-num=2 en-affil=State Key Laboratory of Precision Geodesy, University of Science and Technology of China kn-affil= affil-num=3 en-affil=State Key Laboratory of Precision Geodesy, University of Science and Technology of China kn-affil= affil-num=4 en-affil=State Key Laboratory of Precision Geodesy, University of Science and Technology of China kn-affil= affil-num=5 en-affil=State Key Laboratory of Precision Geodesy, University of Science and Technology of China kn-affil= affil-num=6 en-affil=Center for High Pressure Science and Technology Advanced Research kn-affil= affil-num=7 en-affil=Shanghai Advanced Research Institute, Chinese Academy of Sciences kn-affil= affil-num=8 en-affil=Institute for Planetary Materials, Okayama University kn-affil= en-keyword=spin transition kn-keyword=spin transition en-keyword=δ-(Al,Fe)OOH kn-keyword=δ-(Al,Fe)OOH en-keyword=seismic heterogeneities kn-keyword=seismic heterogeneities en-keyword=deep water cycle kn-keyword=deep water cycle en-keyword=high temperature and high pressure kn-keyword=high temperature and high pressure END start-ver=1.4 cd-journal=joma no-vol=53 cd-vols= no-issue=3 article-no= start-page=e2025GL118991 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260129 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Sound Velocities of FeO‐Bearing Ringwoodite and Majorite: Implication for Martian Mantle Seismic Profiles en-subtitle= kn-subtitle= en-abstract= kn-abstract=Compressional and shear wave velocities (Vp, Vs) of candidate Martian deep-mantle minerals, FeO-rich ringwoodite ((Mg0.66Fe0.34)2SiO4) and majorite (Mg0.75Fe0.10Al0.26Ca0.07Si0.84O3), were measured up to 25 GPa and 700 K using Brillouin light scattering coupled with externally-heated diamond anvil cells. Thermoelastic modeling of our results and literature data along a representative areotherm showed that Vp and Vs of FeO-bearing ringwoodite are approximately 7.5% and 11.0% higher than that of the majorite. Our results reveal that velocity profiles of these Martian deep-mantle minerals are more sensitive to variations in the ringwoodite/majorite (Mg/Si) ratio than to thermal and FeO chemical perturbations. Our best-fit velocity model to a recent seismic model by Samuel et al. (2023, https://doi.org/10.1038/s41586-023-06601-8) indicates the Martian mantle contains approximately 67 vol.% ringwoodite and 33 vol.% majorite, suggesting a ringwoodite-rich aggregate in the Martian lowermost solid mantle. The ringwoodite-majorite mantle likely co-evolved with the FeO and other incompatible elements in the molten silicate layer above the Martian core-mantle boundary. en-copyright= kn-copyright= en-aut-name=LiLuo en-aut-sei=Li en-aut-mei=Luo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IshiiTakayuki en-aut-sei=Ishii en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=RyuYoung Jay en-aut-sei=Ryu en-aut-mei=Young Jay kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZhangDongzhou en-aut-sei=Zhang en-aut-mei=Dongzhou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=CharitonStella en-aut-sei=Chariton en-aut-mei=Stella kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=PrakapenkaVitali B. en-aut-sei=Prakapenka en-aut-mei=Vitali B. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=LinJung‐Fu en-aut-sei=Lin en-aut-mei=Jung‐Fu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Earth and Planetary Sciences, Jackson School of Geosciences, The University of Texas at Austin kn-affil= affil-num=2 en-affil=Institute for Planetary Materials, Okayama University kn-affil= affil-num=3 en-affil=GeoSoilEnviroCARS, University of Chicago kn-affil= affil-num=4 en-affil=GeoSoilEnviroCARS, University of Chicago kn-affil= affil-num=5 en-affil=GeoSoilEnviroCARS, University of Chicago kn-affil= affil-num=6 en-affil=GeoSoilEnviroCARS, University of Chicago kn-affil= affil-num=7 en-affil=Department of Earth and Planetary Sciences, Jackson School of Geosciences, The University of Texas at Austin kn-affil= en-keyword=sound velocity kn-keyword=sound velocity en-keyword=ringwoodite kn-keyword=ringwoodite en-keyword=majorite kn-keyword=majorite en-keyword=Martian mantle kn-keyword=Martian mantle en-keyword=FeO-rich kn-keyword=FeO-rich END start-ver=1.4 cd-journal=joma no-vol=53 cd-vols= no-issue=2 article-no= start-page=18 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260524 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=High-pressure spectroscopic investigation of ε-FeOOH: toward a better understanding of pressure-induced hydrogen-bond symmetrization en-subtitle= kn-subtitle= en-abstract= kn-abstract=High-pressure spectroscopic measurements of ε-FeOOH were conducted up to ~ 65 GPa at room temperature in diamond anvil cells. The pressure evolution of the Raman vibrational modes confirms that a hydrogen-bond-symmetrization-induced phase transition from P21nm to Pnnm occurs at ~ 18 GPa. Infrared (IR) spectroscopic measurements suggest that the Pnnm phase has a disordered hydrogen state, and no spectroscopic evidence for fully centered hydrogen bonds is observed within the investigated pressure range. Above ~ 45 GPa, Fe3+ in ε-FeOOH undergoes a high-spin to low-spin transition as indicated by a reduction of the unit cell volume, together with reductions in IR transmitted and Raman signals. These results demonstrate that ε‑FeOOH preserves a disordered hydrogen‑bond configuration up to at least 45 GPa, whereas δ-AlOOH transforms to a centered hydrogen-bond configuration at ~ 18 GPa. This compositional contrast suggests that Fe‑bearing oxyhydroxides follow a distinct evolution of hydrogen bonding under compression, providing insight into hydrogen behavior in deep Earth materials. en-copyright= kn-copyright= en-aut-name=MashinoIzumi en-aut-sei=Mashino en-aut-mei=Izumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamashitaShigeru en-aut-sei=Yamashita en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshinoTakashi en-aut-sei=Yoshino en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Institute for Planetary Materials, Okayama University kn-affil= affil-num=2 en-affil=Institute for Planetary Materials, Okayama University kn-affil= affil-num=3 en-affil=Institute for Planetary Materials, Okayama University kn-affil= en-keyword=ε-FeOOH kn-keyword=ε-FeOOH en-keyword=High pressure kn-keyword=High pressure en-keyword=Spin transition kn-keyword=Spin transition en-keyword=Hydrogen bond symmetrization kn-keyword=Hydrogen bond symmetrization END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=TGF-β1誘導性関節リウマチ滑膜線維芽細胞の増殖におけるADAM12の関与 kn-title=Involvement of ADAM12 in TGF-β1-induced cell proliferation of rheumatoid arthritis synovial fibroblasts en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=LINDETING en-aut-sei=LIN en-aut-mei=DETING kn-aut-name=林德婷 kn-aut-sei=林 kn-aut-mei=德婷 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=シングルセルおよび空間トランスクリプトミクスによる肺多形癌の病態解明 kn-title=Single-cell and spatial transcriptomic characterization of pulmonary pleomorphic carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=MATSUOKAAtsushi en-aut-sei=MATSUOKA en-aut-mei=Atsushi kn-aut-name=松岡篤志 kn-aut-sei=松岡 kn-aut-mei=篤志 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=アスコクロリン誘導体はIL-9産生CD8T細胞を誘導する kn-title=Induction of IL-9-producing CD8+ T cells by ascochlorin derivatives en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=IMANONatsumi en-aut-sei=IMANO en-aut-mei=Natsumi kn-aut-name=今野なつみ kn-aut-sei=今野 kn-aut-mei=なつみ aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=ニューロフィブロマトーシスタイプ1（NF1）遺伝子によってコードされるニューロフィブロミンは、SPRED2の膜移行を促進し、それによって乳がん細胞のERK経路を阻害する kn-title=Neurofibromin Encoded by the Neurofibromatosis Type 1 (NF1) Gene Promotes the Membrane Translocation of SPRED2, Thereby Inhibiting the ERK Pathway in Breast Cancer Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NANG THEE SU PWINT en-aut-sei=NANG THEE SU PWINT en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=CAR-T細胞療法後の骨髄微小環境の破壊と持続的な炎症は遷延性血球減少と関連する kn-title=Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T-cell therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=KITAMURAWataru en-aut-sei=KITAMURA en-aut-mei=Wataru kn-aut-name=北村亘 kn-aut-sei=北村 kn-aut-mei=亘 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=骨骼筋再生における筋衞星細胞TRPV2の役割 kn-title=TRPV2 in muscle satellite cells is crucial for skeletal muscle remodelling　 en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=CHENYANZHU en-aut-sei=CHEN en-aut-mei=YANZHU kn-aut-name=陈彦竹 kn-aut-sei=陈 kn-aut-mei=彦竹 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=膠芽腫組織内の不均一性を標的とした薬剤併用療法は治療効果を改善する kn-title=Dual molecular therapy targeting tumor cell heterogeneity improves therapeutic efficacy in glioblastoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=HIRANOShuichiro en-aut-sei=HIRANO en-aut-mei=Shuichiro kn-aut-name=平野秀一郎 kn-aut-sei=平野 kn-aut-mei=秀一郎 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=断食ー再摂食の繰り返しは腫瘍血管の正常化を促し、再摂食時にVCAM-1上昇を介してメトホルミン誘導性CXCR6⁺ CD8⁺T細胞の浸潤を促進する kn-title=Repetitive Fasting-Refeeding Enhances Metformin-Induced CXCR6⁺ CD8⁺T Cell Tumor Infiltration via VCAM-1 Upregulation on Normalized Vasculature During Refeeding en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=ZHAOWEIYANG en-aut-sei=ZHAO en-aut-mei=WEIYANG kn-aut-name=赵维洋 kn-aut-sei=赵 kn-aut-mei=维洋 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=デュアルオキシダーゼによって産生される活性酸素種は、コオロギの脚再生過程において細胞増殖と血球細胞の遊走を調節する kn-title=ROS produced by Dual oxidase regulate cell proliferation and haemocyte migration during leg regeneration in the cricket en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=OKUMURAMisa en-aut-sei=OKUMURA en-aut-mei=Misa kn-aut-name=奥村美紗 kn-aut-sei=奥村 kn-aut-mei=美紗 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=p53搭載腫瘍溶解アデノウイルスは、マクロピノサイトーシスを介して膵癌関連膵星細胞にアポトーシスを誘導する　 kn-title=p53-armed oncolytic adenovirus induces apoptosis in pancreatic cancer-associated stellate cells via macropinocytosis en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NISHIYAMATakeyoshi en-aut-sei=NISHIYAMA en-aut-mei=Takeyoshi kn-aut-name=西山岳芳 kn-aut-sei=西山 kn-aut-mei=岳芳 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=非小細胞肺癌に伴う骨転移患者における骨関連事象予測のためのリスク層別化の検討 kn-title=Risk Stratification for the Prediction of Skeletal-Related Events in Patients With Bone Metastases From Non-small Cell Lung Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=SAKAMOTOYoshihiro en-aut-sei=SAKAMOTO en-aut-mei=Yoshihiro kn-aut-name=坂本吉宏 kn-aut-sei=坂本 kn-aut-mei=吉宏 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=GD2を発現する高リスクヒト神経芽腫細胞を標的とした近赤外線光線免疫療法 kn-title=Near-infrared Photoimmunotherapy Targeting High-risk Human Neuroblastoma Cells Expressing GD2 en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NOSOHiroshi en-aut-sei=NOSO en-aut-mei=Hiroshi kn-aut-name=納所洋 kn-aut-sei=納所 kn-aut-mei=洋 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=ラット褐色細胞腫細胞株PC1２におけるバンデタニブのカテコールアミン合成阻害作用 kn-title=Inhibitory Effects of Vandetanib on Catecholamine Synthesis in Rat Pheochromocytoma PC12 Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=ITOYoshihiko en-aut-sei=ITO en-aut-mei=Yoshihiko kn-aut-name=伊藤慶彦 kn-aut-sei=伊藤 kn-aut-mei=慶彦 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=ヒト歯肉線維芽細胞との共培養における機械的伸展刺激がヒトiPS細胞由来心筋細胞の成熟に対する影響 kn-title=Effect of mechanical stretching stimulation on maturation of human iPS cell-derived cardiomyocytes co-cultured with human gingival fibroblasts en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=WANGMENGXUE en-aut-sei=WANG en-aut-mei=MENGXUE kn-aut-name=王梦雪 kn-aut-sei=王 kn-aut-mei=梦雪 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=腫瘍融解ウイルスによるp53活性化は抗腫瘍免疫応答の促進によって大腸癌におけるp53導入樹状細胞ワクチンの効果を増強する kn-title=Oncolytic virus-mediated p53 activation boosts the antitumor immunity of a p53-transduced dendritic cell vaccine en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=YAMADAMotohiko en-aut-sei=YAMADA en-aut-mei=Motohiko kn-aut-name=山田元彦 kn-aut-sei=山田 kn-aut-mei=元彦 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=膵癌患者における術前後のゲノム情報に基づく予後層別化 kn-title=Precise stratification of prognosis in pancreatic ductal adenocarcinoma patients based on pre- and postoperative genomic information en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=MIYAMOTOKokichi en-aut-sei=MIYAMOTO en-aut-mei=Kokichi kn-aut-name=宮本耕吉 kn-aut-sei=宮本 kn-aut-mei=耕吉 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=形質細胞骨髄腫におけるCD56発現の診断的有用性と頻度 kn-title=The diagnostic utility and frequency of CD56 expression in plasma cell myeloma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=IMAIMidori en-aut-sei=IMAI en-aut-mei=Midori kn-aut-name=今井みどり kn-aut-sei=今井 kn-aut-mei=みどり aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Health Sciences, Okayama University kn-affil=岡山大学大学院保健学研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=腫瘍周囲組織が腫瘍関連マクロファージの集簇と分化に与える影響について kn-title=Effect of Oral Peritumoral Tissue on Infiltration and Differentiation of Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=PIAOTIANYAN en-aut-sei=PIAO en-aut-mei=TIANYAN kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=CXCR4阻害は、口腔扁平上皮癌において増殖中の血管を選択的に標的化し腫瘍壊死を誘導する kn-title=CXCR4 Inhibition Induces Tumor Necrosis by Selectively Targeting the Proliferating Blood Vessels in Oral Squamous Cell Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=SOEYAMIN en-aut-sei=SOE en-aut-mei=YAMIN kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol=25 cd-vols= no-issue= article-no= start-page=e70031 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=TFAM-Mediated mtDNA Replication is Essential for Developmental Competence of In Vitro Grown Oocytes en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose
Mitochondria are essential for oocyte maturation and early embryonic development, supplying ATP and maintaining mitochondrial DNA (mtDNA) integrity. During oogenesis, mtDNA undergoes dramatic amplification, but the mechanisms and functional significance of this process remain unclear. The purpose of this study was to elucidate the role of mitochondrial transcription factor A (TFAM) in mouse oocytes using an in vitro growth (IVG) system.
Methods
Oocytes at different growth stages were analyzed for mtDNA copy number and expression of mitochondrial biogenesis genes. To assess TFAM function, siRNA targeting Tfam was microinjected into secondary follicles, which were then cultured for 12 days under IVG conditions. Following culture, oocyte growth, mtDNA content, mitochondrial membrane potential, and developmental competence after in vitro fertilization (IVF) were evaluated.
Results
mtDNA copy number increased nonlinearly during oocyte growth, with a pronounced rise at the secondary follicle stage accompanied by TFAM upregulation. TFAM knockdown reduced mtDNA copy number and mitochondrial function without affecting oocyte size or meiotic maturation, but significantly decreased blastocyst formation and total cell numbers per blastocyst.
Conclusions
TFAM-mediated mtDNA replication is crucial for mitochondrial function and developmental competence of IVG-derived oocytes, underscoring its importance in early embryonic development. en-copyright= kn-copyright= en-aut-name=DoSon Quang en-aut-sei=Do en-aut-mei=Son Quang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TasakiHidetaka en-aut-sei=Tasaki en-aut-mei=Hidetaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FunahashiHiroaki en-aut-sei=Funahashi en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WakaiTakuya en-aut-sei=Wakai en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Animal Science, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Department of Animal Science, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Department of Animal Science, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Department of Animal Science, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=in vitro growth kn-keyword=in vitro growth en-keyword=mitochondrial biogenesis kn-keyword=mitochondrial biogenesis en-keyword=mtDNA kn-keyword=mtDNA en-keyword=oogenesis kn-keyword=oogenesis en-keyword=TFAM kn-keyword=TFAM END start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue=1 article-no= start-page=105 end-page=119 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Programmable synthesis of alkaloidal frameworks integrating Michael acceptor generates covalent probes for targeting POLE3 in HBV replication en-subtitle= kn-subtitle= en-abstract= kn-abstract=The growing need for effective HBV treatments and lead compounds with novel mechanisms prompted us to explore synthetic strategies for generating skeletally diverse alkaloidal Michael acceptors. Our approach uniquely embeds Michael acceptors directly within multicyclic alkaloid-inspired frameworks, exploiting the azepinoindole scaffold—a privileged structure in indole alkaloids. A single-step assembly between the versatile intermediate 13 with methyl propiolate 14 or its derivatives enabled the rapid and divergent synthesis of six alkaloidal Michael acceptors (15–20). This strategy facilitated systematic diversification of three-dimensional functional group arrangements and precise tuning of the electronic and steric properties of the embedded α,β-unsaturated carbonyl moieties. The optimal hit 15 inhibited hepatitis B surface antigen (HBsAg) production with an IC50 of 2.48 μM and significantly reduced levels of covalently closed circular DNA (cccDNA), the master template of HBV. Unlike existing nucleoside/nucleotide-based anti-HBV drugs that primarily inhibit reverse transcription, the alkaloidal Michael acceptor 15 suppressed both cccDNA and relaxed circular DNA (rcDNA) levels, suggesting a potential pathway toward a functional HBV cure. Our study also streamlined the target identification by leveraging the covalent binding properties of the Michael acceptors and the operational simplicity of biotin- or fluorescent-tag attachment via a pre-installed alkyne moiety. Competitive pull-down experiments identified several potential target proteins, involving DNA polymerase epsilon subunit 3 (POLE3). Notably, the alkaloidal Michael acceptor 15 was demonstrated to covalently modify Cys51 in POLE3, providing new insights into virus–host interactions and opening novel avenues for targeted anti-HBV therapies. This approach represents a significant advance beyond traditional screening methods and underscores the potential of skeletally diverse alkaloidal Michael acceptors in antiviral drug development. en-copyright= kn-copyright= en-aut-name=KanekoNobuto en-aut-sei=Kaneko en-aut-mei=Nobuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HimenoMisao en-aut-sei=Himeno en-aut-mei=Misao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KobayashiYuhi en-aut-sei=Kobayashi en-aut-mei=Yuhi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanifujiRyo en-aut-sei=Tanifuji en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KubotaHiroki en-aut-sei=Kubota en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MizoguchiHaruki en-aut-sei=Mizoguchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MuroiMakoto en-aut-sei=Muroi en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SuzukiTakehiro en-aut-sei=Suzuki en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SugiyamaMasaya en-aut-sei=Sugiyama en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=DohmaeNaoshi en-aut-sei=Dohmae en-aut-mei=Naoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OsadaHiroyuki en-aut-sei=Osada en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KidoTaketomo en-aut-sei=Kido en-aut-mei=Taketomo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MiyajimaAtsushi en-aut-sei=Miyajima en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OguriHiroki en-aut-sei=Oguri en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= affil-num=2 en-affil=Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=3 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= affil-num=4 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= affil-num=5 en-affil=Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology kn-affil= affil-num=6 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=8 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=9 en-affil=Department of Viral Pathogenesis and Control, National Institute of Global Health and Medicine, Japan Institute for Health Security kn-affil= affil-num=10 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=11 en-affil=Centre for Sustainable Resource Science, RIKEN kn-affil= affil-num=12 en-affil=Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo kn-affil= affil-num=13 en-affil=Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo kn-affil= affil-num=14 en-affil=Department of Chemistry, Graduate School of Science, The University of Tokyo kn-affil= END start-ver=1.4 cd-journal=joma no-vol=373 cd-vols= no-issue= article-no= start-page=fnag055 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Intercellular signal transduction within the mother cell compartment during Bacillus subtilis sporulation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Intercellular signaling contributes to the spatiotemporal regulation of gene expression during sporulation in Bacillus subtilis. The mother cell transcription factor σE is initially produced as an inactive precursor protein pro-σE and activated by the processing enzyme SpoIIGA in response to the forespore-produced putative signaling molecule SpoIIR. However, the mechanism underlying the SpoIIR-mediated signal transduction remains poorly understood. In this study, we showed that the spoIIR-positive, spoIIGA-deleted strain was able to induce SpoIIGA-dependent pro-σE processing in co-cultured spoIIR-deleted, spoIIGA-positive strains. This signaling was dependent on SpoIIR expression and did not involve DNA transfer. Extracellular materials including secreted proteins and membrane vesicles were unlikely to be involved in this signaling pathway. Interestingly, cessation of co-incubation shaking enhanced the signaling, while the addition of membrane-solubilizing detergent abolished it. In addition, SpoIIR signaling did not necessitate release from the forespore membrane or extracellular translocation. A SpoIIR variant lacking the putative signal peptide-like hydrophobic domain produced solely in the mother cell compartment was still able to activate pro-σE. Overall, the study findings suggested that the forespore-produced SpoIIR is neither secreted nor externally translocated. Instead, SpoIIR appeared to be transferred into the mother cell compartment and interacts with the SpoIIGA cytoplasmic domain to trigger pro-σE processing. en-copyright= kn-copyright= en-aut-name=KuwabaraNobuki en-aut-sei=Kuwabara en-aut-mei=Nobuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AnzueMasato en-aut-sei=Anzue en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MiyoshiShin-ichi en-aut-sei=Miyoshi en-aut-mei=Shin-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SatoTsutomu en-aut-sei=Sato en-aut-mei=Tsutomu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ImamuraDaisuke en-aut-sei=Imamura en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Frontier Bioscience, Hosei University kn-affil= affil-num=2 en-affil=Department of Frontier Bioscience, Hosei University kn-affil= affil-num=3 en-affil=Research Center for Intestinal Health Science, Okayama University kn-affil= affil-num=4 en-affil=Department of Frontier Bioscience, Hosei University kn-affil= affil-num=5 en-affil=Research Center for Intestinal Health Science, Okayama University kn-affil= en-keyword=Bacillus subtilis kn-keyword=Bacillus subtilis en-keyword=sporulation kn-keyword=sporulation en-keyword=sigma cascade kn-keyword=sigma cascade en-keyword=intercellular signal transduction kn-keyword=intercellular signal transduction END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260519 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Incidence of B-cell Malignancies in Patients with Lung Cancer Receiving PD-1 Blockade Therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose: Many patients with various cancer types have received immune checkpoint inhibitors (ICI) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some cases of B-cell lymphoma occurring during PD-1 blockade therapy as such unexpected complications. In this study, we aimed to evaluate the incidence of hematologic malignancies in patients with lung cancer receiving PD-1 blockade therapy and to elucidate the mechanisms underlying the progression of these malignancies.
Experimental Design: We performed IHC staining on the clinical samples from patients with B-cell lymphoma that developed during PD-1 blockade therapy and analyzed large-scale real-world datasets. We further investigated the underlying mechanisms through in vitro and in vivo experiments.
Results: A higher incidence of B-cell malignancies has been observed in patients with lung cancer treated with PD-1 blockade therapies based on large-scale real-world data analyses (n = 15,670). The identified lymphomas had a large amount of CD4+ T follicular helper (TFH) cell infiltration. In addition, PD-1 blockade activated PD-1+ TFH cells, which promoted lymphoma proliferation via the IL4/IL4R, IL21/IL21R, and CD40L/CD40 axes. Notably, the lymphomas exhibited high expression of IL4R, IL21R, and CD40.
Conclusions: Our findings highlight the need for careful monitoring and consideration of the potential B-cell malignancy complications in clinical settings in which ICIs are used. en-copyright= kn-copyright= en-aut-name=NinomiyaToshifumi en-aut-sei=Ninomiya en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FangCaiyang en-aut-sei=Fang en-aut-mei=Caiyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HamanoHirofumi en-aut-sei=Hamano en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MorinagaTeruya en-aut-sei=Morinaga en-aut-mei=Teruya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZhouWenhao en-aut-sei=Zhou en-aut-mei=Wenhao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KoyamaToshihiro en-aut-sei=Koyama en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MikiSakura en-aut-sei=Miki en-aut-mei=Sakura kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ZhuLi en-aut-sei=Zhu en-aut-mei=Li kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NaoiYusuke en-aut-sei=Naoi en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KatsutaTomoya en-aut-sei=Katsuta en-aut-mei=Tomoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MorizaneShin en-aut-sei=Morizane en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=Ohki-IkedaTomoka en-aut-sei=Ohki-Ikeda en-aut-mei=Tomoka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NishiTatsuya en-aut-sei=Nishi en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=UedaYouki en-aut-sei=Ueda en-aut-mei=Youki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=IshinoTakamasa en-aut-sei=Ishino en-aut-mei=Takamasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=OkamotoIsamu en-aut-sei=Okamoto en-aut-mei=Isamu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=ZamamiYoshito en-aut-sei=Zamami en-aut-mei=Yoshito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=NagasakiJoji en-aut-sei=Nagasaki en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pharmacy, Okayama University Hospital, Okayama University kn-affil= affil-num=4 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pharmaceutical Data Science, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=11 en-affil=Department of Respiratory Medicine, Ehime Prefectural Central Hospital kn-affil= affil-num=12 en-affil=Department of Respiratory Medicine, Okayama University Hospital, Okayama University kn-affil= affil-num=13 en-affil=Department of Dermatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=14 en-affil=Department of Pathology, Okayama University Hospital, Okayama University kn-affil= affil-num=15 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=16 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=17 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=18 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=19 en-affil=Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=20 en-affil=Department of Pharmacy, Okayama University Hospital, Okayama University kn-affil= affil-num=21 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=22 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=1 article-no= start-page=48 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260327 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Adverse events of romidepsin versus tucidinostat for peripheral T-cell lymphoma: a pharmacovigilance study using the Japanese adverse drug event report database en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphomas with poor prognosis, particularly in patients with relapsed or refractory (R/R) disease. Romidepsin and tucidinostat are histone deacetylase inhibitors used to treat R/R PTCL. No head-to-head post-marketing surveillance studies have compared adverse events (AEs) between the two agents. In this brief report, the AE profiles of romidepsin and tucidinostat were compared using the Japanese Adverse Drug Event Report (JADER) database to facilitate their differentiation and promote the management of AEs.
Methods We conducted a descriptive analysis using data from the JADER database from April 2018 to July 2025. The reported AEs for romidepsin and tucidinostat were extracted and classified according to preferred terms (PTs) and system organ classes (SOCs). Reporting odds ratios with 95% confidence intervals were calculated to compare the AE profiles between the groups.
Results In total, 998,397 reports were analysed for all drugs, including 323 for romidepsin and 753 for tucidinostat. Compared with all drugs, both agents showed significant disproportionality signals in four SOCs: Blood and lymphatic system disorders; General disorders and administration site conditions; Investigations; and Neoplasms benign, malignant and unspecified. Romidepsin exhibited additional significant signals in six SOCs: Cardiac disorders, Eye disorders, Gastrointestinal disorders, Immune system disorders, Infections and infestations, and Metabolism and nutrition disorders. Direct comparison between the two agents revealed broader AE profiles for romidepsin, with AEs more frequently reported in eight SOCs, whereas tucidinostat showed AEs in only two SOCs. Romidepsin was associated with AEs more frequently reported in several PTs, including atrial fibrillation and gastrointestinal toxicities, such as constipation, tumour lysis syndrome, hepatotoxicity, and peripheral neuropathy, which was consistent with the results at the SOC level. In contrast, several significant PTs for tucidinostat were observed in General disorders and administration site conditions and Investigations.
Conclusions The Japanese real-world pharmacovigilance analysis showed differences in the AE profiles between romidepsin and tucidinostat. These differences in safety profiles may be useful for treatment selection and AE management in routine clinical practice among patients with R/R PTCL. Further studies are warranted to confirm these findings and better characterise the safety profiles of these agents. en-copyright= kn-copyright= en-aut-name=TakatsuNao en-aut-sei=Takatsu en-aut-mei=Nao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsumotoJun en-aut-sei=Matsumoto en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OkaYurie en-aut-sei=Oka en-aut-mei=Yurie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakaiTomonori en-aut-sei=Sakai en-aut-mei=Tomonori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IwataNaohiro en-aut-sei=Iwata en-aut-mei=Naohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HigashionnaTsukasa en-aut-sei=Higashionna en-aut-mei=Tsukasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakedaTatsuaki en-aut-sei=Takeda en-aut-mei=Tatsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HamanoHirofumi en-aut-sei=Hamano en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ZamamiYoshito en-aut-sei=Zamami en-aut-mei=Yoshito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Clinical Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Clinical Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Romidepsin kn-keyword=Romidepsin en-keyword=Tucidinostat kn-keyword=Tucidinostat en-keyword=Adverse event kn-keyword=Adverse event en-keyword=JADER kn-keyword=JADER en-keyword=Pharmacovigilance kn-keyword=Pharmacovigilance END start-ver=1.4 cd-journal=joma no-vol=209 cd-vols= no-issue= article-no= start-page=117914 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202608 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=PPy-coated wire actuators for micromechanostimulation of cells – identification of immediate-early responsive mechanoregulatory genes in osteoblasts en-subtitle= kn-subtitle= en-abstract= kn-abstract=Mechanotransduction, i.e., the conversion of mechanical cues into biochemical signals, is essential for bone development, remodeling, and adaptation. Although mechanical loading is known to regulate osteoblast function and bone homeostasis, dissecting the early and sustained mechanotransductive responses at the microscale remains challenging due to limitations of existing in vitro models. Here, we report the development and application of a mechanostimulation system comprising a polypyrrole (PPy)-based wire actuator that expands and contracts (4 μm in radius) upon electrical actuation and enables precise, localized micromechanical stimulation of a small number of cells within standard culture formats. Using this system, we applied short-term (30 min) cyclic (Cyc30) or static (Stat30), as well as prolonged (120 min) cyclic (Cyc120) stimulations to two osteoblast-like cells (MC3T3-E1 or KUSA-A1). Subsequent transcriptomic profiling and computational network analyses revealed that Cyc30 was not capable of inducing significant changes in mRNA expression, suggesting cellular adaptation to short-term cyclic loading. In contrast, Stat30 induced the upregulation of Fos, Btg2, Egr1, and Fosl1, all known genes associated with mechanotransduction, supporting the validity and reproducibility of our experimental mechanostimulation system. Notably, two long non-coding RNAs (B930036N10Rik and 5430431A17Rik) were identified for the first time as being upregulated in response to Stat30 stimuli. Among the differentially expressed genes (DEGs) upregulated by Cyc120 stimuli, Hmox1, a stress-inducible enzyme known for its roles in maintaining cellular homeostasis and promoting survival, was the only DEG repeatedly observed across the Cyc30/Cyc120 and Stat30/Cyc120 comparisons in both cell types, potentially emerging as a key stress-response gene under prolonged mechanical loading. Collectively, these results establish the PPy-based microactuator as a powerful tool for microscale mechanobiology, and provide molecular insight into immediate-early responsive transcriptional programs underlying osteoblastic mechanoadaptation conserved across different cell types. en-copyright= kn-copyright= en-aut-name=ChenJiamin en-aut-sei=Chen en-aut-mei=Jiamin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Ortega-SantosAmaia B. en-aut-sei=Ortega-Santos en-aut-mei=Amaia B. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HayanoSatoru en-aut-sei=Hayano en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MartinezJose G. en-aut-sei=Martinez en-aut-mei=Jose G. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HaraEmilio Satoshi en-aut-sei=Hara en-aut-mei=Emilio Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=JagerEdwin W.H. en-aut-sei=Jager en-aut-mei=Edwin W.H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Physics, Chemistry and Biology (IFM), Linköping University kn-affil= affil-num=3 en-affil=Department of Orthodontics, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Physics, Chemistry and Biology (IFM), Linköping University kn-affil= affil-num=6 en-affil=Department of Advanced International and Information Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Physics, Chemistry and Biology (IFM), Linköping University kn-affil= affil-num=8 en-affil=Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Mechanotransduction kn-keyword=Mechanotransduction en-keyword=Mechanostimulation kn-keyword=Mechanostimulation en-keyword=Osteoblasts kn-keyword=Osteoblasts en-keyword=Polypyrrole kn-keyword=Polypyrrole END start-ver=1.4 cd-journal=joma no-vol=185 cd-vols= no-issue=6 article-no= start-page=391 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260513 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Drug-induced sarcoidosis-like reaction following IL-4/IL-13 receptor blockade by dupilumab en-subtitle= kn-subtitle= en-abstract= kn-abstract=The purpose of the study is to review reported cases of dupilumab-associated drug-induced sarcoidosis-like reaction (DISR) and consider possible immunologic mechanisms. This short review aims to raise awareness of dupilumab-associated DISR and discuss safety considerations in pediatric patients.
Conclusion: Dupilumab is a human monoclonal antibody that reduces inflammation driven by T helper 2 (Th2) cells and is used to treat type 2 inflammatory disorders, including atopic dermatitis. The most common adverse reactions during the first year of treatment are local reactions at the injection site, conjunctivitis, and headache. Although DISR is rare, it has been documented in dupilumab-treated patients. We hypothesized that dupilumab shifts the Th1/Th2 equilibrium toward Th1 and granulomatous inflammation, which may present as DISR. We identified and reviewed 10 recently reported DISR cases and observed that reported features of DISR—including uveitis, optic neuritis and meningoencephalitis, bilateral hilar lymphadenopathy, and histopathologically noncaseating granulomas—can mimic systemic sarcoidosis. Discontinuation of dupilumab resulted in favorable outcomes in most reported DISR cases; however, symptoms worsened in some cases and sequelae became a concern. Case reports of DISR have so far been limited to adults or adolescents, but awareness of potential adverse effects of dupilumab remains important in pediatric patients. en-copyright= kn-copyright= en-aut-name=YasuiKozo en-aut-sei=Yasui en-aut-mei=Kozo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YashiroMasato en-aut-sei=Yashiro en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Pediatrics, Dentistry and Pharmaceutical Science, Okayama University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Okayama University Hospital Center for Innovative Clinical Medicine kn-affil= en-keyword=Dupilumab kn-keyword=Dupilumab en-keyword=Sarcoidosis kn-keyword=Sarcoidosis en-keyword=IL-4 kn-keyword=IL-4 en-keyword=IL-13 kn-keyword=IL-13 en-keyword=Th1-Th2 balance kn-keyword=Th1-Th2 balance END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260429 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=CDPKs as Ca2+ signaling decoders in guard cell signaling en-subtitle= kn-subtitle= en-abstract= kn-abstract=Stomatal movements are essential for balancing photosynthetic carbon dioxide uptake with water conservation and defense against pathogens. These processes are controlled by complex signaling networks in guard cells, in which calcium ions (Ca2+) act as a ubiquitous second messenger. Although stimulus-specific Ca2+ signatures have been well documented, how these signals are decoded into distinct physiological responses remains a central question in plant biology. Increasing evidence highlights calcium-dependent protein kinases (CDPKs) as key signal decoders in guard cell signaling. This mini-review summarizes recent advances in our understanding of how CDPKs perceive and translate Ca2+ fluctuations into stomatal responses. We focus on the roles of CDPKs in signaling pathways triggered by diverse stimuli, including phytohormones such as abscisic acid ABA, jasmonates, and salicylic acid, as well as biotic cues such as microbe- or pathogen-associated molecular patterns (MAMPs/PAMPs) and pathogen infection. We also discuss how gaseous signals and metabolic cues are integrated into CDPK-mediated pathways. In addition to their established role as downstream decoders of Ca2+ signals, emerging studies suggest that CDPKs can act upstream of Ca2+ oscillations and may also function through Ca2+-independent mechanisms. Together, these findings highlight the context-dependent and integrative roles of CDPKs in regulating stomatal behavior, contributing to plant fitness under fluctuating environmental conditions. en-copyright= kn-copyright= en-aut-name=MoriIzumi C. en-aut-sei=Mori en-aut-mei=Izumi C. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=Ca2+ signaling kn-keyword=Ca2+ signaling en-keyword=CDPK kn-keyword=CDPK en-keyword=Signal decoding kn-keyword=Signal decoding en-keyword=Stomata kn-keyword=Stomata END start-ver=1.4 cd-journal=joma no-vol=63 cd-vols= no-issue= article-no= start-page=2026010 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Supplementation of 5-Aminolevulinic Acid Suppressed Body Weight Loss and Reduced Disease Severity During Eimeria tenella Infection in Broiler Chickens en-subtitle= kn-subtitle= en-abstract= kn-abstract=This study aimed to evaluate the effects of 5-aminolevulinic acid (5-ALA) supplementation in broiler chickens infected with Eimeria tenella. To assess these effects, chickens supplemented with 20 ppm 5-ALA (5-ALA group) were compared with non-supplemented controls (control group). Sporulated E. tenella oocysts (2.0 × 103 oocysts per animal) were administered orally to 2-week-old broiler chickens. Body weight was measured weekly, and fecal samples were collected daily from 4 to 15 days post-infection (dpi). Fecal oocyst shedding was quantified using the sucrose flotation method. Cecal tissues were collected at 5 dpi for histopathological analysis and lesion scoring. The animals in the 5-ALA group exhibited significantly greater weight gain and milder clinical signs than those in the control group. Fecal oocyst shedding was highest at 7 dpi in both groups; however, the 5-ALA group exhibited significantly lower oocyst output than the control group. The total number of fecal oocysts shed during the acute infection period was significantly lower in the 5-ALA group than in the control group. Histopathological analysis revealed that although both groups exhibited epithelial hyperplasia and E. tenella schizonts in the cecal submucosa, inflammatory cell infiltration, cecal tissue damage, and histological lesion scores were significantly lower in the 5-ALA group than in the control group. These results suggest that 5-ALA supplementation may mitigate the clinical, parasitological, and histological effects of E. tenella infection in broiler chickens. en-copyright= kn-copyright= en-aut-name=HanifTaqi Ahmad en-aut-sei=Hanif en-aut-mei=Taqi Ahmad kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsubayashiMakoto en-aut-sei=Matsubayashi en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HatabuToshimitsu en-aut-sei=Hatabu en-aut-mei=Toshimitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Laboratory of Animal Physiology, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Department of Veterinary Science, Graduate School of Veterinary Sciences, Osaka Metropolitan University kn-affil= affil-num=3 en-affil=Laboratory of Animal Physiology, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=5-aminolevulinic acid kn-keyword=5-aminolevulinic acid en-keyword=avian coccidiosis kn-keyword=avian coccidiosis en-keyword=broilers kn-keyword=broilers END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=5 article-no= start-page=e71853 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260427 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Multi-Transcriptomic Analysis Reveals That EREG-Driven TME Crosstalk Defines Anti-EGFR Response in Colorectal Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sidedness influences colorectal cancer (CRC) prognosis and treatment response, yet the mechanism dictating differential EGFR inhibitor (EGFRI) sensitivity is unclear. This study investigated the tumor microenvironment (TME) in relation to EGFRI eligibility―clinically defined by factors such as tumor sidedness (e.g., left-sided), RAS/BRAF wild-type status, and microsatellite stability (MSS)―using integrated single-cell RNA sequencing (scRNA-seq), with bulk RNA-seq and spatial transcriptomics validation. We found cancer cell features reflected EGFRI eligibility more strongly than sidedness. EGFRI eligible tumors exhibited high Epiregulin (EREG) expression by cancer cells. Cell interaction analysis revealed a specific “EREG/EGFR/CSF axis” in EGFRI eligible CRC: EREG derived from cancer cell stimulates EGFR-expressing non-myCAF subtypes of cancer-associated fibroblasts (CAFs), which signal via CSF to M1/M2-like Tumor-Associated Macrophages/Monocytes (TAM/TAMo), potentially promoting M2 polarization. Spatial analysis confirmed the proximity of these interacting cell populations and localized EGFR pathway activation near cancer cells specifically in eligible tumors. This study provides a TME-centric view of EGFRI eligibility, identifying a key intercellular communication network driving differential responses. These findings suggest TME features could offer more precise patient stratification than sidedness alone, potentially improving CRC therapeutic strategies. en-copyright= kn-copyright= en-aut-name=TaniguchiAtsuki en-aut-sei=Taniguchi en-aut-mei=Atsuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NogiShohei en-aut-sei=Nogi en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YagiTomohiko en-aut-sei=Yagi en-aut-mei=Tomohiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KanayaNobuhiko en-aut-sei=Kanaya en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KikuchiSatoru en-aut-sei=Kikuchi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KakiuchiYoshihiko en-aut-sei=Kakiuchi en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=cell–cell interaction kn-keyword=cell–cell interaction en-keyword=colorectal cancer kn-keyword=colorectal cancer en-keyword=EGFR inhibitor eligibility kn-keyword=EGFR inhibitor eligibility en-keyword=Epiregulin (EREG) kn-keyword=Epiregulin (EREG) en-keyword=tumor microenvironment kn-keyword=tumor microenvironment END start-ver=1.4 cd-journal=joma no-vol=29 cd-vols= no-issue=5 article-no= start-page=115667 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202605 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Wnt3-mediated fibrosis and carcinogenesis of lung squamous cell carcinoma in idiopathic pulmonary fibrosis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Idiopathic pulmonary fibrosis (IPF) increases the risk of lung squamous cell carcinoma (LUSC), yet its molecular pathogenesis remains unclear. We conducted multi-omics analysis, including single-cell RNA sequencing and digital spatial profiling, on LUSC specimens from seven patients with usual interstitial pneumonia (UIP). In UIP lung tissue, metaplastic basal cells arising from the transdifferentiation of alveolar type 2 (AT2) cells were increased. LUSC tumors arising within UIP exhibited molecular profiles and trajectory dynamics suggesting derivation from these metaplastic basal cells. Both UIP-affected tissue and associated tumors showed activation of Wnt signaling, particularly WNT3 expression. Additionally, enrichment of the nuclear factor erythroid 2-related factor 2 (NRF2)-linked antioxidant response was observed in LUSC within UIP. Targeting Wnt/β-catenin signaling restored the sensitivity of these stress-adapted cancer cell lines to oxidative damage. These findings suggest that LUSC within UIP originates from AT2-derived metaplastic basal cells and involves aberrant Wnt3 activation, linking fibrosis to carcinogenesis and highlighting a potential therapeutic strategy. en-copyright= kn-copyright= en-aut-name=MatsuokaAtsushi en-aut-sei=Matsuoka en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShienKazuhiko en-aut-sei=Shien en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TomidaShuta en-aut-sei=Tomida en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OhkiMasayoshi en-aut-sei=Ohki en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TorigoeHidejiro en-aut-sei=Torigoe en-aut-mei=Hidejiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HisamatsuKazuya en-aut-sei=Hisamatsu en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FujiwaraRyota en-aut-sei=Fujiwara en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IshimuraKosei en-aut-sei=Ishimura en-aut-mei=Kosei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MoriShunsuke en-aut-sei=Mori en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FujiiRyunosuke en-aut-sei=Fujii en-aut-mei=Ryunosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MimataAsuka en-aut-sei=Mimata en-aut-mei=Asuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OkadaKazuhiro en-aut-sei=Okada en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YoshichikaRyo en-aut-sei=Yoshichika en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YoshikawaMao en-aut-sei=Yoshikawa en-aut-mei=Mao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FukumotoYuma en-aut-sei=Fukumoto en-aut-mei=Yuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=YamamotoHaruchika en-aut-sei=Yamamoto en-aut-mei=Haruchika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=NakajimaKumi en-aut-sei=Nakajima en-aut-mei=Kumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=TanakaShin en-aut-sei=Tanaka en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=SuzawaKen en-aut-sei=Suzawa en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MiyoshiKentaroh en-aut-sei=Miyoshi en-aut-mei=Kentaroh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=OkazakiMikio en-aut-sei=Okazaki en-aut-mei=Mikio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=SugimotoSeiichiro en-aut-sei=Sugimoto en-aut-mei=Seiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=InoueHirofumi en-aut-sei=Inoue en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= affil-num=1 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=18 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=19 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=20 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=21 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=22 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=23 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=24 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=25 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Oncology kn-keyword=Oncology en-keyword=Respiratory medicine kn-keyword=Respiratory medicine en-keyword=Pathology kn-keyword=Pathology en-keyword=Precision medicine kn-keyword=Precision medicine en-keyword=Target identification kn-keyword=Target identification en-keyword=Systems biology kn-keyword=Systems biology en-keyword=Cancer kn-keyword=Cancer en-keyword=Omics kn-keyword=Omics en-keyword=Transcriptomics kn-keyword=Transcriptomics END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260427 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical anatomy of the superior labial branch of infraorbital nerve en-subtitle= kn-subtitle= en-abstract= kn-abstract=The infraorbital nerve (ION), a branch of the maxillary division of the trigeminal nerve, provides sensory innervation to the midface via its terminal divisions. Among these, the superior labial branch (SLb) supplies the upper lip and adjacent mucosa, regions frequently involved in oral, maxillofacial, and cosmetic procedures. Despite its clinical importance, the anatomy of the SLb has received relatively limited attention compared with other ION branches. This review synthesizes current evidence on the SLb’s course, branching patterns, innervation, morphometry, and variations, with emphasis on its relevance to surgical practice. Anatomical studies demonstrate that the SLb is the largest terminal division of the ION, often exhibiting medial and lateral subdivisions that anastomose with neighboring nerves. Its distribution predominantly follows a vertical orientation, supplying both cutaneous and mucosal structures of the upper lip. Variability in origin, branching, and accessory foramina underscores the need for careful surgical planning. Injury to the SLb is a recognized complication of Le Fort I osteotomy, midfacial trauma, and periapical procedures, potentially leading to long-term sensory disturbances. A comprehensive understanding of the SLb enhances intraoperative nerve preservation and may reduce postoperative morbidity, highlighting its significance for clinicians operating in the midfacial region. en-copyright= kn-copyright= en-aut-name=TakakuraHiroaki en-aut-sei=Takakura en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanaiAiri en-aut-sei=Tanai en-aut-mei=Airi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KunisadaYuki en-aut-sei=Kunisada en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KikutaShogo en-aut-sei=Kikuta en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KitagawaNorio en-aut-sei=Kitagawa en-aut-mei=Norio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IbaragiSoichiro en-aut-sei=Ibaragi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HurMi-Sun en-aut-sei=Hur en-aut-mei=Mi-Sun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AslamRizwan en-aut-sei=Aslam en-aut-mei=Rizwan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TubbsR. Shane en-aut-sei=Tubbs en-aut-mei=R. Shane kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IwanagaJoe en-aut-sei=Iwanaga en-aut-mei=Joe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Dental and Oral Medical Center, Kurume University School of Medicine kn-affil= affil-num=5 en-affil=Department of Oral and Maxillofacial Anatomy, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo kn-affil= affil-num=6 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Anatomy, Daegu Catholic University School of Medicine kn-affil= affil-num=8 en-affil=Department of Otolaryngology, Tulane University School of Medicine kn-affil= affil-num=9 en-affil=Department of Neurosurgery, Tulane Center for Clinical Neurosciences, Tulane University School of Medicine kn-affil= affil-num=10 en-affil=Dental and Oral Medical Center, Kurume University School of Medicine kn-affil= en-keyword=Anatomy kn-keyword=Anatomy en-keyword=Cadaver kn-keyword=Cadaver en-keyword=Trigeminal nerve kn-keyword=Trigeminal nerve en-keyword=Oral and maxillofacial kn-keyword=Oral and maxillofacial en-keyword=Histology kn-keyword=Histology END start-ver=1.4 cd-journal=joma no-vol=67 cd-vols= no-issue=2 article-no= start-page=170 end-page=181 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260205 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Development of Linear Interpolation System for SMK Model Parameters Evaluated from Cellular-Scale Simulation (LISMEC) and its application to BNCT dosimetry en-subtitle= kn-subtitle= en-abstract= kn-abstract=Boron neutron capture therapy (BNCT) utilizes high linear energy transfer (LET) α-particles and 7Li ions generated through the 10B(n, α)7Li reaction. Precise dosimetry is essential for maximizing therapeutic efficacy while minimizing normal tissue adverse events, considering the microscopic distribution of 10B and cellular structures. Recently, the photon isoeffective dose (DisoE) has been proposed as a more appropriate metric for BNCT treatment planning and can be evaluated using the stochastic microdosimetric kinetic (SMK) model. However, clinical implementation of the SMK model remains challenging due to the difficulty of evaluating its input parameters, which requires computationally intensive radiation transport simulations at the cellular scale. To address this issue, we developed LISMEC (Linear Interpolation System for Stochastic Microdosimetric Kinetic model parameters Evaluated from Cellular-scale simulation), a rapid estimation framework based on precomputed cellular-scale PHITS (Particle and Heavy Ion Transport code System) simulations covering various cell geometries and boron distributions. By applying a linear interpolation algorithm, LISMEC enables the retrieval of SMK model parameters without the need for computationally intensive cellular-scale simulations. The utility of LISMEC, in conjunction with PHITS, was demonstrated through simulations of various irradiation scenarios in reactor-based BNCT. The results showed that DisoE values ranged from 7.4 to 32.7 Gy, even under a fixed macroscopic 10B concentration of 60 ppm. These findings emphasize the importance of incorporating a microscopic distribution of 10B and cellular structures into BNCT treatment planning. en-copyright= kn-copyright= en-aut-name=ShigehiraTakafumi en-aut-sei=Shigehira en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WatanabeTubasa en-aut-sei=Watanabe en-aut-mei=Tubasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SuzukiMinoru en-aut-sei=Suzuki en-aut-mei=Minoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HirataYuho en-aut-sei=Hirata en-aut-mei=Yuho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OgawaTatsuhiko en-aut-sei=Ogawa en-aut-mei=Tatsuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujimuraAtsushi en-aut-sei=Fujimura en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SakuraiYoshinori en-aut-sei=Sakurai en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SatoTatsuhiko en-aut-sei=Sato en-aut-mei=Tatsuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=2 en-affil=Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=3 en-affil=Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=4 en-affil=Research Group for Radiation Transport Analysis, Nuclear Science and Engineering Center , Japan Atomic Energy Agency (JAEA) kn-affil= affil-num=5 en-affil=Research Group for Radiation Transport Analysis, Nuclear Science and Engineering Center , Japan Atomic Energy Agency (JAEA) kn-affil= affil-num=6 en-affil=Department of Cellular Physiology, Neutron Therapy Research Center, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=8 en-affil=Research Group for Radiation Transport Analysis, Nuclear Science and Engineering Center , Japan Atomic Energy Agency (JAEA) kn-affil= en-keyword=BNCT kn-keyword=BNCT en-keyword=microdosimetry kn-keyword=microdosimetry en-keyword=borondistribution kn-keyword=borondistribution en-keyword=cellmorphology kn-keyword=cellmorphology END start-ver=1.4 cd-journal=joma no-vol=29 cd-vols= no-issue=4 article-no= start-page=115341 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202604 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Human iPSC cardiomyocyte patch transplantation modifies extracellular matrix and fibroblast behavior after myocardial infarction en-subtitle= kn-subtitle= en-abstract= kn-abstract=Myocardial infarction (MI) followed by chronic heart failure is the main cause of mortality of heart diseases. Although reparative cell transplantation therapies with pluripotent stem cell-derived cardiomyocytes (CMs) represent a promising therapeutic strategy, molecular mechanisms of the therapy remain elusive. Here, we show that transplantation of the human induced pluripotent stem cell (hiPSC)-derived CM patch onto the damaged heart after MI increases the ratio of collagen type I against collagen type III to modulate alignment of the collagen fibers at the infarcted zone. As a result, tissue elasticity of the heart is improved, and fibrosis at the remote zone is reduced. Mechanistically, we find that hiPSC-derived CM patches secrete TGF-β1, directly inducing collagen type I production in fibroblasts but not collagen type III. Our results suggest the direct effect of the transplanted CM patch on the cardiac fibroblasts to improve elasticity of the damaged heart, resulting in functional recovery after MI. en-copyright= kn-copyright= en-aut-name=TorigataKosuke en-aut-sei=Torigata en-aut-mei=Kosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsuuraRyohei en-aut-sei=Matsuura en-aut-mei=Ryohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NagatomoFumiya en-aut-sei=Nagatomo en-aut-mei=Fumiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ThihaMoe en-aut-sei=Thiha en-aut-mei=Moe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HikitaTakao en-aut-sei=Hikita en-aut-mei=Takao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IseokaHiroko en-aut-sei=Iseoka en-aut-mei=Hiroko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakagiHiromitsu en-aut-sei=Takagi en-aut-mei=Hiromitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KoshimizuUichi en-aut-sei=Koshimizu en-aut-mei=Uichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SakakimaHiroki en-aut-sei=Sakakima en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=IzumiSatoshi en-aut-sei=Izumi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HatanoAsuka en-aut-sei=Hatano en-aut-mei=Asuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=BraunThomas en-aut-sei=Braun en-aut-mei=Thomas kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SawaYoshiki en-aut-sei=Sawa en-aut-mei=Yoshiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MiyagawaShigeru en-aut-sei=Miyagawa en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NakayamaMasanori en-aut-sei=Nakayama en-aut-mei=Masanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Cuorips Inc. kn-affil= affil-num=2 en-affil=Max Planck Institute for Heart and Lung Research, Laboratory for Cell Polarity and Organogenesis kn-affil= affil-num=3 en-affil=Department of Mechanical Engineering, School of Engineering, The University of Tokyo kn-affil= affil-num=4 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University kn-affil= affil-num=5 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University kn-affil= affil-num=6 en-affil=Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Daiichi Sankyo Co., Ltd. kn-affil= affil-num=8 en-affil=Daiichi Sankyo Co., Ltd. kn-affil= affil-num=9 en-affil=Department of Mechanical Engineering, School of Engineering, The University of Tokyo kn-affil= affil-num=10 en-affil=Department of Mechanical Engineering, School of Engineering, The University of Tokyo kn-affil= affil-num=11 en-affil=Department of Mechanical Engineering, School of Engineering, The University of Tokyo kn-affil= affil-num=12 en-affil=MaxPlanck Institute for Heart and Lung Research, Department of Cardiac Development and Remodeling kn-affil= affil-num=13 en-affil=Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine kn-affil= affil-num=14 en-affil=Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine kn-affil= affil-num=15 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama University kn-affil= en-keyword=cell biology kn-keyword=cell biology en-keyword=fibrosis kn-keyword=fibrosis en-keyword=stem cell research kn-keyword=stem cell research END start-ver=1.4 cd-journal=joma no-vol=34 cd-vols= no-issue=2 article-no= start-page=201180 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202606 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Mitochondrial inhibition enhances the sensitivity of pancreatic ductal adenocarcinoma cells to oncolytic adenovirus en-subtitle= kn-subtitle= en-abstract= kn-abstract=The metabolism of cancer cells is associated with resistance to anticancer therapies. Pancreatic ductal adenocarcinoma (PDAC) cells exhibit glycolytic and non-glycolytic subtypes. Although oncolytic virotherapy is a novel antitumor modality, the relationship between metabolism and virus sensitivity remains unclear. We demonstrated the cytopathic activity of telomerase-specific, replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 against PDAC cells. Here, we show the role of metabolism in the virus sensitivity of PDAC cells. The virus sensitivity of human PDAC cells of glycolytic (MIA PaCa-2, PK-45H) and non-glycolytic (PK-59, Capan-2) subtypes was assessed by evaluating replication, glycolysis, and glutamine metabolism through exposure to hypoxia and glucose deprivation or treatment with the mitochondrial metabolism inhibitor CPI-613. Glycolytic PDAC cells were sensitive, and non-glycolytic cells were resistant to oncolytic adenoviruses, which was improved by hypoxia and glucose deprivation or CPI-613 treatment to induce glycolytic activation. OBP-702-mediated p53 activation modulated glutamine metabolism to promote virus sensitivity. In vivo experiments demonstrated the antitumor efficacy of combination therapy with CPI-613 and OBP-702, and the utility of positron emission tomography/computed tomography metabolic parameters for assessing glycolytic activity. Our results suggest that non-glycolytic PDAC cells are refractory to oncolytic adenoviruses. CPI-613 is a promising reagent for overcoming virotherapy resistance in PDAC tumors. en-copyright= kn-copyright= en-aut-name=ShojiRyohei en-aut-sei=Shoji en-aut-mei=Ryohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishiyamaTakeyoshi en-aut-sei=Nishiyama en-aut-mei=Takeyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KajiwaraYoshinori en-aut-sei=Kajiwara en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YamadaMotohiko en-aut-sei=Yamada en-aut-mei=Motohiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NagaiYasuo en-aut-sei=Nagai en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=InoueHiroaki en-aut-sei=Inoue en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HashimotoNaoyuki en-aut-sei=Hashimoto en-aut-mei=Naoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KikuchiSatoru en-aut-sei=Kikuchi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YoshidaRyuichi en-aut-sei=Yoshida en-aut-mei=Ryuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=UmedaYuzo en-aut-sei=Umeda en-aut-mei=Yuzo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Oncolys BioPharma, Inc. kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=MT: Regular Issue kn-keyword=MT: Regular Issue en-keyword=pancreatic cancer kn-keyword=pancreatic cancer en-keyword=glycolysis kn-keyword=glycolysis en-keyword=oncolytic virotherapy kn-keyword=oncolytic virotherapy en-keyword=CPI-613 kn-keyword=CPI-613 en-keyword=PET/CT kn-keyword=PET/CT END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue=5 article-no= start-page=e00824-24 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250527 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Sodium butyrate inhibits the expression of virulence factors in Vibrio cholerae by targeting ToxT protein en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cholera, a diarrheal disease caused by the gram-negative bacterium Vibrio cholerae, remains a global health threat in developing countries due to its high transmissibility and increased antibiotic resistance. There is a pressing need for alternative strategies, with an emphasis on anti-virulent approaches to alter the outcome of bacterial infections, given the increase in antimicrobial-resistant strains. V. cholerae causes cholera by secreting virulence factors in the intestinal epithelial cells. These virulence factors facilitate bacterial colonization and cholera toxin production during infection. Here, we demonstrate that sodium butyrate (SB), a small molecule, had no effect on bacterial viability but was effective in suppressing the virulence attributes of V. cholerae. The production of cholera toxin (CT) was significantly reduced in a standard V. cholerae El Tor strain and two clinical isolates when grown in the presence of SB. Analysis of mRNA and protein levels further revealed that SB reduced the expression of the ToxT-dependent virulence genes like tcpA and ctxAB. DNA-protein interaction assays, conducted at cellular (ChIP) and in vitro conditions (EMSA), indicated that SB weakens the binding between ToxT and its downstream promoter DNA, likely by blocking DNA binding. Furthermore, the anti-virulence efficacy of SB was confirmed in animal models. These findings suggest that SB could be developed as an anti-virulence agent against V. cholerae, serving as a potential alternative to conventional antibiotics or as an adjunctive therapy to combat cholera. en-copyright= kn-copyright= en-aut-name=KunduSushmita en-aut-sei=Kundu en-aut-mei=Sushmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=DasSuman en-aut-sei=Das en-aut-mei=Suman kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MaitraPriyanka en-aut-sei=Maitra en-aut-mei=Priyanka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HalderProlay en-aut-sei=Halder en-aut-mei=Prolay kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KoleyHemanta en-aut-sei=Koley en-aut-mei=Hemanta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MukhopadhyayAsish K. en-aut-sei=Mukhopadhyay en-aut-mei=Asish K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyoshiShin-ichi en-aut-sei=Miyoshi en-aut-mei=Shin-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=DuttaShanta en-aut-sei=Dutta en-aut-mei=Shanta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ChatterjeeNabendu Sekhar en-aut-sei=Chatterjee en-aut-mei=Nabendu Sekhar kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=BhattacharyaSushmita en-aut-sei=Bhattacharya en-aut-mei=Sushmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=2 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=3 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=4 en-affil=Division of Bacteriology, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=5 en-affil=Division of Bacteriology, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=6 en-affil=Division of Bacteriology, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=7 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Division of Bacteriology, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=9 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= affil-num=10 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections (Formerly ICMR-National Institute of Cholera and Enteric Diseases) kn-affil= en-keyword=sodium butyrate (SB) kn-keyword=sodium butyrate (SB) en-keyword=inhibitor kn-keyword=inhibitor en-keyword=pathogenesis kn-keyword=pathogenesis en-keyword=Vibrio cholerae kn-keyword=Vibrio cholerae en-keyword=ctxAB kn-keyword=ctxAB en-keyword=antimicrobial resistance kn-keyword=antimicrobial resistance en-keyword=toxin-coregulated pilus (TcpA) kn-keyword=toxin-coregulated pilus (TcpA) END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=2 article-no= start-page=75 end-page=83 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202604 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Involvement of ADAM12 in TGF-β1-Induced Proliferation of Rheumatoid Arthritis Synovial Fibroblasts en-subtitle= kn-subtitle= en-abstract= kn-abstract=A disintegrin and metalloproteinase 12 (ADAM12) is known to be involved in chondrocyte proliferation and is upregulated in the synovial tissue of osteoarthritis (OA). However, the underlying mechanisms of ADAM12 on rheumatoid arthritis (RA) synovial cell proliferation remain unknown. Here, we investigated the role of ADAM12 in the proliferation of RA synovial fibroblasts (RASFs). The expression and localization of ADAM12 in RA synovial tissues were examined by immunohistochemistry and compared with OA and healthy control (HC) synovial tissues. The effect of inflammatory cytokines (TNF-α, TGF-β1, and PDGF-BB) on ADAM12 expression in RASFs from RA patients was examined by real-time RT-PCR. The effect of ADAM12 knock-down by ADAM12 siRNA and ADAM12 overexpression on cell proliferation of RASFs were examined by WST-1 assay. ADAM12 was identified predominantly in RA synovial tissue rather than OA and HC synovial tissues. Stimulation with TGF-β1 upregulated the expression of ADAM12 and cell proliferation of RASFs. ADAM12 siRNA suppressed TGF-β1-induced cell proliferation of RASFs, while ADAM12 overexpression promoted the cell proliferation of RASFs. These findings demonstrate that ADAM12 may have a key role in TGF-β1-induced cell proliferation of synovial fibroblasts in patients with RA. en-copyright= kn-copyright= en-aut-name=LinDeting en-aut-sei=Lin en-aut-mei=Deting kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HoritaMasahiro en-aut-sei=Horita en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeMasahito en-aut-sei=Watanabe en-aut-mei=Masahito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HaseiJoe en-aut-sei=Hasei en-aut-mei=Joe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OhtsukiTakashi en-aut-sei=Ohtsuki en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OtsukaNoriaki en-aut-sei=Otsuka en-aut-mei=Noriaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IchikawaChinatsu en-aut-sei=Ichikawa en-aut-mei=Chinatsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShimizuNoriyuki en-aut-sei=Shimizu en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NaniwaShuichi en-aut-sei=Naniwa en-aut-mei=Shuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NishidaKeiichiro en-aut-sei=Nishida en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Orthopaedic Surgery, Faculty of Medical Development Field, Okayama University kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Muscat Orthopaedic Clinic kn-affil= affil-num=4 en-affil=Medical Information and Assistive Technology Development, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Medical Technology, Graduate School of Health Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Division of Chronic Pain Medicine and Division of Comprehensive Rheumatology, Locomotive Pain Center, Faculty of Medical Development Field, Okayama University kn-affil= en-keyword=rheumatoid arthritis kn-keyword=rheumatoid arthritis en-keyword=synovial tissue kn-keyword=synovial tissue en-keyword=TGF-β1 kn-keyword=TGF-β1 en-keyword=ADAM12 kn-keyword=ADAM12 en-keyword=cell proliferation kn-keyword=cell proliferation END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=11550 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260302 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pseudohypoxia induced by iron chelators preserves working memory performance in aged mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pseudohypoxia refers to a physiological condition wherein hypoxia-inducible factor (HIF) is pharmacologically upregulated under normoxia, thereby modulating immune responses. We hypothesized that pseudohypoxia, induced by iron chelators, may similarly potentiate systemic immune responses in aged mice, concurrently triggering neuro-regenerative signaling pathways and enhancing cognitive performance. In this study, aged mice (43–48 weeks old) were orally administered two iron chelators, Super Polyphenol 10 (SP10) or Roxadustat, to induce a pseudohypoxia. An 8-week oral regimen of SP10 and Roxadustat significantly preserved working memory, as assessed by the Y-maze test (YMT). White blood cell counts and hippocampal volume, as assessed by magnetic resonance imaging (MRI), were elevated in the treatment groups relative to controls. Pseudohypoxia induced by SP10 tended to enhance neuro-regenerative signaling, specifically involving the Tau and JNK pathways, and potentially modulated Doublecortin (DCX) expression, although statistical significance was limited by sample size. Importantly, inflammatory markers, such as ionized calcium-binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP), were not elevated by treatment. Collectively, these findings suggest that pseudohypoxia induced by iron chelators preserves working memory performance accompanied by leukocytosis, without concomitant neuroinflammation. en-copyright= kn-copyright= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IwasakiYoshiaki en-aut-sei=Iwasaki en-aut-mei=Yoshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KasaiTomonari en-aut-sei=Kasai en-aut-mei=Tomonari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamashitaToru en-aut-sei=Yamashita en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KomakiShiho en-aut-sei=Komaki en-aut-mei=Shiho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HamadaYusuke en-aut-sei=Hamada en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FujisawaMasayoshi en-aut-sei=Fujisawa en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Health Service Section, Environment Health & Safety Intelligence Department, Okayama University kn-affil= affil-num=3 en-affil=Department of Applied Energy, Graduate School of Engineering, Nagoya University kn-affil= affil-num=4 en-affil=Department of Neurology, Graduate School of Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Hypoxia-inducible factor kn-keyword=Hypoxia-inducible factor en-keyword=Working memory kn-keyword=Working memory en-keyword=Hippocampus kn-keyword=Hippocampus en-keyword=Iron kn-keyword=Iron END start-ver=1.4 cd-journal=joma no-vol=46 cd-vols= no-issue=4 article-no= start-page=1769 end-page=1784 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260327 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=P53-armed Oncolytic Adenovirus Enhances the Efficacy of PD-1 Blockade in Neuroblastoma by Inducing Immunogenic Cell Death en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. Although immunotherapy with immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) has emerged as novel antitumor therapy, high-risk NB tumors are refractory to ICI therapy. Oncolytic virotherapy is expected to potentiate the antitumor immune response by inducing immunogenic cell death (ICD). In the present study, we assessed the therapeutic potential of OBP-301 and OBP-702, telomerase-specific oncolytic adenoviruses, for the induction of ICD and combined effect with PD-1 blockade against NB cells.
Materials and Methods: The cytopathic activity of OBP-301 and OBP-702 was assessed using three human MYCN-amplified NB cell lines (IMR-32, LA-N-5, and NB-1) and a murine non-MYCN-amplified NB cell line (Neuro-2a). Virus-mediated antitumor effect was assessed by analyzing cell viability, secretion of extracellular adenosine triphosphate (ATP) and high-mobility group box protein B1 (HMGB1), apoptosis, autophagy, and PD-L1 levels. A subcutaneous Neuro-2a tumor model was used to evaluate the in vivo antitumor effect of combination therapy with OBP-702 and anti-PD-1 antibody.
Results: OBP-702 exhibited stronger cytopathic activity, inducing ICD with secretion of ATP and HMGB1, compared to OBP-301 in human and murine NB cells. OBP-301 and OBP-702 increased apoptosis, autophagy, and PD-L1 expression in murine NB cells. Moreover, OBP-702 significantly prolonged the survival of tumor-bearing mice compared to monotherapy with PD-1 blockade.
Conclusion: OBP-702 is a promising antitumor strategy to promote the antitumor effect of ICIs by inducing ICD against NB tumors. en-copyright= kn-copyright= en-aut-name=TANIMORIMICHI en-aut-sei=TANI en-aut-mei=MORIMICHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TAZAWAHIROSHI en-aut-sei=TAZAWA en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TANIMOTOTERUTAKA en-aut-sei=TANIMOTO en-aut-mei=TERUTAKA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NOUSOHIROSHI en-aut-sei=NOUSO en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WATANABEHINAKO en-aut-sei=WATANABE en-aut-mei=HINAKO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OYAMATAKANORI en-aut-sei=OYAMA en-aut-mei=TAKANORI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=URATAYASUO en-aut-sei=URATA en-aut-mei=YASUO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KAGAWASHUNSUKE en-aut-sei=KAGAWA en-aut-mei=SHUNSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NODATAKUO en-aut-sei=NODA en-aut-mei=TAKUO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KURODASHINJI en-aut-sei=KURODA en-aut-mei=SHINJI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FUJIWARATOSHIYOSHI en-aut-sei=FUJIWARA en-aut-mei=TOSHIYOSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Oncolys BioPharma, Inc. kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Neuroblastoma kn-keyword=Neuroblastoma en-keyword=oncolytic adenovirus kn-keyword=oncolytic adenovirus en-keyword=p53 kn-keyword=p53 en-keyword=immunogenic cell death kn-keyword=immunogenic cell death en-keyword=PD-1 kn-keyword=PD-1 END start-ver=1.4 cd-journal=joma no-vol=380 cd-vols= no-issue= article-no= start-page=114924 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202604 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Constitutive activation of MC1R in the large-billed crow (Corvus macrorhynchos) and its potential role in black plumage en-subtitle= kn-subtitle= en-abstract= kn-abstract=Melanin-based plumage coloration in birds is largely regulated by the melanocortin 1 receptor (MC1R), a G protein–coupled receptor that promotes eumelanin synthesis via cAMP signaling. In domestic chickens, constitutively activating mutations such as the MC1R^E (E92K) allele cause melanistic phenotypes, demonstrating that persistent MC1R activation can drive generalized darkening. However, to our knowledge, no experimental study has directly demonstrated constitutive MC1R activation in wild birds exhibiting uniformly black plumage. We investigated the sequence and signaling properties of MC1R from the Large-billed Crow (Corvus macrorhynchos), a species with strongly eumelanin-dominant plumage. Crow MC1R exhibited elevated basal cAMP signaling and minimal responsiveness to α-melanocyte-stimulating hormone (α-MSH) in both stable Chinese hamster ovary (CHO-K1) cells and transient CRE-luciferase assays in HEK293T cells, demonstrating ligand-independent activation comparable to that observed in the melanizing chicken MC1R^E (E92K) allele. Comparative sequence analysis identified multiple substitutions conserved across Corvus species. Among these, E12K and E18K were functionally evaluated based on prior associations with melanism in other birds. Although E12K modestly increased basal signaling in chicken MC1R, E18K alone or in combination with E12K did not reproduce crow-level constitutive activity, and reciprocal substitutions in crow MC1R failed to abolish ligand-independent activation. These findings demonstrate that crow MC1R possesses constitutive activity and suggest that this phenotype reflects lineage-specific modifications rather than a single activating substitution. Our results provide experimental evidence that constitutive MC1R activation is a plausible molecular mechanism that may contribute to the black plumage in the Large-billed Crow, although a direct causal relationship remains to be established. en-copyright= kn-copyright= en-aut-name=NakanoSaya en-aut-sei=Nakano en-aut-mei=Saya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TashiroYuichi en-aut-sei=Tashiro en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukuchiHibiki en-aut-sei=Fukuchi en-aut-mei=Hibiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AizawaSayaka en-aut-sei=Aizawa en-aut-mei=Sayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakeuchiSakae en-aut-sei=Takeuchi en-aut-mei=Sakae kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=MC1R kn-keyword=MC1R en-keyword=Constitutive activation kn-keyword=Constitutive activation en-keyword=Ligand-independent signaling kn-keyword=Ligand-independent signaling en-keyword=Melanism kn-keyword=Melanism en-keyword=Plumage coloration kn-keyword=Plumage coloration en-keyword=Corvus macrorhynchos kn-keyword=Corvus macrorhynchos END start-ver=1.4 cd-journal=joma no-vol=29 cd-vols= no-issue=4 article-no= start-page=115137 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202604 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Multifaceted role of POU5F1P1 in regulating its parental stem cell gene, POU5F1 en-subtitle= kn-subtitle= en-abstract= kn-abstract=The human-specific retrogene POU5F1P1 (OCT4-Pseudogene1; OCT4-PG1), derived from stem cell factor POU5F1 (OCT4A), is predicted to encode an OCT4A-like protein; however, its function remains unclear. This study investigated OCT4-PG1 expression, translational control, and its role in endometrial cancer and stem cell regulation. Quantitative analyses revealed that elevated OCT4A, but not OCT4-PG1, expression correlated with clinical risk factors associated with poor prognosis in patients with endometrial cancer. OCT4-PG1 is under strong translational suppression mediated by its untranslated region and does not function as a protein under normal conditions. Instead, it acts as a non-coding RNA that suppresses OCT4A translation. Structural analyses showed that a single amino acid deletion (Gln259) destabilizes the OCT4-PG1 protein, thereby preventing its tumorigenic and transcriptional functions. Nevertheless, OCT4-PG1 forms heterodimers with OCT4A or SOX2, enhancing the regulatory activity of OCT4A. These findings highlight the regulatory role of pseudogenes in cancer and stem cell biology, with implications for therapies targeting OCT4A-related pathways. en-copyright= kn-copyright= en-aut-name=IrieKyohei en-aut-sei=Irie en-aut-mei=Kyohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KosakaMitsuko en-aut-sei=Kosaka en-aut-mei=Mitsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MizunoNobuhiko en-aut-sei=Mizuno en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OmaeRyo en-aut-sei=Omae en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakataniYoshimasa en-aut-sei=Nakatani en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OoSandi Myat Noe en-aut-sei=Oo en-aut-mei=Sandi Myat Noe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MasuyamaHisashi en-aut-sei=Masuyama en-aut-mei=Hisashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawaguchiAyano en-aut-sei=Kawaguchi en-aut-mei=Ayano kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Human Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=2 article-no= start-page=bio062463 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260215 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gap junction-mediated signaling coordinates Rhodopsin coupling for Drosophila color vision en-subtitle= kn-subtitle= en-abstract= kn-abstract=The Drosophila compound eye is composed of approximately 800 ommatidia, and every ommatidium contains eight photoreceptor cells, six outer cells (R1-R6) and two inner cells (R7 and R8), and accessory cells (cone and pigment cells). The expression of rhodopsin genes in R7 and R8 is highly coordinated through an instructive signal from R7 to R8. The activity of the homeodomain protein Defective proventriculus in R1 is also required to transmit this instructive signal, suggesting that cell–cell communication between R7, R1, and R8 is important to generate the pattern of Rh expression in R7/R8 (Rhodopsin coupling). As cell junctions play crucial roles in maintaining the structural and functional integrity of tissues, we tested whether cell junction proteins are involved in the interactions between photoreceptor cells. Here, we demonstrate that gap junction proteins innexin 2 and innexin 7 in accessory cells are necessary for transmitting signals from R7 to R8. In addition, Notch-mediated accessory cell development and Rhodopsin coupling in R7/R8 are highly correlated. Our results provide evidence that functional coupling of two different neurons, R7 and R8, is established through gap junction-mediated signaling from adjacent accessory cells. en-copyright= kn-copyright= en-aut-name=ZhangXuanshuo en-aut-sei=Zhang en-aut-mei=Xuanshuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShinjoRyoki en-aut-sei=Shinjo en-aut-mei=Ryoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KitamataManabu en-aut-sei=Kitamata en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OtsuneShinichi en-aut-sei=Otsune en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakagoshiHideki en-aut-sei=Nakagoshi en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Division of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Division of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Division of Health Science, Advanced Comprehensive Research Organization, Teikyo University kn-affil= affil-num=4 en-affil=Division of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Division of Biological Sciences, Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=Drosophila kn-keyword=Drosophila en-keyword=Eye kn-keyword=Eye en-keyword=Gap junction kn-keyword=Gap junction en-keyword=Innexin kn-keyword=Innexin en-keyword=Opsin kn-keyword=Opsin END start-ver=1.4 cd-journal=joma no-vol=49 cd-vols= no-issue=2 article-no= start-page=364 end-page=370 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260221 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Functional Transport Properties of Human Zinc Transporter 1: Kinetics and pH-Dependency en-subtitle= kn-subtitle= en-abstract= kn-abstract=Intracellular zinc (Zn2+) homeostasis is essential for physiological and pathological processes and is strictly regulated by Zn2+ transporters. Zinc transporter 1 (ZnT1) is a ubiquitously expressed plasma membrane-localized Zn transporter that exports Zn2+ from the cytoplasm to the extracellular space. However, the functional transport properties regarding kinetics and driving forces of ZnT1 remain debatable. In this study, we established a cell-free proteoliposome assay system and demonstrated that ZnT1 transports Zn2+ with high affinity in pH-dependent and pH-independent manners. The Km and Vmax of pH-dependent Zn2+ transport were 0.40 μM and 15.13 nmol/min/mg protein, and those of pH-independent Zn2+ transport were 0.52 μM and 8.88 nmol/min/mg protein (low concentrations of Zn2+), 3.02 μM and 17.59 nmol/min/mg protein (high concentrations of Zn2+), respectively, suggesting biphasic kinetic components of Zn2+ transport. Even without pH gradient formation, ZnT1 exhibits potent Zn2+ transport activity. In pH dependency, Zn2+ transport activity was higher at an inside pH of 6.0 than at 6.5–7.5 for proteoliposomes, despite the same ΔpH of 0.5–1.5. The Zn2+ transport activity decreased at an outside pH of 8.0, despite an increase in ΔpH. Although previous studies have proposed that ZnT1-mediated Zn2+ transport activity is driven by a calcium (Ca2+) gradient and not by a pH gradient, Ca2+ does not enhance Zn2+ transport activity in the presence or absence of a pH gradient. These results strongly suggest that ZnT1 protein transports Zn2+ optimally at a specific pH and exports excess intracellular Zn2+ even without ΔpH. en-copyright= kn-copyright= en-aut-name=YoshiokaYuma en-aut-sei=Yoshioka en-aut-mei=Yuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyajiTakaaki en-aut-sei=Miyaji en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Molecular Membrane Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Molecular Membrane Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=zinc transporter 1 kn-keyword=zinc transporter 1 en-keyword=SLC30A1 kn-keyword=SLC30A1 en-keyword=zinc kn-keyword=zinc en-keyword=pH kn-keyword=pH en-keyword=proteoliposome kn-keyword=proteoliposome END start-ver=1.4 cd-journal=joma no-vol=25 cd-vols= no-issue= article-no= start-page=103265 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202606 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Peptide nanomicelles for NIR light-dependent siRNA delivery en-subtitle= kn-subtitle= en-abstract= kn-abstract=The peptide amphiphile PA8, derived from the GAVILRR peptide, was developed as a carrier for small interfering RNA (siRNA) delivery; however, its RNA interference (RNAi) efficacy was limited owing to predominant endocytotic uptake. In this study, the RNAi efficiency of PA8 nanomicelle/siRNA complexes was enhanced by modifying the nanomicelles with the photosensitizer DY750 and the tumor-homing peptide iRGD. The conjugation of DY750 to the nanomicelles facilitated endosomal escape of the nanomicelle/siRNA complexes, enabling the cytosolic release of siRNA. Additionally, the incorporation of iRGD improved RNAi delivery efficiency in the AsPC-1 pancreatic ductal adenocarcinoma cell line. PA8-DY750-iRGD nanomicelle complexes loaded with siRNA against polo-like kinase 1 (PLK1) achieved an 80% reduction in PLK1 mRNA levels in AsPC-1 cells and a moderate 28% knockdown in NCI-N87 gastric cancer cells. Notably, no RNAi effect was observed in noncancerous 1C3D3 pancreatic cells or HEK293T kidney cells, underscoring the selectivity of this system for AsPC-1 cells. These findings highlight the potential of PA8-DY750-iRGD nanomicelle complexes as a targeted therapeutic platform for specific cancers, particularly pancreatic cancer. en-copyright= kn-copyright= en-aut-name=HakimTaufik Fatwa Nur en-aut-sei=Hakim en-aut-mei=Taufik Fatwa Nur kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KitamatsuMizuki en-aut-sei=Kitamatsu en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FujimotoShoumu en-aut-sei=Fujimoto en-aut-mei=Shoumu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeKazunori en-aut-sei=Watanabe en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OhtsukiTakashi en-aut-sei=Ohtsuki en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Applied Chemistry, Kindai University kn-affil= affil-num=3 en-affil=Department of Applied Chemistry, Kindai University kn-affil= affil-num=4 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=Peptide nanomicelles kn-keyword=Peptide nanomicelles en-keyword=siRNA kn-keyword=siRNA en-keyword=Near infrared light kn-keyword=Near infrared light en-keyword=Targeted delivery kn-keyword=Targeted delivery en-keyword=Photosensitizer kn-keyword=Photosensitizer END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=2 article-no= start-page=831 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260114 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Porphyromonas gingivalis Vesicles Control Osteoclast–Macrophage Lineage Fate en-subtitle= kn-subtitle= en-abstract= kn-abstract=Porphyromonas gingivalis (Pg), a keystone pathogen of chronic periodontitis, releases outer membrane vesicles (OMVs) that act as nanoscale vehicles to disseminate virulence factors within periodontal tissues and systemically beyond the oral cavity. Although Pg-OMVs are increasingly recognized as critical mediators of host–pathogen interactions, their effects on the differentiation and function of monocyte–macrophage/osteoclast lineage cells remain unclear. Here, we examined the impact of Pg-OMVs on the differentiation of RAW264.7 monocyte/macrophage-like cells into osteoclasts (OC) and/or macrophages (MΦ) in the presence of receptor activator of nuclear factor-κB ligand (RANKL). OMVs were isolated from Pg W83 and applied to RANKL-primed RAW264.7 cells using three distinct stimulation schedules: (1) simultaneous treatment with Pg-OMVs and RANKL at Day 0; (2) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 1; and (3) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 3. In all schedules, cells were cultured for 7 days from the initial RANKL exposure. Remarkably, simultaneous exposure to Pg-OMVs and RANKL (Schedule 1) markedly suppressed osteoclastogenesis (OC-genesis) while promoting M1 macrophage polarization. In contrast, delayed Pg-OMV stimulation of RANKL-primed cells (Schedules 2 and 3) significantly enhanced OC-genesis while reducing M1 polarization. These schedule-dependent effects were consistent with altered expression of osteoclastogenic markers, including dc-stamp, oc-stamp, nfatc1, and acp5. Importantly, a monoclonal antibody against OC-STAMP counteracted the Pg-OMV-induced upregulation of OC-genesis in Schedules 2 and 3. Furthermore, levels of Pg-OMV phagocytosis were inversely correlated with osteoclast formation. Finally, co-stimulation with RANKL and Pg-OMVs (Schedule 1) enhanced macrophage migratory capacity, whereas delayed stimulation with Pg-OMVs (Schedules 2 and 3) did not. Collectively, these findings indicate that Pg-OMVs exert stage-specific effects on the OC/MΦ lineage: stimulation at early stages of RANKL priming suppresses OC-genesis and promotes M1 polarization, whereas stimulation at later stages enhances OC-genesis without inducing M1 differentiation. Thus, Pg-OMVs may critically influence the fate of the OC/MΦ unit in periodontal lesions, contributing to disease progression and tissue destruction. en-copyright= kn-copyright= en-aut-name=LeonElizabeth en-aut-sei=Leon en-aut-mei=Elizabeth kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakamuraShin en-aut-sei=Nakamura en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShindoSatoru en-aut-sei=Shindo en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=PastoreMaria Rita en-aut-sei=Pastore en-aut-mei=Maria Rita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KumagaiTomoki en-aut-sei=Kumagai en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HeidariAlireza en-aut-sei=Heidari en-aut-mei=Alireza kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AbdolahiniaElaheh Dalir en-aut-sei=Abdolahinia en-aut-mei=Elaheh Dalir kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UedaTomoya en-aut-sei=Ueda en-aut-mei=Tomoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MemidaTakumi en-aut-sei=Memida en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=Duran-PinedoAna en-aut-sei=Duran-Pinedo en-aut-mei=Ana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=Frias-LopezJorge en-aut-sei=Frias-Lopez en-aut-mei=Jorge kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HanXiaozhe en-aut-sei=Han en-aut-mei=Xiaozhe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=ChenXin en-aut-sei=Chen en-aut-mei=Xin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HuangShengyuan en-aut-sei=Huang en-aut-mei=Shengyuan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=CaoGuoqin en-aut-sei=Cao en-aut-mei=Guoqin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=RuizSunniva en-aut-sei=Ruiz en-aut-mei=Sunniva kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=PotempaJan en-aut-sei=Potempa en-aut-mei=Jan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KawaiToshihisa en-aut-sei=Kawai en-aut-mei=Toshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=2 en-affil=Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=4 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=5 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=6 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=7 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=8 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=9 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=10 en-affil=Department of Oral Biology, College of Dentistry, University of Florida kn-affil= affil-num=11 en-affil=Department of Oral Biology, College of Dentistry, University of Florida kn-affil= affil-num=12 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=13 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=14 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=15 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=16 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=17 en-affil=Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville kn-affil= affil-num=18 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA kn-affil= en-keyword=Porphyromonas gingivalis kn-keyword=Porphyromonas gingivalis en-keyword=outer membrane vesicle kn-keyword=outer membrane vesicle en-keyword=periodontitis pathogenesis kn-keyword=periodontitis pathogenesis en-keyword=macrophage polarization kn-keyword=macrophage polarization en-keyword=osteoclastogenesis kn-keyword=osteoclastogenesis en-keyword=OC/MΦ unit kn-keyword=OC/MΦ unit END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=7 article-no= start-page=3143 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260330 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=CXCR2-Dependent Infiltration of Tumor-Associated Neutrophils Is Linked to Enhanced CD8+ T Cell Effector Function and Reduced Lung Metastasis in 4T1 Breast Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Triple-negative breast cancer (TNBC) is characterized by prominent neutrophil infiltration; however, its significance remains controversial. Here, we investigated the role of neutrophil chemoattractant receptors in TNBC progression and metastasis. In contrast to wild-type (WT), Fpr1−/−, and Fpr2−/− mice, neutrophils were almost completely absent in 4T1 tumors from Cxcr2−/− mice, indicating a dominant role for CXCR2 in the recruitment of tumor-associated neutrophils, leading us to use Cxcr2−/− mice for further studies. Primary tumor growth was comparable between WT and Cxcr2−/− mice, whereas lung metastasis was significantly increased in Cxcr2−/− mice, with reduced expression of inflammatory cytokines, chemokines and cytotoxic molecules, including granzyme B and perforin, in primary tumors and metastatic lungs of Cxcr2−/− mice. In vitro, WT, but not Cxcr2−/−, neutrophils enhanced CD8+ T cell activation, partly via ICAM-1, and directly induced tumor cell death, supporting their anti-tumor function. To assess clinical relevance, transcriptomic data were analyzed. High neutrophil infiltration combined with elevated CXCR2 expression, and to a lesser extent CXCR1 expression, was associated with improved prognosis in patients with basal-like BC that largely overlaps with TNBC. Collectively, these findings suggest that CXCR2-mediated neutrophil recruitment exerts protective, anti-tumor effects and may represent a new prognostic marker for TNBC patients. en-copyright= kn-copyright= en-aut-name=LiTiantian en-aut-sei=Li en-aut-mei=Tiantian kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoshimuraTeizo en-aut-sei=Yoshimura en-aut-mei=Teizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TianMiao en-aut-sei=Tian en-aut-mei=Miao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishidaGakushi en-aut-sei=Nishida en-aut-mei=Gakushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LiChunning en-aut-sei=Li en-aut-mei=Chunning kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujisawaMasayoshi en-aut-sei=Fujisawa en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=breast cancer kn-keyword=breast cancer en-keyword=neutrophils kn-keyword=neutrophils en-keyword=CD8+ T cells kn-keyword=CD8+ T cells en-keyword=chemokines kn-keyword=chemokines en-keyword=chemokine receptors kn-keyword=chemokine receptors en-keyword=tumor microenvironment kn-keyword=tumor microenvironment END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=4 article-no= start-page=760 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260327 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Role of Nitrate-Reducing Bacteria Isolated from Helicobacter pylori-Infected Individuals in Gastric Cancer Development en-subtitle= kn-subtitle= en-abstract= kn-abstract=Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric mucosa, with a global prevalence in humans of approximately 40%. It is likely the cause of 90% of gastric cancer (GC) cases and thus considered the most prominent driver of GC development. However, during gastric mucosal atrophy, other bacteria such as nitrate-reducing bacteria (NRB) also proliferate. In this study, we isolated NRB from patients with gastritis and GC to examine their effects on the epithelial cell cycle and production of various cytokines in monocytic cell lines. Bacterial counts (excluding H. pylori and NRB) increased with the progression of gastric mucosal atrophy and were significantly higher in patients with GC. Gastric epithelial cell lines were stimulated with isolated NRB, and the proportion of cells in each cell cycle was measured. Strains from patients with open-type gastritis progressed more rapidly through cell cycles than those from patients with GC. NRB isolated from gastric cancer had high nitrate-reducing activity. Thus, NRB may contribute to GC progression during H. pylori-induced carcinogenesis. Therefore, evaluating gastric atrophy and microbiota may be important for managing the risk of GC. en-copyright= kn-copyright= en-aut-name=KuwagiSerika en-aut-sei=Kuwagi en-aut-mei=Serika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=GotohKazuyoshi en-aut-sei=Gotoh en-aut-mei=Kazuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KomatsubaraMarina en-aut-sei=Komatsubara en-aut-mei=Marina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TsujiShuma en-aut-sei=Tsuji en-aut-mei=Shuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OkanoueShyoutarou en-aut-sei=Okanoue en-aut-mei=Shyoutarou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OkadaHiroyuki en-aut-sei=Okada en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UchiyamaJumpei en-aut-sei=Uchiyama en-aut-mei=Jumpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=WatanabeAkari en-aut-sei=Watanabe en-aut-mei=Akari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YokotaKenji en-aut-sei=Yokota en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Academic Field of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Himeji Red Cross Hospital kn-affil= affil-num=7 en-affil=Department of Bacteriology, Academic Field of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Oral Health Care and Rehabilitation, Institute of Biomedical Sciences, Graduate School, Tokushima University kn-affil= affil-num=9 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= en-keyword=Helicobacter pylori infection kn-keyword=Helicobacter pylori infection en-keyword=gastric cancer kn-keyword=gastric cancer en-keyword=nitrate-reducing bacteria kn-keyword=nitrate-reducing bacteria en-keyword=gastritis kn-keyword=gastritis END start-ver=1.4 cd-journal=joma no-vol=135 cd-vols= no-issue= article-no= start-page=103134 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202605 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Regulation of brain-specific kinases 1 and 2 (BRSK1/2) by Ca2+/calmodulin en-subtitle= kn-subtitle= en-abstract= kn-abstract=We conducted a genome-wide calmodulin (CaM) interaction screening of 462 GST-fused human protein kinases to identify novel CaM-dependent protein kinases (CaMKs). In addition to known CaMKs, including myosin light chain kinases, CaMK2γ, and death-associated kinase 2, we identified the brain-specific protein kinase 2 (BRSK2, also known as SAD-A) as a novel CaM interactant. Proximity biotinylation and CaM–sepharose chromatography assays revealed that rat BRSK isoforms (BRSK1/2) interact with CaM in a Ca2+-dependent manner in vitro. We found that CaM suppresses the activation-loop phosphorylation of BRSK1 (at Thr189) and BRSK2 (at Thr175) by liver kinase B1 (LKB1), an activating kinase, in a Ca2+-dependent manner (IC50 of ∼7 µM), thereby inhibiting BRSK activation. LKB1-catalyzed phosphorylation of the catalytic domain mutant of BRSK1 (residues 1–294) at Thr189 was suppressed by the addition of Ca2+/CaM, consistent with direct CaM binding of the kinase domain, as well as wild-type BRSK1. We confirmed that the LKB1 activity was not directly suppressed by Ca2+/CaM, supporting the hypothesis that the direct interaction of Ca2+/CaM with the kinase domain blocks the phosphorylation/activation of BRSK1/2 by LKB1. The kinase activity and PP2Cα-catalyzed dephosphorylation of LKB1-phosphorylated BRSK1 were not altered by Ca2+/CaM, although it was demonstrated to bind to Ca2+/CaM like that of unphosphorylated BRSK1. This unrecognized mechanism of BRSK1/2 regulation, involving the direct role of Ca2+/CaM binding, which inhibits phosphorylation/activation by LKB1, may open a new Ca2+ signal transduction pathway in neurons. en-copyright= kn-copyright= en-aut-name=WashidaNaoyuki en-aut-sei=Washida en-aut-mei=Naoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KataokaMoe en-aut-sei=Kataoka en-aut-mei=Moe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=BrunAnna R. en-aut-sei=Brun en-aut-mei=Anna R. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakezakiUryu en-aut-sei=Takezaki en-aut-mei=Uryu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HijikawaKo en-aut-sei=Hijikawa en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YamauchiHaruki en-aut-sei=Yamauchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OhtsukaSatomi en-aut-sei=Ohtsuka en-aut-mei=Satomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MagariMasaki en-aut-sei=Magari en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MorishitaRyo en-aut-sei=Morishita en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TokumitsuHiroshi en-aut-sei=Tokumitsu en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil= kn-affil= affil-num=2 en-affil=Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University kn-affil= affil-num=3 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University kn-affil= affil-num=6 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=9 en-affil=CellFree Sciences Co., Ltd. kn-affil= affil-num=10 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=BRSK1 kn-keyword=BRSK1 en-keyword=BRSK2 kn-keyword=BRSK2 en-keyword=calmodulin kn-keyword=calmodulin en-keyword=LKB1 kn-keyword=LKB1 en-keyword=phosphorylation kn-keyword=phosphorylation en-keyword=Ca2+ kn-keyword=Ca2+ en-keyword=CaM-dependent protein kinase kn-keyword=CaM-dependent protein kinase END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinicopathological and transcriptomic profiles of 101 patients with diffuse large B-cell lymphoma/high-grade B-cell lymphoma with double-hit MYC and BCL2 or BCL6 and triple hit en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aims: Diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBCL) with MYC and BCL2 rearrangements (double-hit lymphoma with BCL2, DHL-BCL2) is a mature aggressive B-cell lymphoma that also includes concurrent triple hit with BCL6 translocation (TH). DHL with MYC and BCL6 (DH-BCL6) can also occur. The differences among these three DLBCL/HGBCL subtypes have not yet been definitively determined.
Methods and Results: This study characterized the clinicopathological features and transcriptomic profiles of a series of 101 cases of DLBCL/HGBCL that were subclassified according to MYC, BCL2 and BCL6 FISH data, including cell-of-origin (COO)-like, molecular high-grade (MHG)-like and double-hit/dark-zone (DHIT/DZsig)-like signatures. DLBCL/HGBCL-DH-BCL2 was characterized by higher HGBCL morphology, CD10 positivity, GCB Hans's, GCB COO and MHG molecular subtype. DLBCL/HGBCL-TH had higher LDH levels and worse overall survival. DLBCL/HGBCL-DH-BCL6 had higher MUM1 expression, non-GCB Hans', ABC/Unclassified COO, non-MHG and low DHIT/DZ signatures. Transcriptomic analysis showed that DLBCL/HGBCL-DH-BCL2 and DLBCL/HGBCL-TH were close but separated from DLBCL/HGBCL-DH-BCL6. Gene set enrichment analysis (GSEA) revealed different levels of enrichment between the subtypes.
Conclusions: DLBCL/HGBCL-DH-BCL6 differs from the DLBCL/HGBCL-DH-BCL2, and the DLBCL/HGBCL-TH is associated with the worst survival. Analysis of all three genes of MYC, BCL2 and BCL6 is recommended in the context of DLBCL/HGBCL diagnosis. en-copyright= kn-copyright= en-aut-name=MiyaokaMasashi en-aut-sei=Miyaoka en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=CarrerasJoaquim en-aut-sei=Carreras en-aut-mei=Joaquim kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KikutiYara Yukie en-aut-sei=Kikuti en-aut-mei=Yara Yukie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IkomaHaruka en-aut-sei=Ikoma en-aut-mei=Haruka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NagaseShunsuke en-aut-sei=Nagase en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ItoAtsushi en-aut-sei=Ito en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OritaMakoto en-aut-sei=Orita en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawadaHiroshi en-aut-sei=Kawada en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SakaiRika en-aut-sei=Sakai en-aut-mei=Rika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SatoYasuharu en-aut-sei=Sato en-aut-mei=Yasuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NishimuraMidori Filiz en-aut-sei=Nishimura en-aut-mei=Midori Filiz kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TsukasakiKunihiro en-aut-sei=Tsukasaki en-aut-mei=Kunihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MomoseShuji en-aut-sei=Momose en-aut-mei=Shuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KameokaYoshihiro en-aut-sei=Kameoka en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=YoshidaMasahiro en-aut-sei=Yoshida en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SatouAkira en-aut-sei=Satou en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KatoSeiichi en-aut-sei=Kato en-aut-mei=Seiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=OishiNaoki en-aut-sei=Oishi en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=SaitoAkio en-aut-sei=Saito en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=SadahiraKen en-aut-sei=Sadahira en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=MasugiYohei en-aut-sei=Masugi en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=NakamuraNaoya en-aut-sei=Nakamura en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=2 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=3 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=4 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=5 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=6 en-affil=Department of Pathology, School of Medicine Tokai University Isehara Japan kn-affil= affil-num=7 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=8 en-affil=Department of Hematology, School of Medicine, Tokai University kn-affil= affil-num=9 en-affil=Department of Medical Oncology, Kanagawa Cancer Center kn-affil= affil-num=10 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=11 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=12 en-affil=Department of Hematology, International Medical Center, Saitama Medical University kn-affil= affil-num=13 en-affil=Department of Pathology, Saitama Medical Center, Saitama Medical University kn-affil= affil-num=14 en-affil=Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine kn-affil= affil-num=15 en-affil=Department of Hematology, Osaka City General Hospital kn-affil= affil-num=16 en-affil=Department of Surgical Pathology, Aichi Medical University Hospital kn-affil= affil-num=17 en-affil=Center for Clinical Pathology, Fujita Health University Hospital kn-affil= affil-num=18 en-affil=Department of Pathology, University of Yamanashi kn-affil= affil-num=19 en-affil=Department of Hematology, NHO Shibukawa Medical Center kn-affil= affil-num=20 en-affil=Division of Hematology, Kawasaki Municipal Kawasaki Hospital kn-affil= affil-num=21 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=22 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= en-keyword=BCL2 kn-keyword=BCL2 en-keyword=BCL6 kn-keyword=BCL6 en-keyword=high-grade B-cell lymphoma kn-keyword=high-grade B-cell lymphoma en-keyword=molecular profile kn-keyword=molecular profile en-keyword=MYC kn-keyword=MYC en-keyword=rearrangements kn-keyword=rearrangements END start-ver=1.4 cd-journal=joma no-vol=75 cd-vols= no-issue=3 article-no= start-page=84 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260225 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A real-world comparison of nivolumab plus cabozantinib and pembrolizumab plus lenvatinib focusing on safety outcomes in metastatic renal cell carcinoma: results from the JK-FOOT consortium en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose Immune checkpoint inhibitor (ICI)-based combination therapy is a standard first-line treatment for metastatic renal cell carcinoma (mRCC), with combinations such as nivolumab plus cabozantinib (Nivo + Cabo) and pembrolizumab plus lenvatinib (Pem + Len) demonstrating favorable oncologic outcomes. However, no direct comparisons between these two regimens have been conducted. This study aimed to compare the safety and oncologic outcomes of Nivo + Cabo and Pem + Len in patients with mRCC.
Methods This retrospective study included 185 patients with mRCC treated with Nivo + Cabo (n = 81) or Pem + Len (n = 104) between January 2018 and June 2025 across multiple institutions. The primary outcome was a comparison of treatment-related adverse events (TrAEs). Oncologic outcomes, including objective response rate (ORR), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were compared using one-to-one propensity score matching.
Results Any-grade TrAEs occurred in 90% of patients in the Nivo + Cabo group and 92% in the Pem + Len group (p = 0.6). Severe TrAEs (grade ≥ 3) were more frequent in the Pem + Len group (44%) than in the Nivo + Cabo group (30%, p = 0.048). Tyrosine kinase inhibitor dose reduction and treatment discontinuation rates were similar between groups. In the matched cohort (Nivo + Cabo: n = 74; Pem + Len: n = 74), ORRs were comparable (66% vs. 71%, p = 0.6). With a median follow-up of 17 months, no significant differences were observed in PFS (p = 0.4), CSS (p = 0.9), or OS (p = 0.5).
Conclusions Nivo + Cabo and Pem + Len demonstrated similar oncologic efficacy as first-line treatments for mRCC. However, Pem + Len was associated with more severe TrAEs. Careful toxicity management and shared decision-making are essential when selecting ICI-based combinations. en-copyright= kn-copyright= en-aut-name=YanagisawaTakafumi en-aut-sei=Yanagisawa en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MoriKeiichiro en-aut-sei=Mori en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KawadaTatsushi en-aut-sei=Kawada en-aut-mei=Tatsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatayamaSatoshi en-aut-sei=Katayama en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TsujinoTakuya en-aut-sei=Tsujino en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MaenosonoRyoichi en-aut-sei=Maenosono en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyodaShingo en-aut-sei=Toyoda en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NukayaTakuhisa en-aut-sei=Nukaya en-aut-mei=Takuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MorinakaHirofumi en-aut-sei=Morinaka en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TamuraKeita en-aut-sei=Tamura en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FukuokayaWataru en-aut-sei=Fukuokaya en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=UrabeFumihiko en-aut-sei=Urabe en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MurakamiMasaya en-aut-sei=Murakami en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=BekkuKensuke en-aut-sei=Bekku en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TakaharaKiyoshi en-aut-sei=Takahara en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=FujitaKazutoshi en-aut-sei=Fujita en-aut-mei=Kazutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AzumaHaruhito en-aut-sei=Azuma en-aut-mei=Haruhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=ArakiMotoo en-aut-sei=Araki en-aut-mei=Motoo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=InamotoTeruo en-aut-sei=Inamoto en-aut-mei=Teruo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KomuraKazumasa en-aut-sei=Komura en-aut-mei=Kazumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KimuraTakahiro en-aut-sei=Kimura en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= affil-num=1 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=2 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=3 en-affil=Department of Urology, Comprehensive Cancer Center, Medical University of Vienna kn-affil= affil-num=4 en-affil=Department of Urology, Comprehensive Cancer Center, Medical University of Vienna kn-affil= affil-num=5 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=6 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=7 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=8 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=9 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=10 en-affil=Department of Urology, Hamamatsu Medical University kn-affil= affil-num=11 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=12 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=13 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=14 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=16 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=17 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=18 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=19 en-affil=Department of Urology, Hamamatsu Medical University kn-affil= affil-num=20 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=21 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= en-keyword=Metastatic renal cell carcinoma kn-keyword=Metastatic renal cell carcinoma en-keyword=Immune checkpoint inhibitor kn-keyword=Immune checkpoint inhibitor en-keyword=Pembrolizumab kn-keyword=Pembrolizumab en-keyword=Lenvatinib kn-keyword=Lenvatinib en-keyword=Nivolumab kn-keyword=Nivolumab en-keyword=Cabozantinib kn-keyword=Cabozantinib END start-ver=1.4 cd-journal=joma no-vol=73 cd-vols= no-issue=3 article-no= start-page=55 end-page=59 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260315 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Low Temperature Formation of Dense Yttria-Stabilized Zirconia Layer Using Hot Isostatic Pressing kn-title=熱間静水圧加圧法を用いたイットリア安定化ジルコニア緻密層の低温形成 en-subtitle= kn-subtitle= en-abstract= kn-abstract=The sintering conditions using hot isostatic press (HIP) of yttria-stabilized zirconia (YSZ) were investigated to obtain a dense YSZ layer at low sintering temperature such as 1000°C for an electrolyte of metal-supported solid oxide fuel cell. It was found that a dense YSZ pellet with relative density of 93% could be obtained under a sintering condition of 1000°C-10 hours with HIP in 195 MPa. On the other hand, in X-ray diffraction analysis of the dense YSZ pellet, peaks of the monoclinic phase were slightly detected in addition to peaks of the cubic phase. From energy dispersive X-ray spectroscopy analysis, a small amount of boron was detected in the dense YSZ pellet. It is considered that the YSZ crystalline phase transformation of cubic to monoclinic phase was occurred by the boron diffusion from the diffusion barrier coating of metal foil capsule used for the HIP. en-copyright= kn-copyright= en-aut-name=MANABEKyohei en-aut-sei=MANABE en-aut-mei=Kyohei kn-aut-name=真鍋享平 kn-aut-sei=真鍋 kn-aut-mei=享平 aut-affil-num=1 ORCID= en-aut-name=ECHIGOMitsuaki en-aut-sei=ECHIGO en-aut-mei=Mitsuaki kn-aut-name=越後満秋 kn-aut-sei=越後 kn-aut-mei=満秋 aut-affil-num=2 ORCID= en-aut-name=KISHIMOTOAkira en-aut-sei=KISHIMOTO en-aut-mei=Akira kn-aut-name=岸本昭 kn-aut-sei=岸本 kn-aut-mei=昭 aut-affil-num=3 ORCID= affil-num=1 en-affil=Osaka Gas Co. Ltd. kn-affil=大阪ガス（株） affil-num=2 en-affil=Osaka Gas Co. Ltd. kn-affil=大阪ガス（株） affil-num=3 en-affil=Institute of Academic and Research, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil=岡山大学学術研究院環境生命自然科学学域 en-keyword=dense yttria-stabilized zirconia kn-keyword=dense yttria-stabilized zirconia en-keyword=hot isostatic press kn-keyword=hot isostatic press en-keyword=low sintering temperature kn-keyword=low sintering temperature en-keyword=electrolyte kn-keyword=electrolyte en-keyword=metal-supported solid oxide fuel cell kn-keyword=metal-supported solid oxide fuel cell END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=35 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260124 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A case of tubulointerstitial nephritis with infiltration of neutrophils and interleukin-17-positive cells associated with Behçet’s disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Behçet’s disease (BD) is a non-infectious inflammatory condition characterized by neutrophilic infiltration. In addition to primary symptoms, including oral and genital ulcers, ocular involvement, and skin lesions, BD can also affect various organs. However, renal involvement, particularly in tubulointerstitial nephritis, has rarely been described. Herein, a rare case of acute tubulointerstitial nephritis in a patient clinically diagnosed with BD is reported. The renal lesion presented with other symptoms of BD and fever, and was considered to be BD-related due to the presence of neutrophilic infiltration and its responsiveness to BD-directed therapy. Alterations in T-helper (Th) 1, Th2, and Th17 cytokine profiles are associated with BD activity. Interleukin (IL)-17 plays a central role in neutrophil activation, and recent studies have demonstrated a strong correlation between IL-17A levels and BD activity. In the present case, elevated serum IL-17A levels and infiltration of IL-17A-positive cells into the renal tissue reflected an active phase of BD and a BD-associated renal lesion. en-copyright= kn-copyright= en-aut-name=UchidaNaruhiko en-aut-sei=Uchida en-aut-mei=Naruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanakaKeiko en-aut-sei=Tanaka en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KubotaNatsuki en-aut-sei=Kubota en-aut-mei=Natsuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatsuyamaTakayuki en-aut-sei=Katsuyama en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TanabeKatsuyuki en-aut-sei=Tanabe en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UchidaHaruhito A. en-aut-sei=Uchida en-aut-mei=Haruhito A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Tubulointerstitial nephritis kn-keyword=Tubulointerstitial nephritis en-keyword=Behçet’s disease kn-keyword=Behçet’s disease en-keyword=Neutrophils kn-keyword=Neutrophils en-keyword=Interleukin-17 kn-keyword=Interleukin-17 en-keyword=T-helper (Th) 1/Th2/Th17 cytokines kn-keyword=T-helper (Th) 1/Th2/Th17 cytokines END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=3 article-no= start-page=e202500639 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=PPy‐Coated Wire Actuators for the Micromechanostimulation of Cells: Fabrication and Characterization en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cellular mechanotransduction signals play a crucial role in physiological and pathological conditions, including skeletal disorders. Although various systems exist to mechanically stimulate cultured cells, most are constrained by incubator incompatibility, limited physiological relevance, nonuniform stimulation, or complexity. The objective of this article is to develop and validate a compact, incubator-compatible tool capable of delivering localized and physiologically relevant mechanical stimulation to small cell populations. Here, we introduce a polypyrrole-based wire-shaped microactuator designed to induce localized mechanical stress to adjacent cells. These wire-shaped microactuators are biocompatible, easy-to-use, and compact for use within standard in vitro cell culture systems. Using a noncontact optical method, we characterize the actuation of polypyrrole-coated wires in an aqueous NaDBS electrolyte, showing radial expansion of 1.5–8 µm depending on the deposited polypyrrole film thickness, comparable to cellular dimensions. Next, the actuation is confirmed to be robust and stable to use in cell culture media at physiological temperature. To evaluate biological relevance, osteoblastic KUSA-A1 cells are mechanically stimulated inside the incubator and transcriptomic changes are assessed. Mechanical stimulation resulted in upregulation of genes previously associated with mechanotransduction, including Fos and Fosb. Additionally, several uncharacterized long noncoding RNAs are differentially expressed, suggesting potential novel players in the mechanotransduction pathway. en-copyright= kn-copyright= en-aut-name=Ortega‐SantosAmaia B. en-aut-sei=Ortega‐Santos en-aut-mei=Amaia B. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HayanoSatoru en-aut-sei=Hayano en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HaraEmilio Satoshi en-aut-sei=Hara en-aut-mei=Emilio Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MartínezJose G. en-aut-sei=Martínez en-aut-mei=Jose G. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=JagerEdwin W. H. en-aut-sei=Jager en-aut-mei=Edwin W. H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Sensor and Actuator Systems, Department of Physics Chemistry and Biology (IFM), Linköping University kn-affil= affil-num=2 en-affil=Department of Orthodontics, Okayama University Hospital kn-affil= affil-num=3 en-affil=Advanced Research Center for Oral and Craniofacial Sciences Dental School, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Sensor and Actuator Systems, Department of Physics Chemistry and Biology (IFM), Linköping University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Sensor and Actuator Systems, Department of Physics Chemistry and Biology (IFM), Linköping University kn-affil= en-keyword=conducting polymers kn-keyword=conducting polymers en-keyword=mechanotransduction kn-keyword=mechanotransduction en-keyword=osteoblasts kn-keyword=osteoblasts en-keyword=polypyrrole kn-keyword=polypyrrole en-keyword=RNA sequencing kn-keyword=RNA sequencing en-keyword=soft-microactuators kn-keyword=soft-microactuators END start-ver=1.4 cd-journal=joma no-vol=2025 cd-vols= no-issue= article-no= start-page=9884345 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251120 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparing the Activity of Peripheral Blood Mononuclear Cells Frozen Under Electromagnetic Field Freezing and Standard Slow-Freezing en-subtitle= kn-subtitle= en-abstract= kn-abstract=Peripheral blood mononuclear cells (PBMCs) are cells obtained from the blood that are used not only in clinical tests but also in various research applications. The slow-freezing (SLF) method, currently the standard for PBMC cryopreservation, involves extended storage at −80°C before transfer to liquid nitrogen. Delays in this transfer, such as overnight or weekend holds, risk a gradual decline in cell viability. Additionally, variability in freezing duration can lead to inconsistent cell quality, emphasizing the need for an alternative freezing method that allows for more timely transfer to liquid nitrogen. This study is aimed at clarifying whether the method of using a freezer with an applied electromagnetic field (EMF) is superior to the currently used standard SLF method for PBMC cryopreservation. A comparison of the number of viable cells, cell viability, and cell activity showed that the EMF method was equivalent to the SLF method. However, the shortest time required for freezing was significantly shorter with the EMF method than the SLF method (0.25 vs. 3 h), allowing for earlier transfer of PBMC to liquid nitrogen. This demonstrates that the EMF method offers an advantage in operational efficiency, particularly for facilities that routinely process and store PBMCs, such as biobanks and other storage-focused departments. en-copyright= kn-copyright= en-aut-name=MatsubaraTakehiro en-aut-sei=Matsubara en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakagiMina en-aut-sei=Takagi en-aut-mei=Mina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UwaboTakahiro en-aut-sei=Uwabo en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SohJunichi en-aut-sei=Soh en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MoritaMizuki en-aut-sei=Morita en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Okayama University Hospital Biobank kn-affil= affil-num=2 en-affil=Faculty of Health Sciences, Okayama University Medical School kn-affil= affil-num=3 en-affil=Department of Biorepository Research and Networking, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Thoracic Surgery, Osaka Metropolitan University Graduate School of Medicine kn-affil= affil-num=5 en-affil=Okayama University Hospital Biobank kn-affil= affil-num=6 en-affil=Okayama University Hospital Biobank kn-affil= END start-ver=1.4 cd-journal=joma no-vol=19 cd-vols= no-issue=2 article-no= start-page=dmm052605 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260201 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A genetic model of congenital intestinal atresia implicates Mypt1 in epithelial organisation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Congenital intestinal atresia (IA) is a birth defect characterised by the absence or closure of part of the intestine. Although genetic factors are implicated, mechanistic understanding has been hindered by the lack of suitable animal models. Here, we describe a medaka (Oryzias latipes) mutant, generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, that develops IA during embryogenesis. Positional cloning identified a nonsense mutation in mypt1, encoding myosin phosphatase target subunit 1. Mutant embryos exhibited ectopic accumulation of F-actin and phosphorylated myosin regulatory light chain (Mrlc) in the intestinal epithelium, consistent with disrupted actomyosin regulation. These cytoskeletal abnormalities were accompanied by epithelial disorganisation, without notable alterations in cell proliferation, motility or apoptosis. Inhibition of myh11a, encoding smooth muscle (SM) myosin heavy chain, ameliorated the IA phenotype, whereas blebbistatin treatment completely rescued the defect, suggesting a non-contractile role prior to SM maturation. Together, these findings demonstrate that mypt1 loss disrupts intestinal morphogenesis through actomyosin dysregulation. Given the recent clinical identification of IA associated with MYPT1 variants, this medaka model offers a valuable platform to investigate the developmental and molecular basis of MYPT1-associated IA in humans. en-copyright= kn-copyright= en-aut-name=KobayashiDaisuke en-aut-sei=Kobayashi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=UrasakiAkihiro en-aut-sei=Urasaki en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KimuraTetsuaki en-aut-sei=Kimura en-aut-mei=Tetsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AnsaiSatoshi en-aut-sei=Ansai en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsuoKazuhiko en-aut-sei=Matsuo en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YokoiHayato en-aut-sei=Yokoi en-aut-mei=Hayato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakashimaShigeo en-aut-sei=Takashima en-aut-mei=Shigeo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KitagawaTadao en-aut-sei=Kitagawa en-aut-mei=Tadao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KageTakahiro en-aut-sei=Kage en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NaritaTakanori en-aut-sei=Narita en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=JindoTomoko en-aut-sei=Jindo en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KinoshitaMasato en-aut-sei=Kinoshita en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=NaruseKiyoshi en-aut-sei=Naruse en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NakajimaYoshiro en-aut-sei=Nakajima en-aut-mei=Yoshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=ShigetaMasaki en-aut-sei=Shigeta en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SakakiShinichiro en-aut-sei=Sakaki en-aut-mei=Shinichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=InoueSatoshi en-aut-sei=Inoue en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SabaRie en-aut-sei=Saba en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=YamadaKei en-aut-sei=Yamada en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=YokoyamaTakahiko en-aut-sei=Yokoyama en-aut-mei=Takahiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=IshikawaYuji en-aut-sei=Ishikawa en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=ArakiKazuo en-aut-sei=Araki en-aut-mei=Kazuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=SagaYumiko en-aut-sei=Saga en-aut-mei=Yumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=TakedaHiroyuki en-aut-sei=Takeda en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=YashiroKenta en-aut-sei=Yashiro en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= affil-num=1 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=2 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=3 en-affil=Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology kn-affil= affil-num=4 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=5 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=6 en-affil=Graduate School of Agricultural Science, Tohoku University kn-affil= affil-num=7 en-affil=Institute for Glyco-core Research (iGCORE)/Life Science Research Centre, Gifu University kn-affil= affil-num=8 en-affil=Program in Environmental Management, Graduate School of Agriculture, Kindai University kn-affil= affil-num=9 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=10 en-affil=Laboratory of Molecular Biology, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University kn-affil= affil-num=11 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=12 en-affil=Department of Applied Biosciences, Graduate School of Agriculture, Kyoto University kn-affil= affil-num=13 en-affil=Laboratory of Bioresources, National Institute for Basic Biology kn-affil= affil-num=14 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=15 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=16 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=17 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=18 en-affil=Department of Radiology, Kyoto Prefectural University of Medicine kn-affil= affil-num=19 en-affil=Department of Radiology, Kyoto Prefectural University of Medicine kn-affil= affil-num=20 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=21 en-affil=Research Centre for Radiation Protection, National Institute of Radiological Sciences kn-affil= affil-num=22 en-affil=Research Center for Aquatic Breeding, National Research Institute of Aquaculture, Fisheries Research Agency kn-affil= affil-num=23 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=24 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=25 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= en-keyword=Intestinal atresia kn-keyword=Intestinal atresia en-keyword=Mypt1 kn-keyword=Mypt1 en-keyword=Disease model kn-keyword=Disease model en-keyword=Actomyosin regulation kn-keyword=Actomyosin regulation en-keyword=Intestinal development kn-keyword=Intestinal development END start-ver=1.4 cd-journal=joma no-vol=68 cd-vols= no-issue=3 article-no= start-page=e70044 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260310 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Simple Method for RNA-Seq of Manually Isolated Chromatophores in Oryzias Fishes en-subtitle= kn-subtitle= en-abstract= kn-abstract=RNA sequencing (RNA-seq) has become an essential tool for analyzing gene expression and exploring cell type–specific transcriptomes. However, sample preparation and quality control remain challenging, as current approaches typically rely on dissecting tissues containing mixed cell populations or using flow cytometry to isolate fluorescently labeled cells. Here we present a simple and reliable method for RNA-seq of chromatophores (pigment cells) by manually isolating cells based on their natural pigmentation. We analyzed four chromatophore types—melanophores, xanthophores, iridophores, and leucophores—in medaka (Oryzias latipes). Remarkably, as few as 100 cells per type yielded reasonably high-quality transcriptomes sufficient to identify differentially expressed genes (DEGs). Furthermore, this method was successfully applied to a non-model medaka species, O. woworae, which shares the same four chromatophore types. Our approach enables efficient, low-cost, and cross-species transcriptome analysis of chromatophores without requiring transgenic markers or flow cytometry. en-copyright= kn-copyright= en-aut-name=GodaMakoto en-aut-sei=Goda en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyagiAsuka en-aut-sei=Miyagi en-aut-mei=Asuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SugiwakaKeisuke en-aut-sei=Sugiwaka en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeMasakatsu en-aut-sei=Watanabe en-aut-mei=Masakatsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=Bessho‐UeharaManabu en-aut-sei=Bessho‐Uehara en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HibiMasahiko en-aut-sei=Hibi en-aut-mei=Masahiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyodaAtsushi en-aut-sei=Toyoda en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanakaRieko en-aut-sei=Tanaka en-aut-mei=Rieko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MasengiKawilarang W. A. en-aut-sei=Masengi en-aut-mei=Kawilarang W. A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YamahiraKazunori en-aut-sei=Yamahira en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AnsaiSatoshi en-aut-sei=Ansai en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HashimotoHisashi en-aut-sei=Hashimoto en-aut-mei=Hisashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Institute of Photonics Medicine, Hamamatsu University School of Medicine kn-affil= affil-num=2 en-affil=Institute of Photonics Medicine, Hamamatsu University School of Medicine kn-affil= affil-num=3 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= affil-num=4 en-affil=Cellular and Structural Physiology Institute (CeSPI) and Graduate School of Pharmaceutical Sciences, Nagoya University kn-affil= affil-num=5 en-affil=Frontier Research Institute for Interdisciplinary Science, Tohoku University kn-affil= affil-num=6 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= affil-num=7 en-affil=Comparative Genomics Laboratory, National Institute of Genetics kn-affil= affil-num=8 en-affil=World Medaka Aquarium, Nagoya Higashiyama Zoo and Botanical Gardens kn-affil= affil-num=9 en-affil=Faculty of Fisheries and Marine Science, Sam Ratulangi University kn-affil= affil-num=10 en-affil=Tropical Biosphere Research Center, University of the Ryukyus kn-affil= affil-num=11 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=12 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=3 article-no= start-page=e72040 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effects of Overload on Imiquimod‐Induced Psoriasis Model Mice: A Basic Experimental Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Aim: Psoriasis is a skin disorder complicated by arthritis and enthesitis. The cytokines interleukin (IL)-17, IL-23, and tumor necrosis factor (TNF)-α are reportedly key effectors of psoriasis. Additionally, gamma delta (γδ) T cells exacerbate inflammation by producing inflammatory cytokines such as IL-17 and TNF-α. However, details regarding the mechanisms linking pathogenesis and mechanical stress remain unclear. This study aimed to investigate the effect of strenuous exercise on the pathology of psoriasis using mouse models of imiquimod (IMQ)-induced psoriasis.
Methods: Twenty mice were randomly assigned to four groups: IMQ − TRED− (control), IMQ − TRED+ (treadmill running mice), IMQ + TRED− group (IMQ treated mice), and IMQ + TRED+ group (IMQ treated and treadmill running mice). The tissue sections from back skin and thymus were immunostained with antibodies against IL-17, IL-23, and γδ T cells. Shoulder sections were stained using hematoxylin and eosin, and Toluidine Blue and Picrosirius Red. Additionally, the shoulder tissue sections were immunostained with antibodies against TNF-α and matrix metalloproteinase (MMP)-13. Serum cytokine level was measured to evaluate systemic inflammation.
Results: Strenuous exercise exacerbated pathological changes associated with psoriasis, including increased γδ T cell infiltration and upregulated IL-17 and IL-23 expression in the skin, as well as enhanced γδ T cell development and IL-17 expression in the thymus. Although strenuous exercise did not further worsen the modified PASI scores, histological and immunological markers of inflammation were significantly enhanced. Serum levels of TNF-α and IL-17 were significantly elevated in IMQ-induced psoriasis model mice. Moreover, pathological changes induced by strenuous exercise were observed in the enthesis, including angiogenesis and upregulated expression of TNF-α and MMP-13.
Conclusion: This study revealed that strenuous exercise exacerbates pathological changes in IMQ-induced psoriasis model mice. en-copyright= kn-copyright= en-aut-name=FurutaniTomoki en-aut-sei=Furutani en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SaitoTaichi en-aut-sei=Saito en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IkedaAsahi en-aut-sei=Ikeda en-aut-mei=Asahi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MashimaKenta en-aut-sei=Mashima en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YukihiroNatsumi en-aut-sei=Yukihiro en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KusakabeSatoki en-aut-sei=Kusakabe en-aut-mei=Satoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakamichiRyo en-aut-sei=Nakamichi en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YoshidaAki en-aut-sei=Yoshida en-aut-mei=Aki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NishidaKeiichiro en-aut-sei=Nishida en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Section of Medicine, Division of Medicine, Dentistry, and Pharmaceutical Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Okayama University Medical School Faculty of Medicine kn-affil= affil-num=4 en-affil=Okayama University Medical School Faculty of Medicine kn-affil= affil-num=5 en-affil=Okayama University Medical School Faculty of Medicine kn-affil= affil-num=6 en-affil=Okayama University Medical School Faculty of Medicine Okayama Japan kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Locomotive Pain Center, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=enthesis kn-keyword=enthesis en-keyword=psoriasis kn-keyword=psoriasis en-keyword=strenuous exercise kn-keyword=strenuous exercise END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=1 article-no= start-page=e70168 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Mechanosensitive Ion Channel PIEZO1 Suppresses BMP2-Induced Ossification of the Annulus Fibrosus Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective: Major cause of low-back pain is intervertebral disc degeneration (IVDD), with mechanical stress playing a crucial role in its progression. A mechanosensitive ion channel, PIEZO1, is involved in various musculoskeletal tissues, but its role in the annulus fibrosus (AF) remains unclear. This study aimed to elucidate the function of PIEZO1 in AF cells under mechanical stimulation.
Methods: Primary rat AF cells were subjected to cyclic tensile strain (CTS) at low (2%) and high (12%) strain levels to investigate strain-dependent effects on osteogenic gene expression. We evaluated the effects of Piezo1, Piezo2, and Trpv4 knockdown by RNA interference to identify the upstream mechanotransducer. Furthermore, PIEZO1 was activated using the agonist Yoda1, followed by RNA-sequencing analysis and evaluation of its effects on BMP2-induced osteogenesis in rat AF cells. We also examined the effects of Yoda1 in primary human AF cells.
Results: Low-strain CTS significantly suppressed osteogenic marker expression, which was not observed with high strain. Piezo1 knockdown reversed this suppression, whereas Piezo2 and Trpv4 had no effect. Piezo1 activation by Yoda1 produced similar anti-osteogenic effects in both rat and human AF cells. RNA sequencing revealed the enrichment of ossification and calcineurin signaling pathways in rat cells. Furthermore, Piezo1 activation inhibited BMP2-induced osteogenesis and nuclear translocation of p-Smad1/5/9.
Conclusions: Piezo1 maintains AF cell homeostasis under mechanical stress by suppressing osteogenic changes via calcineurin-mediated inhibition of BMP signaling, which may represent a novel therapeutic target for IVDD. en-copyright= kn-copyright= en-aut-name=ShitozawaHisakazu en-aut-sei=Shitozawa en-aut-mei=Hisakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakamichiRyo en-aut-sei=Nakamichi en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshidaAki en-aut-sei=Yoshida en-aut-mei=Aki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UedaMasataka en-aut-sei=Ueda en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SaitoTaichi en-aut-sei=Saito en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UotaniKoji en-aut-sei=Uotani en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OdaYoshiaki en-aut-sei=Oda en-aut-mei=Yoshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakatoriRyo en-aut-sei=Takatori en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YamashitaKazutaka en-aut-sei=Yamashita en-aut-mei=Kazutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Orthopaedic Surgery, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=annulus fibrosus kn-keyword=annulus fibrosus en-keyword=calcification kn-keyword=calcification en-keyword=ossification kn-keyword=ossification en-keyword=PIEZO1 kn-keyword=PIEZO1 END start-ver=1.4 cd-journal=joma no-vol=67 cd-vols= no-issue= article-no= start-page=101798 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Alcohol consumption, smoking, and the implications of their cessations for field carcinogenesis in the esophagus: a 10-year prospective cohort study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Alcohol and tobacco are established carcinogens, which promote field carcinogenesis for esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the long-term effects of alcohol and tobacco cessations, and background mucosal status, on risk for metachronous ESCC (mESCC) after endoscopic resection (ER).
Methods This was a multicentre prospective cohort study of patients with intramucosal ESCC treated by ER. All participants received structured education on cessation, and underwent regular endoscopic surveillance. Patients were stratified by Lugol-voiding lesion (LVL) grade (A: none, B: 1–9, C: ≥10). The impacts of alcohol and smoking cessation on field carcinogenesis were assessed.
Findings Among 331 enrolled patients, the median follow-up was 120 months (range: 1.3–176.9). The cumulative incidences of mESCC were 10.4%, 27.2%, and 61.8% in grades A, B, and C, respectively. An increment of 1 unit (22 g ethanol) of alcohol consumption and higher LVL grade independently increased the risk for mESCC. Alcohol or smoking cessation reduced this risk (hazard ratio [HR] 0.52, 95% confidence interval [CI]: 0.31–0.88; HR 0.44, 95% CI: 0.25–0.78, respectively), and combined cessation had the greatest impact (HR 0.21, 95% CI: 0.07–0.65). Complete cessation, rather than partial reduction, was necessary to achieve meaningful risk reduction.
Interpretation Alcohol and tobacco exposure, and a large number of LVL, are major determinants of mESCC. Complete cessation markedly reduces risk, underscoring the importance of behavioural interventions for secondary prevention of field carcinogenesis after ER. en-copyright= kn-copyright= en-aut-name=KatadaChikatoshi en-aut-sei=Katada en-aut-mei=Chikatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YokoyamaTetsuji en-aut-sei=Yokoyama en-aut-mei=Tetsuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YanoTomonori en-aut-sei=Yano en-aut-mei=Tomonori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FurueYasuaki en-aut-sei=Furue en-aut-mei=Yasuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SuzukiHaruhisa en-aut-sei=Suzuki en-aut-mei=Haruhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IshidoKenji en-aut-sei=Ishido en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YamamotoKeiko en-aut-sei=Yamamoto en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakanishiHiroyoshi en-aut-sei=Nakanishi en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KoikeTomoyuki en-aut-sei=Koike en-aut-mei=Tomoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TamaokiMasashi en-aut-sei=Tamaoki en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KawataNoboru en-aut-sei=Kawata en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HiraoMotohiro en-aut-sei=Hirao en-aut-mei=Motohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KawaharaYoshiro en-aut-sei=Kawahara en-aut-mei=Yoshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OgataTakashi en-aut-sei=Ogata en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KatagiriAtsushi en-aut-sei=Katagiri en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=YamanouchiTakenori en-aut-sei=Yamanouchi en-aut-mei=Takenori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KiyokawaHirofumi en-aut-sei=Kiyokawa en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KawakuboHirofumi en-aut-sei=Kawakubo en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KonnoMaki en-aut-sei=Konno en-aut-mei=Maki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=YokoyamaAkira en-aut-sei=Yokoyama en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=OhashiShinya en-aut-sei=Ohashi en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=OmoriTai en-aut-sei=Omori en-aut-mei=Tai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=ShimodaTadakazu en-aut-sei=Shimoda en-aut-mei=Tadakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=OchiaiAtsushi en-aut-sei=Ochiai en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=IshikawaHideki en-aut-sei=Ishikawa en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=YokoyamaAkira en-aut-sei=Yokoyama en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=MutoManabu en-aut-sei=Muto en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= affil-num=1 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Health Promotion, National Institute of Public Health kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East kn-affil= affil-num=4 en-affil=Department of Endoscopy, Saitama Cancer Center kn-affil= affil-num=5 en-affil=Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine kn-affil= affil-num=6 en-affil=Department of Gastroenterology, Kitasato University School of Medicine kn-affil= affil-num=7 en-affil=Division of Endoscopy, Hokkaido University Hospital kn-affil= affil-num=8 en-affil=Department of Gastroenterology, Ishikawa Prefectural Central Hospital kn-affil= affil-num=9 en-affil=Division of Gastroenterology, Tohoku University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Division of Endoscopy, Shizuoka Cancer Center kn-affil= affil-num=12 en-affil=Department of Surgery, NHO Osaka National Hospital kn-affil= affil-num=13 en-affil=Department of Practical Gastrointestinal Endoscopy, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=14 en-affil=Department of Gastrointestinal Surgery, Kanagawa Cancer Center kn-affil= affil-num=15 en-affil=Division of Gastroenterology, Department of Medicine, Showa Medical University Hospital kn-affil= affil-num=16 en-affil=Department of Gastroenterology, Kumamoto Regional Medical Center kn-affil= affil-num=17 en-affil=Department of Gastroenterology, St. Marianna University School of Medicine kn-affil= affil-num=18 en-affil= kn-affil= affil-num=19 en-affil=Department of Gastroenterology, Tochigi Cancer Center kn-affil= affil-num=20 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=21 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=22 en-affil=Department of Surgery, Kawasaki Municipal Kawasaki Hospital kn-affil= affil-num=23 en-affil=Department of Diagnostic Pathology, Shizuoka Cancer Center kn-affil= affil-num=24 en-affil=Exploratory Oncology Research and Clinicai Trial Center, National Cancer Center kn-affil= affil-num=25 en-affil=Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine kn-affil= affil-num=26 en-affil=Clinical Research Unit, National Hospital Organization Kurihama Medical and Addiction Center kn-affil= affil-num=27 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= en-keyword=Esophageal squamous cell carcinoma kn-keyword=Esophageal squamous cell carcinoma en-keyword=Field carcinogenesis kn-keyword=Field carcinogenesis en-keyword=Metachronous cancer kn-keyword=Metachronous cancer en-keyword=Alcohol kn-keyword=Alcohol en-keyword=Tobacco kn-keyword=Tobacco en-keyword=Lugol-voiding lesion kn-keyword=Lugol-voiding lesion END start-ver=1.4 cd-journal=joma no-vol=24 cd-vols= no-issue=1 article-no= start-page=146 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260115 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=MMP-3 cleavage of Lamin A induces pro-migratory nuclear deformity, nucleophagy, and their autophagic secretion with extracellular vesicles in metastatic cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that cleave a plethora of substrates, including components of the extracellular matrix and cell-surface-associated proteins, as well as intracellular targets. MMPs have also been found in extracellular vesicles (EVs), such as exosomes. MMP-3 promotes tumor growth, epithelial-to-mesenchymal transition, genome instability, migration, invasion, and metastasis of cancer cells, and nuclear MMP-3 controls gene transcription. Intranuclear proteolysis by MMPs may significantly alter cancer progression. However, the nuclear substrates of MMP-3 have not been well investigated. In this study, we performed proteomic analyses to identify the nuclear substrates and EV proteins regulated by MMP-3. While rabidly metastatic colon cancer (LuM1) three-dimensionally cultured tumoroids secreted EVs containing 30 protein types, including Lamin A (LMNA), MMP-3, fibronectin (FN1), HSPA8 (Hsc70), β-actin (ACTB), and vimentin (VIM), CRISPR/Cas9-based knockout of MMP-3 reduced the secretion of these proteins in EVs. Notably, EV-bound cleaved Lamin secretion was confirmed by immunoelectron microscopy. Also, MMP-3 formed proteolytic dimers via its hemopexin-like repeat domains in nuclei. Many nuclear MMP-3-binding proteins, including Lamin A/C, histones, topoisomerases, and hnRNPs, were screened by co-immunoprecipitation followed by proteomics. Proteolytic MMP-3 overexpression generated a C-terminal 30-kDa fragment of Lamin A, whose cleavage site was defined via structural analysis. MMP-3 digestion of Lamin A induced nuclear deformity (atypia) required for cell migration in confined space. The cleaved Lamin A and MMP-3 were transported with autophagosomes (LC3B+), nucleophagosomes, and amphisomes (CD63 + LC3B+) and co-secreted with EVs. Proteolytic MMP-3 also induced nuclear speckles of Lamin A, suggesting their roles in transcription and splicing. Clinical analysis revealed that high expressions of MMP3 and LMNA were significantly seen in head and neck squamous cell carcinoma (HNSC) than in the other 16 cancer types, and predicted poor prognosis of patients suffering from HNSC, pancreatic, rectum and lung adenocarcinomas at specific stages. Immunohistochemistry revealed that nuclear MMP-3 and cleaved Lamin were significantly higher expressed in stage IV metastatic HNSC cases than in stage I non-metastatic cases. Taken together, MMP3-cleavage of Lamin A induces nuclear deformity, nucleophagy, and their autophagic co-secretion with EVs in metastatic cancer. Also, high expression of MMP-3 and secretion of Lamin A can predict poor prognosis in multiple cancer types at specific stages. en-copyright= kn-copyright= en-aut-name=EguchiTakanori en-aut-sei=Eguchi en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TahaEman A. en-aut-sei=Taha en-aut-mei=Eman A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakanoKeisuke en-aut-sei=Nakano en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TiwariVikas en-aut-sei=Tiwari en-aut-mei=Vikas kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakebeKatsuki en-aut-sei=Takebe en-aut-mei=Katsuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=InoueTomohiro en-aut-sei=Inoue en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=XingLizi en-aut-sei=Xing en-aut-mei=Lizi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SogawaChiharu en-aut-sei=Sogawa en-aut-mei=Chiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OkamotoKuniaki en-aut-sei=Okamoto en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=CalderwoodStuart K. en-aut-sei=Calderwood en-aut-mei=Stuart K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Biochemistry, Faculty of Science, Ain Shams University kn-affil= affil-num=3 en-affil=Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Council of Scientific & Industrial Research-Indian Institute of Toxicological Research kn-affil= affil-num=5 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Food and Health Sciences, Faculty of Environmental Studies, Hiroshima Institute of Technology kn-affil= affil-num=9 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= en-keyword=Lamin A (LMNA) kn-keyword=Lamin A (LMNA) en-keyword=Matrix metalloprotease (MMP) kn-keyword=Matrix metalloprotease (MMP) en-keyword=Proteolysis kn-keyword=Proteolysis en-keyword=Extracellular vesicle (EV) kn-keyword=Extracellular vesicle (EV) en-keyword=Exosome kn-keyword=Exosome en-keyword=Autophagy kn-keyword=Autophagy en-keyword=Amphisome kn-keyword=Amphisome en-keyword=Proteome kn-keyword=Proteome en-keyword=Nuclear deformity kn-keyword=Nuclear deformity en-keyword=Migration kn-keyword=Migration en-keyword=Metastatic cancer kn-keyword=Metastatic cancer en-keyword=Head and neck squamous cell carcinoma kn-keyword=Head and neck squamous cell carcinoma en-keyword=Colorectal cancer kn-keyword=Colorectal cancer END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=2 article-no= start-page=199 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260128 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Targeting the Gut in Sepsis: Therapeutic Potential of Medical Gases en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, often resulting in multiorgan dysfunction. Among affected systems, the gastrointestinal tract plays a central role in sepsis progression by promoting systemic inflammation through impaired barrier function, immune imbalance, and microbiome alterations. Recent research has identified selected medical gases and gasotransmitters as promising therapeutic candidates for preserving gut integrity in sepsis. In particular, hydrogen, carbon monoxide, and hydrogen sulfide exhibit antioxidative, anti-inflammatory, and cytoprotective properties. These gases act through defined molecular pathways, including activation of Nrf2, inhibition of NF-κB, and preservation of tight junction integrity, thereby supporting intestinal barrier function. In addition, they influence immune cell phenotypes and autophagy, with indirect effects on the gut microbiome. Although most supporting evidence derives from preclinical models, translational findings and emerging safety data highlight the potential of gut-targeted gas-based strategies. This review summarizes current mechanistic and translational evidence for gut-protective medical gases in sepsis and discusses their integration into future organ-specific and mechanism-based therapeutic approaches. en-copyright= kn-copyright= en-aut-name=YumotoTetsuya en-aut-sei=Yumoto en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ObaraTakafumi en-aut-sei=Obara en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NaitoHiromichi en-aut-sei=Naito en-aut-mei=Hiromichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakaoAtsunori en-aut-sei=Nakao en-aut-mei=Atsunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=carbon monoxide kn-keyword=carbon monoxide en-keyword=gastrointestinal tract kn-keyword=gastrointestinal tract en-keyword=gut kn-keyword=gut en-keyword=hydrogen kn-keyword=hydrogen en-keyword=hydrogen sulfide kn-keyword=hydrogen sulfide en-keyword=sepsis kn-keyword=sepsis en-keyword=septic shock kn-keyword=septic shock END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=888 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251215 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=TRPV2 in muscle satellite cells is crucial for skeletal muscle remodelling en-subtitle= kn-subtitle= en-abstract= kn-abstract=Skeletal muscle remodelling relies on muscle stem cells (MuSCs) for regeneration after injury and hypertrophy in response to mechanical loading. However, the mechanisms that trigger MuSC activation and proliferation remain unclear. Transient receptor potential vanilloid 2 (TRPV2) ion channels respond to insulin-like growth factor-1 and mechanical stimuli to regulate the biological characteristics of various cells. Using a temporally inducible MuSC-specific conditional knockout (cKO) mouse, we show that TRPV2 regulates MuSC function and is essential for muscle remodelling. In cultured myofibre, MuSCs express TRPV2 and exhibit Ca2+ responses to the TRPV2 agonists 2-aminoethoxydiphenyl borate and probenecid, which are abolished upon TRPV2 deletion. TRPV2-deficient MuSCs exhibit reduced paired box 7 (Pax7) expression and impaired proliferation, suggesting TRPV2 is a factor that regulates the early stage of MuSC function. Myotube formation in MuSCs was enhanced by overexpression of TRPV2 and suppressed by TRPV2 deficiency, suggesting that TRPV2 is a factor that promotes myogenesis. Muscle-administered cardiotoxin promoted muscle regeneration and resulted in the appearance of numerous Pax7-positive MuSCs between myofibres. MuSC-specific TRPV2 cKO mice exhibit substantially impaired muscle regeneration after cardiotoxin-induced injury, drastically reducing Pax7-positive MuSCs between myofibres. In floxed mice, mechanical loading via synergist ablation induces hypertrophy and greatly increases the number of myonuclei per myofibre. In contrast, MuSC-specific TRPV2 cKO mice show no changes in myofibre thickness or nuclear number, either at baseline or after mechanical loading. Mechanical loading of floxed mice increased TRPV2+/Pax7+ double-positive MuSCs, but MuSC-specific TRPV2 cKO mice showed no change. Additionally, MuSCs exhibit Ca2+ responses to hypo-osmotic stimuli, which are suppressed by TRPV2 inhibitors and TRPV2 deletion, suggesting that MuSCs exhibit TRPV2-dependent mechanical responses. These results establish TRPV2 as a critical regulator of MuSC-mediated muscle remodelling, an important finding that may lead to therapeutic strategies for muscle repair and adaptation. en-copyright= kn-copyright= en-aut-name=ChenYanzhu en-aut-sei=Chen en-aut-mei=Yanzhu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatanosakaKimiaki en-aut-sei=Katanosaka en-aut-mei=Kimiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShibuyaMakoto en-aut-sei=Shibuya en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=DongYubing en-aut-sei=Dong en-aut-mei=Yubing kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZhangLidan en-aut-sei=Zhang en-aut-mei=Lidan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KanagawaMotoi en-aut-sei=Kanagawa en-aut-mei=Motoi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FukadaSo-ichiro en-aut-sei=Fukada en-aut-mei=So-ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NaruseKeiji en-aut-sei=Naruse en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KatanosakaYuki en-aut-sei=Katanosaka en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University kn-affil= affil-num=3 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka kn-affil= affil-num=6 en-affil=Department of Cell Biology and Molecular Medicine, Ehime University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka kn-affil= affil-num=8 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=3303 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260113 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparative efficacy of immune checkpoint inhibitor combination therapies by metastatic site in metastatic renal cell carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Few studies have investigated the efficacy of immuno-oncology (IO) combinations at different metastatic sites in renal cell carcinoma (RCC). We evaluated the differential efficacy of IO–IO and IO–tyrosine kinase inhibitor (TKI) combinations by metastatic site in metastatic RCC (mRCC). This retrospective multicenter study by the JK-FOOT Study Group included 579 patients with intermediate- or poor-risk mRCC (per International Metastatic RCC Database Consortium criteria) treated with first-line IO combinations between September 2018 and December 2024. Metastatic sites were lymph nodes, lungs, bones, liver, brain, and others. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoint was objective response rate. Efficacy was compared between IO–IO and IO–TKI for each site. For lymph node (n = 36), lung (n = 132), or brain (n = 16) metastases, OS or PFS was not significantly different between IO–IO and IO–TKI. In bone metastases (n = 80), OS tended to favor IO–TKI (P = 0.053). In liver metastases (n = 22), OS was significantly longer with IO–TKI (P = 0.011). IO–TKI may be a more appropriate first-line option than IO–IO for mRCC with bone or liver metastases, while efficacy is similar for other sites. en-copyright= kn-copyright= en-aut-name=ToyodaShingo en-aut-sei=Toyoda en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InokiLan en-aut-sei=Inoki en-aut-mei=Lan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HashimotoMamoru en-aut-sei=Hashimoto en-aut-mei=Mamoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FukuokayaWataru en-aut-sei=Fukuokaya en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MoriKeiichiro en-aut-sei=Mori en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NishimuraShingo en-aut-sei=Nishimura en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MaenosonoRyoichi en-aut-sei=Maenosono en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IwataTakehiro en-aut-sei=Iwata en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BekkuKensuke en-aut-sei=Bekku en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NukayaTakuhisa en-aut-sei=Nukaya en-aut-mei=Takuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YanagisawaTakafumi en-aut-sei=Yanagisawa en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TsujinoTakuya en-aut-sei=Tsujino en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KomuraKazumasa en-aut-sei=Komura en-aut-mei=Kazumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TakaharaKiyoshi en-aut-sei=Takahara en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=InamotoTeruo en-aut-sei=Inamoto en-aut-mei=Teruo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=AzumaHaruhito en-aut-sei=Azuma en-aut-mei=Haruhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=FujitaKazutoshi en-aut-sei=Fujita en-aut-mei=Kazutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=JK-FOOT study group en-aut-sei=JK-FOOT study group en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=2 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=3 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=4 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=5 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=6 en-affil=Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=8 en-affil=Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=11 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=12 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=13 en-affil=Department of Urology, Kawasaki University School of Medicine kn-affil= affil-num=14 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=15 en-affil=Department of Urology, Hamamatsu University School of Medicine kn-affil= affil-num=16 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=17 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=18 en-affil= kn-affil= en-keyword=Metastatic renal cell carcinoma kn-keyword=Metastatic renal cell carcinoma en-keyword=Bone metastasis kn-keyword=Bone metastasis en-keyword=liver metastasis kn-keyword=liver metastasis en-keyword=Immuno-oncology kn-keyword=Immuno-oncology END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=RP99825 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250618 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Stimulatory and inhibitory G-protein signaling relays drive cAMP accumulation for timely metamorphosis in the chordate Ciona en-subtitle= kn-subtitle= en-abstract= kn-abstract=Larvae of the ascidian Ciona initiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowing Ciona to maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator of Ciona metamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation. en-copyright= kn-copyright= en-aut-name=HozumiAkiko en-aut-sei=Hozumi en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TotsukaNozomu M en-aut-sei=Totsuka en-aut-mei=Nozomu M kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OnoderaArata en-aut-sei=Onodera en-aut-mei=Arata kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangYanbin en-aut-sei=Wang en-aut-mei=Yanbin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HamadaMayuko en-aut-sei=Hamada en-aut-mei=Mayuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShiraishiAkira en-aut-sei=Shiraishi en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SatakeHonoo en-aut-sei=Satake en-aut-mei=Honoo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HorieTakeo en-aut-sei=Horie en-aut-mei=Takeo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HottaKohji en-aut-sei=Hotta en-aut-mei=Kohji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SasakuraYasunori en-aut-sei=Sasakura en-aut-mei=Yasunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=2 en-affil=Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University kn-affil= affil-num=3 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=4 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=5 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=6 en-affil=Bioorganic Research Institute, Suntory Foundation for Life Sciences kn-affil= affil-num=7 en-affil=Bioorganic Research Institute, Suntory Foundation for Life Sciences kn-affil= affil-num=8 en-affil=Laboratory for Single-cell Neurobiology, Graduate School of Frontier Biosciences, Osaka University kn-affil= affil-num=9 en-affil=Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University kn-affil= affil-num=10 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=1 article-no= start-page=16 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260221 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Hypomyelinating leukodystrophy 15 (HLD15) results from biallelic pathogenic variants in EPRS1, but exonic deletions have not been reported. We describe a 40-year-old woman with mild intellectual disability, ataxia, dystonia, and MRI showing hypomyelination. Whole-exome sequencing identified a heterozygous missense variant in the prolyl-tRNA synthetase domain of EPRS1 (c.3430 C > G; p.Leu1144Val, NM_004446.3), without second variant. Whole-genome sequencing revealed a heterozygous 220-bp deletion spanning exon 15 (c.1743-30_1932del), and segregation analysis confirmed compound heterozygosity. RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele. These findings support loss-of-function for the deletion and classify c.3430 C > G as likely pathogenic under ACMG/AMP criteria (PM1, PM2, PM3, PP3). This case represents the first exonic deletion reported in EPRS1. The relatively mild, adult-onset phenotype broadens both mutational and clinical spectra of HLD15 and highlights the importance of structural-variant anal en-copyright= kn-copyright= en-aut-name=MitsutakeAkihiko en-aut-sei=Mitsutake en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsukawaTakashi en-aut-sei=Matsukawa en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OrimoKenta en-aut-sei=Orimo en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UedaKunihiro en-aut-sei=Ueda en-aut-mei=Kunihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SekiTomonari en-aut-sei=Seki en-aut-mei=Tomonari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShiioYasushi en-aut-sei=Shiio en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MitsuiJun en-aut-sei=Mitsui en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IshiuraHiroyuki en-aut-sei=Ishiura en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MoriHarushi en-aut-sei=Mori en-aut-mei=Harushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TsujiShoji en-aut-sei=Tsuji en-aut-mei=Shoji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TodaTatsushi en-aut-sei=Toda en-aut-mei=Tatsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=2 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=3 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=4 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=5 en-affil=Department of Neurology, Tokyo Teishin Hospital kn-affil= affil-num=6 en-affil=Department of Neurology, Tokyo Teishin Hospital kn-affil= affil-num=7 en-affil=Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=8 en-affil=Department of Neurology, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Radiology, School of Medicine, Jichi Medical University, kn-affil= affil-num=10 en-affil=Institute of Medical Genomics, International University of Health and Welfare kn-affil= affil-num=11 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= en-keyword=Hypomyelinating leukodystrophy kn-keyword=Hypomyelinating leukodystrophy en-keyword=EPRS1 kn-keyword=EPRS1 en-keyword=Structural variant kn-keyword=Structural variant en-keyword=Exon deletion kn-keyword=Exon deletion en-keyword=Nonsense‑mediated decay kn-keyword=Nonsense‑mediated decay en-keyword=Whole‑genome sequencing kn-keyword=Whole‑genome sequencing END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=50 article-no= start-page=e06926 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251031 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Collagen Signaling via DDR1 Exacerbates Barriers to Macromolecular Drug Delivery in a 3D Model of Pancreatic Cancer Fibrosis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Fibrosis is a significant barrier to drug delivery in pancreatic ductal adenocarcinoma (PDAC) and contributes to its dismal prognosis. Pancreatic stellate cells (PSCs) drive fibrosis by excessively secreting extracellular matrix proteins such as collagen I. Collagen I is thought to physically obstruct the delivery of macromolecules, such as albumin, antibodies, and nanomedicines. Apart from its structural role, collagen signals through dedicated cell surface receptors, such as the discoidin domain receptors (DDR) 1/2. However, whether and how collagen signaling contributes to fibrotic barrier generation remains uncharacterized. Here, a 3D culture model of PDAC fibrosis constructed from patient PSCs is used to assess the contribution of DDR1/2-mediated collagen signaling. DDR1/2 inhibition diminishes collagen I expression in PSCs to enhance macromolecular delivery. Moreover, MEK inhibitors exacerbate the fibrotic barrier by up-regulating collagen I, an effect reversed by inhibiting DDR1/2. Through isoform-specific targeting, inhibiting DDR1, but not DDR2, is shown to be effective. Downstream of DDR, the involvement of the PI3K/AKT/mTOR pathway is demonstrated, particularly alternative mTOR complexes involving MEAK7 and GIT1. Altogether, the results show in vitro that DDR1-mediated collagen signaling exacerbates the fibrotic barrier and may be targeted to enhance macromolecular drug delivery in PDAC. en-copyright= kn-copyright= en-aut-name=OhiraMayu en-aut-sei=Ohira en-aut-mei=Mayu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KitamuraMoe en-aut-sei=Kitamura en-aut-mei=Moe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IwasakiHiroyo en-aut-sei=Iwasaki en-aut-mei=Hiroyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=Ohta‐OkanoHaruko en-aut-sei=Ohta‐Okano en-aut-mei=Haruko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TsujiiHiyori en-aut-sei=Tsujii en-aut-mei=Hiyori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakamuraReika en-aut-sei=Nakamura en-aut-mei=Reika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakazawaTakuya en-aut-sei=Nakazawa en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NishiguchiAkihiro en-aut-sei=Nishiguchi en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YamamotoMasaya en-aut-sei=Yamamoto en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OsadaKensuke en-aut-sei=Osada en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=CabralHoracio en-aut-sei=Cabral en-aut-mei=Horacio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MasamuneAtsushi en-aut-sei=Masamune en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KanoMitsunobu R. en-aut-sei=Kano en-aut-mei=Mitsunobu R. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TanakaHiroyoshi Y. en-aut-sei=Tanaka en-aut-mei=Hiroyoshi Y. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Biomaterials Field, Research Center for Macromolecules and Biomaterials, National Institute for Materials Science kn-affil= affil-num=9 en-affil=Department of Materials Processing, Graduate School of Engineering, Tohoku University kn-affil= affil-num=10 en-affil=Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum Sciences and Technology (QST) kn-affil= affil-num=11 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=12 en-affil=Department of Bioengineering, Graduate School of Engineering, The University of Tokyo kn-affil= affil-num=13 en-affil=Division of Gastroenterology, Graduate School of Medicine, Tohoku University kn-affil= affil-num=14 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=15 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=collagen kn-keyword=collagen en-keyword=fibrosis kn-keyword=fibrosis en-keyword=nanomedicine kn-keyword=nanomedicine en-keyword=pancreatic cancer kn-keyword=pancreatic cancer en-keyword=pancreatic stellate cell kn-keyword=pancreatic stellate cell END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue=11 article-no= start-page=e2543107 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251112 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Trastuzumab Deruxtecan for ERBB2-Mutant Metastatic Non–Small Cell Lung Cancer With or Without Brain Metastases: A Secondary Analysis of Randomized Clinical Trials en-subtitle= kn-subtitle= en-abstract= kn-abstract=Importance Brain metastases reduce overall survival rates of patients with non–small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC.
Objective To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases.
Design, Setting, and Participants This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024.
Intervention Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks.
Main Outcome and Measure Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety.
Results This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose.
Conclusions and Relevance In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2-mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population. en-copyright= kn-copyright= en-aut-name=JännePasi A. en-aut-sei=Jänne en-aut-mei=Pasi A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=PlanchardDavid en-aut-sei=Planchard en-aut-mei=David kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GotoKoichi en-aut-sei=Goto en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SmitEgbert F. en-aut-sei=Smit en-aut-mei=Egbert F. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=de LangenAdrianus Johannes en-aut-sei=de Langen en-aut-mei=Adrianus Johannes kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KuboToshio en-aut-sei=Kubo en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=PérolMaurice en-aut-sei=Pérol en-aut-mei=Maurice kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FelipEnriqueta en-aut-sei=Felip en-aut-mei=Enriqueta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HayashiHidetoshi en-aut-sei=Hayashi en-aut-mei=Hidetoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NakagawaKazuhiko en-aut-sei=Nakagawa en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NagasakaMisako en-aut-sei=Nagasaka en-aut-mei=Misako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=PereiraKaline en-aut-sei=Pereira en-aut-mei=Kaline kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TaguchiAyumi en-aut-sei=Taguchi en-aut-mei=Ayumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AliAhmed en-aut-sei=Ali en-aut-mei=Ahmed kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KarnoubMaha en-aut-sei=Karnoub en-aut-mei=Maha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=YonemochiRie en-aut-sei=Yonemochi en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=LeungDavid en-aut-sei=Leung en-aut-mei=David kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=LiBob T. en-aut-sei=Li en-aut-mei=Bob T. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= affil-num=1 en-affil=Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute kn-affil= affil-num=2 en-affil=Department of Medical Oncology, Thoracic Cancer Group, Gustave Roussy, Medical Oncology kn-affil= affil-num=3 en-affil=Department of Thoracic Oncology, Nation Cancer Center Hospital East kn-affil= affil-num=4 en-affil=Department of Pulmonary Diseases, Leiden University Medical Center kn-affil= affil-num=5 en-affil=Department of Thoracic Oncology, Netherlands Cancer Institute kn-affil= affil-num=6 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=7 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=8 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Medical Oncology, Centre Léon Bérard kn-affil= affil-num=10 en-affil=Department of Medical Oncology, Vall d’Hebron University and Vall d’Hebron Institute of Oncology kn-affil= affil-num=11 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=12 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=13 en-affil=Department of Thoracic Oncology, Aichi Cancer Center kn-affil= affil-num=14 en-affil=Division of Hematology-Oncology, Department of Medicine, University of California Irvine kn-affil= affil-num=15 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=16 en-affil=Daiichi Sankyo Co Ltd kn-affil= affil-num=17 en-affil=Daiichi Sankyo Europe GmbH kn-affil= affil-num=18 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=19 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=20 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=21 en-affil=Thoracic Oncology and Early Drug Development Service, Global Research Program, Memorial Sloan Kettering Cancer Center kn-affil= END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=12 article-no= start-page=1814 end-page=1828 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02—A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Trastuzumab deruxtecan (T-DXd) demonstrated strong and durable responses in patients with previously treated HER2 (ERBB2) mutant (HER2m) metastatic NSCLC (mNSCLC) in the DESTINY-Lung02 primary analysis (December 23, 2022, data cutoff). This final analysis evaluated T-DXd efficacy and safety after 8 additional months of follow-up, including clinically relevant subgroups and patient-reported outcomes.
Methods: DESTINY-Lung02 was a randomized, dose-blinded, multicenter, phase 2 trial. Patients with previously treated HER2m mNSCLC were randomized 2:1 to receive T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. Primary end point was confirmed objective response rate by blinded independent central review.
Results: As of August 25, 2023, 102 and 50 patients had received T-DXd 5.4 or 6.4 mg/kg, respectively. Median follow-up (Q1–Q3) was 15.8 (8.2–20.7) months and 16.5 (9.4–20.8) months, respectively. Confirmed objective response rate (95% confidence interval) was 50.0% (51/102; 39.9%–60.1%) and 56.0% (28/50; 41.3%–70.0%), respectively. Safety profile was acceptable and generally manageable. Accordingly, median treatment duration (Q1–Q3) was 7.7 (3.7–14.4) months and 8.3 (2.8–13.1) months; drug-related grade 3 or higher treatment-emergent adverse events occurred in 39.6% (40/101) and 60.0% (30/50), with nausea most common (67.3% [68/101], 82.0% [41/50]). Adjudicated drug-related interstitial lung disease occurred in 14.9% (15/101) and 32.0% (16/50), mostly grade 1 or 2 with one grade 5 in each arm. Health-related quality of life was preserved for the duration of T-DXd treatment while sample size was sufficient for analysis, with no adverse effects on health-related quality of life observed at either dose.
Conclusions: T-DXd demonstrated strong and durable responses at both doses, with no clinically significant changes in toxicity. The approved 5.4-mg/kg dose demonstrated a more favorable benefit-risk profile, including lower adjudicated drug-related interstitial lung disease incidence.
ClinicalTrials.gov identifier: NCT04644237 en-copyright= kn-copyright= en-aut-name=JännePasi A. en-aut-sei=Jänne en-aut-mei=Pasi A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuboToshio en-aut-sei=Kubo en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KimSang-We en-aut-sei=Kim en-aut-mei=Sang-We kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=PlanchardDavid en-aut-sei=Planchard en-aut-mei=David kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AhnMyung-Ju en-aut-sei=Ahn en-aut-mei=Myung-Ju kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SmitEgbert en-aut-sei=Smit en-aut-mei=Egbert kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=Johannes de LangenAdrianus en-aut-sei=Johannes de Langen en-aut-mei=Adrianus kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=PérolMaurice en-aut-sei=Pérol en-aut-mei=Maurice kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=Pons-TostivintElvire en-aut-sei=Pons-Tostivint en-aut-mei=Elvire kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NovelloSilvia en-aut-sei=Novello en-aut-mei=Silvia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=HayashiHidetoshi en-aut-sei=Hayashi en-aut-mei=Hidetoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KimDong-Wan en-aut-sei=Kim en-aut-mei=Dong-Wan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=PereiraKaline en-aut-sei=Pereira en-aut-mei=Kaline kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=ChengFu-Chih en-aut-sei=Cheng en-aut-mei=Fu-Chih kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=TaguchiAyumi en-aut-sei=Taguchi en-aut-mei=Ayumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=ChengYingkai en-aut-sei=Cheng en-aut-mei=Yingkai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=DuntonKyle en-aut-sei=Dunton en-aut-mei=Kyle kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=AliAhmed en-aut-sei=Ali en-aut-mei=Ahmed kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=GotoKoichi en-aut-sei=Goto en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute kn-affil= affil-num=2 en-affil=Department of Thoracic Oncology, National Cancer Central Hospital kn-affil= affil-num=3 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=4 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Oncology Department, Asan Medical Center, Seoul, and University of Ulsan College of Medicine, Ulsan kn-affil= affil-num=6 en-affil=Department of Medical Oncology, Thoracic Cancer Group, Gustave Roussy, and Faculty of Medicine, Paris-Saclay University kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Samsung Medical Center Sungkyunkwan, and University School of Medicine kn-affil= affil-num=8 en-affil=Department of Pulmonary Diseases, Leiden University Medical Center kn-affil= affil-num=9 en-affil=Department of Thoracic Oncology, Netherlands Cancer Institute kn-affil= affil-num=10 en-affil=Department of Medical Oncology, Léon Berard Centre kn-affil= affil-num=11 en-affil=Centre Hospitalier Universitaire Nantes, Nantes University kn-affil= affil-num=12 en-affil=Department of Oncology, University of Turin, Turin, and Azienda Ospedaliero-Universitaria San Luigi Gonzaga kn-affil= affil-num=13 en-affil=Department of Medical Oncology, Kindai University Hospital kn-affil= affil-num=14 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=15 en-affil=Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital kn-affil= affil-num=16 en-affil=Daiichi Sankyo kn-affil= affil-num=17 en-affil=Daiichi Sankyo kn-affil= affil-num=18 en-affil=Daiichi Sankyo kn-affil= affil-num=19 en-affil=Daiichi Sankyo kn-affil= affil-num=20 en-affil=Daiichi Sankyo UK kn-affil= affil-num=21 en-affil=Daiichi Sankyo Europe GmbH kn-affil= affil-num=22 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital East kn-affil= en-keyword=HER2-directed therapy kn-keyword=HER2-directed therapy en-keyword=HER2-mutant kn-keyword=HER2-mutant en-keyword=HER2-targeted kn-keyword=HER2-targeted en-keyword=Non–small cell lung cancer kn-keyword=Non–small cell lung cancer en-keyword=Trastuzumab deruxtecan kn-keyword=Trastuzumab deruxtecan END start-ver=1.4 cd-journal=joma no-vol=88 cd-vols= no-issue=5 article-no= start-page=1003 end-page=1015 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251222 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Claudin-18 expression in gastric type adenocarcinoma and HPV-associated adenocarcinoma of the uterine cervix en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aims: Claudin-18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using the clone 43-14A antibody, or about the gene expression of its isoforms in ECAs.
Methods and results: We examined CLDN18, HIK1083, p16 and Rb expression by immunohistochemistry and high-risk human papillomavirus (HR-HPV) mRNA by in situ hybridization (ISH) in 121 ECAs, including 35 HPV-independent adenocarcinomas (gastric type [GAS], n = 24; non-GAS, n = 11) and 86 HPV-associated ECAs. We also analysed mRNA expression of the CLDN18.1 (lung type) and CLDN18.2 (gastric type) isoforms by quantitative polymerase chain reaction (qPCR) in selected cases. CLDN18 positivity was detected in 8/24 (33%) GASs, 0/11 (0%) non-GASs and 2/86 (2%) HPV-associated ECAs, with positivity defined as staining in ≥75% of tumour cells, as in gastric cancer. When a 5% cut-off was used, CLDN18 positivity was detected in 22/24 (92%) GASs, 0/11 (0%) non-GASs and 6/86 (7%) HPV-associated ECAs; CLDN18 expression was thus significantly associated with GAS histology (P < 0.0001). Among the 6 cases of HPV-associated ECAs with CLDN18 expression (ranging from 5% to 80%), the histological patterns included a mix of usual and mucinous features in 4 cases, pure usual type in 1 and villoglandular variant in 1. Otherwise features such as p16 overexpression and the Rb partial loss pattern were consistent with those of HPV-associated ECAs. Six of 22 (27%) CLDN18-positive GASs were also positive for p16, but their other features—such as CLDN18 expression and the Rb preserved pattern—were the same as in p16 negative GASs. Expression of CLDN18.2 mRNA but not CLDN18.1 mRNA was confirmed in both GASs and HPV-associated ECAs.
Conclusions: CLDN18 (43-14A) emerged as a potential diagnostic and therapeutic marker for GAS. A minor subset of HPV-associated ECAs also can be immunoreactive for CLDN18 and express CLDN18.2 mRNA, suggesting divergent gastric phenotypic differentiation. The caution is that GAS and HPV-associated ECAs can share overlapping histological features and similar expression of CLDN18 and p16. en-copyright= kn-copyright= en-aut-name=YasutakeNobuko en-aut-sei=Yasutake en-aut-mei=Nobuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YokawaYuki en-aut-sei=Yokawa en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MishimaRiri en-aut-sei=Mishima en-aut-mei=Riri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KomamizuMisato en-aut-sei=Komamizu en-aut-mei=Misato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KugaRyosuke en-aut-sei=Kuga en-aut-mei=Ryosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=JiromaruRina en-aut-sei=Jiromaru en-aut-mei=Rina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawatokoShinichiro en-aut-sei=Kawatoko en-aut-mei=Shinichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SonodaKenzo en-aut-sei=Sonoda en-aut-mei=Kenzo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YahataHideaki en-aut-sei=Yahata en-aut-mei=Hideaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KatoKiyoko en-aut-sei=Kato en-aut-mei=Kiyoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OdaYoshinao en-aut-sei=Oda en-aut-mei=Yoshinao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YamamotoHidetaka en-aut-sei=Yamamoto en-aut-mei=Hidetaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=2 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= affil-num=3 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= affil-num=5 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences Kyushu University Fukuoka Japan kn-affil= affil-num=6 en-affil=Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=7 en-affil=Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=8 en-affil=Department of Medicine and Clinical Science, Kyushu University Beppu Hospital kn-affil= affil-num=9 en-affil=Department of Gynecology, Kyushu University Beppu Hospital kn-affil= affil-num=10 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=11 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=12 en-affil=Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=13 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= en-keyword=claudin-18 kn-keyword=claudin-18 en-keyword=endocervical adenocarcinoma kn-keyword=endocervical adenocarcinoma en-keyword=gastric type kn-keyword=gastric type en-keyword=human papillomavirus kn-keyword=human papillomavirus en-keyword=p16 kn-keyword=p16 END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=7 article-no= start-page=e87334 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250705 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Challenge of Diagnosing Scirrhous Gastric Cancer by Endoscopic Biopsy: A Case Report en-subtitle= kn-subtitle= en-abstract= kn-abstract=Scirrhous gastric cancer, also known as linitis plastica, is a rare and aggressive subtype of gastric carcinoma that poses significant diagnostic challenges due to its submucosal infiltration and often normal-appearing mucosa. We report a case involving a 30-year-old Japanese woman who presented with a six-month history of epigastric pain and postprandial vomiting. Initial endoscopic examination revealed erythema and mucosal swelling, with limited antral distensibility and resistance during duodenal intubation. Despite 12 mucosal biopsies, histopathological examination revealed no evidence of malignancy. Given the strong clinical and endoscopic suspicion of scirrhous gastric cancer, additional deep sections and immunohistochemical staining were performed. These revealed scattered signet-ring cell carcinoma and poorly differentiated adenocarcinoma, with positive immunostaining for p53 and Ki67. The patient underwent total gastrectomy, and the diagnosis of scirrhous gastric cancer was confirmed on the resected specimen. This case highlights the importance of a high index of clinical suspicion, close collaboration between endoscopists and pathologists, and the utility of ancillary diagnostic tools, such as immunohistochemistry, in identifying subepithelial gastric malignancies that may be missed on conventional biopsy. en-copyright= kn-copyright= en-aut-name=IkedaYuka en-aut-sei=Ikeda en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshinoTadashi en-aut-sei=Yoshino en-aut-mei=Tadashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IkedaNobumasa en-aut-sei=Ikeda en-aut-mei=Nobumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Internal Medicine, Clinic IkedaDepartment of Internal Medicine, Clinic Ikeda kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pathology, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Internal Medicine, Clinic Ikeda kn-affil= affil-num=6 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=endoscopic biopsy kn-keyword=endoscopic biopsy en-keyword=esophagogastroduodenoscopy kn-keyword=esophagogastroduodenoscopy en-keyword=immunohistochemistry kn-keyword=immunohistochemistry en-keyword=linitis plastica kn-keyword=linitis plastica en-keyword=scirrhous gastric cancer kn-keyword=scirrhous gastric cancer END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=2 article-no= start-page=284 end-page=293 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260201 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical Characteristics and Spatial Transcriptome Analysis of Non–Small Cell Lung Cancers Exhibiting Early Alectinib Resistance: A Retrospective OLCSG Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Some anaplastic lymphoma kinase (ALK) gene rearrangement–positive lung cancers show early resistance, within 3 months, to alectinib. This study investigated the clinical and molecular characteristics of these patients. We analyzed patients with unresectable stage III/IV disease without indications for radical radiotherapy and recurrent ALK-positive lung cancer who received alectinib as the primary ALK tyrosine kinase inhibitor between 2013 and 2021 at nine hospitals. In total, 103 patients were included. The median age was 65 years; 44 were male and 22 had brain metastases. The median progression-free survival and overall survival (OS) were 28.7 and 80.6 months. Nineteen patients treated for ≤3 months and 84 treated for >3 months were categorized into the early resistance and responder groups, respectively. The early resistance group had significantly shorter OS (8.4 months vs. not estimable, P < 0.001) and was significantly more likely to have brain metastases (42% vs. 17%, P = 0.027). They also showed elevated inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR). Univariate analysis identified brain metastases and high NLR as significant predictors of early resistance. Spatial transcriptome analysis and immunohistochemical staining revealed upregulation of annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein involved in inflammation and cancer progression, in the early resistance group. Interleukin 6 stimulation, prompted by elevated inflammatory markers, increased ANXA1 expression and reduced alectinib sensitivity. Knockdown of ANXA1 improved alectinib sensitivity in alectinib-resistant cells. In conclusion, brain metastases and high NLR are associated with early resistance. ANXA1 may play an important role in mediating early resistance. New treatment options for the early resistance group are required. en-copyright= kn-copyright= en-aut-name=KuribayashiTadahiro en-aut-sei=Kuribayashi en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MakimotoGo en-aut-sei=Makimoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TomidaShuta en-aut-sei=Tomida en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=InoueHirofumi en-aut-sei=Inoue en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YokoyamaToshihide en-aut-sei=Yokoyama en-aut-mei=Toshihide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KuyamaShoichi en-aut-sei=Kuyama en-aut-mei=Shoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KatoYuka en-aut-sei=Kato en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KudoKenichiro en-aut-sei=Kudo en-aut-mei=Kenichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HoritaNaokatsu en-aut-sei=Horita en-aut-mei=Naokatsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KayataniHiroe en-aut-sei=Kayatani en-aut-mei=Hiroe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=InoueMasaaki en-aut-sei=Inoue en-aut-mei=Masaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SugimotoKeisuke en-aut-sei=Sugimoto en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital kn-affil= affil-num=7 en-affil=Department of Respiratory Medicine, NHO Iwakuni Clinical Center kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center kn-affil= affil-num=10 en-affil=Department of Respiratory Medicine, Kure Kyosai Hospital kn-affil= affil-num=11 en-affil=Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital kn-affil= affil-num=12 en-affil=Department of Chest Surgery, Shimonoseki City Hospital kn-affil= affil-num=13 en-affil=Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital kn-affil= affil-num=14 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=15 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=17 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= END start-ver=1.4 cd-journal=joma no-vol=95 cd-vols= no-issue=1 article-no= start-page=10 end-page=20 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparison of Fruit Development, Ripening, and Transcriptome Dynamics in Taiwanese and Japanese Cultivars of Japanese Apricot (Prunus mume Sieb. et Zucc.) en-subtitle= kn-subtitle= en-abstract= kn-abstract=In this study, we compared changes in traits associated with fruit development and ripening in Taiwanese and Japanese cultivars of Japanese apricot (Prunus mume Sieb. et Zucc.). We also analyzed transcriptome profiles to comprehensively examine different fruit development and ripening patterns between the two groups in terms of fruit characteristics and gene expression. Early fruit development in Taiwanese cultivars ‘ST’ and ‘Ellching’ and the Japanese cultivar ‘Hakuo’ was ahead of that in other three Japanese cultivars (P1). From late April to early May, around the stone-hardening stage, the developmental differences decreased to the same level. Thereafter, Japanese cultivars showed rapid growth, whereas Taiwanese cultivars showed slower growth, reversing the developmental differences between these lines (P2). Ethylene production was not detected until the full ripening stage and was detected for the first time at this stage in five cultivars, except for ‘Ellching’ (P3). In contrast, no ethylene production was observed during the entire duration of fruit development in ‘Ellching’. A multidimensional scaling plot showed that the overall transcriptome profile changed according to the three stages (P1–P3) of fruit development and ripening. At P1, gene ontologies (GOs) related to cell division, such as the cell cycle and regulation of cyclin-dependent protein serine/threonine kinase activity, were enriched for differentially expressed genes downregulated in Taiwanese cultivars as compared with their expression in Japanese cultivars. At P2, GOs related to fruit development were not enriched, but some genes related to phytohormones, such as auxin, abscisic acid, and cytokinin, which are associated with fruit development and ripening, were differentially expressed. At P3, the expression of genes such as ACS, ACO, and PG, which are involved in ethylene biosynthesis, increased in response to increased ethylene production, but not in ‘Ellching’, which showed no ethylene production. Expression analysis of 115 NAC (NAM-ATAF1/2-CUC2) family genes, which are related to fruit ripening and ripening date in other fruit species, in the ‘Ellching’ genome revealed changes in expression of NAC056 and NAC073 corresponding to fruit development and ripening in Taiwanese and Japanese cultivars. We discuss the differences in fruit development and ripening behaviors between Taiwanese and Japanese cultivars in terms of physiological and transcriptome changes. en-copyright= kn-copyright= en-aut-name=KashiwamotoTomoaki en-aut-sei=Kashiwamoto en-aut-mei=Tomoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KawaiTakashi en-aut-sei=Kawai en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OeTakaaki en-aut-sei=Oe en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NumaguchiKoji en-aut-sei=Numaguchi en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KitamuraYuto en-aut-sei=Kitamura en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KuboYasutaka en-aut-sei=Kubo en-aut-mei=Yasutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FukudaFumio en-aut-sei=Fukuda en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UshijimaKoichiro en-aut-sei=Ushijima en-aut-mei=Koichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Japanese Apricot Laboratory, Wakayama Fruit Tree Experiment Station kn-affil= affil-num=4 en-affil=Japanese Apricot Laboratory, Wakayama Fruit Tree Experiment Station kn-affil= affil-num=5 en-affil=Faculty of Agriculture, Setsunan University kn-affil= affil-num=6 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=8 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=cell division kn-keyword=cell division en-keyword=ethylene production kn-keyword=ethylene production en-keyword=NAC kn-keyword=NAC en-keyword=phytohormone kn-keyword=phytohormone en-keyword=stone hardening kn-keyword=stone hardening END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=5 article-no= start-page=2113 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260224 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland en-subtitle= kn-subtitle= en-abstract= kn-abstract=Mutations in the fibroblast growth factor 10 (FGF10) gene in humans cause aplasia of the lacrimal and salivary glands (ALSG). In patients with ALSG, heterozygous loss-of-function mutations are found, and FGF10 haploinsufficiency results in the absence of these secretory organs. Lacrimal glands (LGs) are formed through epithelial thickening, budding, and branching morphogenesis. To compare the variable phenotypes of the Fgf10+/− Harderian glands (HGs) previously reported, we examined the development of LGs in wild-type (WT), Fgf10+/−, and Fgf10-null mice. Pax6 immunostaining was performed to visualize the LG primordia from embryonic day 15.5 (E15.5) onwards. In situ hybridization of the genes encoding the epithelial receptor of FGF10, FGFR2b, and its other ligands was performed to determine their potential involvement in LG development. LG primordia were not observed in Fgf10+/− mice bilaterally at E16.5 or later stages. At E15.5, budding from the developing conjunctival epithelium (CE) was observed in a small fraction of the Fgf10+/− LG primordia. In contrast, the Fgf10-null CE failed to promote budding. Among Fgf1, Fgf3, Fgf7, Fgf10, and Fgf22, Fgf10 was expressed in the mesenchyme surrounding developing LG epithelial cells, whereas Fgf1 was expressed in the LG epithelium of WT mice. Fgf7 was initially expressed in the mesenchyme surrounding the nascent LG epithelium, but its expression subsequently became diffused. Thus, we conclude that among the FGFR2b ligands, initial LG formation is dependent on the mesenchymal factors FGF10 and FGF7, and FGF1 is likely to function as an epithelial factor in the LG primordia. A single allele of Fgf10 was found to be insufficient to support the budding process during LG morphogenesis. en-copyright= kn-copyright= en-aut-name=IkedaShiori en-aut-sei=Ikeda en-aut-mei=Shiori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SatoKeita en-aut-sei=Sato en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TajikaYuki en-aut-sei=Tajika en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FujitaHirofumi en-aut-sei=Fujita en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=BandoTetsuya en-aut-sei=Bando en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NohnoTsutomu en-aut-sei=Nohno en-aut-mei=Tsutomu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyaishiSatoru en-aut-sei=Miyaishi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OhuchiHideyo en-aut-sei=Ohuchi en-aut-mei=Hideyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Radiological Technology, Gumma Prefectural College of Health Sciences kn-affil= affil-num=4 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Legal Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=fibroblast growth factor kn-keyword=fibroblast growth factor en-keyword=Fgf10 kn-keyword=Fgf10 en-keyword=Fgf1 kn-keyword=Fgf1 en-keyword=Fgf3 kn-keyword=Fgf3 en-keyword=Fgf7 kn-keyword=Fgf7 en-keyword=Fgf22 kn-keyword=Fgf22 en-keyword=Fgfr2b kn-keyword=Fgfr2b en-keyword=mouse kn-keyword=mouse en-keyword=lacrimal gland kn-keyword=lacrimal gland en-keyword=development kn-keyword=development END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue= article-no= start-page=1716939 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251127 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Structural analysis of PSI-ACPI and PSII-ACPII supercomplexes from a cryptophyte alga Rhodomonas sp. NIES-2332 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Light energy is converted to chemical energy by two photosystems (PSI and PSII) in complex with their light-harvesting complex proteins (LHCI and LHCII) in photosynthesis. Rhodomonas is a member of cryptophyte alga whose LHCs contain unique chlorophyll a/c proteins (ACPs) and phycobiliproteins. We purified PSI-ACPI and PSII-ACPII supercomplexes from a cryptophyte Rhodomonas sp. NIES-2332 and analyzed their structures at high resolutions of 2.08 Å and 2.17 Å, respectively, using cryo-electron microscopy. These structures are largely similar to those reported previously from two other species of cryptophytes, but exhibited some differences in both the pigment locations and subunit structures. A part of the antenna subunits of both photosystems is shifted compared with the previously reported structures from other species of cryptophytes, suggesting some differences in the energy transfer rates from the antenna to the PSI and PSII cores. Newly identified lipids are found to occupy the interfaces between the antennae and cores, which may be important for assembly and stabilization of the supercomplexes. Water molecules surrounding three iron-sulfur clusters of the PSI core are found in our high-resolution structure, some of which are conserved from cyanobacteria to higher plants but some are different. In addition, our structure of PSII-ACPII lacks the subunits of oxygen-evolving complex as well as the Mn4CaO5 cluster, suggesting that the cells are in the S-growth phase, yet the PSI-ACPI structure showed the binding of PsaQ, suggesting that it is in an L-phase. These results suggest that the S-phase and L-phase can co-exist in the cryptophytic cells. The high-resolution structures of both PSI-ACPIs and PSII-ACPIIs solved in this study provide a more solid structural basis for elucidating the energy transfer and quenching mechanisms in this group of the organisms. en-copyright= kn-copyright= en-aut-name=ZhangWenyue en-aut-sei=Zhang en-aut-mei=Wenyue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoneharaNozomi en-aut-sei=Yonehara en-aut-mei=Nozomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IshiiMizuki en-aut-sei=Ishii en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=JiangHaowei en-aut-sei=Jiang en-aut-mei=Haowei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=La RoccaRomain en-aut-sei=La Rocca en-aut-mei=Romain kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TsaiPi-Cheng en-aut-sei=Tsai en-aut-mei=Pi-Cheng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=LiHongjie en-aut-sei=Li en-aut-mei=Hongjie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AkitaFusamichi en-aut-sei=Akita en-aut-mei=Fusamichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=ShenJian-Ren en-aut-sei=Shen en-aut-mei=Jian-Ren kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=cryptophytes kn-keyword=cryptophytes en-keyword=Rhodomonas kn-keyword=Rhodomonas en-keyword=photosystem I kn-keyword=photosystem I en-keyword=photosystem II kn-keyword=photosystem II en-keyword=light-harvesting complex kn-keyword=light-harvesting complex en-keyword=photosynthesis kn-keyword=photosynthesis END start-ver=1.4 cd-journal=joma no-vol=19 cd-vols= no-issue=1 article-no= start-page=13 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251208 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pan-cancer profiling links C1orf50 to DNA repair and immune modulation in ovarian cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background C1orf50 encodes a small, evolutionarily conserved protein, the function of which remains unclear. Its significance across various human cancers, particularly its specific role in ovarian cancer within an immunogenomic context, is not yet fully understood. Utilizing The Cancer Genome Atlas and single-cell RNA sequencing (scRNA-seq) public datasets, we conducted a comprehensive profiling of C1orf50 across multiple cancer types, with a particular focus on ovarian cancer, to investigate its associations with copy-number status, genomic instability, tumor programs, and the immune microenvironment.
Results Across cancer types, copy-number gain or amplification of C1orf50 was most frequent in ovarian cancer and closely tracked with higher messenger RNA levels. Higher C1orf50 expression was associated with a greater tumor mutational burden and homologous recombination deficiency, as indicated by gene-set patterns that suggested heightened cell-cycle and cellular stress responses accompanied by reduced oxidative phosphorylation, enrichment of regulatory T cells, and depletion of resting memory CD4 T cells. In ovarian cancer, focal events at chromosome 1p34.2 were accompanied by stepwise increases in C1orf50 expression by clinical stage and were linked to higher tumor mutational burden, homologous recombination deficiency, and greater loss of heterozygosity, together with more frequent gene alterations in BRCA1 or BRCA2. Immune composition clustered into profiles consistent with an immunosuppressive context in tumors with higher C1orf50 expression. The scRNA-seq data further revealed that cancer cells enhanced immune-suppressive interactions with various immune cell populations and diminished antigen-presentation signals. Analyses of genomic instability in ovarian cancer suggested mutational processes compatible with base-substitution patterns associated with cytidine deaminase activity and with insertion-deletion patterns characteristic of homologous recombination failure, while transcript-level patterns pointed to a broad downshift of canonical DNA repair activity with apparent compensatory adjustments in related pathways rather than a uniform change in any single pathway.
Conclusions The overexpression of C1orf50 characterizes an aggressive immunogenomic phenotype in ovarian cancer, distinguished by genomic instability, impaired DNA repair mechanisms, and extensive immunosuppression. These findings indicate that C1orf50 warrants consideration as a potential biomarker and a prospective target for therapeutic investigation. Furthermore, they advocate for the progression to prospective validation and functional studies to ascertain its clinical significance. en-copyright= kn-copyright= en-aut-name=RogachevskayaAnna en-aut-sei=Rogachevskaya en-aut-mei=Anna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OtaniYusuke en-aut-sei=Otani en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhtsuAkira en-aut-sei=Ohtsu en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ChinVanessa D. en-aut-sei=Chin en-aut-mei=Vanessa D. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=PeñaTirso en-aut-sei=Peña en-aut-mei=Tirso kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AraiSeiji en-aut-sei=Arai en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujimuraAtsushi en-aut-sei=Fujimura en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaAtsushi en-aut-sei=Tanaka en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= affil-num=2 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Harvard Medical School kn-affil= affil-num=4 en-affil=UMass Chan Medical School, UMass Memorial Medical Center kn-affil= affil-num=5 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= affil-num=6 en-affil=Department of Urology, Gunma University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=8 en-affil=Department of Molecular Physiology, Faculty of Medicine, Graduate School of Medicine, Kagawa University kn-affil= affil-num=9 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= en-keyword=C1orf50 kn-keyword=C1orf50 en-keyword=Pan-cancer analysis kn-keyword=Pan-cancer analysis en-keyword=DNA repair kn-keyword=DNA repair en-keyword=Gene expression kn-keyword=Gene expression en-keyword=Tumor microenvironment kn-keyword=Tumor microenvironment en-keyword=Immune evasion kn-keyword=Immune evasion en-keyword=Single-cell RNA-seq kn-keyword=Single-cell RNA-seq END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=9 article-no= start-page=4363 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gaseous CO2 electrolysis: latest advances in electrode and electrolyzer technologies toward abating CO2 emissions en-subtitle= kn-subtitle= en-abstract= kn-abstract=The conversion of CO2 into multicarbon (C2+) products via electrochemical reduction is considered a key technology for the sustainable production of fuels and chemicals. The performance of high-rate gaseous CO2 electrolysis is governed by interrelated factors such as the electrocatalysts, electrodes, electrolytes, and cell architectures. Despite the intensive focus on catalyst research, systematic studies addressing the other components remain scarce, leaving critical gaps in our understanding toward achieving higher performance in CO2 electrolysis systems. The nanoscale design of catalyst surface electronic structures and the macroscale design of electrodes and electrolyzer architectures both influence the overall activity of the electrochemical system. In designing macroscale components, it is necessary to establish benchmarks based on a comprehensive evaluation of CO2 emissions for the entire electrolysis process, because these parameters are directly linked to output metrics such as current density and cell voltage under practical operating conditions. This review summarizes recent advances in electrodes and electrolyzers, and through life-cycle assessment (LCA), evaluates key performance indicators (KPIs) for achieving negative emissions and assesses the current technology readiness of CO2 electrolysis. en-copyright= kn-copyright= en-aut-name=KamiyaKazuhide en-aut-sei=Kamiya en-aut-mei=Kazuhide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakasoneSora en-aut-sei=Nakasone en-aut-mei=Sora kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuriharaRyo en-aut-sei=Kurihara en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=InoueAsato en-aut-sei=Inoue en-aut-mei=Asato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IrieHazuki en-aut-sei=Irie en-aut-mei=Hazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakahataShoko en-aut-sei=Nakahata en-aut-mei=Shoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishinaYuta en-aut-sei=Nishina en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TaniguchiSatoshi en-aut-sei=Taniguchi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NguyenThuy T. H. en-aut-sei=Nguyen en-aut-mei=Thuy T. H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KataokaSho en-aut-sei=Kataoka en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=2 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=3 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=4 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=5 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=6 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=7 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= affil-num=8 en-affil=Research Institute for Chemical Process Technology, National Institute of Advanced Industrial Science and Technology (AIST), Central 5 kn-affil= affil-num=9 en-affil=Research Institute for Chemical Process Technology, National Institute of Advanced Industrial Science and Technology (AIST), Central 5 kn-affil= affil-num=10 en-affil=Research Institute for Chemical Process Technology, National Institute of Advanced Industrial Science and Technology (AIST), Central 5 kn-affil= END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue= article-no= start-page=103078 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202502 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): long-term results of a multicentre, single-arm, phase 2 trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi).
Methods We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165).
Findings With a median follow-up of 7.1 years (interquartile range 5.6–8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%–80%) and OS was 78% (95% CI 61%–89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1).
Interpretation Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients.
Funding This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center. en-copyright= kn-copyright= en-aut-name=ShimadaKazuyuki en-aut-sei=Shimada en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamaguchiMotoko en-aut-sei=Yamaguchi en-aut-mei=Motoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuwatsukaYachiyo en-aut-sei=Kuwatsuka en-aut-mei=Yachiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsueKosei en-aut-sei=Matsue en-aut-mei=Kosei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SatoKeijiro en-aut-sei=Sato en-aut-mei=Keijiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KusumotoShigeru en-aut-sei=Kusumoto en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NagaiHirokazu en-aut-sei=Nagai en-aut-mei=Hirokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakizawaJun en-aut-sei=Takizawa en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FukuharaNoriko en-aut-sei=Fukuhara en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NagafujiKoji en-aut-sei=Nagafuji en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MiyazakiKana en-aut-sei=Miyazaki en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OhtsukaEiichi en-aut-sei=Ohtsuka en-aut-mei=Eiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OkamotoAkinao en-aut-sei=Okamoto en-aut-mei=Akinao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SugitaYasumasa en-aut-sei=Sugita en-aut-mei=Yasumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=UchidaToshiki en-aut-sei=Uchida en-aut-mei=Toshiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KayukawaSatoshi en-aut-sei=Kayukawa en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=WakeAtsushi en-aut-sei=Wake en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KondoYukio en-aut-sei=Kondo en-aut-mei=Yukio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MeguroAkiko en-aut-sei=Meguro en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KinYoshihiro en-aut-sei=Kin en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=MinamiYosuke en-aut-sei=Minami en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=HashimotoDaigo en-aut-sei=Hashimoto en-aut-mei=Daigo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=NishiyamaTakahiro en-aut-sei=Nishiyama en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=ShimadaSatoko en-aut-sei=Shimada en-aut-mei=Satoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=MasakiYasufumi en-aut-sei=Masaki en-aut-mei=Yasufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=OkamotoMasataka en-aut-sei=Okamoto en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=KiyoiHitoshi en-aut-sei=Kiyoi en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=SuzukiRitsuro en-aut-sei=Suzuki en-aut-mei=Ritsuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=NakamuraShigeo en-aut-sei=Nakamura en-aut-mei=Shigeo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=KinoshitaTomohiro en-aut-sei=Kinoshita en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Nagoya University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Hematological Malignancies, Mie University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Advanced Medicine, Nagoya University Hospital kn-affil= affil-num=4 en-affil=Division of Hematology/Oncology, Internal Medicine, Kameda Medical Center kn-affil= affil-num=5 en-affil=Department of Hematology, Nagano Red Cross Hospital kn-affil= affil-num=6 en-affil=Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences kn-affil= affil-num=7 en-affil=Department of Hematology, National Hospital Organization Nagoya Medical Center kn-affil= affil-num=8 en-affil=Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine kn-affil= affil-num=9 en-affil=Department of Hematology and Rheumatology, Tohoku University Hospital kn-affil= affil-num=10 en-affil=Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Mie University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Hematology, Oita Prefectural Hospital kn-affil= affil-num=13 en-affil=Department of Hematology, Fujita Health University School of Medicine kn-affil= affil-num=14 en-affil=Department of Hematology, Oami Municipal Hospital kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital kn-affil= affil-num=16 en-affil=Department of Clinical Oncology, Nagoya Memorial Hospital kn-affil= affil-num=17 en-affil=Department of Hematology, Toranomon Hospital Kajigaya kn-affil= affil-num=18 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=19 en-affil=Department of Internal Medicine, Toyama Prefectural Central Hospital kn-affil= affil-num=20 en-affil=Division of Hematology, Tochigi Cancer Center kn-affil= affil-num=21 en-affil=Department of Hematology, Daini Osaka Police Hospital kn-affil= affil-num=22 en-affil=Department of Hematology, National Cancer Center Hospital East kn-affil= affil-num=23 en-affil=Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine kn-affil= affil-num=24 en-affil=Division of Hematology, Ichinomiya Municipal Hospital kn-affil= affil-num=25 en-affil=Department of Pathology and Clinical Laboratories, Nagoya University Hospital kn-affil= affil-num=26 en-affil=Department of Hematology and Immunology, Kanazawa Medical University kn-affil= affil-num=27 en-affil=Department of Hematology, Fujita Health University School of Medicine kn-affil= affil-num=28 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=29 en-affil=Department of Hematology and Oncology, Nagoya University Graduate School of Medicine kn-affil= affil-num=30 en-affil=Department of HSCT Data Management and Biostatistics, Nagoya University School of Medicine kn-affil= affil-num=31 en-affil=Department of Pathology and Clinical Laboratories, Nagoya University Hospital kn-affil= affil-num=32 en-affil=Department of Hematology and Cell Therapy, Aichi Cancer Center kn-affil= en-keyword=Central nervous system-directed therapy kn-keyword=Central nervous system-directed therapy en-keyword=Intravascular large B-Cell lymphoma kn-keyword=Intravascular large B-Cell lymphoma en-keyword=R-CHOP kn-keyword=R-CHOP en-keyword=Secondary central nervous system involvement kn-keyword=Secondary central nervous system involvement END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=6 article-no= start-page=e86575 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250623 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Retreatment With EGFR-Tyrosine Kinase Inhibitor After Disease Progression Following Gefitinib Induction and Chemoradiotherapy in EGFR-Mutant Stage III Non-small Lung Cancer: An Efficacy and Safety Analysis of the LOGIK0902/OLCSG0905 Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and objective: We had previously conducted a phase II study (LOGIK0902/OLCSG0905 study) involving the eight-week administration of gefitinib, followed by cisplatin-based chemoradiotherapy, to treat locally advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC). Despite favorable overall survival outcomes, more than half of the patients relapsed after the protocol therapy, highlighting the need to clarify the clinical significance of retreatment with EGFR-tyrosine kinase inhibitors (TKIs). We investigated the efficacy and safety of EGFR-TKI retreatment after disease progression.
Materials and methods: We included 14 patients who relapsed after the protocol treatment and received any type of EGFR-TKI as post-progression treatment in this sub-analysis. We evaluated the efficacy and safety of retreatment with EGFR-TKI in these patients.
Results: Among the 14 patients, 11 (78.6%) responded to the induction of gefitinib in the treatment protocol. After relapse, 9/14 patients (64.3%) received gefitinib, 3/14 (21.4%) received afatinib, and 2/14 (14.3%) received erlotinib monotherapy, respectively. The median duration of post-progression EGFR-TKI treatment was 17.9 (0.7-45.5) months. The overall response rate (ORR) and disease control rate were 64.3% [9/14 patients; 95% confidence interval (CI): 35.1%-87.2%] and 85.7% (12/14 patients; 95% CI: 57.2%-98.2%), respectively. The median progression-free survival (PFS) and median survival durations after the initiation of EGFR-TKI retreatment were 11.8 months (95% CI: 5.7-20.7 months) and 47.4 months (95% CI: 31.8 months to not estimable), respectively. Adverse events were comparable to those previously reported.
Conclusions: Patients with disease progression after protocol therapy demonstrated sensitivity to retreatment with an EGFR-TKI, with acceptable safety. en-copyright= kn-copyright= en-aut-name=SaekiSho en-aut-sei=Saeki en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SakataShinya en-aut-sei=Sakata en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OdaNaohiro en-aut-sei=Oda en-aut-mei=Naohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=InoueKoji en-aut-sei=Inoue en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TamuraTomoki en-aut-sei=Tamura en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyozawaRyo en-aut-sei=Toyozawa en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HaradaDaijiro en-aut-sei=Harada en-aut-mei=Daijiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaKentaro en-aut-sei=Tanaka en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=InoueKoji en-aut-sei=Inoue en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ShioyamaYoshiyuki en-aut-sei=Shioyama en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=GembaKenichi en-aut-sei=Gemba en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SasakiTomonari en-aut-sei=Sasaki en-aut-mei=Tomonari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=BesshoAkihiro en-aut-sei=Bessho en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KishimotoJunji en-aut-sei=Kishimoto en-aut-mei=Junji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KatsuiKuniaki en-aut-sei=Katsui en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SugioKenji en-aut-sei=Sugio en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Respiratory Medicine, Kumamoto University Hospital kn-affil= affil-num=2 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Kumamoto University Hospital kn-affil= affil-num=4 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Kitakyushu Municipal Medical Center kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=10 en-affil=Department of Respiratory Medicine, Ehime Prefectural Central Hospital kn-affil= affil-num=11 en-affil=Radiation Oncology, Ion Beam Therapy Center, SAGA HIMAT Foundation kn-affil= affil-num=12 en-affil=Department of Respiratory Medicine, Chugoku Central Hospital kn-affil= affil-num=13 en-affil=Department of Radiation Oncology, Iizuka Hospital kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital kn-affil= affil-num=15 en-affil=Center for Clinical and Translational Research, Kyushu University Hospital kn-affil= affil-num=16 en-affil=Department of Radiology, Division of Radiation Oncology, Kawasaki Medical School kn-affil= affil-num=17 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=18 en-affil=Thoracic and Breast Surgery, Oita University kn-affil= en-keyword=chemoradiotherapy kn-keyword=chemoradiotherapy en-keyword=egfr kn-keyword=egfr en-keyword=locally advanced setting kn-keyword=locally advanced setting en-keyword=non-small cell lung cancer kn-keyword=non-small cell lung cancer en-keyword=progression kn-keyword=progression en-keyword=retreatment kn-keyword=retreatment en-keyword=safety kn-keyword=safety en-keyword=targeted therapy kn-keyword=targeted therapy END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=14 article-no= start-page=2155 end-page=2159 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250715 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Myeloid Sarcoma in the Small Intestine en-subtitle= kn-subtitle= en-abstract= kn-abstract=Myeloid sarcoma is a rare extramedullary tumor of immature myeloid cells that is often associated with acute myeloid leukemia (AML). We herein report an 81-year-old man who presented with intestinal obstruction due to myeloid sarcoma of the small intestine. Diagnostic challenges were overcome using double-balloon enteroscopy and a biopsy, which confirmed the diagnosis of myeloid sarcoma. The patient subsequently developed AML but responded well to chemotherapy. This case underscores the importance of considering myeloid sarcoma in the differential diagnosis of small-bowel tumors. Highlighting the significance of a histological analysis, even in patients presenting with small bowel obstruction, the early diagnosis and treatment are crucial for improving outcomes, particularly in patients without a history of hematologic malignancies. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KamioTomohiro en-aut-sei=Kamio en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HirataShoichiro en-aut-sei=Hirata en-aut-mei=Shoichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsuedaKatsunori en-aut-sei=Matsueda en-aut-mei=Katsunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KametakaDaisuke en-aut-sei=Kametaka en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KawanoSeiji en-aut-sei=Kawano en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=acute myeloid leukemia kn-keyword=acute myeloid leukemia en-keyword=double-balloon enteroscopy kn-keyword=double-balloon enteroscopy en-keyword=myeloid sarcoma kn-keyword=myeloid sarcoma en-keyword=small intestine kn-keyword=small intestine END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=2 article-no= start-page=363 end-page=368 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250304 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Microsatellite-high intrahepatic cholangiocarcinoma with favorable treatment outcome using pembrolizumab en-subtitle= kn-subtitle= en-abstract= kn-abstract=Intrahepatic cholangiocarcinoma has a poor prognosis. In unresectable cases, the survival period is short despite combination therapy with cytotoxic anticancer agents and immune checkpoint inhibitors. The usefulness of immune checkpoint inhibitors against malignant tumors with microsatellite instability-high (MSI-H) mutations was shown in the KEYNOTE158 study; however, data for intrahepatic cholangiocarcinoma are insufficient. In the present case, a 65-year-old man with intrahepatic cholangiocarcinoma and lymph node metastasis could not be treated with a combination of gemcitabine, CDDP, and S-1. A comprehensive cancer genomic profiling (CGP) test showed MLH1 pathogenic mutation and MSI-H. When pembrolizumab was administered, the tumor shrinkage effect was rapidly observed, which was sustained even after 30 months. No pathogenic mutations were observed in the germline test, and MSI-high was considered to be due to the MLH1 pathogenic mutation occurring sporadically in somatic cells. MSI-H intrahepatic cholangiocarcinoma is extremely rare. However, because pembrolizumab is expected to be effective, CGP testing should be actively performed. en-copyright= kn-copyright= en-aut-name=HoriguchiShigeru en-aut-sei=Horiguchi en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatoHironari en-aut-sei=Kato en-aut-mei=Hironari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MiyamotoKazuya en-aut-sei=Miyamoto en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MorimotoKosaku en-aut-sei=Morimoto en-aut-mei=Kosaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsumiAkihiro en-aut-sei=Matsumi en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TerasawaHiroyuki en-aut-sei=Terasawa en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FujiiYuki en-aut-sei=Fujii en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsumotoKazuyuki en-aut-sei=Matsumoto en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= en-keyword=Microsatellite instability (MSI)-high kn-keyword=Microsatellite instability (MSI)-high en-keyword=Tumor mutation burden (TMB)-high kn-keyword=Tumor mutation burden (TMB)-high en-keyword=Intrahepatic cholangiocarcinoma kn-keyword=Intrahepatic cholangiocarcinoma en-keyword=Comprehensive genome profiling kn-keyword=Comprehensive genome profiling END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=2 article-no= start-page=e79651 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250225 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gastric Metastasis of Renal Cell Carcinoma Initially Diagnosed by Esophagogastroduodenoscopy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Here, we report a rare case of renal cell carcinoma (RCC) initially detected as a gastric metastasis. A 58-year-old man with epigastric discomfort underwent esophagogastroduodenoscopy, which revealed a reddish semi-pedunculated lesion with a whitish coating. Biopsy and imaging confirmed clear cell RCC metastasis. Contrast-enhanced computed tomography (CT) revealed a primary renal tumor with pancreatic and lymph node metastases. Despite chemotherapy treatment, the patient died after 10 months. Gastric metastases from RCC, although rare, should be considered in highly vascular gastric lesions with white coatings. Clinicians must be vigilant for metastatic diseases with atypical gastric findings. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KamioTomohiro en-aut-sei=Kamio en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HirataShoichiro en-aut-sei=Hirata en-aut-mei=Shoichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=clear renal cell carcinoma kn-keyword=clear renal cell carcinoma en-keyword=esophagogastroduodenoscopy (egd) kn-keyword=esophagogastroduodenoscopy (egd) en-keyword=gastric metastasis kn-keyword=gastric metastasis en-keyword=metastatic tumor, renal cell carcinoma (rcc) kn-keyword=metastatic tumor, renal cell carcinoma (rcc) END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=1 article-no= start-page=57 end-page=66 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Piezo1-mediated mechanotransduction in cementocytes via protein kinase B and p38 mitogen-activated protein kinase signaling en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/purpose: Cementocytes, terminally differentiated cells embedded within cellular cementum, are morphologically similar to osteocytes; however, their mechanosensory function remains poorly understood. This study aimed to investigate whether Piezo1, a mechanosensitive ion channel, contributes to the regulation of osteo/cementogenic gene expression in murine cementocyte-like IDG-CM6 cells.
Materials and methods: IDG-CM6 cells were subjected to cyclic stretch or treated with Piezo1-specific agonist Yoda1 or antagonist GsMTx4. Expression levels of osteo/cementogenic genes (Wnt1, Sost, Opg) and protein levels were analyzed. The involvement of intracellular signaling pathways was assessed using pharmacological inhibitors targeting mitogen-activated protein kinase and protein kinase B (PKB/AKT) pathways.
Results: Cyclic stretch upregulated Wnt1 and Opg, and downregulated Sost expression, without altering Piezo1 expression, suggesting an enhanced osteo/cementogenic potential. These effects were abolished by GsMTx4 and closely mimicked by Yoda1 stimulation. The Yoda1-induced gene expression changes were transient and diminished after withdrawal. Inhibitor experiments confirmed that Piezo1-mediated gene expression is modulated primarily through the AKT and p38 signaling pathways. Phosphorylation of AKT and p38 was rapidly induced by cyclic stretch.
Conclusion: Our findings demonstrate that Piezo1 functions as a mechanosensor in cementocytes, modulating the expression of osteo/cementogenic genes via the AKT and p38 pathways. This study provides new insight into the molecular mechanisms of cementocyte mechanotransduction and may inform strategies for periodontal regeneration and orthodontic treatment. en-copyright= kn-copyright= en-aut-name=XiongKaixin en-aut-sei=Xiong en-aut-mei=Kaixin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakisakaYukihiko en-aut-sei=Sakisaka en-aut-mei=Yukihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TenkumoTaichi en-aut-sei=Tenkumo en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NemotoEiji en-aut-sei=Nemoto en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MaruyamaKentaro en-aut-sei=Maruyama en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MuhammadFaisal en-aut-sei=Muhammad en-aut-mei=Faisal kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SuzukiShigeki en-aut-sei=Suzuki en-aut-mei=Shigeki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TadaHiroyuki en-aut-sei=Tada en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YamadaSatoru en-aut-sei=Yamada en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Stomatology, Chengdu Integrated TCM and Western Medicine Hospital (Chengdu First People’s Hospital) kn-affil= affil-num=2 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=3 en-affil=Division of Advanced Prosthetic Dentistry, Tohoku University Graduate School of Dentistry kn-affil= affil-num=4 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=5 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=6 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=7 en-affil=Department of Operative Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Division of Oral Microbiology and Immunology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=9 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= en-keyword=Cementocytes kn-keyword=Cementocytes en-keyword=Mechanotransduction kn-keyword=Mechanotransduction en-keyword=Piezo1 kn-keyword=Piezo1 en-keyword=Signal transduction kn-keyword=Signal transduction END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=5 article-no= start-page=372 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260224 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Periodontal disease damages the tissues that support teeth and can ultimately lead to tooth loss, yet effective treatments to regenerate these tissues are still limited. Recent studies have shown that substances produced during normal cellular metabolism can influence how genes are regulated, but their role in periodontal regeneration has not been fully clarified. In this study, we investigated whether alpha-ketoglutarate, a naturally occurring metabolite involved in energy production, could promote periodontal tissue regeneration. We found that alpha-ketoglutarate enhanced bone-related and extracellular matrix-related gene expression in human periodontal ligament cells by reducing a repressive gene-regulatory signal that normally suppresses these genes. Importantly, alpha-ketoglutarate did not broadly alter chromatin accessibility, indicating that its effects were mediated through selective gene regulation. Furthermore, oral administration of alpha-ketoglutarate promoted alveolar bone regeneration and collagen-rich tissue formation in a mouse model of periodontal disease. Because alpha-ketoglutarate is a naturally occurring molecule in the body, these findings suggest that metabolite-based regulation of gene activity may represent a promising and safe approach for periodontal tissue regeneration. en-copyright= kn-copyright= en-aut-name=HasegawaRyu en-aut-sei=Hasegawa en-aut-mei=Ryu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SuzukiShigeki en-aut-sei=Suzuki en-aut-mei=Shigeki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FahrezaRahmad Rifqi en-aut-sei=Fahreza en-aut-mei=Rahmad Rifqi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TsaiShin-Ho en-aut-sei=Tsai en-aut-mei=Shin-Ho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=DaidoujiYoshino en-aut-sei=Daidouji en-aut-mei=Yoshino kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OmoriMasato en-aut-sei=Omori en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KajikawaTetsuhiro en-aut-sei=Kajikawa en-aut-mei=Tetsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamadaSatoru en-aut-sei=Yamada en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=2 en-affil=Department of Operative Dentistry, Okayama University Graduate School, Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=4 en-affil=Department of Operative Dentistry, Okayama University Graduate School, Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=6 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=7 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=8 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= en-keyword=alpha-ketoglutarate kn-keyword=alpha-ketoglutarate en-keyword=periodontal ligament kn-keyword=periodontal ligament en-keyword=extracellular matrix kn-keyword=extracellular matrix en-keyword=epigenetic regulation kn-keyword=epigenetic regulation en-keyword=H3K27me3 kn-keyword=H3K27me3 END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=4 article-no= start-page=715 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260223 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Antigen Remodeling in Colorectal Cancer: How Radiotherapy and Chemotherapy Enhance Immunotherapy Responsiveness en-subtitle= kn-subtitle= en-abstract= kn-abstract=Colorectal cancer (CRC) is traditionally considered a “cold tumor” characterized by low immunogenicity and limited responsiveness to immune checkpoint inhibitors (ICIs). However, recent findings reveal that cytotoxic modalities can reprogram this immunologically inert landscape. This review integrates these evolving concepts to guide the optimization of future treatments. Radiotherapy induces extensive DNA double-strand breaks, which may generate de novo mutations through error-prone repair while simultaneously exposing cryptic antigens via increased transcriptional instability, alternative splicing, and enhanced proteasomal processing. Chemoradiation also amplifies epigenetic and epitranscriptomic sources of neoepitope diversity, including RNA editing and stress-induced splicing alterations, expanding the immunopeptidome beyond canonical mutation-driven neoantigens. These changes collectively enhance antigen presentation and facilitate T-cell priming. Chemotherapy further reduces immunosuppressive cell populations and promotes dendritic cell activation, creating a permissive milieu for subsequent immune engagement. Clinically, the VOLTAGE studies demonstrated that long-course chemoradiotherapy can sensitize even mismatch repair–proficient rectal cancers to PD-1 blockade, yielding clinically meaningful pathological responses. In contrast, mismatch repair–deficient rectal tumors may respond completely to ICIs alone. Short-course radiotherapy combined with chemotherapy and ICIs has also shown encouraging activity in the setting of total neoadjuvant therapy. Collectively, these findings support a paradigm in which radiotherapy, chemotherapy, and epigenetic/epitranscriptomic alterations—including RNA editing—act as potent modulators of tumor antigenicity. By expanding the neoantigen repertoire and reshaping the tumor microenvironment, these strategies can transform CRC from a cold tumor into one that is increasingly responsive to immunotherapy. en-copyright= kn-copyright= en-aut-name=MatsumiYuki en-aut-sei=Matsumi en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakahashiToshiaki en-aut-sei=Takahashi en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MoriwakeKazuya en-aut-sei=Moriwake en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KayanoMasashi en-aut-sei=Kayano en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=colorectal cancer kn-keyword=colorectal cancer en-keyword=immunotherapy kn-keyword=immunotherapy en-keyword=radiotherapy kn-keyword=radiotherapy en-keyword=chemotherapy kn-keyword=chemotherapy en-keyword=neoantigens kn-keyword=neoantigens END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260221 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Turning pancreatic cancer from cold to hot: the promise of a p53-expressing oncolytic adenovirus (OBP-702) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and poor responsiveness to immune checkpoint inhibitors (ICIs). This resistance is largely attributed to its profoundly immunosuppressive and desmoplastic tumor microenvironment (TME), characterized by low tumor mutational burden, dense stroma, and abundant immunosuppressive cell populations. Therefore, strategies capable of enhancing tumor immunogenicity and overcoming immune evasion are urgently needed. Oncolytic virotherapy is a promising approach, offering not only tumor-selective cytotoxicity, but also potent immunomodulatory effects. Of these agents, Telomelysin (OBP-301, Suratadenoturev), a telomerase-specific oncolytic adenovirus, demonstrated clinical safety but limited efficacy in refractory tumors. To address this challenge, we developed OBP-702, a next-generation, p53-armed, oncolytic adenovirus designed to augment antitumor activity. Preclinical studies have shown that OBP-702 exerts robust cytotoxicity through multiple mechanisms, including p53-mediated apoptosis and autophagy, E1A–E2F1-mediated p21 suppression, and inhibition of oncogenic KRAS pathways. Importantly, OBP-702 induces strong immunogenic cell death, activates dendritic cells, and promotes tumor-specific T-cell responses, effectively converting immunologically “cold” pancreatic tumors into “hot” tumors. OBP-702 also remodels the immunosuppressive TME by reducing granulocyte–macrophage colony-stimulating factor (GM-CSF) secretion, suppressing myeloid-derived suppressor cells (MDSCs), and targeting stromal components, such as cancer-associated fibroblasts (CAFs). These effects contribute to enhanced responses to ICIs and standard chemotherapies. Given its multifaceted antitumor functions and ability to overcome key barriers in pancreatic cancer, OBP-702 represents a highly promising therapeutic candidate. A first-in-human clinical trial evaluating endoscopic ultrasonography-guided intratumoral injection of OBP-702 is currently in preparation, expected to advance clinical translation of this novel virotherapeutic strategy. en-copyright= kn-copyright= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HashimotoMasashi en-aut-sei=Hashimoto en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KanayaNobuhiko en-aut-sei=Kanaya en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KakiuchiYoshihiko en-aut-sei=Kakiuchi en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Oncolys BioPharma Inc kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Oncolytic adenovirus kn-keyword=Oncolytic adenovirus en-keyword=p53 kn-keyword=p53 en-keyword=OBP-702 kn-keyword=OBP-702 en-keyword=Immunogenic cell death kn-keyword=Immunogenic cell death en-keyword=Tumor microenvironment kn-keyword=Tumor microenvironment en-keyword=Pancreatic cancer kn-keyword=Pancreatic cancer END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260219 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Induction of IL-9-producing CD8+ T cells by ascochlorin derivatives en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Purpose: Ascochlorin (ASC) is an antiviral antibiotic from the fermented broth of Ascochyta viciae which exerts an inhibitory effect to cancers. Its impact on immune cells has not been examined. In this study, we obtained ASC derivatives with less cytotoxicity and determined whether they affected T cells, indicating possible immune-mediated antitumour effects.
Experimental Approach: Newly synthesised ASC derivatives were screened for inhibitory effects on T-cell antigen receptor (TCR)-stimulated proliferative responses using murine CD4+ and CD8+ T cells. Two compounds were identified that exhibited >10-fold less toxicity compared with ASC. N184, the less toxic of the two, was analysed for its in vivo antitumour effects, and in vitro effects on CD8+ T-cell proliferation, survival, cytokine production and exhaustion, using microscopy, qPCR and flow cytometry.
Key Results: N184 induced limited IL-9 production in CD8+ T cells following TCR stimulation, thereby improving cell survival. It also enhanced cytokine production in the late phase of proliferation and suppressed the induction of exhaustion. N184 suppressed tumour growth in mice in a CD8+ T cell-dependent manner. The effect was partially prevented by an IL-9-neutralising antibody.
Conclusion and Implications: N184 induces differentiation of IL-9-producing CD8+ T cells in vitro and elicits antitumour immunity in an IL-9-dependent manner. en-copyright= kn-copyright= en-aut-name=ImanoNatsumi en-aut-sei=Imano en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishidaMikako en-aut-sei=Nishida en-aut-mei=Mikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TokumasuMiho en-aut-sei=Tokumasu en-aut-mei=Miho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZhaoWeiyang en-aut-sei=Zhao en-aut-mei=Weiyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamashitaNahoko en-aut-sei=Yamashita en-aut-mei=Nahoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UdonoHeiichiro en-aut-sei=Udono en-aut-mei=Heiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Immunology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Immunology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Immunology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=ascochlorin derivative kn-keyword=ascochlorin derivative en-keyword=CD8 positive T lymphocytes kn-keyword=CD8 positive T lymphocytes en-keyword=cell survival kn-keyword=cell survival en-keyword=IFN-γ kn-keyword=IFN-γ en-keyword=interleukin-9 kn-keyword=interleukin-9 en-keyword=Tc9 kn-keyword=Tc9 en-keyword=tumour immunity kn-keyword=tumour immunity END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue= article-no= start-page=1673581 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260107 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Binding of IgA1 and surface-expressed collagen-binding protein of Streptococcus mutans contributes to IgA nephropathy pathogenesis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: The present study was conducted to examine the interaction between collagen-binding protein (Cnm) of Streptococcus mutans and immunoglobulin (IgA) to clarify the possible involvement in IgA nephropathy (IgAN) development.
Methods: The binding of Cnm to human immunoglobulins was examined using an enzyme-linked immunosorbent assay. A nephritis-induced rat model was employed to confirm the localization of Cnm.
Results: IgA1 showed significantly greater binding ability to Cnm than to other bacterial surface proteins, and Cnm showed significantly greater binding ability to IgA1 than to other immunoglobulins. In rats administered Cnm, IgA deposition was observed in the glomerular mesangial region. Furthermore, biotin-labeled Cnm was observed in the same region as IgA deposition in the Cnm group.
Conclusions: Taken together, it is considered that following invasion into the bloodstream, Cnm binds to and forms a complex with IgA1, leading to deposition of IgA1 in renal glomeruli. en-copyright= kn-copyright= en-aut-name=MatsuokaDaiki en-aut-sei=Matsuoka en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SueharaKana en-aut-sei=Suehara en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakaShuhei en-aut-sei=Naka en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MisakiTaro en-aut-sei=Misaki en-aut-mei=Taro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NagasawaYasuyuki en-aut-sei=Nagasawa en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ItoSeigo en-aut-sei=Ito en-aut-mei=Seigo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SuehiroYuto en-aut-sei=Suehiro en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NomuraRyota en-aut-sei=Nomura en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NakanoKazuhiko en-aut-sei=Nakano en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=Matsumoto-NakanoMichiyo en-aut-sei=Matsumoto-Nakano en-aut-mei=Michiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Nephrology, Seirei Hamamatsu General Hospital kn-affil= affil-num=5 en-affil=Department of General Internal Medicine, Hyogo Medical University kn-affil= affil-num=6 en-affil=Department of Internal Medicine, Japan Self-Defense Force Iruma Hospital kn-affil= affil-num=7 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=8 en-affil=Department of Pediatric Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=9 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=10 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=bacterial surface proteins kn-keyword=bacterial surface proteins en-keyword=collagen-binding protein kn-keyword=collagen-binding protein en-keyword=human immunoglobulins kn-keyword=human immunoglobulins en-keyword=IgA nephropathy kn-keyword=IgA nephropathy en-keyword=Streptococcus mutans kn-keyword=Streptococcus mutans END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=1 article-no= start-page=69 end-page=74 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effective Treatment of Advanced Hepatocellular Carcinoma with Extensive Peritoneal Dissemination Using Lenvatinib en-subtitle= kn-subtitle= en-abstract= kn-abstract=Patients with hepatocellular carcinoma (HCC) and extensive peritoneal dissemination generally have a poor prognosis and are often resistant to systemic therapy. We report the case of a 47-year-old woman with HCC and massive peritoneal dissemination who presented with malignant ascites requiring repeated cell-free and concentrated ascites reinfusion therapy and peritoneovenous shunt placement, as well as malignant pleural effusion requiring pleurodesis. Combined immunotherapy with durvalumab/tremelimumab was initiated;however, disease progression was observed after three treatment courses, prompting a switch to lenvatinib therapy. Two months after initiation of lenvatinib, CT imaging demonstrated complete disappearance of arterial enhancement in the primary hepatic lesion, along with reduction in the size of peritoneal dissemination nodules. Thirteen months after switching to lenvatinib (16 months after the initial diagnosis), the alpha-fetoprotein level continued to decrease, and the disease remained stable under treatment. Despite the extremely high tumor burden, lenvatinib achieved disease stabilization and symptomatic improvement. en-copyright= kn-copyright= en-aut-name=WakatsukiShinya en-aut-sei=Wakatsuki en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakamotoShinya en-aut-sei=Sakamoto en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UenoAkiko en-aut-sei=Ueno en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NambaTakaomi en-aut-sei=Namba en-aut-mei=Takaomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamamotoYorito en-aut-sei=Yamamoto en-aut-mei=Yorito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MatsumotoManabu en-aut-sei=Matsumoto en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IwataJun en-aut-sei=Iwata en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OkabayashiTakehiro en-aut-sei=Okabayashi en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Kochi Health Sciences Center kn-affil= affil-num=3 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=4 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=5 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=6 en-affil=Department of Diagnostic Pathology, Kochi Health Sciences Center kn-affil= affil-num=7 en-affil=Department of Diagnostic Pathology, Kochi Health Sciences Center kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Kochi Health Sciences Center kn-affil= en-keyword=diagnostic laparoscopy kn-keyword=diagnostic laparoscopy en-keyword=hepatocellular carcinoma kn-keyword=hepatocellular carcinoma en-keyword=peritoneal dissemination kn-keyword=peritoneal dissemination en-keyword=lenvatinib kn-keyword=lenvatinib END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=1 article-no= start-page=63 end-page=67 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Metastatic Intraocular Tumor Likely from Hepatocellular Carcinoma Mimicking Panuveitis en-subtitle= kn-subtitle= en-abstract= kn-abstract=A 77-year-old man undergoing treatment for hepatocellular carcinoma (HCC) presented with blurred vision in his right eye, persisting for 2 months. Slit-lamp microscopy and fundus examination revealed inflammatory cells in the anterior chamber, severe vitreous opacities, and retinal vasculitis in the right eye. The patient underwent vitreous surgery with biopsy, and vitreous cytology confirmed a metastatic intraocular tumor originating from the HCC. Radiotherapy was administered to the right eye, with no recurrence of intraocular inflammation observed at 10 months post-irradiation. en-copyright= kn-copyright= en-aut-name=TakasuEri en-aut-sei=Takasu en-aut-mei=Eri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShiodeYusuke en-aut-sei=Shiode en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KindoHiroya en-aut-sei=Kindo en-aut-mei=Hiroya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KimuraShuhei en-aut-sei=Kimura en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HosokawaMio en-aut-sei=Hosokawa en-aut-mei=Mio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MatobaRyo en-aut-sei=Matoba en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KanzakiYuki en-aut-sei=Kanzaki en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MoritaTetsuro en-aut-sei=Morita en-aut-mei=Tetsuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AdachiTakuya en-aut-sei=Adachi en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MorizaneYuki en-aut-sei=Morizane en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=metastatic intraocular tumor kn-keyword=metastatic intraocular tumor en-keyword=hepatocellular carcinoma kn-keyword=hepatocellular carcinoma en-keyword=panuveitis kn-keyword=panuveitis en-keyword=uveitis masquerade syndrome kn-keyword=uveitis masquerade syndrome END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=1 article-no= start-page=55 end-page=62 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Changes in Prescribing Patterns of Antiviral Drugs before and after Public Coverage Termination among Hospitalized COVID-19 Patients in Regional Hospitals in Japan: A Retrospective, Multicenter Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=In Japan, antiviral agents for COVID-19 were freely available until September 2023 as part of national policy. This study evaluated changes in these agents’ prescribing patterns and the patient outcomes following the policy shift. We conducted a multicenter retrospective study at four hospitals in Japan’s Okayama and Kagawa prefectures from January 2022 to March 2024. The study period was divided into the public-expenditure phase (January 2022 to September 2023) and the post-expenditure phase (October 2023 to March 2024). We extracted the hospitalized patients’ clinical data from the electronic database. The study’s primary outcome was the antiviral prescription rate; the secondary outcome was in-hospital mortality. Among the 302 hospitalized patients (median age 85 years), 52.0% were classified as having a mild condition. Of the patients with mild conditions, 37.7% were diagnosed in outpatient settings prior to hospitalization. During the public-expenditure phase, 47.4% of the patients received antivirals as outpatients, mainly molnupiravir (80.9%). In the post-expenditure period, 80.0% of the patients were prescribed antivirals, mostly molnupiravir (91.7%). The antiviral prescription rate was significantly higher after the policy change. The overall in-hospital mortality was 15.8%, with no significant difference between the two periods (17.0% vs. 10.5%). Despite the termination of government funding, antiviral prescriptions remained frequent at community hospitals located in highly aging regions of western Japan such as Okayama and Kagawa prefectures. Mortality remains high among the elderly, highlighting the need for continued antiviral therapy and booster vaccinations. en-copyright= kn-copyright= en-aut-name=AkazawaHidemasa en-aut-sei=Akazawa en-aut-mei=Hidemasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HagiyaHideharu en-aut-sei=Hagiya en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukushimaShinnosuke en-aut-sei=Fukushima en-aut-mei=Shinnosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamotoShohei en-aut-sei=Yamamoto en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakanoYasuhiro en-aut-sei=Nakano en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= affil-num=2 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= affil-num=5 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= affil-num=6 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= en-keyword=coronavirus disease 2019 kn-keyword=coronavirus disease 2019 en-keyword=public expenditure kn-keyword=public expenditure en-keyword=prescribing pattern kn-keyword=prescribing pattern en-keyword=prognosis kn-keyword=prognosis en-keyword=Japan kn-keyword=Japan END start-ver=1.4 cd-journal=joma no-vol=33 cd-vols= no-issue=4 article-no= start-page=201045 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Collagen depletion by pirfenidone enhances antitumor effect of oncolytic adenovirus against peritoneal metastases of gastric cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cancer-associated fibroblasts (CAFs) play a crucial role in collagen accumulation, which develops and promotes peritoneal metastasis (PM) in gastric cancer (GC). In addition, the abundant stromal collagens in the tumor microenvironment function as a physical barrier against penetration of antitumor drugs and oncolytic viruses. This study investigated whether collagen depletion by pirfenidone (PFD), an antifibrotic drug, enhances the antitumor effects of oncolytic adenoviruses. Analysis of the clinical samples revealed a significant association of high expression of collagen 1 and α-smooth muscle actin (α-SMA) with PM development and poor prognosis of advanced GC. Human and murine GC cells enhanced collagen production by fibroblasts, which was suppressed by PFD. Abundant fibroblasts and collagen inhibited the penetration of OBP-702, which reduced the antitumor effects of OBP-702 in the spheroid model. Intraperitoneal co-injection of GC cells and fibroblasts promoted the development of collagen-rich PM and reduced the antitumor effects of OBP-702 in vivo model. PFD suppressed collagen production in PM and improved viral penetration into the tumors, which enhanced the antitumor effects of OBP-702 against PM of GC. Collagen depletion by PFD enhances the penetration of OBP-702 into PM of GC, in turn enhancing the antitumor effects of OBP-702 against PM of GC. en-copyright= kn-copyright= en-aut-name=OkuraTomohiro en-aut-sei=Okura en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KikuchiSatoru en-aut-sei=Kikuchi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MikaneYu en-aut-sei=Mikane en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KanayaNobuhiko en-aut-sei=Kanaya en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MitsuiEma en-aut-sei=Mitsui en-aut-mei=Ema kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UneYuta en-aut-sei=Une en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NomaKazuhiro en-aut-sei=Noma en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OhtsukaJunko en-aut-sei=Ohtsuka en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OhkiRieko en-aut-sei=Ohki en-aut-mei=Rieko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Laboratory of Fundamental Oncology, National Cancer Center Research Institute kn-affil= affil-num=13 en-affil=Laboratory of Fundamental Oncology, National Cancer Center Research Institute kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil= Oncolys BioPharma, Inc. kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=MT: Regular Issue kn-keyword=MT: Regular Issue en-keyword=oncolytic virotherapy kn-keyword=oncolytic virotherapy en-keyword=peritoneal metastasis kn-keyword=peritoneal metastasis en-keyword=gastric cancer kn-keyword=gastric cancer en-keyword=collagen kn-keyword=collagen en-keyword=pirfenidone kn-keyword=pirfenidone END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=1 article-no= start-page=9 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260212 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Influence of Fluidic Flow Stress on the Development of the Secondary Palate en-subtitle= kn-subtitle= en-abstract= kn-abstract=Craniofacial development is orchestrated by a finely regulated interplay of numerous genes and signaling pathways. Palatogenesis proceeds through a complex, stepwise process, in which endogenous mechanical stresses within tissues have been implicated. However, the impact of exogenous fluidic flow mechanical stress derived from maternal movement on palatal development remains unclear. In this study, we investigated the effect of exogenous fluidic flow mechanical stress on palatal morphogenesis, focusing on the horizontal outgrowth of palatal shelves after elevation. Palatal tissues dissected from mouse embryos were subjected to organ culture with or without mechanical loading (loaded and unloaded groups, respectively). Stress magnitude was quantified by calculating wave energy, and morphometric and molecular analyses were performed. Compared with the unloaded group, palatal shelves in the loaded group showed significant increases in thickness and volume, accompanied by enhanced cell proliferation, nuclear translocation of YAP and β-catenin, and upregulation of the osteogenic markers Osterix and Osteocalcin. No significant difference in apoptosis was observed. These findings indicate that exogenous mechanical stress promotes cell proliferation and osteogenic differentiation through the Hippo and WNT/β-catenin pathways in palate explants. Our results suggest that moderate maternal movement-induced mechanical stress contributes to normal palatogenesis, providing new insights into the mechanisms underlying cleft palate. en-copyright= kn-copyright= en-aut-name=NagataMasayo en-aut-sei=Nagata en-aut-mei=Masayo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HayanoSatoru en-aut-sei=Hayano en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KosamiTakahiro en-aut-sei=Kosami en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Orthodontics, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Orthodontics, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=mechanical stress kn-keyword=mechanical stress en-keyword=palatal development kn-keyword=palatal development en-keyword=β-catenin kn-keyword=β-catenin en-keyword=YAP kn-keyword=YAP END start-ver=1.4 cd-journal=joma no-vol=178 cd-vols= no-issue=1 article-no= start-page=e70775 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Reactive Carbonyl Species Mediate Isothiocyanate Signaling Pathway in Arabidopsis thaliana Guard Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Our previous results demonstrated that depletion of glutathione (GSH) rather than elevation of levels of reactive oxygen species (ROS) is highly correlated with the decrease in stomatal aperture induced by isothiocyanates (ITCs), although ROS is considered a key second messenger in stomatal closure, suggesting that another signal component regulates stomatal apertures along with GSH depletion. This study, using Arabidopsis, clarified that reactive carbonyl species (RCS), especially acrolein and 4-hydroxy-(E)-2-nonenal, are determinants of stomatal aperture responses to ITCs. All tested ITCs, allyl isothiocyanate (AITC), sulforaphane (SFN), benzyl isothiocyanate (BITC), and phenethyl isothiocyanate (PEITC), significantly induced stomatal closure, which was inhibited by the RCS scavengers, carnosine and pyridoxamine. The RCS scavengers suppressed ITC-induced depletion of GSH but not elevation of ROS levels. All tested ITCs (AITC, SFN, BITC, and PEITC) increased levels of RCS and non-RCS aldehydes in the epidermal tissues. However, acrolein, 4-hydroxy-(E)-2-nonenal, crotonaldehyde, and (E)-2-pentenal induced stomatal closure at 10 and 100 μM, whereas propionaldehyde, butyraldehyde, and n-pentanal did not at concentrations up to 100 μM. Acrolein and 4-hydroxy-(E)-2-nonenal more effectively induced stomatal closure and GSH depletion than crotonaldehyde and (E)-2-pentenal did. The contents of RCS were more strongly correlated with GSH levels and stomatal closure than with ROS levels. These results suggest that RCS, especially acrolein and 4-hydroxy-(E)-2-nonenal, acts as key regulators of stomatal closure in guard cells in response to ITCs. en-copyright= kn-copyright= en-aut-name=FarzanaSumaiya en-aut-sei=Farzana en-aut-mei=Sumaiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IslamMd. Moshiul en-aut-sei=Islam en-aut-mei=Md. Moshiul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakamuraToshiyuki en-aut-sei=Nakamura en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakamuraYoshimasa en-aut-sei=Nakamura en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MunemasaShintaro en-aut-sei=Munemasa en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ManoJun'ichi en-aut-sei=Mano en-aut-mei=Jun'ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MurataYoshiyuki en-aut-sei=Murata en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=6 en-affil=Science Research Center, Yamaguchi University kn-affil= affil-num=7 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=arabidopsis kn-keyword=arabidopsis en-keyword=GSH depletion kn-keyword=GSH depletion en-keyword=isothiocyanate kn-keyword=isothiocyanate en-keyword=reactive carbonyl species kn-keyword=reactive carbonyl species en-keyword=reactive oxygen species kn-keyword=reactive oxygen species END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=1 article-no= start-page=9 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260105 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Sodium butyrate augments the antibacterial activity of tetracycline against clinical isolates of multidrug-resistant Vibrio cholerae en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Antibiotic resistance poses a major challenge in treating Vibrio cholerae infections. One promising method to counter resistance is the co-administration of antibiotics with non-antibiotic adjuvants to enhance their efficacy. This study investigated the combined action of sodium butyrate (SB) and tetracycline on tetracycline-resistant V. cholerae strains.
Results The combined activity of SB and antibiotics was assessed on eight V. cholerae clinical isolates using the Fractional Inhibitory Concentration Index (FICI), with SB-Tetracycline showing strong synergy (FICI: 0.09–0.5). Functional and mechanistic studies, including time-kill kinetics, live/dead staining, SEM-based morphological analysis, and fluorometric assays, demonstrated a synergistic antibacterial effect of SB and Tetracycline. This effect was associated with increased membrane permeability, disruption of membrane integrity, dissipation of the proton motive force, and suppression of efflux activity. These changes collectively led to membrane damage, enhanced intracellular accumulation of Tetracycline, decreased intracellular ATP levels, and ultimately, bacterial cell death. Moreover, GM1-CT ELISA and fluorescence microscopy revealed the synergistic anti-virulence activity of the SB- Tetracycline combination. Finally, the combination of SB and Tetracycline showed enhanced efficacy in animal models compared with monotherapy.
Conclusion: The observed SB-Tetracycline synergy provides a promising therapeutic approach to overcome tetracycline resistance in V. cholerae, offering a potential adjunct strategy for the management of antibiotic-resistant cholera infections. en-copyright= kn-copyright= en-aut-name=KunduSushmita en-aut-sei=Kundu en-aut-mei=Sushmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AluSourin en-aut-sei=Alu en-aut-mei=Sourin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SinghAbhishek en-aut-sei=Singh en-aut-mei=Abhishek kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=GopeAnimesh en-aut-sei=Gope en-aut-mei=Animesh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NandyRanjan Kumar en-aut-sei=Nandy en-aut-mei=Ranjan Kumar kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MukhopadhyayAsish K. en-aut-sei=Mukhopadhyay en-aut-mei=Asish K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyoshiShin-ichi en-aut-sei=Miyoshi en-aut-mei=Shin-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ChatterjeeNabendu Sekhar en-aut-sei=Chatterjee en-aut-mei=Nabendu Sekhar kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BhattacharyaSushmita en-aut-sei=Bhattacharya en-aut-mei=Sushmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=2 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=3 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=4 en-affil=Division of General Medicine, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=5 en-affil=Division of Bacteriology, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=6 en-affil=Division of Bacteriology, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=7 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=9 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= en-keyword=V. cholerae kn-keyword=V. cholerae en-keyword=Sodium butyrate kn-keyword=Sodium butyrate en-keyword=Tetracycline kn-keyword=Tetracycline en-keyword=Synergy kn-keyword=Synergy en-keyword=Antibiotic adjuvant kn-keyword=Antibiotic adjuvant END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue= article-no= start-page=RP106917 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260205 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Dorsoventral-mediated Shh induction is required for axolotl limb regeneration en-subtitle= kn-subtitle= en-abstract= kn-abstract=Axolotls (Ambystoma mexicanum) exhibit a remarkable ability to regenerate limbs. Classical experiments have suggested that contact between cells derived from distinct orientations—dorsal, ventral, anterior, and posterior—within the regenerating blastema is necessary for accurate limb pattern formation. However, the molecular basis for this requirement has remained largely unknown. Here, we demonstrate that both dorsal and ventral tissues are required for limb formation via induction of Shh expression, which plays a crucial role in limb patterning. Using the accessory limb model, we induced position-specific blastemas lacking cells derived from a single orientation (anterior, posterior, dorsal, or ventral). Limb patterning occurred only in blastemas containing both dorsal- and ventral-derived cells. We further observed that Shh expression requires dorsoventral contact within a blastema, highlighting the necessity of dorsoventral contact for inducing Shh expression. Additionally, we identified WNT10B and FGF2 as dorsal- and ventral-mediated signals, respectively, that create the inductive environment for Shh expression. Our findings clarify the role of dorsal and ventral cells in inducing Shh, a mechanism that has rarely been studied in the context of limb regeneration and pattern formation. This model provides new insights into how cells with different positional identities drive the regeneration process. en-copyright= kn-copyright= en-aut-name=YamamotoSakiya en-aut-sei=Yamamoto en-aut-mei=Sakiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FurukawaSaya en-aut-sei=Furukawa en-aut-mei=Saya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiAyaka en-aut-sei=Ohashi en-aut-mei=Ayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HamadaMayuko en-aut-sei=Hamada en-aut-mei=Mayuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SatohAkira en-aut-sei=Satoh en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=2 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=3 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=4 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=5 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=12 article-no= start-page=5742 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250615 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Specific Heat-Killed Lactic Acid Bacteria Enhance Mucosal Aminopeptidase N Activity in the Small Intestine of Aged Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aminopeptidase N (APN), an enzyme expressed in the small intestinal mucosa, is involved in dietary protein digestion. Previous studies have shown that oral administration of fermented milk containing lactic acid bacteria (LAB) enhances mucosal APN activity in young mice. This study aimed to investigate whether LAB strains stimulate mucosal APN activity in aged mice and to evaluate its relevance to age-related changes in body composition. The underlying molecular mechanisms were also explored in vitro. Experiment 1: Aged C57BL/6J mice were fed diets supplemented with heat-killed LAB strains—Enterococcus faecalis OU-23 (EF), Leuconostoc mesenteroides OU-03 (LM), or Lactiplantibacillus plantarum SNK12 (LP). Compared to the aged Control group, the ileal APN activity was significantly higher in the LP group. LP administration also elevated serum Gla-osteocalcin levels and decreased serum CTX-1 levels. Experiment 2: IEC-6 cells were co-cultured with LP that had been treated with RNase, DNase, or lysozyme. APN activity was significantly lower in cells co-cultured with DNase- or lysozyme-treated LP compared to those co-cultured with untreated LP. A specific LAB strain may enhance mucosal APN activity in the aged intestine, potentially contributing to improved bone metabolism. This effect may be mediated by bacterial DNA and peptidoglycan. en-copyright= kn-copyright= en-aut-name=TsurutaTakeshi en-aut-sei=Tsuruta en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WakisakaMami en-aut-sei=Wakisaka en-aut-mei=Mami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeTakumi en-aut-sei=Watanabe en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishijimaAoi en-aut-sei=Nishijima en-aut-mei=Aoi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IkedaAkihito en-aut-sei=Ikeda en-aut-mei=Akihito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TeraokaMao en-aut-sei=Teraoka en-aut-mei=Mao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WangTianyang en-aut-sei=Wang en-aut-mei=Tianyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ChenKuiyi en-aut-sei=Chen en-aut-mei=Kuiyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NishinoNaoki en-aut-sei=Nishino en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Bio-Lab Co., Ltd. kn-affil= affil-num=4 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=aging kn-keyword=aging en-keyword=aminopeptidase N kn-keyword=aminopeptidase N en-keyword=bone metabolism kn-keyword=bone metabolism en-keyword=lactic acid bacteria kn-keyword=lactic acid bacteria en-keyword=small intestine kn-keyword=small intestine END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260202 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pediatric autologous peripheral blood stem cell collection without heparin using a highly concentrated sodium citrate anticoagulant: A retrospective comparison with standard ACD-A en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Heparin combined with sodium citrate has been used in leukocytapheresis for pediatric patients. Since 2022, we have performed leukocytapheresis using a highly concentrated sodium citrate solution (HSC, 5.32%) instead of acid citrate dextrose solution A (ACD-A). We conducted this study to determine whether HSC use reduces run time and the total amount of anticoagulant solution in children.
Study Design and Methods: We retrospectively analyzed data from consecutive autologous peripheral blood stem cell harvests (auto-PBSCHs) between June 2012 and May 2025, including patient characteristics, mobilization methods, protocol used, anticoagulant type, run time, total anticoagulant solution volume, and collection efficiency.
Results: Auto-PBSCH was performed using the mononuclear cell collection (MNC) protocol in 28 procedures and the continuous MNC protocol in 20 procedures. ACD-A was used in 35 procedures and HSC in 13. The run time was significantly shorter (204 [range, 117–302] vs. 157 min [range, 103–227], p = .02) in the HSC group and also confirmed in multivariable regression analysis (coefficient, −55.6; 95% confidence interval, −106.2 to −5.04; p = .03). In a subgroup analysis of cMNC procedures, CD34+ collection efficiency showed a strong negative correlation with the proportion of run time devoted to establishing the initial interface (r = −.73, p = .0003).
Conclusion: Delays in establishing the initial interface can reduce the duration of the effective MNC collection phase and may negatively affect collection efficiency. Careful attention to the initial interface phase is therefore warranted when using HSC. en-copyright= kn-copyright= en-aut-name=FujiiKeiko en-aut-sei=Fujii en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KitamuraWataru en-aut-sei=Kitamura en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WashioKana en-aut-sei=Washio en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IkeuchiKazuhiro en-aut-sei=Ikeuchi en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ShimonoJoji en-aut-sei=Shimono en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MurakamiHiroyuki en-aut-sei=Murakami en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Pediatrics, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Division of Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Hematology, Okayama University Hospital kn-affil= en-keyword=acid citrate dextrose solution kn-keyword=acid citrate dextrose solution en-keyword=autologous kn-keyword=autologous en-keyword=continuous mononuclear cell collection kn-keyword=continuous mononuclear cell collection en-keyword=highly concentrated sodium kn-keyword=highly concentrated sodium en-keyword=pediatric kn-keyword=pediatric en-keyword=peripheral blood stem cells kn-keyword=peripheral blood stem cells END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260120 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=SPRED2 suppresses the stemness of hepatocellular carcinoma through the p53/miR-506-3p/KLF4 pathway en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective: We previously reported that endogenous Sprouty-related, EVH1 domain-containing protein 2 (SPRED2), an inhibitor of the Ras/Raf/ERK-MAPK pathway, controls hepatocellular carcinoma (HCC) cell stemness by downregulating the expression of pluripotency factors, such as Nanog, c-Myc, and KLF4, in an ERK-dependent fashion. However, the exact mechanisms by which SPRED2 regulates HCC cell stemness have not been established.
Methods: Three human HCC cell lines [HepG2 (parental and SPRED2-deficient), HLE, and Hep3B] were used. Cells were transfected to downregulate or overexpress proteins. Western blot and RT-qPCR were used to evaluate the level of protein and mRNA expression. Co-immunoprecipitation and ChIP-qPCR were used to examine protein-protein interactions and the activation of gene transcription. Clinical HCC tissues were also used to validate in vitro data.
Results: KLF4 was identified as the major pluripotency factor responsible for SPRED2-mediated downregulation of HCC cell stemness and KLF4 expression was regulated by miR-506-3p. SPRED2 formed a protein complex with the tumor suppressor (p53) and upregulated miR-506 gene transcription by binding to the promoter region, resulting in subsequent downregulation of KLF4 mRNA expression. There was a negative correlation between KLF4 expression and miR-506-3p and a positive correlation between miR-506-3p expression and SPRED2 in human HCC samples, highlighting the relevance of the study findings.
Conclusions: The current study revealed a novel SPRED2/p53/miR-506-3p/KLF4 axis through which SPRED2 contributes to the suppression of HCC cell stemness and provides a potential new target to prevent HCC progression. en-copyright= kn-copyright= en-aut-name=GaoTong en-aut-sei=Gao en-aut-mei=Tong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ItoSachio en-aut-sei=Ito en-aut-mei=Sachio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Moh-Moh-AungAye en-aut-sei=Moh-Moh-Aung en-aut-mei=Aye kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangTianyi en-aut-sei=Wang en-aut-mei=Tianyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=FujisawaMasayoshi en-aut-sei=Fujisawa en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshimuraTeizo en-aut-sei=Yoshimura en-aut-mei=Teizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=SPRED2 kn-keyword=SPRED2 en-keyword=p53 kn-keyword=p53 en-keyword=KLF4 kn-keyword=KLF4 en-keyword=miR-506-3p kn-keyword=miR-506-3p en-keyword=stemness kn-keyword=stemness END start-ver=1.4 cd-journal=joma no-vol=45 cd-vols= no-issue=1 article-no= start-page=116781 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Immunopeptidomics combined with full-length transcriptomics uncovers diverse neoantigens en-subtitle= kn-subtitle= en-abstract= kn-abstract=Neoantigens are crucial for antitumor immunity and immune checkpoint inhibitor (ICI) efficacy by triggering strong immune responses. However, conventional methods for identifying neoantigens, such as whole-exon sequencing and short-read RNA sequencing (RNA-seq), appear to be insufficient, and the tumor mutational burden cannot sufficiently predict ICI efficacy. In this study, we employed a proteogenomic approach using long-read RNA-seq with Pacific Biosciences Single-Molecule Real-Time Sequencing technology to analyze full-length transcripts in combination with the human leukocyte antigen ligandome. As a result, many neoantigen candidates were identified, which were unregistered in a comprehensive database, including those from non-coding regions. Additionally, we validated the responses of specific T cell receptors (TCRs) to these candidates and identified several pairs of TCRs and neoantigens. These findings highlight the presence of more diverse neoantigens than expected that cannot be identified by conventional methods. en-copyright= kn-copyright= en-aut-name=IshinoTakamasa en-aut-sei=Ishino en-aut-mei=Takamasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WatanabeTomofumi en-aut-sei=Watanabe en-aut-mei=Tomofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TokitaSerina en-aut-sei=Tokita en-aut-mei=Serina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UedaYouki en-aut-sei=Ueda en-aut-mei=Youki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawaseKatsushige en-aut-sei=Kawase en-aut-mei=Katsushige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakanoYuka en-aut-sei=Takano en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ThuYin Min en-aut-sei=Thu en-aut-mei=Yin Min kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SuzukiYuta en-aut-sei=Suzuki en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OwaChie en-aut-sei=Owa en-aut-mei=Chie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=InozumeTakashi en-aut-sei=Inozume en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ZhouWenhao en-aut-sei=Zhou en-aut-mei=Wenhao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NagasakiJoji en-aut-sei=Nagasaki en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KochinVitaly en-aut-sei=Kochin en-aut-mei=Vitaly kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=UenoToshihide en-aut-sei=Ueno en-aut-mei=Toshihide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KojimaShinya en-aut-sei=Kojima en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=Honobe-TabuchiAkiko en-aut-sei=Honobe-Tabuchi en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KawamuraTatsuyoshi en-aut-sei=Kawamura en-aut-mei=Tatsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=OhnumaTakehiro en-aut-sei=Ohnuma en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=MatsuzawaTakamitsu en-aut-sei=Matsuzawa en-aut-mei=Takamitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KawaharaYu en-aut-sei=Kawahara en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=YamashitaKazuo en-aut-sei=Yamashita en-aut-mei=Kazuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=LinJason en-aut-sei=Lin en-aut-mei=Jason kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=KosekiJun en-aut-sei=Koseki en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=NishikawaHiroyoshi en-aut-sei=Nishikawa en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=ArakiMotoo en-aut-sei=Araki en-aut-mei=Motoo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=KatoNaoya en-aut-sei=Kato en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=ShimamuraTeppei en-aut-sei=Shimamura en-aut-mei=Teppei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=MorishitaShinichi en-aut-sei=Morishita en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=SuzukiYutaka en-aut-sei=Suzuki en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=ManoHiroyuki en-aut-sei=Mano en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=TorigoeToshihiko en-aut-sei=Torigoe en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=KanasekiTakayuki en-aut-sei=Kanaseki en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= en-aut-name=KawazuMasahito en-aut-sei=Kawazu en-aut-mei=Masahito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=33 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=34 ORCID= affil-num=1 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Division of Cancer Immunology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=4 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute kn-affil= affil-num=6 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo kn-affil= affil-num=9 en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo kn-affil= affil-num=10 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Immunology, Nagoya University Graduate School of Medicine kn-affil= affil-num=14 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=15 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=16 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=17 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=18 en-affil=Department of Dermatology, Kumamoto Kenhoku Hospital kn-affil= affil-num=19 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=20 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=21 en-affil=KOTAI Biotechnologies, Inc kn-affil= affil-num=22 en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute kn-affil= affil-num=23 en-affil=Division of Systems Biology, Nagoya University Graduate School of Medicine kn-affil= affil-num=24 en-affil=Department of Immunology, Nagoya University Graduate School of Medicine kn-affil= affil-num=25 en-affil=Department of Urology, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=26 en-affil=Department of Gastroenterology, Graduate School of Medicine, Chiba University kn-affil= affil-num=27 en-affil=Division of Systems Biology, Nagoya University Graduate School of Medicine kn-affil= affil-num=28 en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo kn-affil= affil-num=29 en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo kn-affil= affil-num=30 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=31 en-affil= kn-affil= affil-num=32 en-affil=Division of Cancer Immunology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=33 en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute kn-affil= affil-num=34 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=cancer immunology kn-keyword=cancer immunology en-keyword=neoantigen kn-keyword=neoantigen en-keyword=long-read RNA sequencing kn-keyword=long-read RNA sequencing en-keyword=HLA ligandome kn-keyword=HLA ligandome en-keyword=single-cell RNA sequencing kn-keyword=single-cell RNA sequencing en-keyword=single-cell TCR sequencing kn-keyword=single-cell TCR sequencing en-keyword=exhausted T cell kn-keyword=exhausted T cell END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=12 article-no= start-page=110594 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251216 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Endoscopic features of oral and pharyngolaryngeal papillomas and their role in distinguishing squamous cell carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=BACKGROUND
Oral and pharyngolaryngeal papillomas are occasionally detected during esophagogastroduodenoscopy. However, their endoscopic features have not been sufficiently investigated.
AIM
To distinguish oral and pharyngolaryngeal papillomas from elevated squamous carcinomas, this study examined their endoscopic features.
METHODS
Forty-seven patients with oral or pharyngeal papilloma participated in this study. The endoscopic characteristics of papillomas were identified by focusing on narrowband and blue laser imaging representations.
RESULTS
Papillomas were classified into three patterns based on their endoscopic features: Salmon roe-like polyps, polyps without capillary transparency, and pinecone-like polyps, with salmon roe-like polyps most prevalent (48.9%). We subsequently analyzed features differentiating papillomas and squamous cell carcinomas in the same region and found that squamous cell carcinomas exhibited at least one of the following three features: Uneven or absent lobulated structure, irregular morphology of capillaries, and coexistence of flat lesions. In contrast, papillomas displayed a uniform lobulated structure, homogeneous or non-visible capillaries, and an absence of flat components. When any of these characteristics were present, two endoscopic specialists evaluated the lesions for the diagnosis of squamous cell carcinoma, with sensitivities of 100% and 97.6% and specificities of 68.9% and 93.3%.
CONCLUSION
Understanding distinct endoscopic patterns of oropharyngeal papillomas and squamous cell carcinomas provides valuable guidance to endoscopists performing esophagogastroduodenoscopy. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HamadaKenta en-aut-sei=Hamada en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KonoYoshiyasu en-aut-sei=Kono en-aut-mei=Yoshiyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawanoSeiji en-aut-sei=Kawano en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KawaharaYoshiro en-aut-sei=Kawahara en-aut-mei=Yoshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Practical Gastrointestinal Endoscopy, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Esophagogastroduodenoscopy kn-keyword=Esophagogastroduodenoscopy en-keyword=Human papillomavirus kn-keyword=Human papillomavirus en-keyword=Laryngeal polyp kn-keyword=Laryngeal polyp en-keyword=Papilloma kn-keyword=Papilloma en-keyword=Pharyngeal polyp kn-keyword=Pharyngeal polyp END start-ver=1.4 cd-journal=joma no-vol=145 cd-vols= no-issue= article-no= start-page=105021 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Assessing the role of folate syntrophy and folate cross-feeding in the pathobiology of infectious-inflamed milieu caused by Fusobacterium nucleatum en-subtitle= kn-subtitle= en-abstract= kn-abstract=Diet and nutrition affect almost every biological process, including multiple chronic diseases, diabetes, and some cancers. However, there are still significant gaps in our understanding of the importance of nutrition and healthy diets in syntrophy with respect to cross-feeding of the microbe-microbe and the microbe-host in the pathobiology of the infectious-inflamed intestinal milieu caused by anaerobic opportunistic bacteria such as Fusobacterium nucleatum (F. nucleatum). We examined the immune outcomes of three-member folate syntrophy and cross-feeding between F. nucleatum bacteria, endogenous folate-producing gut bacteria, and host cells at the host-pathogen interface using a triple co-culture model. T84, THP-1, and Huh7 cells were inoculated with F. nucleatum for 6 h in regular DMEM, DMEM with 9.5 μM folic acid, or with/without a mixture of Bifidobacterium longum subsp. infantis (B. infantis) and Escherichia coli Nissle 1917 (EcN). Cytokine secretion, cometabolite levels (ammonia, indoles), cell viability, and barrier integrity were assessed. F. nucleatum-induced folate depletion was associated with increased IL-1β and IL-6 and decreased IL-22, along with reduced transepithelial electrical resistance (TEER) and cell viability in T84 cells. Folate supplementation mitigated these effects. The mixture of B. infantis and EcN reduced F. nucleatum-induced pro-inflammatory cytokines, increased IL-22, and improved TEER and cell viability. These protective effects were enhanced by the addition of folate. F. nucleatum also elevated ammonia and reduced indoles, effects reversed by B. infantis and EcN. In addition to the intrinsic pathogenicity of harmful bacteria, folate deprivation, microbe–microbe folate syntrophy, and microbe–host folate cross-feeding contribute to the pathobiology of anaerobic opportunistic bacteria and influence the physiological fate of host cells. A combination of B. infantis and EcN modulates the infectious-inflamed interface through a cytoprotective effect and mechanical competitive extrusion of pathogenic F. nucleatum. These results provide potential insights into the mechanisms of early-onset colorectal cancer, and evidently, require future studies using patient-derived organoids and in vivo systems to improve clinical relevance. en-copyright= kn-copyright= en-aut-name=GhadimiDarab en-aut-sei=Ghadimi en-aut-mei=Darab kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=BlömerSophia en-aut-sei=Blömer en-aut-mei=Sophia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Şahin KayaAysel en-aut-sei=Şahin Kaya en-aut-mei=Aysel kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KrügerSandra en-aut-sei=Krüger en-aut-mei=Sandra kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=RöckenChristoph en-aut-sei=Röcken en-aut-mei=Christoph kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SchäferHeiner en-aut-sei=Schäfer en-aut-mei=Heiner kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UchiyamaJumpei en-aut-sei=Uchiyama en-aut-mei=Jumpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsuzakiShigenobu en-aut-sei=Matsuzaki en-aut-mei=Shigenobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BockelmannWilhelm en-aut-sei=Bockelmann en-aut-mei=Wilhelm kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= affil-num=2 en-affil=Faculty of Medicine, Christian-Albrechts-University of Kiel kn-affil= affil-num=3 en-affil=Department of Nutrition and Dietetics, Faculty of Health Sciences, Antalya Bilim University kn-affil= affil-num=4 en-affil=Institute of Pathology, Kiel University, University Hospital, Schleswig-Holstein kn-affil= affil-num=5 en-affil=Institute of Pathology, Kiel University, University Hospital, Schleswig-Holstein kn-affil= affil-num=6 en-affil=Laboratory of Molecular Gastroenterology & Hepatology, Christian-Albrechts-University & UKSH Campus Kiel kn-affil= affil-num=7 en-affil=Department of Bacteriology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Laboratory Science, Faculty of Health Sciences, Kochi Gakuen University kn-affil= affil-num=9 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= en-keyword=Nutrition kn-keyword=Nutrition en-keyword=Metaflammation kn-keyword=Metaflammation en-keyword=Folate kn-keyword=Folate en-keyword=Cytokines kn-keyword=Cytokines en-keyword=Infection kn-keyword=Infection en-keyword=Host cells kn-keyword=Host cells END start-ver=1.4 cd-journal=joma no-vol=35 cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Addition of human platelet lysate to islet culture medium suppresses islet loss and improves transplantation outcomes en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NoguchiHirofumi en-aut-sei=Noguchi en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Miyagi-ShiohiraChika en-aut-sei=Miyagi-Shiohira en-aut-mei=Chika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SadahiraTakuya en-aut-sei=Sadahira en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeMasami en-aut-sei=Watanabe en-aut-mei=Masami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SaitohIssei en-aut-sei=Saitoh en-aut-mei=Issei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus kn-affil= affil-num=2 en-affil=Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus kn-affil= affil-num=3 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Pediatric Dentistry, Asahi University School of Dentistry kn-affil= END start-ver=1.4 cd-journal=joma no-vol=74 cd-vols= no-issue=11 article-no= start-page=1023 end-page=1032 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=2025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Bioconversion and Metabolic Fate of the n-1 Polyunsaturated Fatty Acids, 6,9,12,15- Hexadecatetraenoic (C16:4 n-1) and 8,11,14,17- Octadecatetraenoic (C18:4 n-1) Acids, in HepG2 Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Fish oil contains not only major fatty acids with double bonds at the n-3, n-6, n-7, and n-9 positions but also those with a double bond at the n-1 position, such as 6,9,12,15-hexadecatetraenoic acid (C16:4 n-1; HDTA). However, intracellular bioconversion and metabolic fate of n-1 polyunsaturated fatty acids (PUFA) remain unclear. Therefore, in this study, we aimed to assess the intracellular bioconversion and metabolic fate of HDTA and its metabolite, 8,11,14,17- octadecatetraenoic acid (C18:4 n-1; ODTA), using HepG2 cells. Based on the results of cell viability and cytotoxicity assays for HDTA and ODTA, the concentration of each fatty acid supplemented in the experiments was set at 10 μM. HepG2 cell culture with HDTA revealed C20:4 n-1 as a new HDTA metabolite, along with previously reported ODTA. Our findings suggest that the HDTA taken up by HepG2 cells undergoes elongation to form ODTA and C20:4 n-1. Following supplementation with HDTA, ODTA, and 5,8,11,14,17-eicosapentaenoic acid (C20:5 n-3; EPA), fatty acids disappeared from the culture medium within 24 h. Notably, the total relative level of HDTA and its metabolites, including ODTA and C20:4 n-1 in HDTA- and ODTA-supplemented cells were significantly lower than the total relative level of EPA and its metabolites, including 7,10,13,16,19-docosapentaenoic acid (C22:5 n-3), C24:6 n-3, and 4,7,10,13,16,19-docosahexaenoic acid (C22:6 n-3) in the EPA-supplemented cells. Except for a portion that was intracellularly elongated, most HDTA was taken up by HepG2 cells and may undergo rapid fatty acid β-oxidation. However, RNA-sequencing and real-time polymerase chain reaction analysis revealed no significant changes in fatty acid β-oxidation–related gene expression levels in HDTA-supplemented cells. Collectively, these results provide novel insights into the intracellular bioconversion mechanisms and metabolic fate of HDTA and ODTA in HepG2 cells, suggesting that the metabolic fate of n-1 PUFA is distinct from that of common PUFA. en-copyright= kn-copyright= en-aut-name=SugimotoKoki en-aut-sei=Sugimoto en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishiguchiHideto en-aut-sei=Nishiguchi en-aut-mei=Hideto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HosomiRyota en-aut-sei=Hosomi en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanizakiToshifumi en-aut-sei=Tanizaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TsushimaTadahiro en-aut-sei=Tsushima en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=BabaNaomichi en-aut-sei=Baba en-aut-mei=Naomichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MisawaYoshihisa en-aut-sei=Misawa en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OnoMitsuaki en-aut-sei=Ono en-aut-mei=Mitsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MurakamiYuki en-aut-sei=Murakami en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KandaSeiji en-aut-sei=Kanda en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FukunagaKenji en-aut-sei=Fukunaga en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Faculty of Food and Nutritional Sciences, Toyo University kn-affil= affil-num=2 en-affil=Faculty of Chemistry, Materials, and Bioengineering, Kansai University kn-affil= affil-num=3 en-affil=Faculty of Chemistry, Materials, and Bioengineering, Kansai University kn-affil= affil-num=4 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=5 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=6 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=7 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=8 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Hygiene and Public Health, Kansai Medical University kn-affil= affil-num=11 en-affil=Department of Hygiene and Public Health, Kansai Medical University kn-affil= affil-num=12 en-affil=Faculty of Chemistry, Materials, and Bioengineering, Kansai University kn-affil= en-keyword=n-1 polyunsaturated fatty acids kn-keyword=n-1 polyunsaturated fatty acids en-keyword=hexadecatetraenoic acid kn-keyword=hexadecatetraenoic acid en-keyword=octadecatetraenoic acid kn-keyword=octadecatetraenoic acid en-keyword=HepG2 kn-keyword=HepG2 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251231 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Efficient resuscitation of early-stage viable but non-culturable cells of Vibrio cholerae using treatment with proteolytic enzymes en-subtitle= kn-subtitle= en-abstract= kn-abstract=Vibrio cholerae, the etiological agent of cholera, is ubiquitous in environmental brackish waters. Exposure to low water temperatures induces the bacterium to enter a viable but non-culturable (VBNC) state. In this study, a stepwise decrease in water temperature to 4°C was found to delay the transition to the non-culturable state compared to an abrupt temperature drop, suggesting that V. cholerae cells partially adapt to low temperatures. V. cholerae VBNC cells maintained at 4°C gradually lost their ability to revert to a culturable state. However, VBNC cells in the early stage of dormancy were efficiently resuscitated following treatment with proteolytic enzymes, including proteinase K. The abundance of culturable V. cholerae cells in brackish estuarine waters was quantified using the most probable number (MPN)–quantitative polymerase chain reaction (qPCR) method. Although culturable cells were undetectable in samples treated with bovine serum albumin, they were estimated at 93 and 1,500 MPN/mL in two water samples collected on different days and pre-incubated with proteinase K. Similarly, the abundance of Vibrio species increased markedly following treatment with this enzyme. Additionally, cells of Vibrio species were enumerated by the plating method using CHROMagar Vibrio plates. Consistent with the results of the MPN–qPCR method, treatment with proteinase K resulted in over a 100-fold increase in colony formation. Collectively, these findings suggest that treatment with proteinase K is effective for resuscitating and quantifying V. cholerae VBNC cells in environmental water samples. en-copyright= kn-copyright= en-aut-name=MiyoshiShin-ichi en-aut-sei=Miyoshi en-aut-mei=Shin-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OgasawaraMona en-aut-sei=Ogasawara en-aut-mei=Mona kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NiwakiShiho en-aut-sei=Niwaki en-aut-mei=Shiho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SugiharaRena en-aut-sei=Sugihara en-aut-mei=Rena kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MuzemboBasilua Andre en-aut-sei=Muzembo en-aut-mei=Basilua Andre kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ImamuraDaisuke en-aut-sei=Imamura en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Research Institute of Nursing Care for People and Community, University of Hyogo kn-affil= affil-num=6 en-affil=Research Center for Intestinal Health Science, Okayama University kn-affil= en-keyword=Vibrio cholerae kn-keyword=Vibrio cholerae en-keyword=viable but non-culturable kn-keyword=viable but non-culturable en-keyword=VBNC kn-keyword=VBNC en-keyword=protease kn-keyword=protease en-keyword=proteolytic enzyme kn-keyword=proteolytic enzyme END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=29639 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250813 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Single cell spatial transcriptomics links Wnt signaling disruption to extracellular matrix development in a cleft palate model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Despite advances in understanding the morphological disruptions that lead to defects in palate formation, the precise perturbations within the signaling microenvironment of palatal clefts remain poorly understood. To explore in greater depth the genomic basis of palatal clefts, we designed and implemented the first single cell spatial RNA-sequencing study in a cleft palate model, utilizing the Pax9−/− murine model at multiple developmental timepoints, which exhibits a consistent cleft palate defect. Visium HD, an emerging platform for true single-cell resolution spatially resolved transcriptomics, was employed using custom bins of 2 × 2 μm spatial gene expression data. Validation of spatial gene expression was then validated using custom designed Xenium In Situ mRNA spatial profiling and RNAscope Multiplex assays. Functional enrichment analysis revealed a palate cell-specific perturbation in Wnt signaling effector function in tandem with disrupted expression of extracellular matrix genes in developing mesenchyme. As a key step toward laying the framework for identifying key molecular targets these data can be used for translational studies aimed at developing effective therapies for human palatal clefts. en-copyright= kn-copyright= en-aut-name=PiñaJeremie Oliver en-aut-sei=Piña en-aut-mei=Jeremie Oliver kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=RajuResmi en-aut-sei=Raju en-aut-mei=Resmi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=StipanoEvan en-aut-sei=Stipano en-aut-mei=Evan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MyoAye Chan en-aut-sei=Myo en-aut-mei=Aye Chan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OnoMitsuaki en-aut-sei=Ono en-aut-mei=Mitsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ChattarajParna en-aut-sei=Chattaraj en-aut-mei=Parna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FurukawaMasae en-aut-sei=Furukawa en-aut-mei=Masae kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=D’SouzaRena N. en-aut-sei=D’Souza en-aut-mei=Rena N. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=2 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=3 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=4 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=5 en-affil=Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Department of Molecular Biology and Biochemistry, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Department of Molecular Biology and Biochemistry, Okayama University kn-affil= affil-num=7 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=8 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=9 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= en-keyword=Spatial biology kn-keyword=Spatial biology en-keyword=Cleft palate kn-keyword=Cleft palate en-keyword=Genomics kn-keyword=Genomics en-keyword=Single cell kn-keyword=Single cell en-keyword=Gene expression kn-keyword=Gene expression en-keyword=Profiling kn-keyword=Profiling en-keyword=Extracellular matrix kn-keyword=Extracellular matrix en-keyword=Wnt kn-keyword=Wnt en-keyword=Transcriptome kn-keyword=Transcriptome END start-ver=1.4 cd-journal=joma no-vol=31 cd-vols= no-issue=12 article-no= start-page=102845 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Whole-genome sequencing and in vitro characterization of a disseminated ST398 Staphylococcus aureus infection: A case report en-subtitle= kn-subtitle= en-abstract= kn-abstract=Staphylococcus aureus potentially causes systemic infections such as disseminated abscesses and bloodstream infections, leading to high mortality rates. We herein describe a case of disseminated muscle abscesses caused by sequence type (ST) 398 methicillin-sensitive S. aureus (MSSA), along with in vitro investigation results for potential pathogenic factors. A 67-year-old healthy woman was admitted to our hospital with complaints of systemic body pain. Blood cultures identified MSSA and contrast-enhanced computed tomography revealed multiple muscle abscesses extending from her neck to her soles. She received antibiotic treatment with intravenous cephazolin and underwent repeated surgical drainage, and was finally discharged. Notably, the MSSA strain exclusively affected her muscle tissues, prompting us to perform genetic analysis to uncover the underlying reason. Short-read genome analysis revealed the isolate to be ST398, harboring chp and scn genes known for immune evasion from human immunity. However, no other known pathogenic factors were identified despite rigorous assays for biofilm formation, surface and cell wall proteins, protease production, and hyaluronidase activity. ST398 S. aureus is commonly isolated from livestock, and her prior experience of being flooded could be related to the disease onset. The present case underscores the possibility of severe ST398 MSSA infections in humans, even in the absence of direct animal exposure. en-copyright= kn-copyright= en-aut-name=SazumiYosuke en-aut-sei=Sazumi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FukushimaShinnosuke en-aut-sei=Fukushima en-aut-mei=Shinnosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HagiyaHideharu en-aut-sei=Hagiya en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatoAtsushi en-aut-sei=Kato en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SuyamaAtsuhito en-aut-sei=Suyama en-aut-mei=Atsuhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OguniKohei en-aut-sei=Oguni en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=GotohKazuyoshi en-aut-sei=Gotoh en-aut-mei=Kazuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KutsunoShoko en-aut-sei=Kutsuno en-aut-mei=Shoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HisatsuneJunzo en-aut-sei=Hisatsune en-aut-mei=Junzo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SugaiMotoyuki en-aut-sei=Sugai en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TsujiShuma en-aut-sei=Tsuji en-aut-mei=Shuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IioKoji en-aut-sei=Iio en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Bacteriology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences kn-affil= affil-num=8 en-affil=Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security kn-affil= affil-num=9 en-affil=Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security kn-affil= affil-num=10 en-affil=Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security kn-affil= affil-num=11 en-affil=Department of Bacteriology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Microbiology Division, Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Staphylococcus aureus kn-keyword=Staphylococcus aureus en-keyword=Sequence type 398 kn-keyword=Sequence type 398 en-keyword=Disseminated infection kn-keyword=Disseminated infection en-keyword=Immune evasion cluster gene kn-keyword=Immune evasion cluster gene END start-ver=1.4 cd-journal=joma no-vol=35 cd-vols= no-issue=2 article-no= start-page=101548 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202506 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cerebellar abscess caused by Cladophialophora bantiana involving an elderly Japanese woman en-subtitle= kn-subtitle= en-abstract= kn-abstract=Phaeohyphomycosis is a rare fungal infection that presents significant challenges in diagnosis and treatment. Herein, we document a case of a cerebellar abscess caused by Cladophialophora bantiana. A 77-year-old woman with type 2 diabetes mellitus and a previous history of diffuse large B-cell lymphoma gradually developed ataxia and was transferred to an emergency department. Head imaging investigations indicated a cerebellar mass and the patient underwent an emergent endoscopic drainage. Although bacterial cultures of the drainage specimen yielded no growth, a dematiaceous fungus was isolated and subsequently identified as C. bantiana through ITS sequencing analysis. The patient received antifungal combination therapy, initially with liposomal amphotericin B and voriconazole, and finally posaconazole and 5-fluorocytosine. Brain abscesses caused by C. bantiana are rarely documented, and an optimal treatment strategy has yet to be established. Given the high fatality rate, an early surgical intervention is crucial for both diagnosis and treatment. The present case was successfully treated with minimally invasive surgical intervention alongside the antifungal combination therapy. en-copyright= kn-copyright= en-aut-name=NakamotoKenta en-aut-sei=Nakamoto en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HagiyaHideharu en-aut-sei=Hagiya en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukushimaShinnosuke en-aut-sei=Fukushima en-aut-mei=Shinnosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OguniKohei en-aut-sei=Oguni en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YokoyamaYukika en-aut-sei=Yokoyama en-aut-mei=Yukika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IioKoji en-aut-sei=Iio en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HiranoShuichiro en-aut-sei=Hirano en-aut-mei=Shuichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YaguchiTakashi en-aut-sei=Yaguchi en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BanSayaka en-aut-sei=Ban en-aut-mei=Sayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=WatanabeAkira en-aut-sei=Watanabe en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OkunobuHiroki en-aut-sei=Okunobu en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SuyamaAtsuhito en-aut-sei=Suyama en-aut-mei=Atsuhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KawaguchiMarina en-aut-sei=Kawaguchi en-aut-mei=Marina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SazumiYousuke en-aut-sei=Sazumi en-aut-mei=Yousuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=5 en-affil=Microbiology Division, Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=6 en-affil=Microbiology Division, Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Division of Clinical Research, Medical Mycology Research Center kn-affil= affil-num=9 en-affil=Division of Clinical Research, Medical Mycology Research Center kn-affil= affil-num=10 en-affil=Division of Clinical Research, Medical Mycology Research Center kn-affil= affil-num=11 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Brain abscess kn-keyword=Brain abscess en-keyword=Cladophialophora bantiana kn-keyword=Cladophialophora bantiana en-keyword=Black fungus kn-keyword=Black fungus en-keyword=Phaeohyphomycosis kn-keyword=Phaeohyphomycosis en-keyword=Posaconazole kn-keyword=Posaconazole END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=1 article-no= start-page=e70066 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Procedural Transhiatal Approach for the Thoracic Para‐Aortic Lymph Node: A Case Report en-subtitle= kn-subtitle= en-abstract= kn-abstract=The thoracic posterior para-aortic lymph node (TPAN) is classified as an extra-regional lymph node in esophageal cancer, with metastasis indicating poor prognosis. However, some cases with suspected TPAN metastasis may benefit from esophagectomy with lymph node dissection, including TPAN. This report presents the case of a 58-year-old man with upper thoracic esophageal squamous cell carcinoma and suspected simultaneous TPAN metastasis who underwent neoadjuvant chemotherapy followed by thoracoscopic subtotal esophagectomy and procedural transhiatal TPAN dissection. This transhiatal approach provided direct access to the lymph node without additional thoracic incisions, ensuring safe resection in coordination with the assistant and following anatomical landmarks systematically. Pathological examination showed a false-positive TPAN finding, though the patient later developed distant recurrence. Compared with conventional approaches, this transhiatal technique allows for procedural and reproducible lymphadenectomy while minimizing respiratory burden. This case highlights the feasibility of a transhiatal approach for TPAN dissection. en-copyright= kn-copyright= en-aut-name=HashimotoMasashi en-aut-sei=Hashimoto en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NomaKazuhiro en-aut-sei=Noma en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakedaYasushige en-aut-sei=Takeda en-aut-mei=Yasushige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsumotoHijiri en-aut-sei=Matsumoto en-aut-mei=Hijiri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawasakiKento en-aut-sei=Kawasaki en-aut-mei=Kento kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KunitomoTomoyoshi en-aut-sei=Kunitomo en-aut-mei=Tomoyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MaedaNaoaki en-aut-sei=Maeda en-aut-mei=Naoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanabeShunsuke en-aut-sei=Tanabe en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=112aoP kn-keyword=112aoP en-keyword=esophageal cancer kn-keyword=esophageal cancer en-keyword=thoracic posterior para-aortic lymph node kn-keyword=thoracic posterior para-aortic lymph node END start-ver=1.4 cd-journal=joma no-vol=23 cd-vols= no-issue=5 article-no= start-page=101 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250922 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Prolonged exposure to axitinib alters the molecular profile of Caki‑2 renal cell carcinoma cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Axitinib, an oral second‑generation multitargeted tyrosine kinase inhibitor, is used as a second‑line treatment for metastatic renal cell carcinoma (RCC). However, patients often develop resistance after initial responsiveness, necessitating the elucidation of the underlying resistance mechanisms. Therefore, the present study aimed to investigate the mechanisms underlying axitinib resistance using the Caki‑2 human papillary RCC model cells. Cells tolerating 0.1 µM axitinib were designated as Caki/AX cells. Cell viability was assessed using the water‑soluble tetrazolium salt assay. Notably, the 50% inhibitory concentration (IC50) values of axitinib and sunitinib were significantly higher in Caki/AX cells than those in Caki‑2 cells, indicating 2.83‑ and 1.2‑fold resistance, respectively. By contrast, the IC50 values of sorafenib and erlotinib were decreased in Caki/AX cells. Moreover, Caki/AX cells showed resistance to everolimus, temsirolimus and rapamycin, and decreased sensitivity to vinblastine, vincristine, paclitaxel, doxorubicin and SN‑38 compared with Caki‑2 cells. Notably, etoposide, 5‑fluorouracil, cisplatin and carboplatin sensitivities were comparable in both cell types. Reverse transcription‑quantitative polymerase chain reaction (PCR) analysis revealed that the mRNA levels of the ATP‑binding cassette subfamily B member 1 and subfamily G member 2 were significantly higher in Caki/AX cells than those in Caki‑2 cells. A PCR array related to vascular endothelial growth factor signalling showed that the mRNA levels of FIGF (also known as vascular endothelial growth factor D) and sphingosine kinase 1 were upregulated, whereas those of Rac family small GTPase 2 were downregulated in Caki/AX cells. Overall, these findings suggested that the upregulation of the ATP‑binding cassette subfamily B member 1, FIGF and sphingosine kinase 1 mRNA levels, and downregulation of the Rac family small GTPase 2 mRNA levels may contribute to acquired resistance in Caki/AX cells. en-copyright= kn-copyright= en-aut-name=NakayamaYuko en-aut-sei=Nakayama en-aut-mei=Yuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InoAya en-aut-sei=Ino en-aut-mei=Aya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamamotoKazuhiro en-aut-sei=Yamamoto en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakaraKohji en-aut-sei=Takara en-aut-mei=Kohji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University kn-affil= affil-num=2 en-affil=Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Hyogo Medical University kn-affil= affil-num=3 en-affil=Department of Integrated Clinical and Basic Pharmaceutical Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Hyogo Medical University kn-affil= en-keyword=axitinib kn-keyword=axitinib en-keyword=renal cell carcinoma kn-keyword=renal cell carcinoma en-keyword=drug resistance kn-keyword=drug resistance en-keyword=ABC transporter kn-keyword=ABC transporter END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251211 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Atezolizumab + Chemotherapy for Advanced Non-Small Cell Lung Cancer in Japanese Clinical Practice (J-TAIL-2) en-subtitle= kn-subtitle= en-abstract= kn-abstract=First-line atezolizumab combination therapies were approved for the treatment of metastatic non-small cell lung cancer (NSCLC) based on results from the global phase 3 trials IMpower130, IMpower132, and IMpower150. These trials reported 12-month overall survival (OS) rates of 60%–67% with atezolizumab combination therapy. J-TAIL-2 (NCT04501497), a prospective, multicenter, observational study, evaluated atezolizumab combination therapy in routine clinical practice in Japan. Patients ≥ 20 years old with NSCLC received atezolizumab plus carboplatin and nab-paclitaxel (atezo + CnP), atezolizumab plus carboplatin or cisplatin plus pemetrexed (atezo + PP), or atezolizumab plus bevacizumab plus carboplatin and paclitaxel (atezo + bev + CP) in clinical practice. The primary endpoint was the 12-month OS rate. Secondary endpoints included OS, progression-free survival, and subgroup analyses, including IMpower-unlike (did not meet the main eligibility criteria of each IMpower trial) and IMpower-like patients. In total, 814 patients were enrolled (atezo + CnP, n = 217; atezo + PP, n = 211; atezo + bev + CP, n = 386). The IMpower-unlike group included patients with Eastern Cooperative Oncology Group performance status ≥ 2, autoimmune disease, or interstitial lung disease. Twelve-month OS rates (95% confidence interval [CI]) were 62.9% (55.8–69.2), 72.1% (65.2–77.9), and 68.3% (63.2–72.9) with atezo + CnP, atezo + PP, and atezo + bev + CP, respectively. OS hazard ratios (95% CI) in the IMpower-unlike vs. -like subgroups were 1.36 (0.91–2.05), 1.08 (0.70–1.68), and 1.49 (1.09–2.06), respectively. No new safety signals were observed. Real-world efficacy and safety for each atezolizumab combination were comparable to those in the relevant IMpower trials. en-copyright= kn-copyright= en-aut-name=YoshiokaHiroshige en-aut-sei=Yoshioka en-aut-mei=Hiroshige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishioMakoto en-aut-sei=Nishio en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OsoegawaAtsushi en-aut-sei=Osoegawa en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KikuchiEiki en-aut-sei=Kikuchi en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KimuraHideharu en-aut-sei=Kimura en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MiyauchiEisaku en-aut-sei=Miyauchi en-aut-mei=Eisaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YoshinoIchiro en-aut-sei=Yoshino en-aut-mei=Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MisumiToshihiro en-aut-sei=Misumi en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=WatanabeYasutaka en-aut-sei=Watanabe en-aut-mei=Yasutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=HataAkito en-aut-sei=Hata en-aut-mei=Akito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KisoharaAkira en-aut-sei=Kisohara en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KuyamaShoichi en-aut-sei=Kuyama en-aut-mei=Shoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=YamaguchiMasafumi en-aut-sei=Yamaguchi en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=MiwaAsako en-aut-sei=Miwa en-aut-mei=Asako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=IwasawaShunichiro en-aut-sei=Iwasawa en-aut-mei=Shunichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=TanakaMisa en-aut-sei=Tanaka en-aut-mei=Misa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=GemmaAkihiko en-aut-sei=Gemma en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Thoracic Oncology, Kansai Medical University kn-affil= affil-num=2 en-affil=Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Kanazawa University Hospital kn-affil= affil-num=7 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Tohoku University Hospital kn-affil= affil-num=10 en-affil=International University of Health and Welfare, Narita Hospital kn-affil= affil-num=11 en-affil=Department of Data Science, National Cancer Center Hospital East kn-affil= affil-num=12 en-affil=Department of Thoracic Oncology, Saitama Cancer Center kn-affil= affil-num=13 en-affil=Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, Kasukabe Medical Center kn-affil= affil-num=15 en-affil=Department of Respiratory Medicine, NHO Iwakuni Clinical Center kn-affil= affil-num=16 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=17 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=18 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=19 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=20 en-affil=Nippon Medical School kn-affil= en-keyword=atezolizumab kn-keyword=atezolizumab en-keyword=chemotherapy kn-keyword=chemotherapy en-keyword=lung cancer kn-keyword=lung cancer en-keyword=non-small cell kn-keyword=non-small cell en-keyword=observational kn-keyword=observational END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue=4 article-no= start-page=1041 end-page=1054 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250904 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Asian Subgroup Analysis of Patients in the Phase 2 DeLLphi-301 Study of Tarlatamab for Previously Treated Small Cell Lung Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Tarlatamab is a bispecific T-cell engager (BiTE®) immunotherapy that binds delta-like ligand 3 on the surface of small cell lung cancer (SCLC) cells and CD3 on T cells, facilitating T cell-mediated cancer cell lysis. In the primary analysis of the phase 2 DeLLphi-301 study (NCT05060016), tarlatamab showed a favourable benefit-to-risk profile with durable objective responses and promising survival outcomes in patients with previously treated SCLC. Here, phase 2 data for the Asia region subgroup are presented.
Methods: Patients with previously treated, advanced SCLC received 10 mg tarlatamab every 2 weeks. The primary endpoint was objective response rate (ORR) by blinded independent central review (RECIST version 1.1). Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. The present analysis includes patients enrolled at sites in Asia.
Results: A total of 43 patients were enrolled at sites in Asia. ORR was 46.3% (95% confidence interval [CI], 30.7–62.6) and median DOR was 7.2 months (95% CI 3.9 to not estimable). The median follow-up was 16.6 months for PFS and 21.2 months for OS. Median PFS was 5.4 months (95% CI 3.0–8.1) and median OS was 19.0 months (95% CI 11.4 to not estimable). The most common treatment-emergent adverse event (AE) was cytokine release syndrome (48.8%), and all such events were grade 1 or 2. There were no discontinuations due to treatment-related AEs.
Conclusions: Tarlatamab demonstrated durable responses and promising survival outcomes with a manageable safety profile in this post hoc analysis of patients from Asia with previously treated SCLC.
Trial Registration: ClinicalTrials.gov, NCT05060016. en-copyright= kn-copyright= en-aut-name=AhnMyung-Ju en-aut-sei=Ahn en-aut-mei=Myung-Ju kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ChoByoung Chul en-aut-sei=Cho en-aut-mei=Byoung Chul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IzumiHiroki en-aut-sei=Izumi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LeeJong-Seok en-aut-sei=Lee en-aut-mei=Jong-Seok kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HanJi-Youn en-aut-sei=Han en-aut-mei=Ji-Youn kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ChiangChi-Lu en-aut-sei=Chiang en-aut-mei=Chi-Lu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HuangShuang en-aut-sei=Huang en-aut-mei=Shuang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HamidiAli en-aut-sei=Hamidi en-aut-mei=Ali kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MukherjeeSujoy en-aut-sei=Mukherjee en-aut-mei=Sujoy kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=XuKrista Lin en-aut-sei=Xu en-aut-mei=Krista Lin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=AkamatsuHiraoki en-aut-sei=Akamatsu en-aut-mei=Hiraoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Hematology-Oncology Department, Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine kn-affil= affil-num=2 en-affil=Medical Oncology Department-501, ABMRC, Yonsei University kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Thoracic Oncology, National Cancer Center Hospital East kn-affil= affil-num=5 en-affil=Hematology/Oncology, Seoul National University Bundang Hospital kn-affil= affil-num=6 en-affil=Center for Lung Cancer, National Cancer Center-Graduate School of Cancer Science and Policy kn-affil= affil-num=7 en-affil=Department of Chest Medicine, Taipei Veterans General Hospital kn-affil= affil-num=8 en-affil=Amgen Inc. kn-affil= affil-num=9 en-affil=Amgen Inc. kn-affil= affil-num=10 en-affil=Amgen Inc. kn-affil= affil-num=11 en-affil=Amgen Asia Pacific Pte. Ltd. kn-affil= affil-num=12 en-affil=Internal Medicine III, Wakayama Medical University kn-affil= en-keyword=Small cell lung cancer (SCLC) kn-keyword=Small cell lung cancer (SCLC) en-keyword=Tarlatamab kn-keyword=Tarlatamab en-keyword=DLL3 kn-keyword=DLL3 en-keyword=Bispecific T-cell engager kn-keyword=Bispecific T-cell engager en-keyword=Asian patients kn-keyword=Asian patients END start-ver=1.4 cd-journal=joma no-vol=193 cd-vols= no-issue= article-no= start-page=118724 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Deciphering the structural impact of norepinephrine analog radiopharmaceuticals on organic cation transporter affinity en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose: Previous studies have investigated the kinetics and affinities of norepinephrine transporter (NET)-targeting radiotracers, including [123I]MIBG, but the role of organic cation transporters (OCTs) remains unclear. This study aimed to evaluate how the structural design of selective NET-targeting tracers affects OCT-mediated non-specific uptake, identifying factors influencing both NET and OCT affinity.
Methods: Cellular uptake assays were conducted using SK-N-SH cells expressing human NET, and human OCT1-, OCT2-, and OCT3-expressing cells with [3H]norepinephrine, [3H]MPP+, and [131I]MIBG. Competitive uptake assays used non-radioactive reference compounds for several NET-targeting radiopharmaceuticals (MIBG, HED, EPI, PHEN, LMI1195, and PHPG), along with a new PET radiotracer [18F]AF78, and its two analogs with meta-iodide [18F]AF78(I) or hydroxyl group [18F]AF78(OH). Dynamic PET imaging in non-human primates assessed the in vivo uptake of [18F]AF78 after NET inhibition with desipramine.
Results: Monoamine-based tracers (EPI, PHEN, HED) exhibited high NET selectivity with minimal OCTs interaction, while guanidine-containing tracers (e.g., MIBG, LMI1195) displayed substantial OCTs affinity. Lower lipophilicity in guanidine-containing compounds, influenced by substitutions on the benzene ring (e.g., PHPG, AF78), correlated with weaker OCT interactions. PET imaging confirmed that cardiac uptake of [18F]AF78 is sensitive to desipramine pretreatment (***P < 0.0005), indicating its NET-specificity, while persistent hepatic retention suggests an OCT-mediated transport mechanism.
Conclusion: This study highlights the critical influence of the compounds’ chemical structure on NET and OCT affinities. Structural modifications that reduce OCT-mediated uptake while maintaining high NET affinity could improve the specificity and theranostic potential of NET-targeting ligands. These findings provide insights for designing next-generation radiotracers with enhanced selectivity and clinical utility. en-copyright= kn-copyright= en-aut-name=MühligSaskia en-aut-sei=Mühlig en-aut-mei=Saskia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ChenXinyu en-aut-sei=Chen en-aut-mei=Xinyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TutovAnna en-aut-sei=Tutov en-aut-mei=Anna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NoseNaoko en-aut-sei=Nose en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LapaConstantin en-aut-sei=Lapa en-aut-mei=Constantin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=WernerRudolf A. en-aut-sei=Werner en-aut-mei=Rudolf A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=DeckerMichael en-aut-sei=Decker en-aut-mei=Michael kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital Würzburg kn-affil= affil-num=2 en-affil=Nuclear Medicine, Faculty of Medicine, University of Augsburg kn-affil= affil-num=3 en-affil=Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg kn-affil= affil-num=4 en-affil=Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Nuclear Medicine, Faculty of Medicine, University of Augsburg kn-affil= affil-num=6 en-affil=Department of Nuclear Medicine, LMU Hospital, Ludwig-Maximilians-University of Munich kn-affil= affil-num=7 en-affil=Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg kn-affil= affil-num=8 en-affil=Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Norepinephrine transporter kn-keyword=Norepinephrine transporter en-keyword=Organic cation transporter kn-keyword=Organic cation transporter en-keyword=Neuroendocrine tumor kn-keyword=Neuroendocrine tumor en-keyword=Competitive cell uptake kn-keyword=Competitive cell uptake en-keyword=PET radiotracer kn-keyword=PET radiotracer END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=7 article-no= start-page=oyaf201 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202507 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pharmacovigilance study for the identification of mogamulizumab-induced immune-related adverse events using a real-world database en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Mogamulizumab is a humanized anti-CCR4 monoclonal antibody used for relapsed/refractory adult T-cell leukemia, cutaneous T-cell lymphoma, and/or Sézary syndrome. Reports of immune-related adverse events (irAEs) in these patients are increasing, and the association between irAEs and mogamulizumab remains to be elucidated. This study aimed to evaluate the association between mogamulizumab and immune-related adverse events (irAEs), as well as to characterize the irAEs associated with mogamulizumab using data from a large-scale spontaneous reporting system.
Methods: We performed an exploratory hypothesis-generating analysis of patients from 1967 to September 2023 using VigiBase, a World Health Organization spontaneous adverse event reporting system database. We performed a disproportionality analysis and determined the reporting odds ratios and information components between the drugs of interest and each irAE.
Results: Mogamulizumab was associated with some irAEs, including myocarditis, severe cutaneous adverse reactions, hepatitis, and myositis. Mogamulizumab exhibited significantly higher reporting rates of these 4 irAEs compared to the anticancer agents other than mogamulizumab. Conversely, the reporting rate of other irAEs, including endocrine autoimmune diseases induced by immune checkpoint inhibitors, was not significant in patients who received mogamulizumab.
Conclusions: Mogamulizumab is associated with irAEs, including myocarditis, severe cutaneous adverse reactions, hepatitis, and myositis. en-copyright= kn-copyright= en-aut-name=MiyataKoji en-aut-sei=Miyata en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Izawa-IshizawaYuki en-aut-sei=Izawa-Ishizawa en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NiimuraTakahiro en-aut-sei=Niimura en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YoshiokaToshihiko en-aut-sei=Yoshioka en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HyodoMizusa en-aut-sei=Hyodo en-aut-mei=Mizusa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ItokazuShuto en-aut-sei=Itokazu en-aut-mei=Shuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyataTatsumi en-aut-sei=Miyata en-aut-mei=Tatsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AizawaFuka en-aut-sei=Aizawa en-aut-mei=Fuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YagiKenta en-aut-sei=Yagi en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KawadaKei en-aut-sei=Kawada en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HamanoHirofumi en-aut-sei=Hamano en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ZamamiYoshito en-aut-sei=Zamami en-aut-mei=Yoshito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=GodaMitsuhiro en-aut-sei=Goda en-aut-mei=Mitsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=IshizawaKeisuke en-aut-sei=Ishizawa en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=2 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=3 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=4 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=5 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=6 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=7 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=8 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=9 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=10 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=11 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=14 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= en-keyword=irAEs kn-keyword=irAEs en-keyword=mogamulizumab kn-keyword=mogamulizumab en-keyword=VigiBase kn-keyword=VigiBase en-keyword=disproportionality analysis kn-keyword=disproportionality analysis en-keyword=sézary syndrome kn-keyword=sézary syndrome END start-ver=1.4 cd-journal=joma no-vol=5 cd-vols= no-issue=2 article-no= start-page=100820 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Feasibility and Diagnostic Utility of Mucosal T-Cell Flow Cytometry for Intestinal Graft-Versus-Host Disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Aims: Timely diagnosis of intestinal complications after hematopoietic stem cell transplantation (HSCT), including graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy, and cytomegalovirus infection, is essential for appropriate management. This study evaluated whether mucosal T-cell profiling from endoscopic biopsies could support the diagnosis of these post-transplant conditions.
Methods: We prospectively analyzed 58 intestinal biopsy specimens from 21 post-HSCT patients. Paired samples were obtained from the stomach and duodenum during upper endoscopy and from the ileum and large intestine during colonoscopy. Lymphocytes were isolated from each specimen and analyzed using flow cytometry. These data were integrated with those of a previously collected cohort (35 patients, 51 samples) for comparative immunophenotypic analysis across histologically defined groups.
Results: Duodenal biopsies yielded more lymphocytes than did gastric biopsies (mean ± standard deviation: 532 ± 823 vs 233 ± 392 cells; P = .070), with comparable yields between the ileum and colon. Among 41 evaluable cases, the CD56+:CD3+ ratio was significantly lower in patients with GVHD (5.5 ± 2.2%) than in those with nonspecific or no inflammation (28.4 ± 16.3%; P = .006). A cutoff value of <11% provided 85.7% sensitivity and 83.3% specificity for diagnosing GVHD (area under the curve = 0.91).
Conclusion: Mucosal T-cell profiling using endoscopic biopsies is feasible and may aid in the diagnosis of GVHD after HSCT. A decreased CD56+:CD3+ ratio is a promising marker for distinguishing GVHD from other post-transplant intestinal conditions. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KondoTakumi en-aut-sei=Kondo en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HiramatsuMai en-aut-sei=Hiramatsu en-aut-mei=Mai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HirabataAraki en-aut-sei=Hirabata en-aut-mei=Araki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakahashiTakahide en-aut-sei=Takahashi en-aut-mei=Takahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Division of Medical Support, Okayama University Hospital kn-affil= affil-num=6 en-affil=Division of Medical Support, Okayama University Hospital kn-affil= affil-num=7 en-affil=Division of Medical Support, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=cytomegalovirus infection kn-keyword=cytomegalovirus infection en-keyword=flow cytometry kn-keyword=flow cytometry en-keyword=graft-versus-host disease kn-keyword=graft-versus-host disease en-keyword=hematopoietic stem cell transplantation kn-keyword=hematopoietic stem cell transplantation en-keyword=T lymphocytes kn-keyword=T lymphocytes END start-ver=1.4 cd-journal=joma no-vol=122 cd-vols= no-issue=5 article-no= start-page=733 end-page=743 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250715 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Intravenous umbilical cord-derived mesenchymal stromal cell therapy may improve overall survival in Japanese patients with idiopathic pneumonia syndrome after hematopoietic stem cell transplantation: a multicenter, single-arm, phase II trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Idiopathic pneumonia syndrome (IPS) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT) and has a poor prognosis. Although IPS is often treated with steroids, the disease can become resistant to or dependent on steroid treatment, and there is no effective cure for patients with refractory or steroid-dependent IPS. This multicenter, open-label, single-arm, phase II clinical trial investigated the efficacy and safety of HLC-001 (allogeneic umbilical cord-derived mesenchymal stromal cells) in patients with progressive steroid-dependent or refractory IPS after HSCT. Seven male patients (all male; mean age: 43.3 years) received HLC-001 and three completed the trial. The survival rate at day 56 (primary endpoint) was 71.4% (5/7 patients; 95% confidence interval: 29.0%–96.3%) and was sustained at day 100, suggesting that HLC-001 was more effective than previously reported treatment. Three of the five patients with ≥ 100 days of follow-up died. Five patients experienced at least one adverse drug reaction, none of which were serious. These findings indicate that HLC-001 was potentially effective and generally well tolerated in Japanese patients with steroid-dependent or refractory IPS after HSCT. Given there is no effective cure for steroid-dependent or refractory IPS, HLC-001 may be a promising treatment option and further clinical evaluation is warranted.
Trial registration: Japan Registry of Clinical Trials identifier: jRCT2063220014. en-copyright= kn-copyright= en-aut-name=DokiNoriko en-aut-sei=Doki en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KakoShinichi en-aut-sei=Kako en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakaidaEmiko en-aut-sei=Sakaida en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KandaYoshinobu en-aut-sei=Kanda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= affil-num=4 en-affil=Department of Hematology, Chiba University Hospital kn-affil= affil-num=5 en-affil=Division of Hematology, Department of Medicine, Jichi Medical University kn-affil= en-keyword=Graft-versus-host disease kn-keyword=Graft-versus-host disease en-keyword=Hematopoietic stem cell transplantation kn-keyword=Hematopoietic stem cell transplantation en-keyword=Idiopathic pneumonia syndrome kn-keyword=Idiopathic pneumonia syndrome en-keyword=Overall survival kn-keyword=Overall survival en-keyword=Umbilical cord-derived mesenchymal stromal cells kn-keyword=Umbilical cord-derived mesenchymal stromal cells END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=45 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260105 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Magnetic Detection of Cancer Cells Using Tumor-Homing Peptide-Modified Magnetic Nanoparticles en-subtitle= kn-subtitle= en-abstract= kn-abstract=Magnetic nanoparticles (MNPs) provide a platform for target detection because of their magnetic responsiveness to alternating magnetic fields (AMFs). We developed a detection method using MNPs modified with tumor-homing peptides (THPs), PL1 and PL3, which selectively bind to protein components enriched in malignant tissues. THP-MNPs were synthesized using maleimide-PEG-NHS linkers and characterized using transmission electron microscopy. Human glioblastoma cancer U87MG and normal tissue-derived HEK293 cells were incubated with THP-MNPs, and the magnetic signals were measured using a high-temperature superconducting quantum interference device (SQUID) magnetometer under an AMF (1.06 kHz). Dark-field microscopy confirmed the preferential binding of THP-MNPs to U87MG cells. In the absence of cells, THP-MNPs exhibited AMF-dependent signal enhancement, which correlated with particle size reduction due to THP release. This increase was completely suppressed in the presence of U87MG cells, indicating a strong THP-mediated interaction. PL3-MNPs exhibited superior discrimination between malignant and non-malignant cells. These results demonstrate that SQUID-based magnetic measurements using THP-MNPs enable rapid and label-free cancer cell detection. en-copyright= kn-copyright= en-aut-name=ZhouShengli en-aut-sei=Zhou en-aut-mei=Shengli kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FurutaniYuji en-aut-sei=Furutani en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamashitaKei en-aut-sei=Yamashita en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KakoSakuya en-aut-sei=Kako en-aut-mei=Sakuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WatanabeKazunori en-aut-sei=Watanabe en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KiwaToshihiko en-aut-sei=Kiwa en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OhtsukiTakashi en-aut-sei=Ohtsuki en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=magnetic nanoparticle kn-keyword=magnetic nanoparticle en-keyword=tumor-homing peptide kn-keyword=tumor-homing peptide en-keyword=superconducting quantum interference devices kn-keyword=superconducting quantum interference devices END start-ver=1.4 cd-journal=joma no-vol=74 cd-vols= no-issue= article-no= start-page=6009610 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=2025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Small Distance Increment Method for Measuring Complex Permittivity With mmWave Radar en-subtitle= kn-subtitle= en-abstract= kn-abstract=Measuring the complex permittivity of material is essential in many scenarios, such as quality checks in material manufacturing. Generally, measurement methods for characterizing the material are based on the use of a vector network analyzer (VNA), which is large and not easy for on-site measurement, especially in high-frequency range such as millimeter wave (mmWave). In addition, some measurement methods require the destruction of samples, which is not suitable for nondestructive inspection. In this work, a small distance increment (SDI) method is proposed to nondestructively measure the complex permittivity of a material. In SDI, the transmitter and receiver are formed as a monostatic radar, which is facing toward the material under test (MUT). During the measurement, the distance between the radar and the MUT changes with small increments, and the signals are recorded at each position. A mathematical model is formulated to depict the relationship among the complex permittivity, distance increment, and measured signals. By fitting the model, the complex permittivity of MUT is estimated. To implement and evaluate the proposed SDI method, a commercial off-the-shelf (COTS) mmWave radar is utilized, and the measurement system is developed. Then, the evaluation was carried out on the acrylic plate. With the proposed method, the estimated complex permittivity of the acrylic plate shows good agreement with the literature values, demonstrating the efficacy of the SDI method for characterizing the complex permittivity of the material. en-copyright= kn-copyright= en-aut-name=SongHang en-aut-sei=Song en-aut-mei=Hang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KimHyun Joon en-aut-sei=Kim en-aut-mei=Hyun Joon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WanMingxia en-aut-sei=Wan en-aut-mei=Mingxia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WeiBo en-aut-sei=Wei en-aut-mei=Bo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KikkawaTakamaro en-aut-sei=Kikkawa en-aut-mei=Takamaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakadaJun-Ichi en-aut-sei=Takada en-aut-mei=Jun-Ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Research Institute for Semiconductor Engineering, Hiroshima University kn-affil= affil-num=2 en-affil=Department of Transdisciplinary Science and Engineering, Institute of Science Tokyo kn-affil= affil-num=3 en-affil=Department of Transdisciplinary Science and Engineering, Institute of Science Tokyo kn-affil= affil-num=4 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Research Institute for Semiconductor Engineering, Hiroshima University kn-affil= affil-num=6 en-affil=Department of Transdisciplinary Science and Engineering, Institute of Science Tokyo kn-affil= en-keyword=Complex permittivity measurement kn-keyword=Complex permittivity measurement en-keyword=material characterization kn-keyword=material characterization en-keyword=millimeter wave (mmWave) radar kn-keyword=millimeter wave (mmWave) radar en-keyword=nondestructive inspection kn-keyword=nondestructive inspection en-keyword=small distance increment (SDI) method kn-keyword=small distance increment (SDI) method END start-ver=1.4 cd-journal=joma no-vol=93 cd-vols= no-issue= article-no= start-page=102631 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202504 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Detection of the nuclear translocation of androgen receptor using quantitative and automatic cell imaging analysis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Testosterone signaling mediates diseases such as androgenetic alopecia and prostate cancer and is controlled by the activation of the androgen receptor (AR) and nuclear translocation of the ligand-receptor complex. This study established an immortalized dermal papilla cell line that stably expresses the AR labeled with a monomeric green fluorescence marker. The cells expressed the histone H2B protein as visualized using a red fluorescence marker, enabling the Detection of nuclear translocation under live cell conditions using image analysis. The AR was observed to be translocated from the cytoplasm to the nucleus of cells after stimulation with dihydrotestosterone (DHT). The signal intensity of the nuclear/cytoplasm ratio was analyzed using automatic image analysis and a newly developed algorithm. The quantitation method to detect nuclear translocation revealed that the AR nuclear signal plateaued approximately 20 min after DHT exposure. Our developed method has the potential to save human labor by the automatic process of the image. en-copyright= kn-copyright= en-aut-name=BaiLanlan en-aut-sei=Bai en-aut-mei=Lanlan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WuTao en-aut-sei=Wu en-aut-mei=Tao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukasawaMizuki en-aut-sei=Fukasawa en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KashiwagiSayo en-aut-sei=Kashiwagi en-aut-mei=Sayo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TateHaruka en-aut-sei=Tate en-aut-mei=Haruka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OzakiTaku en-aut-sei=Ozaki en-aut-mei=Taku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SuganoEriko en-aut-sei=Sugano en-aut-mei=Eriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TomitaHiroshi en-aut-sei=Tomita en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IshiiTsuyoshi en-aut-sei=Ishii en-aut-mei=Tsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AkashiTakuya en-aut-sei=Akashi en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FukudaTomokazu en-aut-sei=Fukuda en-aut-mei=Tomokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=2 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=3 en-affil=Neuro-AI Integration Science Laboratory, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Rohto Pharmaceutical Co., Ltd., Basic Research Development Division kn-affil= affil-num=5 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=6 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=7 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=8 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=9 en-affil=Rohto Pharmaceutical Co., Ltd., Basic Research Development Division kn-affil= affil-num=10 en-affil=Neuro-AI Integration Science Laboratory, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=11 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= en-keyword=Dermal papilla cell kn-keyword=Dermal papilla cell en-keyword=Nuclear translocation kn-keyword=Nuclear translocation en-keyword=Androgen receptor kn-keyword=Androgen receptor en-keyword=Live cell imaging kn-keyword=Live cell imaging en-keyword=Digital image analysis kn-keyword=Digital image analysis en-keyword=Quantitation algorithm kn-keyword=Quantitation algorithm END start-ver=1.4 cd-journal=joma no-vol=75 cd-vols= no-issue=1 article-no= start-page=10 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251218 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gut microbial metabolite butyrate boosts p53-expressing telomerase-specific oncolytic adenovirus efficacy by enhancing infectivity and activating MHC-I/cGAS-STING en-subtitle= kn-subtitle= en-abstract= kn-abstract=The gut microbiota plays an essential role in regulating host immunity, and its metabolites such as butyrate exert immunomodulatory effects by acting as histone deacetylase inhibitors. Oncolytic virotherapy has emerged as a promising approach for cancer treatment, and we have developed OBP-702, a telomerase-specific oncolytic adenovirus that expresses p53 and elicits strong systemic antitumor responses. In this study, the potential synergy between butyrate and OBP-702 was investigated in colorectal cancer models. Using human and murine colorectal carcinoma cell lines, butyrate was found to directly enhance the infectivity of OBP-702 by upregulating CAR and integrins, thereby promoting apoptosis and autophagy in tumor cells. In addition, butyrate indirectly boosted systemic antitumor immunity by upregulating MHC-I expression through activation of the cGAS-STING pathway and enhancing CD8 + T cell recruitment via CXCL10 secretion. These findings were supported by in vivo experiments using CT26 subcutaneous, bilateral, and orthotopic tumor models, in which the combination of oral butyrate and intratumoral OBP-702 administration produced synergistic antitumor effects. These results highlight the therapeutic potential of integrating gut microbial metabolites with oncolytic virotherapy as a novel immunotherapeutic strategy for colorectal cancer. en-copyright= kn-copyright= en-aut-name=SakamotoMasaki en-aut-sei=Sakamoto en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KatayamaTetsuya en-aut-sei=Katayama en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MikaneYu en-aut-sei=Mikane en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HanzawaShunya en-aut-sei=Hanzawa en-aut-mei=Shunya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KadowakiDaisuke en-aut-sei=Kadowaki en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshidaYusuke en-aut-sei=Yoshida en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HamadaYuki en-aut-sei=Hamada en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SugimotoRyoma en-aut-sei=Sugimoto en-aut-mei=Ryoma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YagiChiaki en-aut-sei=Yagi en-aut-mei=Chiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HashimotoMasashi en-aut-sei=Hashimoto en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KanayaNobuhiko en-aut-sei=Kanaya en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KakiuchiYoshihiko en-aut-sei=Kakiuchi en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KikuchiSatoru en-aut-sei=Kikuchi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=18 en-affil=Oncolys BioPharma, Inc. kn-affil= affil-num=19 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Butyrate kn-keyword=Butyrate en-keyword=Oncolytic adenovirus kn-keyword=Oncolytic adenovirus en-keyword=MHC-I kn-keyword=MHC-I en-keyword=CD8 + T cells kn-keyword=CD8 + T cells en-keyword=Cancer immunotherapy kn-keyword=Cancer immunotherapy END start-ver=1.4 cd-journal=joma no-vol=137 cd-vols= no-issue=3 article-no= start-page=95 end-page=97 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251201 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=The 2024 Incentive Award of the Okayama Medical Association in Cardiovascular and Pulmonary Research (2024 Sunada Prize) kn-title=令和６年度岡山医学会賞　胸部・循環研究奨励賞（砂田賞） en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=KawanaShinichi en-aut-sei=Kawana en-aut-mei=Shinichi kn-aut-name=川名伸一 kn-aut-sei=川名 kn-aut-mei=伸一 aut-affil-num=1 ORCID= affil-num=1 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil=岡山大学大学院医歯薬学総合研究科 呼吸器・乳腺内分泌外科学 END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=20 article-no= start-page=4309 end-page=4317 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251009 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Characterization of Autonomous and Ca2+/Calmodulin-Dependent Activities of CaMKK Isoforms In Vitro and in Mouse Tissues en-subtitle= kn-subtitle= en-abstract= kn-abstract=Ca2+/CaM-dependent protein kinase kinase (CaMKK) phosphorylates and activates downstream kinases, including CaMKI, CaMKIV, PKB, and AMPK, regulating various cellular functions such as neuronal morphogenesis, metabolic control, and pathophysiological pathways, such as cancer progression. CaMKKα/1 is tightly regulated by an autoinhibitory mechanism. CaMKKβ/2 activity is highly Ca2+/CaM-independent (autonomous activity) in vitro and Ca2+/CaM-dependent in cultured cells. Whether these two activity states of CaMKKβ/2 exist in vivo and the detailed regulatory mechanisms for the transition of both activity states remain unclear due to the difficulty in distinguishing the two activity states. In this study, we detected Ca2+-dependent and autonomous CaMKK activity in HeLa cells and successfully separated both activity states of CaMKKβ/2 in mouse brain and testis extracts using a recently developed CaMKK inhibitor (TIM-063)-coupled sepharose, which binds to the catalytic domain in the active state but not in the autoinhibited state. Furthermore, lambda protein phosphatase treatment converted the Ca2+/CaM-dependent form to the autonomous form of CaMKKβ/2, which was not affected by Ala mutation of Ser128, Ser132, and Ser136. The two activity forms of CaMKKβ/2 had equivalent Ca2+/CaM-binding ability. The findings demonstrate the presence of autonomous and Ca2+/CaM-dependent forms of CaMKKβ/2 independently in mouse tissues and cultured cells. The transition of these states of CaMKKβ/2 may be dynamically regulated by the phosphorylation/dephosphorylation of serine residues in the N-terminal regulatory domain. en-copyright= kn-copyright= en-aut-name=OhtsukaSatomi en-aut-sei=Ohtsuka en-aut-mei=Satomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ChenYerun en-aut-sei=Chen en-aut-mei=Yerun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MagariMasaki en-aut-sei=Magari en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IshikawaTeruhiko en-aut-sei=Ishikawa en-aut-mei=Teruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SakagamiHiroyuki en-aut-sei=Sakagami en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SuizuFutoshi en-aut-sei=Suizu en-aut-mei=Futoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TokumitsuHiroshi en-aut-sei=Tokumitsu en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Science Education, Graduate School of Education, Okayama University kn-affil= affil-num=5 en-affil=Department of Anatomy, Kitasato University School of Medicine kn-affil= affil-num=6 en-affil=Clinical Examination Department, Kagawa Prefectural University of Health Sciences kn-affil= affil-num=7 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=8 article-no= start-page=938 end-page=943 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202508 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical outcomes of Japanese patients treated with out-of-specification tisagenlecleucel in a phase 3b trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: The final manufactured tisagenlecleucel product should meet the commercial product release specifications to ensure the quality in terms of safety, purity, identity, and potency. However, it may occasionally fail to meet these specifications due to the nature of patient-derived cells with variable properties as starting material and the complex manufacturing process. The final product that does not meet at least one of the commercial release specifications is referred to as “out-of-specification” (OOS). However, the benefit-risk profile of OOS tisagenlecleucel has not yet been fully elucidated.
Aims: To evaluate the safety and efficacy of OOS tisagenlecleucel in Japanese patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).
Methods: This is a single-arm, open-label, multicenter phase 3b study (NCT04094311). Patients consistent with label indication were enrolled and followed-up for 3 months.
Results: Of the 29 patients enrolled between December 2019 and May 2022 across 13 qualified sites in Japan, 28 received tisagenlecleucel, and of these, 23 had r/r DLBCL and 5 had r/r B-ALL. The primary reasons for OOS were low cell viability (15 of 24 batches) and low dose (8 of 23 batches) tisagenlecleucel in the r/r DLBCL group, and high dose (4 of 5 batches) in the r/r B-ALL group. In patients with r/r DLBCL, the grade 3 or 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 3 and 1 patients, respectively. Response assessments were performed for 15 of 23 patients with r/r DLBCL: 6 achieved a complete response, and 1 achieved a partial response as the best response within 3 months.
Conclusions: Despite the limited patient sample size, our findings affirm that the infusion of OOS tisagenlecleucel is a viable option, with no observed increase in toxicity and outcomes comparable to those of in-specification products in clinical and real-world studies. en-copyright= kn-copyright= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatoJun en-aut-sei=Kato en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GotoHideki en-aut-sei=Goto en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KobayashiTakeshi en-aut-sei=Kobayashi en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakahashiYoshiyuki en-aut-sei=Takahashi en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SakaidaEmiko en-aut-sei=Sakaida en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HiramatsuHidefumi en-aut-sei=Hiramatsu en-aut-mei=Hidefumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamamotoMasahide en-aut-sei=Yamamoto en-aut-mei=Masahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YoshiharaSatoshi en-aut-sei=Yoshihara en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AndoJun en-aut-sei=Ando en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KohKatsuyoshi en-aut-sei=Koh en-aut-mei=Katsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FukushimaKentaro en-aut-sei=Fukushima en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=IwamotoFumiko en-aut-sei=Iwamoto en-aut-mei=Fumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TiwariRanjan en-aut-sei=Tiwari en-aut-mei=Ranjan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital kn-affil= affil-num=2 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=3 en-affil=Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital kn-affil= affil-num=4 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital kn-affil= affil-num=5 en-affil=Department of Pediatrics, Nagoya University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Hematology, Chiba University Hospital kn-affil= affil-num=7 en-affil=Department of Pediatrics, Graduate School of Medicine, Kyoto University kn-affil= affil-num=8 en-affil=Department of Hematology, Institute of Science Tokyo Hospital kn-affil= affil-num=9 en-affil=Department of Hematology, Hyogo Medical University Hospital kn-affil= affil-num=10 en-affil=Department of Cell Therapy and Transfusion Medicine, Juntendo University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Department of Hematology/Oncology, Saitama Children’s Medical Center kn-affil= affil-num=12 en-affil=Department of Hematology and Oncology, Osaka University Graduate School of Medicine kn-affil= affil-num=13 en-affil=Medical Affairs, Novartis Pharma K.K. kn-affil= affil-num=14 en-affil=Development Advance Quantitative Sciences, Novartis Healthcare Private Limited kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=CAR-T kn-keyword=CAR-T en-keyword=DLBCL kn-keyword=DLBCL en-keyword=Out-of-specification kn-keyword=Out-of-specification en-keyword=Safety kn-keyword=Safety en-keyword=Tisagenlecleucel kn-keyword=Tisagenlecleucel END start-ver=1.4 cd-journal=joma no-vol=46 cd-vols= no-issue=1 article-no= start-page=69 end-page=84 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251230 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=P53-Armed Oncolytic Virotherapy Promotes the Efficacy of PD1 Blockade in Murine Osteosarcoma Tumors en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: Osteosarcoma (OS) is refractory to immune checkpoint inhibitors targeting programmed cell death 1 (PD1)/PD ligand 1 (PD-L1) due to poor immune response. We previously developed telomerase-specific, replication-competent oncolytic adenoviruses non-armed OBP-301 and P53-armed OBP-702 that exert antitumor efficacy against human OS cells. Recently, we demonstrated that P53-armed OBP-702 induces more profound immunogenic cell death and antitumor immune response against human and murine OS cells than does non-armed OBP-301. In the present study, we assessed the combined efficacy of PD1 blockade and P53-armed OBP-702 against murine OS cells.
Materials and Methods: Three murine OS cell lines (K7M2, NHOS, NHOS-LM4) were used to assess the cytopathic effect of non-armed OBP-301 and P53-armed OBP-702 by XTT assay. Virus-induced immunogenic cell death was assessed by analyzing the levels of extracellular adenosine triphosphate and high-mobility group box protein B1. The expression of PD-L1 and PD-L2 was analyzed by flow cytometry. The malignant potential of NHOS-LM4 cells was analyzed by a migration and invasion assay. An orthotopic NHOS-LM4 tumor model was used to evaluate the antitumor efficacy of combination therapy with P53-armed OBP-702 and anti-PD1.
Results: P53-armed OBP-702 exhibited antitumor potential for the induction of immunogenic cell death, apoptosis, autophagy, and PD-L1/2 upregulation in K7M2 and NHOS cells. NHOS-LM4 cells showed increased migratory and invasive ability compared to NHOS cells. P53-armed OBP-702 significantly suppressed the malignant potential of NHOS-LM4 cells. Combination dosing showed that P53-armed OBP-702 significantly promoted the antitumor effect of PD1 blockade against NHOS-LM4 tumors.
Conclusion: Our results suggest that P53-armed OBP-702 is a promising agent for improving the antitumor effect of PD1 blockade in treating invasive OS. en-copyright= kn-copyright= en-aut-name=KUREMIHO en-aut-sei=KURE en-aut-mei=MIHO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TAZAWAHIROSHI en-aut-sei=TAZAWA en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=DEMIYAKOJI en-aut-sei=DEMIYA en-aut-mei=KOJI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KONDOHIROYA en-aut-sei=KONDO en-aut-mei=HIROYA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MOCHIZUKIYUSUKE en-aut-sei=MOCHIZUKI en-aut-mei=YUSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KOMATSUBARATADASHI en-aut-sei=KOMATSUBARA en-aut-mei=TADASHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YOSHIDAAKI en-aut-sei=YOSHIDA en-aut-mei=AKI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UOTANIKOJI en-aut-sei=UOTANI en-aut-mei=KOJI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HASEIJOE en-aut-sei=HASEI en-aut-mei=JOE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FUJIWARATOMOHIRO en-aut-sei=FUJIWARA en-aut-mei=TOMOHIRO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KUNISADATOSHIYUKI en-aut-sei=KUNISADA en-aut-mei=TOSHIYUKI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=URATAYASUO en-aut-sei=URATA en-aut-mei=YASUO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KAGAWASHUNSUKE en-aut-sei=KAGAWA en-aut-mei=SHUNSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OZAKITOSHIFUMI en-aut-sei=OZAKI en-aut-mei=TOSHIFUMI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FUJIWARATOSHIYOSHI en-aut-sei=FUJIWARA en-aut-mei=TOSHIYOSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Osteosarcoma kn-keyword=Osteosarcoma en-keyword=oncolytic adenovirus kn-keyword=oncolytic adenovirus en-keyword=P53 kn-keyword=P53 en-keyword=immunogenic cell death kn-keyword=immunogenic cell death en-keyword=PD1 kn-keyword=PD1 END start-ver=1.4 cd-journal=joma no-vol=46 cd-vols= no-issue=1 article-no= start-page=25 end-page=38 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251230 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Near-infrared Photoimmunotherapy Targeting High-risk Human Neuroblastoma Cells Expressing GD2 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system in infancy. Despite advances in treatment, the prognosis remains poor for high-risk NB patients. Although immunotherapy using anti-GD2 antibodies is available for high-risk NB, the therapeutic efficacy is insufficient. Near-infrared photoimmunotherapy (NIR-PIT) is an antitumor strategy that induces tumor-specific cytotoxicity by combining an antibody-photoabsorber conjugate (APC) with NIR light irradiation. In this study, we investigated the therapeutic efficacy of GD2-targeted NIR-PIT against human NB cells.
Materials and Methods: GD2 expression was analyzed on the surface of high-risk human NB cells (CHP-134, LA-N-5, IMR-32) and non-high-risk human NB cells (SK-N-SH) by flow cytometry. The APC was synthesized by incubating anti-GD2 antibody and IR700. The cytotoxic effect of GD2-targeted NIR-PIT was evaluated using the XTT assay. The distribution of dead cells within tumor spheres was evaluated using a live/dead assay. The in vivo antitumor effect of GD2-targeted NIR-PIT was assessed using a subcutaneous human NB xenograft tumor model.
Results: GD2 protein was expressed on the surface of CHP-134, LA-N-5, and IMR-32 cells but not SK-N-SH cells. GD2-targeted NIR-PIT significantly suppressed the viability of GD2-positive NB cells but not GD2-negative NB cells, compared to the control and monotherapy groups. GD2-targeted NIR-PIT significantly reduced the volume of GD2-positive CHP-134 tumor spheres by inducing the accumulation of dead cells. Subcutaneous CHP-134 xenograft tumor models demonstrated that GD2-targeted NIR-PIT significantly inhibited tumor growth compared with the control and monotherapy groups.
Conclusion: GD2-targeted NIR-PIT is a promising antitumor strategy for treating high-risk NB tumors expressing GD2. en-copyright= kn-copyright= en-aut-name=NOUSOHIROSHI en-aut-sei=NOUSO en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TAZAWAHIROSHI en-aut-sei=TAZAWA en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TANIMOTOTERUTAKA en-aut-sei=TANIMOTO en-aut-mei=TERUTAKA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TANIMORIMICHI en-aut-sei=TANI en-aut-mei=MORIMICHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WATANABEHINAKO en-aut-sei=WATANABE en-aut-mei=HINAKO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OYAMATAKANORI en-aut-sei=OYAMA en-aut-mei=TAKANORI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NOMAKAZUHIRO en-aut-sei=NOMA en-aut-mei=KAZUHIRO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KAGAWASHUNSUKE en-aut-sei=KAGAWA en-aut-mei=SHUNSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KOBAYASHIHISATAKA en-aut-sei=KOBAYASHI en-aut-mei=HISATAKA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NODATAKUO en-aut-sei=NODA en-aut-mei=TAKUO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KURODASHINJI en-aut-sei=KURODA en-aut-mei=SHINJI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FUJIWARATOSHIYOSHI en-aut-sei=FUJIWARA en-aut-mei=TOSHIYOSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health kn-affil= affil-num=10 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Neuroblastoma kn-keyword=Neuroblastoma en-keyword=GD2 kn-keyword=GD2 en-keyword=near-infrared photoimmunotherapy kn-keyword=near-infrared photoimmunotherapy en-keyword=IR700 kn-keyword=IR700 END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=RP99936 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250811 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes en-subtitle= kn-subtitle= en-abstract= kn-abstract=In cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Depletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2 cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+ levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensures proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage. en-copyright= kn-copyright= en-aut-name=GekkoHaruna en-aut-sei=Gekko en-aut-mei=Haruna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NomuraRuri en-aut-sei=Nomura en-aut-mei=Ruri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuzuharaDaiki en-aut-sei=Kuzuhara en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KaneyasuMasato en-aut-sei=Kaneyasu en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KosekiGenpei en-aut-sei=Koseki en-aut-mei=Genpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AdhikariDeepak en-aut-sei=Adhikari en-aut-mei=Deepak kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MioYasuyuki en-aut-sei=Mio en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=CarrollJohn en-aut-sei=Carroll en-aut-mei=John kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KonoTomohiro en-aut-sei=Kono en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FunahashiHiroaki en-aut-sei=Funahashi en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=WakaiTakuya en-aut-sei=Wakai en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Reproductive Centre, Mio Fertility Clinic kn-affil= affil-num=4 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=5 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=6 en-affil=Development and Stem Cell Program and Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University kn-affil= affil-num=7 en-affil=Reproductive Centre, Mio Fertility Clinic kn-affil= affil-num=8 en-affil=Development and Stem Cell Program and Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University kn-affil= affil-num=9 en-affil=Department of Bioscience, Tokyo University of Agriculture kn-affil= affil-num=10 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=11 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=53 cd-vols= no-issue=22 article-no= start-page=gkaf1322 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251126 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=eIF2D promotes 40S ribosomal subunit recycling during intrinsic ribosome destabilization en-subtitle= kn-subtitle= en-abstract= kn-abstract=Although eukaryotic initiation factor 2D (eIF2D) is implicated in translation initiation, reinitiation, and ribosome recycling, its precise role remains unclear. Here, we show that eIF2D promotes 40S ribosome recycling during intrinsic ribosome destabilization (IRD), a process in which ribosomes stochastically destabilize while translating proteins with consecutive acidic amino acids at their NH2-terminus. Unrecycled 40S ribosomes accumulate in eIF2D-deficient cells, leading to 80S ribosome stalling. Selective translation complex profiling (TCP-seq) reveals that eIF2D preferentially associates with IRD-prone regions. The winged helix domain, unique to eIF2D but absent in MCTS1–DENR, enhances its binding to 40S subunits, but likely clashes with ABCE1 during stop-codon-associated recycling. Loss of eIF2D reduces the expression of IRD-inducing proteins, including splicing factors. Together, these findings define a previously unappreciated role for eIF2D in 40S recycling and clarify its mechanistic divergence from the MCTS1–DENR complex. en-copyright= kn-copyright= en-aut-name=IchiharaKazuya en-aut-sei=Ichihara en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShiraishiTaichi en-aut-sei=Shiraishi en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ChadaniYuhei en-aut-sei=Chadani en-aut-mei=Yuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KitoYuki en-aut-sei=Kito en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ShiraishiChisa en-aut-sei=Shiraishi en-aut-mei=Chisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HirataMina en-aut-sei=Hirata en-aut-mei=Mina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakahashiYuta en-aut-sei=Takahashi en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KoboAkinao en-aut-sei=Kobo en-aut-mei=Akinao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HatanoAtsushi en-aut-sei=Hatano en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MatsumotoMasaki en-aut-sei=Matsumoto en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MachidaKodai en-aut-sei=Machida en-aut-mei=Kodai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ImatakaHiroaki en-aut-sei=Imataka en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=ToyodaAtsushi en-aut-sei=Toyoda en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=Mishiro-SatoEmi en-aut-sei=Mishiro-Sato en-aut-mei=Emi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NojimaTakayuki en-aut-sei=Nojima en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=ItoTakuhiro en-aut-sei=Ito en-aut-mei=Takuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TaguchiHideki en-aut-sei=Taguchi en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NakayamaKeiichi I en-aut-sei=Nakayama en-aut-mei=Keiichi I kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=MatsumotoAkinobu en-aut-sei=Matsumoto en-aut-mei=Akinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=2 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=3 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University kn-affil= affil-num=5 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=6 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=7 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=8 en-affil=School of Life Science and Technology, Institute of Science Tokyo kn-affil= affil-num=9 en-affil=Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=10 en-affil=Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=11 en-affil=Graduate School of Engineering, University of Hyogo kn-affil= affil-num=12 en-affil=Graduate School of Engineering, University of Hyogo kn-affil= affil-num=13 en-affil=Advanced Genomics Center, National Institute of Genetics kn-affil= affil-num=14 en-affil=Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University kn-affil= affil-num=15 en-affil=Medical Institute of Bioregulation, Kyushu University kn-affil= affil-num=16 en-affil=Laboratory for Translation Structural Biology, RIKEN Center for Integrative Medical Sciences kn-affil= affil-num=17 en-affil=School of Life Science and Technology, Institute of Science Tokyo kn-affil= affil-num=18 en-affil=Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University kn-affil= affil-num=19 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=63 cd-vols= no-issue=13 article-no= start-page=1863 end-page=1872 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240701 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Activated CD4+ T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion.
Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022.
Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included.
Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4+CD25+CD127+ T cells (hereafter referred to as "activated CD4+ T cells" ) among the total CD4+ T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4+ T cells among the total CD4+ T cells <0.73 (p=0.01, and p<0.01, respectively).
Conclusion These results suggest that the proportion of activated CD4+ T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations. en-copyright= kn-copyright= en-aut-name=KitamuraWataru en-aut-sei=Kitamura en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IkegawaShuntaro en-aut-sei=Ikegawa en-aut-mei=Shuntaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FujiwaraHideaki en-aut-sei=Fujiwara en-aut-mei=Hideaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KamoiChihiro en-aut-sei=Kamoi en-aut-mei=Chihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishimoriHisakazu en-aut-sei=Nishimori en-aut-mei=Hisakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujiiKeiko en-aut-sei=Fujii en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MatsuokaKen-ichi en-aut-sei=Matsuoka en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Hematology and Oncology, Okayama University Hospital, Japan kn-affil= affil-num=4 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Division of Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=9 en-affil=Division of Blood Transfusion, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=chimeric antigen receptor T cell therapy kn-keyword=chimeric antigen receptor T cell therapy en-keyword=diffuse large B cell lymphoma kn-keyword=diffuse large B cell lymphoma en-keyword=flow cytometry kn-keyword=flow cytometry en-keyword=cytokine release syndrome kn-keyword=cytokine release syndrome en-keyword=prolonged cytopenia kn-keyword=prolonged cytopenia END start-ver=1.4 cd-journal=joma no-vol=19 cd-vols= no-issue=4 article-no= start-page=e70051 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Interaction between nuclear‐translocated cellular communication network factor 2 and purine‐rich box 1 regulates the expression of fibrosis‐related genes en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cellular communication network factor 2 (CCN2) with a nuclear localization signal-like peptide is known to promote fibrosis. However, translocation of CCN2 into the nucleus and its role in fibrosis remain unclear. We hypothesized that nuclear-translocated CCN2 is associated with purine-rich box 1 (PU.1), which is a transcription factor regulating the differentiation of myofibroblasts. Western blot analysis of the cytoplasmic and nuclear fractions of cell lysate and immunofluorescence analysis revealed that CCN2 was detectable in both the cytoplasm and nuclei of murine fibroblastic NIH3T3 cells. Additionally, chromatin immunoprecipitation (IP)-PCR and an electrophoretic mobility shift assay revealed that recombinant CCN2 protein bound to the regulatory region of Spi1, which encodes PU.1. Furthermore, IP-Western blot analysis showed that CCN2 interacted with PU.1. Finally, the forced expression of both Ccn2 and Spi1 significantly promoted the production of angiotensin II, and increased fibrosis-related molecules, such as Col1a1 and Acta2, at the gene and protein levels. These findings indicate that CCN2 translocated to the nucleus interacts with PU.1 and that the complex promotes the markers of myofibroblast differentiation, suggesting that CCN2 plays an important role in fibrosis via cooperation with PU.1, as a transcription co-factor. en-copyright= kn-copyright= en-aut-name=NguyenXuan Thi en-aut-sei=Nguyen en-aut-mei=Xuan Thi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KubotaSatoshi en-aut-sei=Kubota en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakigawaMasaharu en-aut-sei=Takigawa en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishidaTakashi en-aut-sei=Nishida en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan kn-affil= affil-num=4 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=cellular communication network factor 2 (CCN2) kn-keyword=cellular communication network factor 2 (CCN2) en-keyword=fibrosis kn-keyword=fibrosis en-keyword=myofibroblast kn-keyword=myofibroblast en-keyword=purine‐rich box 1 (PU.1) kn-keyword=purine‐rich box 1 (PU.1) en-keyword=transcription co‐factor kn-keyword=transcription co‐factor END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=4 article-no= start-page=e70082 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Case of Retinopathy–Sensory Neuropathy Syndrome With a Novel Compound Heterozygous FLVCR1 Variant en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Aims: Retinopathy–sensory neuropathy syndrome (RETSNS), also known as posterior column ataxia with retinitis pigmentosa (PCARP), is a rare neurodegenerative disorder that is caused by biallelic pathogenic variants in FLVCR1. Here, we report a case of a Japanese patient with RETSNS.
Methods: Clinical, neuroradiological, and electrophysiological findings were documented. Whole-genome sequencing was performed. Subcloning was carried out to confirm compound heterozygosity. A functional assay was performed to assess the pathogenicity of the variants.
Results: The patient showed retinitis pigmentosa and sensory ataxia. Over the course of the disease, autonomic dysfunction has become increasingly evident. Despite consanguinity in the family, whole-genome sequencing identified two heterozygous variants in FLVCR1 (c.369T>G, p.Phe123Leu and c.733A>G, p.Asn245Asp). Cloning of the PCR product followed by Sanger sequencing indicated compound heterozygosity of the variants. Immunocytochemistry of HEK293FT cells transfected with plasmids containing wild-type or variant FLVCR1 cDNA demonstrated altered subcellular localization of the variant FLVCR1 proteins, characterized by reduced membrane localization.
Interpretation: We report a novel variant in FLVCR1 causing RETSNS. The functional assay supports the pathogenicity of the variants. en-copyright= kn-copyright= en-aut-name=NakanoYumiko en-aut-sei=Nakano en-aut-mei=Yumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FukuiYusuke en-aut-sei=Fukui en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=DeguchiKentaro en-aut-sei=Deguchi en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsuokaChika en-aut-sei=Matsuoka en-aut-mei=Chika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawanoTomohito en-aut-sei=Kawano en-aut-mei=Tomohito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TairaYuki en-aut-sei=Taira en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MatsuoAyaka en-aut-sei=Matsuo en-aut-mei=Ayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OsakadaYosuke en-aut-sei=Osakada en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YunokiTaijun en-aut-sei=Yunoki en-aut-mei=Taijun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NomuraEmi en-aut-sei=Nomura en-aut-mei=Emi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TakemotoMami en-aut-sei=Takemoto en-aut-mei=Mami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MoriharaRyuta en-aut-sei=Morihara en-aut-mei=Ryuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YamashitaToru en-aut-sei=Yamashita en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=IshiuraHiroyuki en-aut-sei=Ishiura en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Neurology, Okayama City General Medical Center kn-affil= affil-num=4 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=FLCVR1 kn-keyword=FLCVR1 en-keyword=functional analysis kn-keyword=functional analysis en-keyword=posterior column ataxia with retinitis pigmentosa kn-keyword=posterior column ataxia with retinitis pigmentosa en-keyword=subcellular localization kn-keyword=subcellular localization END