start-ver=1.4 cd-journal=joma no-vol=31 cd-vols= no-issue=8 article-no= start-page=1658 end-page=1667 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260611 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Differential impact of host-related factors on survival outcomes between IO+IO and IO+TKI in metastatic renal cell carcinoma: a multicenter retrospective study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Immune checkpoint inhibitor (ICI)-based combination therapies, including immune checkpoint inhibitor plus immune checkpoint inhibitor (IO?+?IO) and immune checkpoint inhibitor plus tyrosine kinase inhibitor (IO?+?TKI) regimens, have significantly improved outcomes in metastatic renal cell carcinoma (mRCC). However, the prognostic impact of host-related factors in patients receiving these therapies remains unclear.
Methods We retrospectively analyzed 493 patients with mRCC treated with IO+IO (n?=?205) or IO+TKI (n?=?288) as first-line therapy. Survival outcomes and treatment responses were evaluated according to host-related factors using Cox proportional hazards models.
Results In the IO+IO cohort, multiple host-related factors were independently associated with worse overall survival, including BMI? Conclusion The prognostic impact of host-related factors differs according to treatment regimen in mRCC. These findings suggest that host immune and metabolic conditions play a more prominent role in immune-driven IO+IO therapy, whereas tumor-related factors may predominate in IO+TKI therapy. en-copyright= kn-copyright= en-aut-name=SugimotoKoichi en-aut-sei=Sugimoto en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 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=4 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=5 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=6 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=7 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=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=NishimuraShingo en-aut-sei=Nishimura en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 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=12 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=13 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=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=FujitaKazutoshi en-aut-sei=Fujita en-aut-mei=Kazutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Urology, Kindai University Faculty of Medicine kn-affil= affil-num=2 en-affil=Department of Urology, Kindai University Faculty of Medicine kn-affil= affil-num=3 en-affil=Department of Urology, Kindai University Faculty of Medicine 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, Hamamatsu University School of Medicine kn-affil= affil-num=7 en-affil=Department of Urology, Fujita Health University School of Medicine kn-affil= affil-num=8 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=9 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=10 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=13 en-affil=Department of Urology, Fujita Health University School of Medicine kn-affil= affil-num=14 en-affil=Department of Urology, Hamamatsu 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, Kindai University Faculty of Medicine kn-affil= en-keyword=Metastatic renal cell carcinoma kn-keyword=Metastatic renal cell carcinoma en-keyword=Immune checkpoint inhibitors kn-keyword=Immune checkpoint inhibitors en-keyword=Host-related factors kn-keyword=Host-related factors en-keyword=Prognosis kn-keyword=Prognosis en-keyword=Combination therapy kn-keyword=Combination therapy END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=5 article-no= start-page=309 end-page=316 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202610 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Dynamics of Serum Amyloid A Levels in the Blood, Brain and Liver in a Mouse Model of Focal Cerebral Ischemia en-subtitle= kn-subtitle= en-abstract= kn-abstract=This study examined the dynamics of serum amyloid A (SAA) levels in the blood, brain, and liver over time using a mouse model of focal cerebral ischemia induced by occlusion of the middle cerebral artery (MCA) for 4 h followed by reperfusion. Blood SAA concentrations increased transiently after cerebral infarction, coinciding with changes in brain and liver SAA gene expression and protein levels. SAA concentrations in the brain, liver, and blood increased at similar time points after cerebral infarction, suggesting that SAA may serve as an important indicator of the associated pathological condition. en-copyright= kn-copyright= en-aut-name=EgashiraSaki en-aut-sei=Egashira en-aut-mei=Saki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakanoTakafumi en-aut-sei=Nakano en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IrieKeiichi en-aut-sei=Irie en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=ManabeAkiko en-aut-sei=Manabe en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MasakiAyuko en-aut-sei=Masaki en-aut-mei=Ayuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MukaiRie en-aut-sei=Mukai en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakamuraYoshihiko en-aut-sei=Nakamura en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HosokawaMasato en-aut-sei=Hosokawa en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SathoTomomitsu en-aut-sei=Satho en-aut-mei=Tomomitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=SanoKazunori en-aut-sei=Sano en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MishimaKenichi en-aut-sei=Mishima en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=2 en-affil=Department of Oncology and Infectious Disease Pharmacy, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=3 en-affil=Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=4 en-affil=Department of Emergency and Disaster Medical Pharmacy, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=5 en-affil=Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=6 en-affil=Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=7 en-affil=Department of Microbiology Laboratory, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=8 en-affil=Department of Emergency and Critical Care Medicine, Fukuoka University Hospital kn-affil= affil-num=9 en-affil=Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=10 en-affil=Department of Microbiology Laboratory, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=11 en-affil=Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= affil-num=12 en-affil=Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University kn-affil= en-keyword=stroke kn-keyword=stroke en-keyword=cerebral ischemia kn-keyword=cerebral ischemia en-keyword=serum amyloid A kn-keyword=serum amyloid A en-keyword=temporal dynamics kn-keyword=temporal dynamics END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=5 article-no= start-page=299 end-page=308 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202610 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Prognostic Value of Combined Preoperative CALLY and SII Assessment in Patients Undergoing Resection for Esophageal Squamous Cell Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=This study evaluated the prognostic significance of the C-reactive protein?albumin?lymphocyte (CALLY) index and systemic immune-inflammation (SII) index in predicting postoperative outcomes in patients with esophageal squamous cell carcinoma (ESCC). A retrospective analysis was performed on clinical data from 102 patients with ESCC who underwent surgical resection at Western Theater General Hospital of China between January 2020 and July 2023. The associations between preoperative CALLY and SII indices and relapse-free survival (RFS) and overall survival (OS) were examined. Survival curves were generated using the Kaplan?Meier method, and prognostic factors were identified using Cox proportional hazards regression analysis. Patients with a high CALLY index had significantly longer RFS (HR=0.30, 95% CI: 0.13-0.71), and those with a low SII index also had significantly longer RFS (HR=2.23, 95% CI: 1.12-4.41). Similarly, patients with a high CALLY index had significantly longer OS (HR=0.27, 95% CI: 0.13-0.55), and those with a low SII index had significantly longer OS (HR=2.27, 95% CI: 1.09-4.71). When patients were stratified into four groups, the low-CALLY?high-SII group showed significantly shorter RFS than the high-CALLY?low-SII group (HR=0.26, 95% CI: 0.11-0.61; p=0.013), and OS was also significantly worse in the low-CALLY?high-SII group (HR=0.22, 95% CI: 0.09-0.54; p=0.016). Univariate Cox regression analysis identified both CALLY and SII as significant prognostic factors. In multivariate analysis, the CALLY index and N stage were independently associated with RFS, whereas only tumor size remained independently associated with OS. The combined assessment of preoperative CALLY and SII indices may be useful for prognostic stratification in patients with ESCC undergoing upfront surgical resection. It may help identify high-risk patient subgroups with distinct survival outcomes, thereby providing a potential rationale for stratifying postoperative surveillance and tailoring individualized adjuvant strategies, although validation in larger prospective cohorts is warranted. en-copyright= kn-copyright= en-aut-name=XuTao en-aut-sei=Xu en-aut-mei=Tao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ZhengYing en-aut-sei=Zheng en-aut-mei=Ying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HuangXuemei en-aut-sei=Huang en-aut-mei=Xuemei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=LuoHong en-aut-sei=Luo en-aut-mei=Hong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Oncology, The General Hospital of Western Theater Command kn-affil= affil-num=2 en-affil=Department of Oncology, The General Hospital of Western Theater Command kn-affil= affil-num=3 en-affil=Department of Oncology, The General Hospital of Western Theater Command kn-affil= affil-num=4 en-affil=Department of Oncology, The General Hospital of Western Theater Command kn-affil= en-keyword=CALLY index kn-keyword=CALLY index en-keyword=SII index kn-keyword=SII index en-keyword=esophageal squamous cell carcinoma kn-keyword=esophageal squamous cell carcinoma en-keyword=prognosis kn-keyword=prognosis END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=5 article-no= start-page=279 end-page=288 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202610 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Diabetes Mellitus as a Risk Factor for Severe COVID-19 and Pneumonia: A Comparison Between the Pre-Omicron and Omicron-Dominant Periods in Okayama City, Japan en-subtitle= kn-subtitle= en-abstract= kn-abstract=Diabetes mellitus is a well-established risk factor for severe COVID-19; however, few studies have examined this association during the Omicron-dominant period. We conducted a population-based study using surveillance data from the Okayama City Public Health Center in Japan to compare the risk of severe COVID-19 and pneumonia among patients with diabetes mellitus between the pre-Omicron (March 2020?December 2021) and Omicron-dominant (January?September 2022) periods. Among 98,905 COVID-19 patients aged 10 years or older, we calculated adjusted odds ratios (aORs) controlling for age, sex, smoking status, comorbidities, obesity, and the number of COVID-19 vaccine doses received. In the pre-Omicron period, diabetes mellitus was significantly associated with severe COVID-19 (aOR: 1.36; 95% CI: 1.03-1.78), and this association persisted in the Omicron-dominant period (aOR: 1.54; 95% CI: 1.10-2.17). Similar findings were observed for pneumonia. The association was more pronounced among patients aged 40-69 years than among those aged 70 years or older. These findings suggest that diabetes mellitus remains an important risk factor for severe COVID-19 even during the Omicron-dominant period, highlighting the need for continued clinical vigilance and early intervention in patients with diabetes mellitus. en-copyright= kn-copyright= en-aut-name=MiyamotoSatoshi en-aut-sei=Miyamoto en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsumotoNaomi en-aut-sei=Matsumoto en-aut-mei=Naomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=TakaoSoshi en-aut-sei=Takao en-aut-mei=Soshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YorifujiTakashi en-aut-sei=Yorifuji 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 Epidemiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Epidemiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Center for Innovative Clinical Medicine, Medical Development Field, Okayama University kn-affil= affil-num=4 en-affil=Department of Epidemiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Epidemiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=COVID-19 kn-keyword=COVID-19 en-keyword=diabetes mellitus kn-keyword=diabetes mellitus en-keyword=Omicron variant kn-keyword=Omicron variant en-keyword=severity kn-keyword=severity en-keyword=population-based study kn-keyword=population-based study END start-ver=1.4 cd-journal=joma no-vol=51 cd-vols= no-issue=10 article-no= start-page=533 end-page=547 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=Integration of QSAR modeling and in vitro validation for identification of food-derived Nrf2 activators against arsenic-induced toxicity en-subtitle= kn-subtitle= en-abstract= kn-abstract=Arsenic exposure is a major public health concern due to its toxicity and carcinogenicity, largely mediated by oxidative stress, and activation of the Nrf2 signaling pathway is considered a promising strategy to mitigate such damage. In this study, a quantitative structure?activity relationship (QSAR) model was developed to identify potential Nrf2 activators from food-derived compounds. Machine learning algorithms, including Random Forest (RF), Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), and a stacking model, were developed and optimized. The optimized RF, SVM, and LDA models were subsequently integrated into a stacking framework, which was selected as the final predictive model for virtual screening based on its robust and balanced predictive performance. The stacking model achieved the highest accuracy during five-fold cross-validation (0.77) and demonstrated competitive performance on the independent test set (0.742 } 0.040), with balanced precision, sensitivity, and F-measure. Consequently, the stacking model was selected as the final model for virtual screening. A total of 70,926 compounds retrieved from a food-derived database were filtered based on physicochemical criteria, and QSAR-based virtual screening predicted 920 compounds as potential activators of the Nrf2 signaling pathway, from which 5,7-Dimethylchrysin (FooDB ID: FDB015537) and Demethylvestitol (FooDB ID: FDB012218) were selected for experimental validation. In vitro assays using HepG2 cells demonstrated that 5,7-Dimethylchrysin significantly enhanced cell viability against sodium arsenite (150 ƒÊM)-induced cytotoxicity, with an effective concentration (EC50) of 0.54 ƒÊM, whereas Demethylvestitol exhibited only limited protective effects. Furthermore, luciferase reporter assays confirmed that 5,7-Dimethylchrysin activated antioxidant response element (ARE)-driven transcription in a concentration-dependent manner, producing a 1.5 to 2.4-fold increase at concentrations ranging from 0.78 to 6.25 ƒÊM. Overall, these findings highlight the effectiveness of integrating QSAR modeling with experimental validation to identify food-derived compounds with protective potential against arsenic-induced toxicity, with 5,7-Dimethylchrysin emerging as a promising candidate for further investigation. en-copyright= kn-copyright= en-aut-name=HuongNgo Thanh en-aut-sei=Huong en-aut-mei=Ngo Thanh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KodamaSusumu en-aut-sei=Kodama en-aut-mei=Susumu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OnoAtsushi en-aut-sei=Ono en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Laboratory of Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Laboratory of Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Laboratory of Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Arsenic toxicity kn-keyword=Arsenic toxicity en-keyword=Nrf2 activator kn-keyword=Nrf2 activator en-keyword=QSAR modeling kn-keyword=QSAR modeling en-keyword=Food-derived compounds kn-keyword=Food-derived compounds en-keyword=In vitro kn-keyword=In vitro END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=10 article-no= start-page=2213 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20261002 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Single-Cell Genomics Uncovers an Unexpectedly Abundant, Phylogenetically Hyperdiverse Patescibacteria (Candidate Phyla Radiation) Community in Agricultural Paddy Soil en-subtitle= kn-subtitle= en-abstract= kn-abstract=Patescibacteria, also known as the Candidate Phyla Radiation (CPR), are among the most diverse yet functionally reduced bacterial lineages whose diversity in agricultural soils remains poorly characterized. We applied single-cell genomics to bulk soil from an unfertilized paddy field after rice harvest and drainage. From 384 randomly sorted single cells, 126 medium-to-high-quality SAGs (Single-Amplified Genomes) were recovered, spanning 24 bacterial and archaeal phyla. Unexpectedly, 108 of the 384 SAGs (28.1%) were assigned to Patescibacteria?the most frequently recovered phylum?including 42 of the 126 reliable SAGs. These genomes were notably small (mean 973 kb vs. 1.4?3.2 Mb for other phyla). Because CheckM underestimates completeness in reduced CPR genomes, CheckM2 was applied, raising mean completeness from 59.9% to 83.3% and reclassifying 15 genomes as near-complete (>90%). Phylogenomic analysis using 16 ribosomal protein markers revealed extensive diversity and low average amino acid identity to reference genomes (mean 44.6%), indicating substantial taxonomic novelty. Despite this diversity, functional annotation and OrthoFinder analysis showed a conserved, reduced gene repertoire dominated by translation and DNA repair genes and depleted in amino acid, cofactor, and nucleotide biosynthesis. These results show that modest soil sampling can recover outsized Patescibacteria diversity, underscoring the need for CPR-appropriate completeness assessment. en-copyright= kn-copyright= en-aut-name=AliArslan en-aut-sei=Ali en-aut-mei=Arslan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SaishoDaisuke en-aut-sei=Saisho en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=TaniAkio en-aut-sei=Tani en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=3 en-affil=RIKEN Center for Sustainable Resource Science kn-affil= affil-num=4 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=Patescibacteria kn-keyword=Patescibacteria en-keyword=Candidate Phyla Radiation (CPR) kn-keyword=Candidate Phyla Radiation (CPR) en-keyword=single-cell genomics kn-keyword=single-cell genomics en-keyword=paddy soil kn-keyword=paddy soil END start-ver=1.4 cd-journal=joma no-vol=248 cd-vols= no-issue= article-no= start-page=117443 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202611 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Molecular characteristics and clinical outcomes of ERBB2-activating mutation-positive non-small cell lung cancer: A Japanese nationwide real-world cohort en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Erb-b2 receptor tyrosine kinase 2 (ERBB2)-activating mutations are well-documented oncogenic drivers in non-small cell lung cancer (NSCLC), occurring in approximately 1?4% of cases. These alterations include a heterogeneous spectrum of variant subtypes; however, the clinicogenomic characteristics and clinical significance of the individual variants have yet to be elucidated.
Methods: We searched the nationwide Center for Cancer Genomics and Advanced Therapeutics database, which integrates comprehensive genome profiling data generated in routine clinical practice across Japan, to investigate the molecular landscape and clinical outcomes of patients with ERBB2-mutated NSCLC.
Results: A total of 319 patients with ERBB2-activating mutations were included in this retrospective analysis. Although 74% of the patients harbored canonical tyrosine kinase domain (TKD) in-frame insertions, 26% carried noncanonical variants, including TKD missense (8%), transmembrane/juxtamembrane domain (10%), and extracellular domain (ECD) mutations (8%). Co-occurring oncogenic driver alterations were identified in only 18 cases (5.6%) and were largely restricted to noncanonical variants, whereas no co-occurring driver alterations were detected among patients with TKD in-frame mutations. Noncanonical variants?TKD missense and ECD mutations in particular?were associated with an increased tumor mutational burden. Among 288 patients with available survival data, 78 (27%) received trastuzumab deruxtecan (T-DXd) during their clinical course. After excluding patients who had started treatment with T-DXd before undergoing comprehensive genome profiling testing, time-dependent T-DXd exposure was associated with a reduced risk of death (adjusted hazard ratio, 0.63; 95% confidence interval, 0.39?1.01; P?=?0.057).
Conclusions: ERBB2-mutated NSCLC exhibited substantial molecular heterogeneity, with canonical TKD in-frame insertions characterized by a low frequency of co-occurring oncogenic driver alterations. Among patients harboring ERBB2-activating mutations, exposure to T-DXd was associated with improved overall survival. en-copyright= kn-copyright= en-aut-name=YamashitaMasahiro en-aut-sei=Yamashita en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=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=NakataEiji en-aut-sei=Nakata en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 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=6 ORCID= en-aut-name=TakadaKenji en-aut-sei=Takada en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 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=9 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=10 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=11 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=12 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=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=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 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=Center for Comprehensive Genomic 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=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Respiratory Medicine, 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, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Respiratory 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=Department of Respiratory Medicine, 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 Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=15 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= en-keyword=ERBB2 mutation kn-keyword=ERBB2 mutation en-keyword=Variant subtype kn-keyword=Variant subtype en-keyword=Comprehensive genomic profiling kn-keyword=Comprehensive genomic profiling en-keyword=Trastuzumab-deruxtecan kn-keyword=Trastuzumab-deruxtecan en-keyword=Non-small cell lung cancer kn-keyword=Non-small cell lung cancer END start-ver=1.4 cd-journal=joma no-vol=32 cd-vols= no-issue=17 article-no= start-page=3880 end-page=3890 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260526 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Sequential Immune Activation of Effector T Cells as Biomarkers of Response to Durvalumab in Patients with Locally Advanced NSCLC en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose: Durvalumab therapy following concurrent chemoradiotherapy (cCRT) improves progression-free survival (PFS) in patients with unresectable locally advanced non?small cell lung cancer. In this prospective observational study, we evaluated the changes in peripheral blood immune cell counts to elucidate the immunologic mechanisms underlying cCRT and durvalumab therapy.
Experimental Design: Peripheral blood mononuclear cell (PBMC) samples were collected at four time points: before cCRT, after cCRT, at the start of durvalumab, and 8 weeks after the start of durvalumab, and analyzed by multicolor flow cytometry.
Results: Of the 149 enrolled patients, 115 received durvalumab consolidation therapy after cCRT. The median PFS in the overall population was 24.2 months, and the 3-year PFS rate was 38.9%. PBMC analysis showed an increased effector fraction of CD4+ T cells before and after cCRT but no change in CD8+ T cells. Following durvalumab therapy, the effector fraction ratio of CD8+ T cells (CD62Llow CD8+ T cells) increased and positively correlated with increased CD62Llow CD4+ T cells during cCRT. Patients whose proportion of CD62Llow CD4+ T cells exceeded the threshold for cCRT had better PFS than those below the threshold. Patients whose CD62Llow CD8+ T-cell proportion exceeded the threshold after durvalumab therapy showed prolonged PFS compared with those below the threshold.
Conclusions: cCRT promotes an increase in effector CD4+ T cells, and the subsequent increase in CD8+ T cells following durvalumab therapy prolongs PFS. Peripheral blood effector?type CD4+ and CD8+ T cells are potential biomarkers for evaluating the immune status of patients and predicting treatment efficacy. en-copyright= kn-copyright= en-aut-name=MouriAtsuto en-aut-sei=Mouri en-aut-mei=Atsuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KenmotsuHirotsugu en-aut-sei=Kenmotsu en-aut-mei=Hirotsugu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KagamuHiroshi en-aut-sei=Kagamu en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=SaitoRyota en-aut-sei=Saito en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AkamatsuHiroaki en-aut-sei=Akamatsu en-aut-mei=Hiroaki 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=KakegawaMikiko en-aut-sei=Kakegawa en-aut-mei=Mikiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NagashimaHiromi en-aut-sei=Nagashima en-aut-mei=Hiromi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TakahashiSatoshi en-aut-sei=Takahashi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FujitaMasaki en-aut-sei=Fujita en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=YanagitaniNoriko en-aut-sei=Yanagitani en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=13 ORCID= en-aut-name=NishiokaYasuhiko en-aut-sei=Nishioka en-aut-mei=Yasuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=MoriKeita en-aut-sei=Mori en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KitanoShigehisa en-aut-sei=Kitano en-aut-mei=Shigehisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TamadaKoji en-aut-sei=Tamada en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=YamamotoNobuyuki en-aut-sei=Yamamoto en-aut-mei=Nobuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 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=19 ORCID= en-aut-name=MitsudomiTetsuya en-aut-sei=Mitsudomi en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Respiratory Medicine, International Medical Center, Saitama Medical University kn-affil= affil-num=2 en-affil=Division of Thoracic Oncology, Shizuoka Cancer Center kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, International Medical Center, Saitama Medical University kn-affil= affil-num=4 en-affil=Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Tohoku University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Internal Medicine III, Wakayama Medical University 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 Respiratory Medicine, Kitasato University School of Medicine kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Iwate Medical University School of Medicine kn-affil= affil-num=10 en-affil=Department of Thoracic Surgery, Tokyo Medical University Hospital kn-affil= affil-num=11 en-affil=Department of Respiratory Medicine, Fukuoka University Hospital kn-affil= affil-num=12 en-affil=Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research kn-affil= affil-num=13 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=15 en-affil=Department of Biostatistics, Clinical Research Support Center, Shizuoka Cancer Center kn-affil= affil-num=16 en-affil=Department of Advanced Medical Development, The Cancer Institute Hospital of Japanese Foundation for Cancer Research kn-affil= affil-num=17 en-affil=Department of Immunology, Yamaguchi University Graduate School of Medicine kn-affil= affil-num=18 en-affil=Internal Medicine III, Wakayama Medical University kn-affil= affil-num=19 en-affil=Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School kn-affil= affil-num=20 en-affil=Division of Thoracic Surgery, Izumi City General Hospital kn-affil= END start-ver=1.4 cd-journal=joma no-vol=218 cd-vols= no-issue= article-no= start-page=109516 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=ULK1, a novel therapeutic target to delay drug tolerance to EGFR?TKIs in an EGFR-mutant non-small cell lung cancer model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: The presence of drug-tolerant persister (DTP) cells reduces the effectiveness of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC). Although autophagy is a potential target for eliminating DTP cells, clinical trials targeting autophagy in EGFR-mutant NSCLC have been unsuccessful?likely because most trials have utilized chloroquine, non-specifically inhibiting autophagy targeting lysosomes with dose limitations. This study focused on unc-51-like autophagy activating kinase 1 (ULK1), a more specific target for autophagy inhibition, to assess whether ULK1 inhibition delays the emergence of tolerance to EGFR-tyrosine kinase inhibitors in EGFR-mutant NSCLC cells.
Methods: DTP cells were generated by treating EGFR-mutant NSCLC cell lines with osimertinib. Autophagy status and ULK1 expression were evaluated using immunofluorescence, western blotting, and quantitative real-time PCR. The effects of both pharmacological and genetic inhibition of ULK1 were examined in vitro and in vivo.
Results: ULK1 and LC3-II, markers of autophagy, were upregulated in DTP cells. Inhibition of ULK1, either pharmacologically or genetically, suppressed autophagy, prevented the formation of DTP cells, and enhanced the antitumor activity of osimertinib in both in vitro and in vivo models. Furthermore, upregulation of ULK1 expression through serum starvation conferred tolerance to osimertinib, reinforcing ULK1Œs role in drug tolerance. Notably, ULK1 inhibition showed modest efficacy even after cells transitioned to the DTP or acquired resistance states.
Conclusion: ULK1 plays a critical role in mediating drug tolerance in EGFR-mutant NSCLC. Targeting ULK1 represents a promising therapeutic approach to enhance the efficacy of EGFR-TKIs and to delay the development of drug tolerance. en-copyright= kn-copyright= en-aut-name=MoritaAyako en-aut-sei=Morita en-aut-mei=Ayako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=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=NishiTatsuya en-aut-sei=Nishi en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 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=8 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=9 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=10 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=11 ORCID= en-aut-name=OchiNobuaki en-aut-sei=Ochi en-aut-mei=Nobuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=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=IchiharaEiki en-aut-sei=Ichihara en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, 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 Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=8 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=9 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=10 en-affil=Center for Innovative Clinical 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=Department of General Internal Medicine 4, Kawasaki Medical School kn-affil= affil-num=13 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=14 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= en-keyword=ULK1 kn-keyword=ULK1 en-keyword=Autophagy kn-keyword=Autophagy en-keyword=EGFR kn-keyword=EGFR en-keyword=TKI kn-keyword=TKI en-keyword=Osimertinib kn-keyword=Osimertinib en-keyword=Non-small cell lung cancer kn-keyword=Non-small cell lung cancer END start-ver=1.4 cd-journal=joma no-vol=33 cd-vols= no-issue=6 article-no= start-page=315 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260527 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Limited Immune-Mediated Efficacy of Anti-PD-L1/VEGF in EGFR-TKI-Na?ve Egfr-Mutant Lung Cancer with Non-Inflamed Tumor Microenvironment en-subtitle= kn-subtitle= en-abstract= kn-abstract=Immune checkpoint inhibitors (ICIs) show limited efficacy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma due to its non-inflamed tumor microenvironment (TME). While quadruple therapy combining chemotherapy, anti-programmed death-ligand 1 (PD-L1), and anti-vascular endothelial growth factor (VEGF) antibodies has shown inconsistent results in EGFR-tyrosine kinase inhibitor (TKI)-pretreated patients, whether anti-VEGF therapy can modulate the intrinsic non-inflamed TME remains unknown. We employed an EGFR-TKI-na?ve syngeneic Egfr-mutant mouse model and evaluated effects of anti-VEGF, anti-PD-L1, carboplatin, and paclitaxel as monotherapies and combinations, with TME analysis via immunohistochemistry (IHC), flow cytometry, and RNA sequencing. Anti-PD-L1 showed no antitumor effect, and adding anti-VEGF failed to convert the TME to an inflamed status. Although paclitaxel?but not carboplatin?combined with low-dose anti-VEGF inhibited tumor growth, adding anti-PD-L1 provided no benefit, indicating the anti-VEGF-A antibody evaluated here has a limited role in sensitizing tumors to anti-PD-L1 regardless of chemotherapy. CD8+ T-cell depletion did not attenuate the effect of paclitaxel plus low-dose anti-VEGF, and IHC and RNA sequencing revealed increased natural killer cell infiltration, suggesting a CD8+ T-cell-independent, innate immune mechanism. These findings provide preclinical evidence that the evaluated anti-VEGF has limited immunomodulatory activity in EGFR-TKI-na?ve Egfr-mutant tumors with a non-inflamed TME, and suggest immunotherapeutic strategies beyond CD8+ T-cell-mediated immunity warrant investigation. en-copyright= kn-copyright= en-aut-name=HirabaeAtsuko en-aut-sei=Hirabae en-aut-mei=Atsuko 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=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=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=NakasukaTakamasa en-aut-sei=Nakasuka en-aut-mei=Takamasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NishiiKazuya en-aut-sei=Nishii en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=8 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=9 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=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=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=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, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=9 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 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=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=14 en-affil=Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd. 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, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 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 mutation kn-keyword=EGFR mutation en-keyword=non-small cell lung cancer kn-keyword=non-small cell lung cancer en-keyword=syngeneic mouse model kn-keyword=syngeneic mouse model en-keyword=antitumor immunity kn-keyword=antitumor immunity en-keyword=non-inflamed tumor kn-keyword=non-inflamed tumor en-keyword=VEGF kn-keyword=VEGF en-keyword=PD-L1 kn-keyword=PD-L1 END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=10 article-no= start-page=e70299 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=Interstitial Lung Disease in Patients With Unresectable Stage III NSCLC Treated With Chemoradiotherapy Followed by Durvalumab in Japan: Analysis From the Multicenter Prospective AYAME Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Interstitial lung disease (ILD) is a concerning adverse event associated with immune checkpoint inhibitors, including durvalumab. This analysis of the multicenter AYAME study assessed the longterm safety of durvalumab, focusing on ILD.
Methods: AYAME enrolled patients prescribed durvalumab for unresectable stage III non-small cell lung cancer (NSCLC) after chemoradiotherapy (CRT) from July 2019 to December 2020 in Japan. Patients received durvalumab for ??12?months and were prospectively followed for 3?years. Incidence, severity, and management of ILD were examined. Multivariable logistic regression analysis was conducted to investigate the association of patient characteristics with grade ??2 ILD occurrence.
Results: Of 511 patients in the safety analysis population, ILD occurred in 383 patients (75.0%) from durvalumab initiation to subsequent treatment start; median time to occurrence was 44.0?days. ILD led to permanent durvalumab discontinuation in 121/383 patients (31.6%), dose interruption in 111/383 (29.0%), and corticosteroid intervention in 168/383 (43.9%). Grade ??2 ILD occurrence was higher in patients with volume of lung parenchyma that received 20?Gy (V20) ??25% versus Conclusions: This study of durvalumab for NSCLC after CRT in a real-world setting indicated factors associated with grade ??2 ILD and provided valuable insights into ILD management strategies. These findings may contribute to establishing effective approaches to minimize ILD risk in practice.
Trial Registration: UMIN000037090/NCT03995875 en-copyright= kn-copyright= en-aut-name=YamamotoNobuyuki en-aut-sei=Yamamoto en-aut-mei=Nobuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KenmotsuHirotsugu en-aut-sei=Kenmotsu en-aut-mei=Hirotsugu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=AkdemirBurak en-aut-sei=Akdemir en-aut-mei=Burak kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=UematsuShinya en-aut-sei=Uematsu en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FukuiAyako en-aut-sei=Fukui en-aut-mei=Ayako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KotoRyo en-aut-sei=Koto en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujiwaraMasakazu en-aut-sei=Fujiwara en-aut-mei=Masakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IwaoChikako en-aut-sei=Iwao en-aut-mei=Chikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KitagawaHiroshi en-aut-sei=Kitagawa en-aut-mei=Hiroshi 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=GemmaAkihiko en-aut-sei=Gemma en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MitsudomiTetsuya en-aut-sei=Mitsudomi en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SaitoYoshinobu en-aut-sei=Saito en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Internal Medicine III, Wakayama Medical University kn-affil= affil-num=2 en-affil=Division of Thoracic Oncology, Shizuoka Cancer Center kn-affil= affil-num=3 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Oncology Medical, AstraZeneca K.K kn-affil= affil-num=5 en-affil=Oncology Medical, AstraZeneca K.K kn-affil= affil-num=6 en-affil=Evidence and Observational Research, Medical, AstraZeneca K.K kn-affil= affil-num=7 en-affil=Evidence and Observational Research, Medical, AstraZeneca K.K kn-affil= affil-num=8 en-affil=Evidence and Observational Research, Medical, AstraZeneca K.K kn-affil= affil-num=9 en-affil=Oncology Medical, AstraZeneca K.K kn-affil= affil-num=10 en-affil=Oncology Medical, AstraZeneca K.K kn-affil= affil-num=11 en-affil=Department of Thoracic Surgery, International University of Health and Welfare Narita Hospital kn-affil= affil-num=12 en-affil=Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School kn-affil= affil-num=13 en-affil=Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine kn-affil= affil-num=14 en-affil=Department of Pulmonary Medicine, Nippon Medical School Musashi Kosugi Hospital kn-affil= en-keyword=carcinoma kn-keyword=carcinoma en-keyword=chemoradiotherapy kn-keyword=chemoradiotherapy en-keyword=durvalumab kn-keyword=durvalumab en-keyword=interstitial kn-keyword=interstitial en-keyword=lung diseases kn-keyword=lung diseases en-keyword=non-small- cell lung kn-keyword=non-small- cell lung END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=5 article-no= start-page=e84709 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250523 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Phase II Study of Platinum Re-administration in Non-small Cell Lung Cancer Following Chemoimmunotherapy Resistance en-subtitle= kn-subtitle= en-abstract= kn-abstract=Platinum compounds represent standard treatments for various cancers. However, the efficacy of re-administrating platinum compounds has been demonstrated only in ovarian cancer and small cell lung cancer (SCLC), with its utility in non-small cell lung cancer (NSCLC) remaining unclear. Given that the prognosis of NSCLC has improved with effective treatments such as immune checkpoint inhibitors (ICIs), we propose a multicenter, single-arm, prospective phase II trial of re-administrating platinum-based combination therapy for NSCLC. Patients with NSCLC who have progressed after chemoimmunotherapy and exhibit a platinum-free interval of 85 days or more will receive carboplatin combination therapy. The drugs combined with carboplatin - pemetrexed, nab-paclitaxel, or gemcitabine - must not have been administered previously. The primary endpoint is progression-free survival (PFS), assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Assuming a threshold PFS of 4.2 months and an expected hazard ratio of 0.60, the required sample size is calculated as 40 patients to achieve 70% power with a 5% alpha error. Secondary endpoints included objective response rate, toxicity, and overall survival. This study will clarify the efficacy of re-administrating platinum compounds to patients with NSCLC who have developed resistance to chemoimmunotherapy. en-copyright= kn-copyright= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HosokawaShinobu en-aut-sei=Hosokawa en-aut-mei=Shinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 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=4 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=5 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=6 ORCID= en-aut-name=OkadaToshiaki en-aut-sei=Okada en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MaedaTadashi en-aut-sei=Maeda en-aut-mei=Tadashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KawaiHaruyuki en-aut-sei=Kawai en-aut-mei=Haruyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YasugiMasayuki en-aut-sei=Yasugi en-aut-mei=Masayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 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=12 ORCID= en-aut-name=NinomiyaTakashi en-aut-sei=Ninomiya en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OzeIsao en-aut-sei=Oze en-aut-mei=Isao 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=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=2 en-affil=Respiratory Medicine, Japanese Red Cross Okayama Hospital kn-affil= affil-num=3 en-affil=Respiratory Medicine, Kurashiki Central Hospital kn-affil= affil-num=4 en-affil=Chest Surgery, Shimonoseki City Hospital kn-affil= affil-num=5 en-affil=Respiratory Medicine, Japanese Red Cross Kobe Hospital kn-affil= affil-num=6 en-affil=Respiratory Medicine, National Hospital Organization Okayama Medical Center kn-affil= affil-num=7 en-affil=Respiratory Medicine, National Hospital Organization Fukuyama Medical Center kn-affil= affil-num=8 en-affil=Respiratory Medicine, National Hospital Organization Yamaguchi Ube Medical Center kn-affil= affil-num=9 en-affil=Internal Medicine, Okayama Saiseikai General Hospital kn-affil= affil-num=10 en-affil=Respiratory Medicine, Chugoku Central Hospital kn-affil= affil-num=11 en-affil=Respiratory Medicine, Ehime Prefectural Central Hospital kn-affil= affil-num=12 en-affil=Respiratory Medicine, Iwakuni Medical Center kn-affil= affil-num=13 en-affil=Respiratory Medicine, National Hospital Organization Shikoku Cancer Center kn-affil= affil-num=14 en-affil=Division of Molecular Medicine, Aichi Cancer Center Research Institute kn-affil= affil-num=15 en-affil=Hematology, Oncology, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= en-keyword=carboplatin kn-keyword=carboplatin en-keyword=clinical trial kn-keyword=clinical trial en-keyword=non-small cell lung cancer kn-keyword=non-small cell lung cancer en-keyword=platinum-free interval kn-keyword=platinum-free interval en-keyword=re-administration kn-keyword=re-administration END start-ver=1.4 cd-journal=joma no-vol=234 cd-vols= no-issue= article-no= start-page=112260 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202612 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The eukaryotic host?microbe?phage?nutrition interplay determines the bacterial effectors of supplemental lysinefs health benefits: An experimental cellular senescence model of digestive conditions in older adults en-subtitle= kn-subtitle= en-abstract= kn-abstract=Recently, the consumption of various forms of the nutritive amino acid lysine (e.g., nutraceuticals and dietary supplements) has increased, particularly among the elderly, as it cannot be synthesized by the human body and plays a crucial role in several cellular physiological processes, including intestinal calcium and iron absorption, proteinogenesis, and fatty acid metabolism. However, the biochemical and immunological events that occur within the eukaryotic host-microbe-phage-nutrition interaction, especially when high amounts of lysine are consumed in nutraceutical or dietary supplement form by the elderly due to age-related requirements, as well as the impact on gut bacteria-derived metabolites, have not yet been fully studied. We hypothesized that (1) within an infectious-inflamed digestive milieu, the metabolism of excess extracellular lysine differs between young and senescent digestive cells, and (2) phages within the milieu exhibit alterations in host-microbe cometabolite signal profiles. To address this, we examined how gut microbes and phages, key regulators of eukaryotic host physiology, influence the immunometabolism of excess lysine. By combining two models of young and senescent digestive cells, the pathogenic P. aeruginosa PAO1, the Pseudomonas phage KPP22, and the anti-inflammatory bacterium Intestinimonas butyriciproducens, and simulating the pathogenesis of the interactive process of excessive lysine ingestion, we developed a five-way screening approach to explore key cell readouts, including viability, integrity, and function of the epithelial barrier, as well as cellular immunometabolic responses to exogenous lysine supplementation in cultures under infectious inflammation. Our findings are consistent with the possibility that host?microbe?microbe interactions involving lysine utilization and cross-feeding may influence the effects of lysine supplementation. These effects, whether beneficial or detrimental, can depend on the bacterial community, including the presence of pathogenic or potentially beneficial bacteria, interactions with intestinal phages, and the physiological conditions and metabolic requirements of the host and individual microbial taxa. 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=Bl?merSophia en-aut-sei=Bl?mer en-aut-mei=Sophia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KAYAAysel ?AH?N en-aut-sei=KAYA en-aut-mei=Aysel ?AH?N kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=Kr?gerSandra en-aut-sei=Kr?ger en-aut-mei=Sandra kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=R?ckenChristoph en-aut-sei=R?cken en-aut-mei=Christoph kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=Sch?ferHeiner en-aut-sei=Sch?fer en-aut-mei=Heiner kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=de HeerGeraldine en-aut-sei=de Heer en-aut-mei=Geraldine kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=JarczakDominik en-aut-sei=Jarczak en-aut-mei=Dominik kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 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=10 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=11 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=University Center for Nutritional Medicine, University Medical Centre Hamburg-Eppendorf kn-affil= affil-num=8 en-affil=University Center for Nutritional Medicine, University Medical Centre Hamburg-Eppendorf kn-affil= affil-num=9 en-affil=Department of Bacteriology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Medical Laboratory Science, Faculty of Health Sciences, Kochi Gakuen University kn-affil= affil-num=11 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= en-keyword=Inflammaging kn-keyword=Inflammaging en-keyword=Lysine kn-keyword=Lysine en-keyword=Host cells kn-keyword=Host cells en-keyword=Phages kn-keyword=Phages en-keyword=Syntrophy kn-keyword=Syntrophy en-keyword=Cell senescence kn-keyword=Cell senescence 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=20260913 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical Significance of a Cell-Of-Origin-Based Classification in Pancreatic Ductal Adenocarcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited therapeutic options and poor clinical outcomes. Although PDAC has traditionally been thought to arise from ductal epithelial cells, recent studies using genetically engineered mouse models have demonstrated that acinar cells can also serve as a cell of origin, giving rise to tumors with distinct biological properties. Here, we investigated whether such lineage-specific differences are preserved in human PDAC. RNA sequencing was performed on resected specimens from 40 treatment-na?ve patients with PDAC, and tumors were classified into Acinar- and Ductal-subtypes using lineage-specific gene expression signatures derived from mouse models. This classification strategy was further applied to human PDAC cell lines, followed by in vitro drug sensitivity assays. Patients with Acinar-subtype tumors had significantly longer overall survival than those with Ductal-subtype tumors (median, 54.0 vs. 26.5?months; p? Methods: We retrospectively analyzed 207 patients with R/M HNSCC treated with nivolumab or pembrolizumab at a single institution. Early progression was defined as disease progression within 90 days after ICI initiation. Associations between clinicopathological factors and early progression were evaluated using logistic regression analyses.
Results: Early progression was observed in 80 patients (38.6%). In an exploratory survival comparison, patients with early progression had significantly shorter overall survival than those without early progression. Early progression rates increased from distant-only disease to locoregional-only disease and combined locoregional and distant disease. In multivariable analysis, combined locoregional, and distant disease showed the strongest independent association with early progression. Elevated neutrophil-to-lymphocyte ratio and hypoalbuminemia were also independently associated with early progression. In contrast, treatment regimen, treatment line, number of lesions, and bulky disease were not significantly associated with early progression.
Conclusion: Disease distribution was associated with early progression after ICI initiation in patients with R/M HNSCC, with combined locoregional and distant disease showing the strongest independent association. These findings suggest that both disease status and host condition may influence failure to achieve adequate disease control shortly after ICI initiation. en-copyright= kn-copyright= en-aut-name=NodaHiroki en-aut-sei=Noda en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MakinoTakuma en-aut-sei=Makino en-aut-mei=Takuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=FujimotoShohei en-aut-sei=Fujimoto en-aut-mei=Shohei 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 Otolaryngology?Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Otolaryngology?Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical 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=head and neck squamous cell carcinoma kn-keyword=head and neck squamous cell carcinoma en-keyword=immune checkpoint inhibitor kn-keyword=immune checkpoint inhibitor en-keyword=early progression kn-keyword=early progression en-keyword=locoregional disease kn-keyword=locoregional disease en-keyword=recurrent/metastatic disease kn-keyword=recurrent/metastatic disease 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=20260929 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Natural Variation in Brachypodium distachyon Primarily Links Lignin Reinforcement to Rhizoctonia solani Resistance en-subtitle= kn-subtitle= en-abstract= kn-abstract= 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=WatanabeMegumi en-aut-sei=Watanabe en-aut-mei=Megumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 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=5 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=6 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=7 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=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=Tea Research Institute of Sri Lanka 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= 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= END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=6 article-no= start-page=775 end-page=785 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=A Single-Arm Phase 2 Study of Sotorasib Plus Carboplatin and Pemetrexed in Patients With Advanced Nonsquamous NSCLC With KRAS G12C Mutation (WJOG14821L, SCARLET) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: The efficacy and safety of sotorasib plus platinum doublet chemotherapy in KRAS G12C-mutated nonsquamous NSCLC (nonsq NSCLC) have been previously reported with a limited follow-up period.
Methods: SCARLET is a single-arm phase 2 study involving chemotherapy-naive patients with KRAS G12C?mutated nonsq NSCLC. The participants received 960 mg daily plus four cycles of carboplatin (area under the curve = 5)/pemetrexed 500 mg/m2, followed by sotorasib/pemetrexed until disease progression. The primary end point was the overall response rate (ORR) and the secondary end points were progression-free survival (PFS), overall survival, and safety. Using plasma samples, next-generation sequencing was performed at baseline, 3 weeks, and during disease progression (the Japan Registry of Clinical Trials number 2051210086).
Results: Thirty patients were enrolled between October 2021 and July 2022 with a median follow-up of 14.8 months. ORR was 88.9% (80% confidence interval [CI]: 78.5%?94.8%, 95% CI: 70.8%?97.6%), median PFS was 6.6 months (95% CI: 5.3?16.7 mo), and median overall survival was 20.6 months (95% CI: 8.1 mo?not estimated). Among patients with programmed death-ligand 1 expression levels of 1% or higher and less than 1%, the ORRs were 82.3 and 100%, respectively, and the median PFS was 7.6 and 9.7 months, respectively. Using plasma samples, patients without KRAS G12C at baseline, without KRAS-related pathway co-alterations, or who cleared KRAS G12C at 3 weeks had better median PFS (16.7, 13.9, 8.7 mo, respectively). Tumor protein 53 mutations and EGFR and MET amplification were detected as acquired resistance.
Conclusions: In patients with KRAS G12C-mutated nonsq NSCLC, sotorasib plus carboplatin/pemetrexed reported favorable efficacy, particularly for patients with less than 1% programmed death-ligand 1, with manageable toxicity. en-copyright= kn-copyright= en-aut-name=AkamatsuHiroaki en-aut-sei=Akamatsu en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 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=4 ORCID= en-aut-name=UemuraTakehiro en-aut-sei=Uemura en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=Tsuchiya-KawanoYuko en-aut-sei=Tsuchiya-Kawano en-aut-mei=Yuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=EsumiSeiya en-aut-sei=Esumi en-aut-mei=Seiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KurosakiTakashi en-aut-sei=Kurosaki en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SatoYuki en-aut-sei=Sato en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SakamotoTomohiro en-aut-sei=Sakamoto en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 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=12 ORCID= en-aut-name=YoneshimaYasuto en-aut-sei=Yoneshima en-aut-mei=Yasuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=ShukuyaTakehito en-aut-sei=Shukuya en-aut-mei=Takehito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KozukiToshiyuki en-aut-sei=Kozuki en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=WatanabeKana en-aut-sei=Watanabe en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=DagaHaruko en-aut-sei=Daga en-aut-mei=Haruko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KatoTerufumi en-aut-sei=Kato en-aut-mei=Terufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 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=19 ORCID= en-aut-name=OsugaMitsuo en-aut-sei=Osuga en-aut-mei=Mitsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KohYasuhiro en-aut-sei=Koh en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=MoritaSatoshi en-aut-sei=Morita en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=YamamotoNobuyuki en-aut-sei=Yamamoto en-aut-mei=Nobuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= affil-num=1 en-affil=Internal Medicine III, Wakayama Medical University kn-affil= affil-num=2 en-affil=Department of Respiratory Medicine, Kumamoto University Hospital kn-affil= affil-num=3 en-affil=Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine kn-affil= affil-num=4 en-affil=Department of Thoracic Oncology, Kansai Medical University kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Kitakyushu Municipal Medical Center kn-affil= affil-num=7 en-affil=Respiratory Center, Matsusaka Municipal Hospital 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 Respiratory Medicine, Kobe City Medical Center General Hospital kn-affil= affil-num=10 en-affil=Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University kn-affil= affil-num=11 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=13 en-affil=Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, Juntendo University Graduate School of Medicine kn-affil= affil-num=15 en-affil=Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center kn-affil= affil-num=16 en-affil=Department of Respiratory Medicine, Miyagi Cancer Center kn-affil= affil-num=17 en-affil=Department of Medical Oncology, Osaka City General Hospital kn-affil= affil-num=18 en-affil=Department of Thoracic Oncology, Kanagawa Cancer Center kn-affil= affil-num=19 en-affil=Division of Thoracic Oncology, Shizuoka Cancer Center kn-affil= affil-num=20 en-affil=Center for Biomedical Sciences, Wakayama Medical University kn-affil= affil-num=21 en-affil=Internal Medicine III, Wakayama Medical University kn-affil= affil-num=22 en-affil=Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine kn-affil= affil-num=23 en-affil=Internal Medicine III, Wakayama Medical University kn-affil= en-keyword=KRAS G12C kn-keyword=KRAS G12C en-keyword=Sotorasib kn-keyword=Sotorasib en-keyword=Nonsquamous non?small cell lung cancer kn-keyword=Nonsquamous non?small cell lung cancer END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue= article-no= start-page=1 end-page=16 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=Clinical impact of hypomagnesemia induced by necitumumab plus cisplatin and gemcitabine treatment in patients with advanced lung squamous cell carcinoma: a subanalysis of the NINJA study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: The clinical impact of hypomagnesemia induced by necitumumab plus gemcitabine and cisplatin (GCN) as a second-line or later therapy is unclear.
Objective: We aimed to evaluate the clinical characteristics and survival impact of hypomagnesemia induced by this therapy.
Design: This was a sub-analysis of the retrospective multicenter NINJA study.
Methods: Among the 93 patients enrolled in the NINJA study, this subanalysis included 75 patients with baseline serum magnesium concentrations.
Results: The incidence of grade ?2 hypomagnesemia was 18.0% in the patients with normal baseline serum magnesium concentrations and 42.8% in those with low concentrations (p?=?0.073). The discontinuation rates of GCN treatment owing to hypomagnesemia in each group were 0% and 7.1%, respectively (p?=?0.187). The number of necitumumab doses and severity of hypomagnesemia were positively correlated (r?=?0.389, p? Conclusion: GCN as a second-line or later therapy may be tolerable regardless of the patientfs baseline serum magnesium concentration. On the other hand, early serum magnesium reduction with this therapy is associated with a poor prognosis. However, caution should be needed because our results lacked sufficient information for confounding variables other than those analyzed here that may influence the correlation between hypomagnesemia and survival. en-copyright= kn-copyright= en-aut-name=TanzawaShigeru en-aut-sei=Tanzawa en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 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=4 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=5 ORCID= en-aut-name=MurataYasunori en-aut-sei=Murata en-aut-mei=Yasunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakeshitaMasafumi en-aut-sei=Takeshita en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KinoshitaFumihiko en-aut-sei=Kinoshita en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujishitaTakatoshi en-aut-sei=Fujishita en-aut-mei=Takatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SugawaraShunichi en-aut-sei=Sugawara en-aut-mei=Shunichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KawashimaYosuke en-aut-sei=Kawashima en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HashimotoKazuki en-aut-sei=Hashimoto en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MoriMasahide en-aut-sei=Mori en-aut-mei=Masahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MiyanagaAkihiko en-aut-sei=Miyanaga en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=HayashiAnna en-aut-sei=Hayashi en-aut-mei=Anna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TanakaHisashi en-aut-sei=Tanaka en-aut-mei=Hisashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=HondaRyoichi en-aut-sei=Honda en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NojiriMasafumi en-aut-sei=Nojiri en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=SatoYuki en-aut-sei=Sato en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 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=20 ORCID= en-aut-name=IshikawaNobuhisa en-aut-sei=Ishikawa en-aut-mei=Nobuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=KozukiToshiyuki en-aut-sei=Kozuki en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=KawamuraTakahisa en-aut-sei=Kawamura en-aut-mei=Takahisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=SaitoGo en-aut-sei=Saito en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=YamaguchiTeppei en-aut-sei=Yamaguchi en-aut-mei=Teppei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=AsadaKazuhiro en-aut-sei=Asada en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=TetsumotoSatoshi en-aut-sei=Tetsumoto en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=TanakaHiroshi en-aut-sei=Tanaka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=WatanabeSatoshi en-aut-sei=Watanabe en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=UmedaYukihiro en-aut-sei=Umeda en-aut-mei=Yukihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=YamaguchiKakuhiro en-aut-sei=Yamaguchi en-aut-mei=Kakuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=NishiiKazuya en-aut-sei=Nishii en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= en-aut-name=TsurunoKosuke en-aut-sei=Tsuruno en-aut-mei=Kosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=33 ORCID= en-aut-name=MisumiYuki en-aut-sei=Misumi en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=34 ORCID= en-aut-name=KuraishiHiroshi en-aut-sei=Kuraishi en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=35 ORCID= en-aut-name=YoshiharaKen en-aut-sei=Yoshihara en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=36 ORCID= en-aut-name=NakaoAkira en-aut-sei=Nakao en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=37 ORCID= en-aut-name=KuboAkihito en-aut-sei=Kubo en-aut-mei=Akihito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=38 ORCID= en-aut-name=YokoyamaToshihiko en-aut-sei=Yokoyama en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=39 ORCID= en-aut-name=WatanabeKana en-aut-sei=Watanabe en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=40 ORCID= en-aut-name=SekiNobuhiko en-aut-sei=Seki en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=41 ORCID= affil-num=1 en-affil=Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine kn-affil= affil-num=2 en-affil=Department of Thoracic Oncology, Kansai Medical University Hospital kn-affil= affil-num=3 en-affil=Department of Data Science, National Cancer Center Hospital East kn-affil= affil-num=4 en-affil=Department of Respiratory Medicine, Tohoku 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, Ichinomiya Nishi Hospital kn-affil= affil-num=7 en-affil=Department of Respiratory Medicine, Ichinomiya Nishi Hospital kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=9 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=10 en-affil=Department of Pulmonary Medicine, Sendai Kousei Hospital kn-affil= affil-num=11 en-affil=Department of Pulmonary Medicine, Sendai Kousei Hospital kn-affil= affil-num=12 en-affil=Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center kn-affil= affil-num=13 en-affil=Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center kn-affil= affil-num=14 en-affil=Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School kn-affil= affil-num=15 en-affil=Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School kn-affil= affil-num=16 en-affil=Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Department of Respiratory Medicine, Asahi General Hospital kn-affil= affil-num=18 en-affil=Department of Respiratory Medicine, Kanazawa Medical University kn-affil= affil-num=19 en-affil=Department of Respiratory Medicine, Kobe City Medical Center General Hospital kn-affil= affil-num=20 en-affil=Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center kn-affil= affil-num=21 en-affil=Department of Respiratory Medicine, Hiroshima Prefectural Hospital kn-affil= affil-num=22 en-affil=Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center kn-affil= affil-num=23 en-affil=Department of Thoracic Oncology, Osaka International Cancer Institute kn-affil= affil-num=24 en-affil=Department of Respirology, Graduate School of Medicine, Chiba University kn-affil= affil-num=25 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=26 en-affil=Department of Respiratory Medicine, Shizuoka General Hospital kn-affil= affil-num=27 en-affil=Department of Respiratory Medicine and Clinical Immunology, Suita Municipal Hospital kn-affil= affil-num=28 en-affil=Department of Internal Medicine, Niigata Cancer Center Hospital kn-affil= affil-num=29 en-affil=Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences kn-affil= affil-num=30 en-affil=Department of Respiratory Medicine, Faculty of Medical Sciences, University of Fukui kn-affil= affil-num=31 en-affil=Department of Respiratory Medicine, Hiroshima University Hospital kn-affil= affil-num=32 en-affil=Department of Respiratory Medicine, NHO Iwakuni Clinical Center, Iwakuni, Yamaguchi, Japan kn-affil= affil-num=33 en-affil=Department of Respiratory Medicine, Iizuka Hospital kn-affil= affil-num=34 en-affil=Department of Respiratory Medicine, Yokohama Municipal Citizenfs Hospital kn-affil= affil-num=35 en-affil=Department of Pulmonary Medicine, Nagano Red Cross Hospital kn-affil= affil-num=36 en-affil=Department of Internal Medicine, Division of Medical Oncology and Respiratory Medicine, Shimane University Faculty of Medicine kn-affil= affil-num=37 en-affil=Department of Respiratory Medicine, Fukuoka University Hospital kn-affil= affil-num=38 en-affil=Department of Respiratory Medicine and Allergology, Aichi Medical University kn-affil= affil-num=39 en-affil=Department of Respiratory Medicine, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital kn-affil= affil-num=40 en-affil=Department of Respiratory Medicine, Miyagi Cancer Center kn-affil= affil-num=41 en-affil=Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine kn-affil= en-keyword=adverse event kn-keyword=adverse event en-keyword=hypomagnesemia kn-keyword=hypomagnesemia en-keyword=lung squamous cell carcinoma kn-keyword=lung squamous cell carcinoma en-keyword=necitumumab kn-keyword=necitumumab en-keyword=prognosis kn-keyword=prognosis END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=3 article-no= start-page=276 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250307 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Influence of Educational Films on Antiviral Prescription for COVID-19: Insights from Web-Based Survey in Japan en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Prescribing antiviral agents for severe acute respiratory syndrome coronavirus 2 requires careful consideration based on the patientfs risk factors for severe disease progression and their vaccination status. However, effective interventions ensuring the appropriate use of antiviral agents by physicians have yet to be fully established. Thus, this study evaluated the impact of an educational film on antiviral prescription rates for coronavirus disease 2019 (COVID-19). Methods: This prospective, nationwide, web-based survey enrolled 1500 physicians. They were instructed to view a short educational film and assess the necessity of prescribing antiviral agents in 16 fictitious scenarios featuring adult patients with COVID-19 with varying risk factors for severe disease and vaccination statuses. We compared the antiviral prescription rates before and after viewing the educational film. Results: There was a significant increase in the antiviral prescription rates after viewing the educational film, particularly nirmatrelvir/ritonavir prescribed in cases involving immunocompromised patients (from 31.3% to 49.4%) and those with obesity (from 15.1% to 33.7%) who were unvaccinated and had no risk of drug interactions. However, viewing the educational film made little to no impact on the prescription rates for the patients with hypertension and hyperlipidemia or those with no underlying conditions. Conclusions: Short educational films may promote the appropriate use of antiviral agents for COVID-19. However, their impact on altering prescription behavior appears limited and varies according to the clinical context. en-copyright= kn-copyright= en-aut-name=KomiyaKosaku en-aut-sei=Komiya en-aut-mei=Kosaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HagiwaraAkihiko en-aut-sei=Hagiwara en-aut-mei=Akihiko 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, Japan 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 University School of Medicine kn-affil= affil-num=19 en-affil=Center for Pulmonary Disease, National Hospital Organization Tokyo 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=education kn-keyword=education END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue= article-no= start-page=1 end-page=13 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=Skin disorder within 30?days is a favorable prognostic factor in patients with lung squamous cell carcinoma treated with necitumumab plus gemcitabine and cisplatin: a sub-analysis of the NINJA study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Skin disorders are major adverse events associated with necitumumab plus gemcitabine and cisplatin (Neci?+?GC) administration. However, the prognostic effect of skin disorders in patients with lung squamous cell carcinoma (LSCC) administered Neci?+?GC is unclear.
Objectives: We examined this prognostic effect in patients with LSCC, and the usefulness of minocycline administration.
Design: This was a sub-analysis of the retrospective multicenter NINJA study.
Methods: We performed a landmark survival analysis according to the presence of skin disorders at Day 30 of treatment and examined the usefulness of minocycline for treating skin disorders.
Results: Among the 93 patients, 62 (66.7%) had a skin disorder at Day 30. Nineteen, 30, and 13 patients experienced Grade 1, 2, and 3 skin disorders, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with skin disorders at Day 30 were longer than those of patients without skin disorders (median OS: 434 vs 278?days, p?=?0.0201; median PFS: 148 vs 82?days, p?=?0.0835). Multivariable analysis showed that a skin disorder at Day 30 was an independent prognostic factor for both OS (p?=?0.0044) and PFS (p?=?0.0514). Of the 62 patients with skin disorders at Day 30, 38 (61.3%) were taking minocycline, and their time to treatment failure (TTF) was better than that in patients not taking minocycline (median TTF: 148 vs 101?days, p?=?0.0495).
Conclusion: A skin disorder within 30?days was a favorable prognostic factor for patients with LSCC administered Neci?+?GC. Additionally, minocycline administration may be beneficial in patients who develop skin disorders within 30?days. en-copyright= kn-copyright= en-aut-name=KinoshitaFumihiko en-aut-sei=Kinoshita en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanzawaShigeru en-aut-sei=Tanzawa en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 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=4 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=5 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=6 ORCID= en-aut-name=MurataYasunori en-aut-sei=Murata en-aut-mei=Yasunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakeshitaMasafumi en-aut-sei=Takeshita en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 ORCID= en-aut-name=SugawaraShunichi en-aut-sei=Sugawara en-aut-mei=Shunichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KawashimaYosuke en-aut-sei=Kawashima en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HashimotoKazuki en-aut-sei=Hashimoto en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MoriMasahide en-aut-sei=Mori en-aut-mei=Masahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MiyanagaAkihiko en-aut-sei=Miyanaga en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=HayashiAnna en-aut-sei=Hayashi en-aut-mei=Anna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TanakaHisashi en-aut-sei=Tanaka en-aut-mei=Hisashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=HondaRyoichi en-aut-sei=Honda en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NojiriMasafumi en-aut-sei=Nojiri en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=SatoYuki en-aut-sei=Sato en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=YamamotoKen en-aut-sei=Yamamoto en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=MasudaKen en-aut-sei=Masuda en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=KozukiToshiyuki en-aut-sei=Kozuki en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=KawamuraTakahisa en-aut-sei=Kawamura en-aut-mei=Takahisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=SuzukiTakuji en-aut-sei=Suzuki en-aut-mei=Takuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=YamaguchiTeppei en-aut-sei=Yamaguchi en-aut-mei=Teppei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=AsadaKazuhiro en-aut-sei=Asada en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=TetsumotoSatoshi en-aut-sei=Tetsumoto en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=TanakaHiroshi en-aut-sei=Tanaka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=WatanabeSatoshi en-aut-sei=Watanabe en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=UmedaYukihiro en-aut-sei=Umeda en-aut-mei=Yukihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=YamaguchiKakuhiro en-aut-sei=Yamaguchi en-aut-mei=Kakuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 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=32 ORCID= en-aut-name=TsurunoKosuke en-aut-sei=Tsuruno en-aut-mei=Kosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=33 ORCID= en-aut-name=MisumiYuki en-aut-sei=Misumi en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=34 ORCID= en-aut-name=KuraishiHiroshi en-aut-sei=Kuraishi en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=35 ORCID= en-aut-name=YoshiharaKen en-aut-sei=Yoshihara en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=36 ORCID= en-aut-name=NakaoAkira en-aut-sei=Nakao en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=37 ORCID= en-aut-name=KuboAkihito en-aut-sei=Kubo en-aut-mei=Akihito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=38 ORCID= en-aut-name=YokoyamaToshihiko en-aut-sei=Yokoyama en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=39 ORCID= en-aut-name=WatanabeKana en-aut-sei=Watanabe en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=40 ORCID= en-aut-name=SekiNobuhiko en-aut-sei=Seki en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=41 ORCID= affil-num=1 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=2 en-affil=Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine kn-affil= affil-num=3 en-affil=Department of Data Science, National Cancer Center Hospital East kn-affil= affil-num=4 en-affil=Department of Thoracic Oncology, Kansai Medical University kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Tohoku 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 Respiratory Medicine, Ichinomiya Nishi Hospital kn-affil= affil-num=8 en-affil=Department of Respiratory Medicine, Ichinomiya Nishi Hospital kn-affil= affil-num=9 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=10 en-affil=Department of Pulmonary Medicine, Sendai Kousei Hospital kn-affil= affil-num=11 en-affil=Department of Pulmonary Medicine, Sendai Kousei Hospital kn-affil= affil-num=12 en-affil=Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center kn-affil= affil-num=13 en-affil=Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center kn-affil= affil-num=14 en-affil=Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School kn-affil= affil-num=15 en-affil=Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School kn-affil= affil-num=16 en-affil=Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Department of Respiratory Medicine, Asahi General Hospital kn-affil= affil-num=18 en-affil=Department of Respiratory Medicine, Kanazawa Medical University kn-affil= affil-num=19 en-affil=Department of Respiratory Medicine, Kobe City Medical Center General Hospital kn-affil= affil-num=20 en-affil=Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center kn-affil= affil-num=21 en-affil=Department of Respiratory Medicine, Hiroshima Prefectural Hospital kn-affil= affil-num=22 en-affil=Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center kn-affil= affil-num=23 en-affil=Department of Thoracic Oncology, Osaka International Cancer Institute kn-affil= affil-num=24 en-affil=Department of Respirology, Graduate School of Medicine, Chiba University kn-affil= affil-num=25 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=26 en-affil=Department of Respiratory Medicine, Shizuoka General Hospital kn-affil= affil-num=27 en-affil=Department of Respiratory Medicine and Clinical Immunology, Suita Municipal Hospital kn-affil= affil-num=28 en-affil=Department of Internal Medicine, Niigata Cancer Center Hospital kn-affil= affil-num=29 en-affil=Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences kn-affil= affil-num=30 en-affil=Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui kn-affil= affil-num=31 en-affil=Department of Respiratory Medicine, Hiroshima University Hospital kn-affil= affil-num=32 en-affil=Department of Respiratory medicine, NHO Iwakuni Clinical Center kn-affil= affil-num=33 en-affil=Department of Respiratory Medicine, Iizuka Hospital kn-affil= affil-num=34 en-affil=Department of Respiratory Medicine, Yokohama Municipal Citizenfs Hospital kn-affil= affil-num=35 en-affil=Department of Respiratory Medicine, Nagano Red Cross Hospital kn-affil= affil-num=36 en-affil=Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine kn-affil= affil-num=37 en-affil=Department of Respiratory Medicine, Fukuoka University Hospital kn-affil= affil-num=38 en-affil=Department of Respiratory Medicine and Allergology, Aichi Medical University School of Medicine kn-affil= affil-num=39 en-affil=Department of Respiratory Medicine, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital kn-affil= affil-num=40 en-affil=Department of Respiratory Medicine, Miyagi Cancer Center kn-affil= affil-num=41 en-affil=Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine kn-affil= en-keyword=adverse event kn-keyword=adverse event en-keyword=lung cancer kn-keyword=lung cancer en-keyword=necitumumab kn-keyword=necitumumab en-keyword=skin disorder kn-keyword=skin disorder en-keyword=squamous cell carcinoma kn-keyword=squamous cell carcinoma END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=9 article-no= start-page=2110 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260921 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Virotherapy for Spinal and Spinal Cord Tumors: Current Evidence and Future Perspectives en-subtitle= kn-subtitle= en-abstract= kn-abstract=Tumors of the spine and spinal cord, including primary and metastatic vertebral tumors, intramedullary gliomas, and refractory intradural lesions, are challenging to treat because curative local therapy is limited by the eloquent, nonregenerating neural tissue surrounding them. Oncolytic virotherapy may offer a rational alternative by combining tumor-selective oncolysis with the induction of systemic antitumor immunity, while sparing normal neural cells. This review summarizes the current field of oncolytic viruses, including adenovirus, herpes simplex virus, reovirus, and others, in the context of spinal and spinal cord tumors. Clinical data in the spine remain scarce; however, the rationale is based on histological evidence from sarcomas and other tumors, extensive glioma experience, including diffuse intrinsic pontine glioma, and preclinical activity in nerve sheath and meningioma models. We discuss the telomerase-specific oncolytic adenovirus OBP-301 and its derivatives, whose hTERT-driven replication provides histology-agnostic tumor selectivity, while sparing the telomerase-silent spinal cord. This telomerase dependence, however, limits activity against tumors that maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, such as many osteosarcomas and some spinal cord astrocytomas. We also discuss delivery and safety within the confined spinal canal, combination strategies, and future directions, such as extracellular vesicle-mediated delivery and biomarker-guided patient selection. Although clinical translation to the spine will require dedicated preclinical and early-phase studies, virotherapy represents a promising, mechanistically grounded modality for these therapeutically challenging tumors. en-copyright= kn-copyright= en-aut-name=UotaniKoji en-aut-sei=Uotani en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 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=4 ORCID= en-aut-name=MatsumotoKenzaburo en-aut-sei=Matsumoto en-aut-mei=Kenzaburo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=ShinoharaKensuke en-aut-sei=Shinohara en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=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= 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=Department of Orthopaedic 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 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 Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=oncolytic virotherapy kn-keyword=oncolytic virotherapy en-keyword=spinal cord tumor kn-keyword=spinal cord tumor en-keyword=spinal metastasis kn-keyword=spinal metastasis en-keyword=oncolytic adenovirus kn-keyword=oncolytic adenovirus en-keyword=OBP-301 kn-keyword=OBP-301 en-keyword=hTERT kn-keyword=hTERT en-keyword=telomerase kn-keyword=telomerase en-keyword=glioma kn-keyword=glioma en-keyword=blood?spinal cord barrier kn-keyword=blood?spinal cord barrier en-keyword=cancer immunotherapy kn-keyword=cancer immunotherapy END start-ver=1.4 cd-journal=joma no-vol=35 cd-vols= no-issue=10 article-no= start-page=e70808 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260923 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Conformational stability and domain]specific structural features of tumor autoantigens regulate autoantibody epitope propensity en-subtitle= kn-subtitle= en-abstract= kn-abstract=Autoantibodies against tumor-associated autoantigens are clinically valuable biomarkers for cancer diagnosis; however, the structural determinants governing epitope selectivity remain unknown. Here, we investigated whether the intrinsic conformational stability of target autoantigens regulates the epitope propensity of tumor-associated autoantibodies in non-small cell lung cancer. Using a dual-antigen Luminex bead-based assay that presents each autoantigen in both native and S-cationized denatured forms, we directly compared IgG autoantibody reactivity toward conformational and linear epitopes across 11 autoantigens. Intrinsically disordered aggregation-prone autoantigens, including cancer/testis antigens, NY-ESO-1, and XAGE-1b, predominantly elicit linear epitope-directed responses, whereas thermodynamically stable soluble autoantigens generally drive conformational epitope recognition. Intriguingly, for autoantigens harboring both ordered and disordered segments, the immune response is strictly guided by domain-specific biophysics: while p53-specific antibodies preferentially target their flanking disordered regions, the Wilms' tumor protein 1 exceptionally drives conformational recognition directed toward its structured zinc-finger domains. Recombinant solubility in Escherichia coli broadly correlated with epitope class across all 11 autoantigens, confirming that prokaryotic folding efficiency generally reflects intrinsic conformational stability in vivo for autonomously folding monomeric cytosolic proteins. Independent computational validation was provided by the concordance between the experimental solubility ratios and AlphaFold3-derived Rosetta energy unit/solvent-accessible surface area values, demonstrating the convergence of thermodynamic estimates and patient-derived immune data within a unifying biophysical framework. These findings establish that the autoantibody epitope propensity is closely associated with the thermodynamic stability of the target autoantigen and provide a rational basis for tailoring antigen preparation strategies for autoantibody-based cancer diagnosis. en-copyright= kn-copyright= en-aut-name=MiyamotoAi en-aut-sei=Miyamoto en-aut-mei=Ai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamamotoRika en-aut-sei=Yamamoto en-aut-mei=Rika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SakaguchiRyui en-aut-sei=Sakaguchi en-aut-mei=Ryui kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KutsumaRikako en-aut-sei=Kutsuma en-aut-mei=Rikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MoriTakeru en-aut-sei=Mori en-aut-mei=Takeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MasuiMirei en-aut-sei=Masui en-aut-mei=Mirei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HonjoTomoko en-aut-sei=Honjo en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FutamiMidori en-aut-sei=Futami en-aut-mei=Midori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MoriiMariko en-aut-sei=Morii en-aut-mei=Mariko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=10 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=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=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=FutamiJunichiro en-aut-sei=Futami en-aut-mei=Junichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 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=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, 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 Bioscience, Faculty of Life Science, Okayama University of Science kn-affil= affil-num=9 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=10 en-affil=Department of Respiratory 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=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=14 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=autoantibody kn-keyword=autoantibody en-keyword=biomarker kn-keyword=biomarker en-keyword=cancer/testis antigen kn-keyword=cancer/testis antigen en-keyword=epitope propensity kn-keyword=epitope propensity en-keyword=intrinsically disordered regions kn-keyword=intrinsically disordered regions en-keyword=protein engineering kn-keyword=protein engineering en-keyword=tumor-associated antigens kn-keyword=tumor-associated antigens END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=pcag119 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260928 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Disrupted FLOWERING LOCUS C alleles from weedy radish enhance the florigenic potential of rootstocks for graft-mediated floral induction in Brassicaceae en-subtitle= kn-subtitle= en-abstract= kn-abstract=Graft-mediated floral induction is a classical yet promising breeding technique that accelerates seed production and shortens generation time in crops. However, its application remains limited to a few species because floral induction is often unstable. Even among florally induced rootstocks, grafted scions can differ in their flowering response depending on rootstock genotype, but the genetic basis of this variation remains unclear. Here, using a Brassicaceae grafting model, we investigated two early-bolting radish (Raphanus sativus) accessions differing in their ability to induce flowering. We focused on a significant difference in FLOWERING LOCUS T (FT) expression between these accessions and identified two quantitative trait loci (QTLs) associated with FT levels. Transcriptomic and genomic analyses revealed that both QTLs harbored previously unreported disrupted alleles of FLOWERING LOCUS C (FLC) homologs, key floral repressors involved in vernalization, which showed reduced expression and produced defective transcripts. Grafting experiments demonstrated that these disrupted FLC alleles enhanced floral induction, with RsFLC1 having a major effect. Our results indicate that the FT expression threshold required for graft-mediated floral induction is higher than that for rootstock flowering itself and that this threshold is reached when FLC-mediated repression is substantially reduced. These alleles were inferred to have originated from weedy radish (Raphanus raphanistrum), likely contributing to early flowering in disturbed environments. This study suggests that exploring genetic variations in FT expression is an effective strategy to develop highly florigenic rootstocks, thereby broadening the application of graft-mediated floral induction in crop breeding. en-copyright= kn-copyright= en-aut-name=MotokiKo en-aut-sei=Motoki en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KobayashiSaki en-aut-sei=Kobayashi en-aut-mei=Saki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NishimuraKazusa en-aut-sei=Nishimura en-aut-mei=Kazusa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KinoshitaYu en-aut-sei=Kinoshita en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KashimaMakoto en-aut-sei=Kashima en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=GotoTanjuro en-aut-sei=Goto en-aut-mei=Tanjuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YasubaKen-ichiro en-aut-sei=Yasuba en-aut-mei=Ken-ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HosokawaMunetaka en-aut-sei=Hosokawa en-aut-mei=Munetaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Graduate School of Environmental, Life and Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental, Life and Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental, Life and Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Agriculture, Kyoto University kn-affil= affil-num=5 en-affil=Faculty of Science, Department of Biomolecular Science, Toho University kn-affil= affil-num=6 en-affil=Graduate School of Environmental, Life and Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Environmental, Life and Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Graduate School of Environmental, Life and Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Faculty of Agriculture, Kindai University kn-affil= en-keyword=Brassica oleracea kn-keyword=Brassica oleracea en-keyword=FLOWERING LOCUS C kn-keyword=FLOWERING LOCUS C en-keyword=FLOWERING LOCUS T kn-keyword=FLOWERING LOCUS T en-keyword=graft-mediated floral induction kn-keyword=graft-mediated floral induction en-keyword=vernalization kn-keyword=vernalization en-keyword=weedy radish (Raphanus raphanistrum) kn-keyword=weedy radish (Raphanus raphanistrum) END start-ver=1.4 cd-journal=joma no-vol=68 cd-vols= no-issue=6 article-no= start-page=100819 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202612 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Synaptic transmission in Type III taste cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Type III taste cells are the primary taste receptor cells that form conventional chemical synapses with gustatory nerve fibers. Since the first ultrastructural identification of synaptic vesicles in Type III cells, numerous studies have demonstrated that these cells have synapse-associated proteins and vesicular release machinery that is similar to that in the central nervous system.
Highlight: This review summarizes historical and ultrastructural studies describing synaptic vesicles in taste bud cells across a range of animal species. The classical mechanisms of chemical synaptic transmission in the central nervous system are then outlined, followed by review studies demonstrating the expression of synapse-associated proteins in taste bud cells, with particular emphasis on the putative mechanisms of synaptic transmission in Type III taste cells. Finally, the current evidence for candidate neurotransmitters, including 5-hydroxytryptamine, gamma-aminobutyric acid, noradrenaline, acetylcholine, and ATP, is discussed.
Conclusion: Although several proteins related to conventional chemical synapses in the central nervous system and some candidate neurotransmitters have been identified in Type III cells, their contributions to sour taste transmission have not been fully elucidated. Further molecular and physiological studies are required to establish their roles in the synaptic transmission of sour taste signals from Type III cells. en-copyright= kn-copyright= en-aut-name=TatsukawaHinata en-aut-sei=Tatsukawa en-aut-mei=Hinata kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 ORCID= affil-num=1 en-affil=Department of Oral Physiology, 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= en-keyword=Type III cell kn-keyword=Type III cell en-keyword=Conventional chemical synapse kn-keyword=Conventional chemical synapse en-keyword=SNARE complex kn-keyword=SNARE complex en-keyword=Neurotransmitter kn-keyword=Neurotransmitter END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=e77909 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260927 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=SPRED2 Negatively Regulates CD8+ T Cell-Mediated Antitumor Immunity in Breast Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Activation of the RAS/RAF/ERK pathway is crucial for adaptive immunity. Here, we provide evidence that Sprouty-related EVH1 domain containing 2 (SPRED2), an endogenous inhibitor of this pathway, negatively regulates CD8+ T cell-mediated antitumor immunity in breast cancer. In EO771 and 4T1 mouse models, Spred2?/? mice exhibit reduced tumor growth, with lower endpoint lung metastatic burden in the 4T1 model, accompanied by increased T-cell infiltration and activation. Spred2?/? T cells show enhanced cytokine expression, proliferation,survival, in vitro cytotoxicity, and memory-like phenotypes, particularly among CD8+ T cells. Adoptive transfer of Spred2?/? CD8+ T cells into tumor-bearing wild-type hosts similarly reduces endpoint lung metastatic burden. MEK inhibition with U0126 attenuates increased interferon-gamma and granzyme B expression in Spred2?/? CD8+ T cells. Transcriptomic analyses reveal an inverse correlation between SPRED2 expression and antitumor CD8+ T cell states in both humans and mice. In tumor-infiltrating T cells from patients with breast cancer, SPRED2low T cells show enriched effector and cytotoxicity programs and are associated with gimmune-hoth tumors, whereas survival associations vary with CD8+ T cell context. Collectively, these findings suggest that SPRED2 functions as a cell-intrinsic negative regulator of CD8+ T-cell activation and highlight its potential as a therapeutic target to enhance T cell?based cancer immunotherapy. en-copyright= kn-copyright= en-aut-name=TianMiao en-aut-sei=Tian en-aut-mei=Miao 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=ZhaoKun en-aut-sei=Zhao en-aut-mei=Kun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=GaoTong en-aut-sei=Gao en-aut-mei=Tong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=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=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 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 Oral Rehabilitation and Regenerative 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 Advanced International and Information Dentistry, Faculty 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= affil-num=9 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=CD8+ T cells kn-keyword=CD8+ T cells en-keyword=immunotherapy kn-keyword=immunotherapy en-keyword=MAPK/ERK kn-keyword=MAPK/ERK en-keyword=tumor microenvironment kn-keyword=tumor microenvironment END start-ver=1.4 cd-journal=joma no-vol=32 cd-vols= no-issue=5 article-no= start-page=573 end-page=583 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250401 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tob negatively regulates NF-ƒÈB activation in breast cancer through its association with the TNF receptor complex en-subtitle= kn-subtitle= en-abstract= kn-abstract=NF-ƒÈB mediates transcriptional regulation crucial to many biological functions, and elevated NF-ƒÈB activity leads to autoimmune and inflammatory diseases, as well as cancer. Since highly aggressive breast cancers have few therapeutic molecular targets, clarification of key molecular mechanisms of NF-ƒÈB signaling would facilitate the development of more effective therapy. In this report, we show that Tob, a member of the Tob/BTG family of antiproliferative proteins, acts as a negative regulator of the NF-ƒÈB signal in breast cancer. Studies with 35 human breast cancer cell lines reveal that Tob expression is negatively correlated with NF-ƒÈB activity. Analysis of The Cancer Genome Atlas (TCGA) database of clinical samples reveals an inverse correlation between Tob expression and NF-ƒÈB activity. Tob knockdown in human breast cancer cells promoted overactivation of NF-ƒÈB upon TNF-ƒ¿ treatment, whereas overexpression of Tob inhibited TNF-ƒ¿ stimulation-dependent NF-ƒÈB activation. Mechanistically, Tob associates with the TNF receptor complex I and consequently inhibits RIPK1 polyubiquitylation, leading to possible prevention of overwhelming activation of NF-ƒÈB. en-copyright= kn-copyright= en-aut-name=TokumasuMiho en-aut-sei=Tokumasu en-aut-mei=Miho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SatoAtsuko en-aut-sei=Sato en-aut-mei=Atsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Ito-KurehaTaku en-aut-sei=Ito-Kureha en-aut-mei=Taku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamotoMizuki en-aut-sei=Yamamoto en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OhmineNao en-aut-sei=Ohmine en-aut-mei=Nao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SembaKentaro en-aut-sei=Semba en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=InoueJun-ichiro en-aut-sei=Inoue en-aut-mei=Jun-ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamamotoTadashi en-aut-sei=Yamamoto en-aut-mei=Tadashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University kn-affil= affil-num=3 en-affil=Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University kn-affil= affil-num=4 en-affil=Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo kn-affil= affil-num=5 en-affil=Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University kn-affil= affil-num=6 en-affil=Department of Life Science and Medical Bioscience, Waseda University kn-affil= affil-num=7 en-affil=The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA) kn-affil= affil-num=8 en-affil=Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=9 article-no= start-page=218 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260829 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=First-Order Wall-Slip-Induced Departure from Inverse-Cubic Scaling of Levitation-Pressure RMS in a Push?Pull Levitation Stage en-subtitle= kn-subtitle= en-abstract= kn-abstract=This study clarifies how rarefaction-induced wall slip in a thin gas film affects the established inverse-cubic scaling law for the spatial nonuniformity of levitation pressure in a push?pull levitation stage. The levitation force in this stage is generated by the combined action of blowing and suction. The continuum-based stress description is retained, and only the wall boundary condition is changed from the no-slip condition to a first-order slip condition. Three-dimensional incompressible unsteady Stokes simulations in a thin-gap unit-cell model are combined with a lubrication-theory scaling analysis. The effects of levitation height, blowing-velocity distribution, port-radius ratio, and computational-domain width are examined systematically. The results show that wall slip has only a minor influence at relatively large levitation heights. As the levitation height decreases, however, rarefaction-induced slip increases the flow-rate conductance. Consequently, the intensity of the spatial variation in levitation pressure is systematically reduced below that predicted by the no-slip inverse-cubic scaling law. This departure is well described by a correction relation derived from the lubrication approximation and remains robust against changes in the prescribed blowing-velocity distribution and geometric conditions. These findings provide an incompressible baseline for predicting levitation-pressure nonuniformity within the nominal gap-based Knudsen-number range examined here. en-copyright= kn-copyright= en-aut-name=UmesakiEisuke en-aut-sei=Umesaki en-aut-mei=Eisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SuzukiHiroki en-aut-sei=Suzuki en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SakamotoJunji en-aut-sei=Sakamoto en-aut-mei=Junji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KouchiToshinori en-aut-sei=Kouchi en-aut-mei=Toshinori 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=push?pull levitation kn-keyword=push?pull levitation en-keyword=wall slip kn-keyword=wall slip en-keyword=rarefaction kn-keyword=rarefaction en-keyword=lubrication approximation kn-keyword=lubrication approximation en-keyword=pressure RMS kn-keyword=pressure RMS en-keyword=thin gas film kn-keyword=thin gas film en-keyword=Knudsen number kn-keyword=Knudsen number END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=1 end-page=15 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260828 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=MIT/TFE family transcription factors, Mitf and Tfec, redundantly promote pigment cell differentiation and retinal epithelium pigmentation in teleosts en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Transcription factors of the MIT/TFE family?mitfa, mitfb, and tfec?play essential roles in specifying pigment cells derived from neural crest cells in vertebrates. In teleosts, which possess multiple pigment cell types, these factors exhibit partially redundant but largely distinct functions across different pigment lineages. We previously reported that the combined loss of mitfa and mitfb leads to a complete absence of melanophores, xanthophores, and leucophores in medaka.
Results: Here, we describe newly generated hypomorphic alleles of mitfa and mitfb, which result in delayed melanophore development. Using these hypomorphic mutants in combination with a newly generated null allele of tfec, we show that Tfec can partially compensate for the loss of Mitfa and Mitfb in melanophore, xanthophore, and leucophore differentiation. Consistent with previous findings in zebrafish, loss of tfec alone results in the complete absence of iridophores. Importantly, simultaneous null mutations in all three genes cause a complete loss of all four chromatophore types and lead to defective pigmentation of the retinal pigmented epithelium (RPE), which is not derived from the neural crest in both Oryzias species and in zebrafish. Using an RPE-specific marker, we further show that the RPE is specified and structurally intact but fails to melanize.
Conclusions: These findings indicate that the redundant functions of Mitfa, Mitfb, and Tfec are not only essential for the specification of diverse pigment cell types but also critical for RPE pigmentation. en-copyright= kn-copyright= en-aut-name=ListerJames en-aut-sei=Lister en-aut-mei=James kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=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=TanakaRieko en-aut-sei=Tanaka en-aut-mei=Rieko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=GodaMakoto en-aut-sei=Goda en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KobayashiHikaru en-aut-sei=Kobayashi en-aut-mei=Hikaru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=InoueChikako en-aut-sei=Inoue en-aut-mei=Chikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 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=9 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=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=KelshRobert N. en-aut-sei=Kelsh en-aut-mei=Robert N. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=13 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=14 ORCID= affil-num=1 en-affil=Department of Human and Molecular Genetics and Massey Cancer Center, Virginia Commonwealth University School of Medicine kn-affil= affil-num=2 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= affil-num=3 en-affil=Department of Basic Biology, School of Life Science, Graduate University of Advanced Studies (SOKENDAI) & Laboratory of Bioresources, National Institute for Basic Biology kn-affil= affil-num=4 en-affil=World Medaka Aquarium, Nagoya Higashiyama Zoo and Botanical Gardens kn-affil= affil-num=5 en-affil=Institute of Photonics Medicine, Hamamatsu University School of Medicine 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=R&D Fish Breeding Group, Regional Fish Institute, Ltd. kn-affil= affil-num=8 en-affil=Faculty of Fisheries and Marine Science, Sam Ratulangi University kn-affil= affil-num=9 en-affil=Tropical Biosphere Research Center, University of the Ryukyus kn-affil= affil-num=10 en-affil=Department of Basic Biology, School of Life Science, Graduate University of Advanced Studies (SOKENDAI) & Laboratory of Bioresources, National Institute for Basic Biology kn-affil= affil-num=11 en-affil=Ushimado Marine Institute, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=12 en-affil=Department of Life Sciences, University of Bath kn-affil= affil-num=13 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= affil-num=14 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= en-keyword=compound mutants kn-keyword=compound mutants en-keyword=melanization kn-keyword=melanization en-keyword=neural crest kn-keyword=neural crest en-keyword=retina kn-keyword=retina en-keyword=RPE kn-keyword=RPE END start-ver=1.4 cd-journal=joma no-vol=98 cd-vols= no-issue= article-no= start-page=107057 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2027 dt-pub=202701 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Transcriptional remodeling of local thyroid hormone metabolism is associated with feather growth termination in chicken wing feathers en-subtitle= kn-subtitle= en-abstract= kn-abstract=Feather elongation is sustained by continuous cell proliferation within the feather follicle; however, the molecular mechanisms responsible for feather growth termination remain poorly understood. In this study, we investigated molecular changes associated with feather growth termination by comparing two chicken wing feather types with contrasting growth characteristics: primary wing feathers and primary coverts. Histological and bromodeoxyuridine incorporation analyses demonstrated that primary wing feathers remained in an active growth phase, whereas primary coverts exhibited pulp regression, reduced cell proliferation, and characteristics of growth termination. Gene expression analyses showed that primary coverts exhibited reduced expression of prolactin receptor (PRLR), type 2 iodothyronine deiodinase (DIO2), and insulin-like growth factor 2 (IGF2), together with marked induction of the thyroid hormone (TH)-inactivating enzyme type 3 iodothyronine deiodinase (DIO3). In contrast, primary wing feathers exhibited relatively higher expression of PRLR, DIO2, and IGF2 than primary coverts, while maintaining consistently low DIO3 expression. Reporter assays showed increased IGF2 promoter activity following triiodothyronine (T3) treatment in all three independent experiments, although the increase did not reach statistical significance. Thus, the reporter assay provides only tentative support for T3 responsiveness of the IGF2 promoter, consistent with our previous in vivo and primary-culture findings showing T3-dependent increases in IGF2 expression. These coordinated transcriptional changes are consistent with remodeling of local TH metabolism during the transition from active feather growth to growth termination. While local TH concentrations and direct deiodinase activities remain to be quantified, and the causal relationship between PRL/PRLR signaling and DIO3 induction remains unresolved, this study provides a molecular framework for understanding how local endocrine regulation translates systemic hormonal signals into feather type-specific growth responses during avian feather development. Graphical abstract en-copyright= kn-copyright= en-aut-name=ShinoharaMasamichi en-aut-sei=Shinohara en-aut-mei=Masamichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NozawaYuri en-aut-sei=Nozawa en-aut-mei=Yuri 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=TakeuchiYu en-aut-sei=Takeuchi en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 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=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 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= 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=Feather growth termination kn-keyword=Feather growth termination en-keyword=Prolactin kn-keyword=Prolactin en-keyword=Thyroid hormone metabolism kn-keyword=Thyroid hormone metabolism en-keyword=DIO3 kn-keyword=DIO3 en-keyword=Chicken kn-keyword=Chicken END start-ver=1.4 cd-journal=joma no-vol=2 cd-vols= no-issue=1 article-no= start-page=100037 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=Older patients with LBCL show comparable outcomes to younger patients and product-specific profiles in CAR-T therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a key treatment option for patients with relapsed or refractory large B-cell lymphoma (LBCL). However, data on its effectiveness and safety in older populations remain limited, particularly in real-world clinical practice. Moreover, comparative outcomes among different CAR-T products across age groups have not yet been fully characterized. We conducted a nationwide retrospective cohort study using data from the Japanese Society for Transplantation and Cellular Therapy. A total of 908 patients who received CAR-T therapy between January 2019 and September 2024 were included. Patients were categorized as younger (aged <65 years) or older (aged ?65 years). Subgroup analyses were performed by CAR-T product (tisagenlecleucel [tisa-cel], lisocabtagene maraleucel [liso-cel], and axicabtagene ciloleucel [axi-cel]). In univariate analysis, 1-year overall survival (OS) and progression-free survival (PFS) were comparable between younger and older patients (OS, 69.4% vs 65.7% [P = .40]; PFS, 47.9% vs 54.1% [P = .17]). In multivariate analysis, age ?65 years showed no significant association with OS (hazard ratio, 0.88; 95% confidence interval, 0.65-1.21; P = .44). The incidence of immune effector cell?associated neurotoxicity syndrome was significantly higher in older patients (12.7% vs 7.0%; P = .005). Compared with tisa-cel, axi-cel and liso-cel were associated with superior PFS, predominantly in younger patients. Among older patients, axi-cel was associated with higher nonrelapse mortality rate than tisa-cel. CAR-T therapy is feasible and effective for older patients with LBCL. These findings support age-adapted treatment strategies that consider both the efficacy and toxicity of each product. en-copyright= kn-copyright= en-aut-name=ShibataSho en-aut-sei=Shibata en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AraiYasuyuki en-aut-sei=Arai en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 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=4 ORCID= en-aut-name=MinakataDaisuke en-aut-sei=Minakata 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=SakaidaEmiko en-aut-sei=Sakaida en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 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=15 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=16 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=17 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=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=GotoHideki en-aut-sei=Goto en-aut-mei=Hideki 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, Kyoto University Hospital kn-affil= affil-num=2 en-affil=Department of Hematology, Kyoto University Hospital kn-affil= affil-num=3 en-affil=Department of Hematology, Kyoto University Hospital kn-affil= affil-num=4 en-affil=Department of Hematology, Toranomon Hospital kn-affil= affil-num=5 en-affil=Division of Hematology, Department of Medicine, Jichi Medical University kn-affil= affil-num=6 en-affil=Department of Hematology, Kyoto University Hospital 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=Department of Medical 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, Tokyo 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=Department of Hematology, Chiba University Hospital kn-affil= affil-num=14 en-affil=Department of Hematology, Osaka Metropolitan University Hospital kn-affil= affil-num=15 en-affil=Division of Transfusion Medicine, Kanazawa University Hospital kn-affil= affil-num=16 en-affil=Department of Hematology, Institute of Science Tokyo Hospital kn-affil= affil-num=17 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=18 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine 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=Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital kn-affil= affil-num=21 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=22 en-affil=Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital kn-affil= END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=8 article-no= start-page=e00484-26 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260804 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=High-throughput screening system for antimycobacterial compounds using in vitro infected cells: construction and application to compounds in the ?mura Natural Compound Library en-subtitle= kn-subtitle= en-abstract= kn-abstract=The global increase in multidrug-resistant tuberculosis strains poses a major threat; consequently, there is an urgent need to identify and develop novel drugs. We have previously presented a simple fibroblast assay (SFA) screening method that enables the simultaneous assessment of antibacterial activity and cytotoxicity toward host cells. This method was developed based on our finding that live (but not dead) Mycobacterium tuberculosis bacilli exhibit cytotoxic activity against human lung fibroblasts, and that this cytotoxicity, which is proportional to the number of viable bacterial cells, is inhibited by known antimycobacterial drugs. While conventional methods to measure M. tuberculosis growth require 2?4 weeks to detect antibacterial activity; the SFA method enables detection within 2?3 days and can detect compounds that are active within host cells. Here, we applied high-throughput screening, based on assessment of cytotoxicity, to identify candidate antimycobacterial agents. In parallel, by comparing the direct antibacterial activity of compounds in liquid medium (using the broth dilution test) with that observed via SFA, we developed a new SFA-based screening system to select compounds with low cytotoxicity that are active outside or inside the host cells. Using this dual system, we screened 742 compounds from the ?mura Natural Compound Library (Kitasato University, Japan), with 62 hits. Of these, 19 were excluded owing to their toxicity, and six exhibited antibacterial activity only via SFA screening. Four promising antimycobacterial candidates with no cytotoxicity at the 10 ƒÊg/mL threshold?aridicin A, lankamycin, streptovaricin, and lariatin A?were identified. identified.This novel system supports the rapid identification of low-cytotoxicity antimycobacterial compounds that are active inside or outside the host cells. en-copyright= kn-copyright= en-aut-name=TakiiTakemasa en-aut-sei=Takii en-aut-mei=Takemasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KimishimaAoi en-aut-sei=Kimishima en-aut-mei=Aoi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IwatsukiMasato en-aut-sei=Iwatsuki en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeYoshihiro en-aut-sei=Watanabe en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OharaNaoya en-aut-sei=Ohara en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AsamiYukihiro en-aut-sei=Asami en-aut-mei=Yukihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Mycobacterium Reference and Research, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association kn-affil= affil-num=2 en-affil=?mura Satoshi Memorial Institute, Kitasato University kn-affil= affil-num=3 en-affil=?mura Satoshi Memorial Institute, Kitasato University kn-affil= affil-num=4 en-affil=?mura Satoshi Memorial Institute, Kitasato University kn-affil= affil-num=5 en-affil=Department of Oral Microbiology, Graduate School of Medicine, Density and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=?mura Satoshi Memorial Institute, Kitasato University kn-affil= en-keyword=Mycobacterium tuberculosis kn-keyword=Mycobacterium tuberculosis en-keyword=Mycobacterium avium kn-keyword=Mycobacterium avium en-keyword=Mycobacterium abscessus kn-keyword=Mycobacterium abscessus en-keyword=fibroblasts kn-keyword=fibroblasts en-keyword=the ?mura Natural Compound Library kn-keyword=the ?mura Natural Compound Library en-keyword=antibacterial activity kn-keyword=antibacterial activity END start-ver=1.4 cd-journal=joma no-vol=2026 cd-vols= no-issue=1 article-no= start-page=1926696 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=Phenotypic Characterization of Porphyromonas gulae Fimbria Mutants en-subtitle= kn-subtitle= en-abstract= kn-abstract=Porphyromonas gulae has been established as a pathogen in animal periodontal disease and expresses several virulence factors, including fimbriae, lipopolysaccharide, and proteases. P. gulae fimbriae are classified into three genotypes (A, B, and C) based on the fimbrillin (fimA) gene encoding a fimbrial subunit protein. We previously reported that P. gulae organisms with type C fimbriae were clearly more virulent as compared to those with other fimbria types, though the basic function of this is not fully understood. Here, we investigated the function of fimbriae using fimA-deficient mutants. In the present study, bacterial fimbriae were related to biofilm tenacity, whereas biofilm formation was not. Also, P. gulae fimbriae are involved in bacterial adhesion and entry into gingival epithelial cells. The role of P. gulae fimbriae in bacterial pathogenicity was then determined using fimA-deficient mutants with a silkworm infection model. Additionally, P. gulae infection can induce inflammatory responses in gingival epithelial cells and also inhibit cell migration and proliferation. In contrast, a P. gulae fimA-deficient mutant did not cause several of those cellular responses. Together, the results show that fimbriae contribute to the pathogenicity of P. gulae by affecting bacterial functions and host cell interactions. en-copyright= kn-copyright= en-aut-name=InabaHiroaki en-aut-sei=Inaba en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoshidaSho en-aut-sei=Yoshida en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OharaNaoya en-aut-sei=Ohara en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 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=5 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=6 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 Oral Microbiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pediatric Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=5 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=6 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=biofilm kn-keyword=biofilm en-keyword=cell invasion kn-keyword=cell invasion en-keyword=cell migration kn-keyword=cell migration en-keyword=fimbriae kn-keyword=fimbriae en-keyword=periodontitis kn-keyword=periodontitis en-keyword=Porphyromonas gulae kn-keyword=Porphyromonas gulae en-keyword=silkworm larvae kn-keyword=silkworm larvae END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=1 article-no= start-page=cr.26-0502 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=Successful Lung Transplantation after Plasma Exchange in a Patient with High Thermal Amplitude Cold Agglutinins: A Case Report en-subtitle= kn-subtitle= en-abstract= kn-abstract=INTRODUCTION: Cold agglutinins (CAs) are immunoglobulin M autoantibodies that induce red blood cell agglutination at low temperatures and may cause hemolytic or thrombotic complications during procedures associated with hypothermia. In lung transplantation (LT), blood may be exposed to low temperatures within the reperfused lung graft and the extracorporeal circulation circuit, potentially increasing the risk of CA-mediated complications. However, the perioperative significance of CAs in this setting remains unclear, and optimal management has not been established. We report a case of successful bilateral LT in a patient with high-thermal-amplitude CAs managed with preoperative plasma exchange (PLEX) and strict intraoperative temperature control.
CASE PRESENTATION: A 55-year-old man with diffuse panbronchiolitis and secondary pulmonary hypertension was listed for bilateral LT. Preoperative testing incidentally revealed clinically significant CAs, with a titer of 1:128 at 4‹C and a thermal amplitude of 30‹C. Because intraoperative blood temperature might approach this threshold despite active warming, a single preoperative session of PLEX using 36 units of fresh frozen plasma was performed to reduce the risk of a CA-mediated complication. Bilateral LT was subsequently completed under meticulous temperature management, including extracorporeal circulation maintained at 37.5‹C, continuous systematic warming, avoidance of topical ice application, and rewarming of the donor lungs before reperfusion. After surgery, the CA titer decreased to 1:32. The postoperative course was uneventful, without thromboembolic events, primary graft dysfunction, or bronchial complications.
CONCLUSIONS: LT may be performed safely in selected patients with high-thermal-amplitude CAs when careful perioperative temperature control is combined with preoperative PLEX. PLEX should be considered when the anticipated intraoperative temperature is expected to approach the patientfs thermal amplitude threshold. en-copyright= kn-copyright= en-aut-name=MiyoshiYuya en-aut-sei=Miyoshi en-aut-mei=Yuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=AsanoNaomi en-aut-sei=Asano en-aut-mei=Naomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 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=5 ORCID= en-aut-name=OkaharaShuji en-aut-sei=Okahara en-aut-mei=Shuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=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=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of General Thoracic Surgery, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of General Thoracic Surgery, Okayama University Hospital kn-affil= affil-num=3 en-affil=Division of Transfusion and Cell Therapy, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of General Thoracic Surgery, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of General Thoracic Surgery, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of General Thoracic Surgery, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of General Thoracic Surgery, Okayama University Hospital, Okayama, Okayama, Japan kn-affil= affil-num=8 en-affil=Department of General Thoracic Surgery, Okayama University Hospital kn-affil= affil-num=9 en-affil=Division of Transfusion and Cell Therapy, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of General Thoracic Surgery, Okayama University Hospital kn-affil= en-keyword=cold agglutinins kn-keyword=cold agglutinins en-keyword=thermal amplitude kn-keyword=thermal amplitude en-keyword= lung transplantation kn-keyword= lung transplantation en-keyword=plasma exchange kn-keyword=plasma exchange en-keyword=extracorporeal circulation kn-keyword=extracorporeal circulation en-keyword=perioperative management kn-keyword=perioperative management END start-ver=1.4 cd-journal=joma no-vol=76 cd-vols= no-issue=3 article-no= start-page=100085 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202611 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effects of serotonin transporters on myocardial cell injury during ischemia/reperfusion in rats en-subtitle= kn-subtitle= en-abstract= kn-abstract=Serotonin (5-HT) reuptake in the heart is mediated by the platelet serotonin reuptake transporter (SERT) and the cardiomyocyte plasma membrane monoamine transporter (PMAT). However, the specific roles of these transporters in myocardial cell injury during ischemia/reperfusion remain unclear. Sprague-Dawley rats underwent left coronary artery occlusion followed by reperfusion. Using cardiac microdialysis technique, fluoxetine (SERT inhibitor, 900?ƒÊM) or decynium 22 (PMAT inhibitor, 100?ƒÊM) was administered locally to the ischemic region. Myoglobin concentrations in the dialysate were measured during ischemia followed by reperfusion. In the fluoxetine-treated group, peak myoglobin concentration (14,889?}?1364?ng/mL) during 0?15?min of reperfusion was significantly higher compared to both the control group (9800?}?1627?ng/mL) and the decynium 22-treated group (8172?}?877?ng/mL) (P? Methods: We used glycemic challenges and hypoinsulinaemic clamp studies to identify the effect of systemic changes in glycaemia on hypothalamic oligodendrocyte lineage cells. We used conditional knockout mouse models to dissect the respective contributions of adult oligodendrogenesis and new myelin formation to glucose homeostasis in adult male mice. Analyses combined immunofluorescence, serial electron microscopy, whole-brain tissue clearing, and transcriptomic analyses.
Results: We found that adult oligodendrogenesis in the median eminence (ME) is modulated by changes in circulating glucose levels and rapidly upregulated by hypoglycaemia. Genetic blockade of new oligodendrocyte production in adult male mice impairs the regulation of glucose homeostasis, the integrity of the ME blood-hypothalamus barrier, and hypothalamic glucose sensing. Unexpectedly, functional integrity of adult-formed myelin is not required for the maintenance of glucose homeostasis. Instead, we show that blockade of adult oligodendrogenesis disrupts hypothalamic expression of A disintegrin and metallopeptidase with thrombospondin motifs 4 (ADAMTS4), a metallopeptidase whose brain expression is restricted to the oligodendrocyte lineage and whose ME expression requires ongoing adult oligodendrogenesis. We show that ADAMTS4 regulates hypothalamic perineuronal net deposition, vascular permeability and glucose sensing. Finally, we show that ME ADAMTS4 expression is regulated by changes in peripheral glycaemia and is dysregulated in diabetes, providing a mechanism by which ME oligodendrocytes contribute to the regulation of glucose homeostasis. en-copyright= kn-copyright= en-aut-name=BullerSophie en-aut-sei=Buller en-aut-mei=Sophie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=StaricoffEmily O. en-aut-sei=Staricoff en-aut-mei=Emily O. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=RichesChristine en-aut-sei=Riches en-aut-mei=Christine kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TsangAnthony en-aut-sei=Tsang en-aut-mei=Anthony kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=GiavaraGiada en-aut-sei=Giavara en-aut-mei=Giada kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=JosipovicMasa en-aut-sei=Josipovic en-aut-mei=Masa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IkemuraKentaro en-aut-sei=Ikemura en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OpokuGabriel en-aut-sei=Opoku en-aut-mei=Gabriel kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SatoIkumi en-aut-sei=Sato en-aut-mei=Ikumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HirohataSatoshi en-aut-sei=Hirohata en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=StenzelSaskia en-aut-sei=Stenzel en-aut-mei=Saskia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NayarStuart G. en-aut-sei=Nayar en-aut-mei=Stuart G. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=Ramos VegaMarta en-aut-sei=Ramos Vega en-aut-mei=Marta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=Hecksher-S?rensenJacob en-aut-sei=Hecksher-S?rensen en-aut-mei=Jacob kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TimmlerSebastian en-aut-sei=Timmler en-aut-mei=Sebastian kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=DowsettGeorgina K.C. en-aut-sei=Dowsett en-aut-mei=Georgina K.C. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=LamBrian Y.H. en-aut-sei=Lam en-aut-mei=Brian Y.H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=YeoGiles S.H. en-aut-sei=Yeo en-aut-mei=Giles S.H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=AlongeKimberly M. en-aut-sei=Alonge en-aut-mei=Kimberly M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=LiHuiliang en-aut-sei=Li en-aut-mei=Huiliang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=RichardsonWilliam D. en-aut-sei=Richardson en-aut-mei=William D. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=EvansMark L. en-aut-sei=Evans en-aut-mei=Mark L. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=BlouetClemence en-aut-sei=Blouet en-aut-mei=Clemence kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= affil-num=1 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=2 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=3 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=4 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=5 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=6 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=7 en-affil=Department of Medical Technology, Graduate School of Health Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Technology, Graduate School of Health Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Medical Technology, Graduate School of Health Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Medical Technology, Graduate School of Health Sciences, Okayama University kn-affil= affil-num=11 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=12 en-affil=Wolfson Institute for Biomedical Research, University College London kn-affil= affil-num=13 en-affil=GUBRA kn-affil= affil-num=14 en-affil=GUBRA kn-affil= affil-num=15 en-affil=Cambridge Stem Cell Institute, University of Cambridge kn-affil= affil-num=16 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=17 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=18 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=19 en-affil=Diabetes Institute, University of Washington kn-affil= affil-num=20 en-affil=Wolfson Institute for Biomedical Research, University College London kn-affil= affil-num=21 en-affil=Wolfson Institute for Biomedical Research, University College London kn-affil= affil-num=22 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= affil-num=23 en-affil=Institute of Metabolic Science Metabolic Research Laboratories, University of Cambridge kn-affil= en-keyword=Oligodendrogenesis kn-keyword=Oligodendrogenesis en-keyword=Median eminence kn-keyword=Median eminence en-keyword=Blood-hypothalamus barrier kn-keyword=Blood-hypothalamus barrier en-keyword=ADAMTS4 kn-keyword=ADAMTS4 en-keyword=Glucose sensing kn-keyword=Glucose sensing en-keyword=Hypoglycaemia kn-keyword=Hypoglycaemia END start-ver=1.4 cd-journal=joma no-vol=25 cd-vols= no-issue=5 article-no= start-page=e70502 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=UNC45B Reduction With Aging: A Myofiber-Intrinsic Promoting Factor for Sarcopenia en-subtitle= kn-subtitle= en-abstract= kn-abstract=Skeletal muscle mass and force decline with age, and the loss of muscle force precedes muscle atrophy. However, the underlying mechanisms remain unclear. Here, we investigated the role of the myosin co-chaperone, uncoordinated mutant number-45 myosin chaperone B (UNC45B), in regulating muscle mass and force. UNC45B expression decreased in mouse gastrocnemius muscle with age, particularly at 24?months old, and adeno-associated virus vector-mediated knockdown of Unc45b in 3-month-old mouse triceps surae muscle first reduced plantar flexor torque and then decreased gastrocnemius muscle mass. In addition, Unc45b knockdown in the triceps surae muscle resulted in lower bone mineral density. While maximum Ca2+-activated force in mechanically skinned fibers was not affected by Unc45b knockdown, Unc45b knockdown decreased the ratio of depolarization-induced force to the maximum Ca2+-activated force. We established tamoxifen-inducible skeletal muscle-specific Unc45b knockout (Unc45b imKO) mice to investigate whether the muscle atrophy and weakness due to the loss of Unc45b impacts metabolism and behavior. We found that Unc45b imKO reduced muscle mass and force at a whole-body level, but did not influence systemic glucose tolerance, insulin sensitivity, or the respiratory exchange ratio. However, Unc45b imKO mice reduced the amount of deeper non-rapid eye movement sleep, locomotor activity, and body temperature during the sleep phase. We conclude that UNC45B is essential for maintaining fast-twitch muscle mass and muscle force. In addition, Unc45b deficiency-mediated muscle loss is also associated with bone fragility, decreased body temperature, and impaired sleep quality. en-copyright= kn-copyright= en-aut-name=MishimaTaiga en-aut-sei=Mishima en-aut-mei=Taiga kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NagamuneTaiga en-aut-sei=Nagamune en-aut-mei=Taiga kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TadaSaori en-aut-sei=Tada en-aut-mei=Saori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeDaiki en-aut-sei=Watanabe en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TokudaNao en-aut-sei=Tokuda en-aut-mei=Nao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YamadaTakashi en-aut-sei=Yamada en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=Hashimoto]HachiyaAkiko en-aut-sei=Hashimoto]Hachiya en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=Higo]YamamotoSayaka en-aut-sei=Higo]Yamamoto en-aut-mei=Sayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KidoKohei en-aut-sei=Kido en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NagaokaNoriyuki en-aut-sei=Nagaoka en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=IkedoAoi en-aut-sei=Ikedo en-aut-mei=Aoi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ImaiYuuki en-aut-sei=Imai en-aut-mei=Yuuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=FujitaRyo en-aut-sei=Fujita en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MizunoSeiya en-aut-sei=Mizuno en-aut-mei=Seiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TakahashiSatoru en-aut-sei=Takahashi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=OishiKatsutaka en-aut-sei=Oishi en-aut-mei=Katsutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AtoSatoru en-aut-sei=Ato en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=OgasawaraRiki en-aut-sei=Ogasawara en-aut-mei=Riki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=2 en-affil=Department of Life Science and Applied Chemistry, Nagoya Institute of Technology kn-affil= affil-num=3 en-affil=Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=4 en-affil=Graduate School of Sport and Health Sciences, Osaka University of Health and Sport Sciences kn-affil= affil-num=5 en-affil=Graduate School of Health Sciences, Sapporo Medical University kn-affil= affil-num=6 en-affil=Graduate School of Health Sciences, Sapporo Medical University kn-affil= affil-num=7 en-affil=Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=8 en-affil=Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=9 en-affil=Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=10 en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Dental School, Okayama University kn-affil= affil-num=11 en-affil=Division of Integrative Pathophysiology, Proteo]Science Center, PIAS, Ehime University kn-affil= affil-num=12 en-affil=Division of Integrative Pathophysiology, Proteo]Science Center, PIAS, Ehime University kn-affil= affil-num=13 en-affil=Division of Regenerative Medicine, Transborder Medical Research Center, Institute of Medicine, University of Tsukuba kn-affil= affil-num=14 en-affil=Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba kn-affil= affil-num=15 en-affil=Laboratory Animal Resource Center in Transborder Medical Research Center, Institute of Medicine, University of Tsukuba kn-affil= affil-num=16 en-affil=Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=17 en-affil=Faculty of Medical Science, Nippon Sport Science University kn-affil= affil-num=18 en-affil=Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= en-keyword=chaperone kn-keyword=chaperone en-keyword=muscle atrophy kn-keyword=muscle atrophy en-keyword=muscle force kn-keyword=muscle force en-keyword=sarcopenia kn-keyword=sarcopenia END start-ver=1.4 cd-journal=joma no-vol=31 cd-vols= no-issue=9 article-no= start-page=1890 end-page=1900 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260616 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Event-free survival and recurrence patterns after curative resection for locally advanced head and neck squamous cell carcinoma: single-institution real-world outcomes prior to the introduction of perioperative immunotherapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Perioperative immune checkpoint inhibitors have improved outcomes for resectable locally advanced head and neck squamous cell carcinoma (HNSCC). However, real-world surgical outcome data based on contemporary endpoints remain limited.
Methods We retrospectively analyzed 233 patients who underwent curative-intent surgery for locally advanced HNSCC. Event-free survival (EFS) and overall survival (OS) were evaluated. Unresectable recurrence-free survival (URFS) was explored as an additional endpoint to capture post-recurrence treatment feasibility. Prognostic factors were assessed using Cox proportional hazards models.
Results The median follow-up duration was 18.2 months. The 1-year EFS and OS rates were 67.1% and 89.4%, respectively. pN2 or higher disease, venous invasion, and perineural invasion were identified as independent adverse prognostic factors. Recurrence occurred in 34.8% of patients; among these, disease control at the last follow-up was achieved in 61.7% following curative-intent salvage treatment. Salvage surgery was associated with significantly improved post-recurrence survival (p? Conclusions This study provides real-world surgical outcome data for resectable locally advanced HNSCC prior to the introduction of perioperative immunotherapy. Recurrence remains a major clinical challenge, with heterogeneous post-recurrence outcomes influenced by treatment feasibility. These findings may help inform interpretation of treatment outcomes and clinical decision-making in the evolving era of perioperative immunotherapy. 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=NaoiYuto en-aut-sei=Naoi en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HasegawaGo en-aut-sei=Hasegawa en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamasakiTakuto en-aut-sei=Yamasaki en-aut-mei=Takuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NodaHiroki en-aut-sei=Noda en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujimotoShohei en-aut-sei=Fujimoto en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MatsumotoJunya en-aut-sei=Matsumoto en-aut-mei=Junya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 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 Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical 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= affil-num=6 en-affil=Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Head and neck squamous cell carcinoma kn-keyword=Head and neck squamous cell carcinoma en-keyword=Surgery kn-keyword=Surgery en-keyword=Event-free survival kn-keyword=Event-free survival en-keyword=Recurrence kn-keyword=Recurrence en-keyword=Salvage surgery kn-keyword=Salvage surgery END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=3 article-no= start-page=26 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260828 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Antioxidant Activity of ƒ¿-Tocopherol Metabolites in Comparison with the Parent Compound in Hepatocytes en-subtitle= kn-subtitle= en-abstract= kn-abstract=ƒ¿-Tocopherol (ƒ¿T) is the major form of vitamin E. Although it is metabolized in the liver when high levels of ƒ¿T are present, the function of its metabolites has not yet been fully elucidated. This study aimed to evaluate the antioxidant activities of the ƒ¿T metabolites, ƒ¿-carboxyethyl hydroxychroman (ƒ¿CEHC) and ƒ¿-carboxymethylbutyl hydroxychroman (ƒ¿CMBHC), in comparison with their parent compound. The pretreatment with ƒ¿T and its metabolites showed a cytoprotective effect on the cytotoxicity induced by hydrogen peroxide in the mouse hepatoma Hepa1c1c7 cells. To elucidate the mechanism underlying the effect, in vitro assays and assessments of antioxidant-related genes and proteins were conducted. The in vitro assays showed that these compounds showed little scavenging activity against hydrogen peroxide but exhibited scavenging activity against DPPH radicals. On the other hand, assessments of antioxidant-related genes and proteins showed that ƒ¿T and its metabolites significantly upregulated the expression of heme oxygenase-1 (HO-1) possibly through activation of the transcript factor Nrf2. Moreover, the cytoprotective effects of ƒ¿T and its metabolites against hydrogen peroxide were counteracted by HO-1 inhibitors. These results suggest that not only ƒ¿T but also its metabolites are potential cytoprotective factors against oxidative stress-induced cytotoxicity, and that their effects are exerted not through a direct action of scavenging hydrogen peroxide in the body, but rather through the regulation of gene expression. en-copyright= kn-copyright= en-aut-name=NishioTomoka en-aut-sei=Nishio en-aut-mei=Tomoka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AmakoKasumi en-aut-sei=Amako en-aut-mei=Kasumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MoriyaDaiki en-aut-sei=Moriya en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=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= en-aut-name=NakamuraYoshimasa en-aut-sei=Nakamura en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=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=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= en-keyword=ƒ¿-tocopherol kn-keyword=ƒ¿-tocopherol en-keyword=ƒ¿-carboxyethyl hydroxychroman kn-keyword=ƒ¿-carboxyethyl hydroxychroman en-keyword=ƒ¿-carboxymethylbutyl hydroxychroman kn-keyword=ƒ¿-carboxymethylbutyl hydroxychroman en-keyword=metabolite kn-keyword=metabolite en-keyword=antioxidant activity kn-keyword=antioxidant activity END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=3 article-no= start-page=1178 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260123 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Chloride-Transporting OsHKT1;1 Splice Variants and Their Expression Profiles Under Salinity Stress in Rice en-subtitle= kn-subtitle= en-abstract= kn-abstract=OsHKT1;1, a member of the high-affinity K+ transporter (HKT) family, plays a key role in Na+ homeostasis and salinity tolerance in rice. In our previous study, multiple potential OsHKT1;1 splicing variants were identified, as well as the full-length (FL) OsHKT1;1 transcript from the salt-tolerant rice Pokkali. However, most previous studies focused solely on the full-length protein, leaving the transport functions of splice variants largely unexamined. In this study, we focused on the splice variant OsHKT1;1-V2 and compared its function and gene expression with those of OsHKT1;1-FL. Two-electrode voltage clamp experiments using Xenopus laevis oocytes revealed that the 1st start codon of OsHKT1;1-V2 is functional to exhibit bidirectional currents in bath solutions containing NaCl. Unlike the Na+-selective feature of OsHKT1;1-FL, OsHKT1;1-V2 primarily mediated Cl? transport with weak Na+ selectivity, which was supported by the higher Cl? accumulation in OsHKT1;1-V2?expressing oocytes. Subcellular localization analyses using oocytes and Arabidopsis mesophyll cells indicated plasma membrane localization of OsHKT1;1-V2, similar to OsHKT1;1-FL. Functional assays using a yeast mutant further indicated that OsHKT1;1-FL, but not OsHKT1;1-V2, mediates Na+ uptake. The same OsHKT1;1 variants were identified in the japonica cultivar Nipponbare, and OsHKT1;1-V2 of the cultivar showed Cl? transport properties similar to the one from Pokkali. Quantitative PCR analyses revealed higher abundance of OsHKT1;1-FL transcripts in Nipponbare than in Pokkali with markedly lower OsHKT1;1-V2 levels in Pokkali under salt stress. This study provides a new insight into HKT-mediated ion homeostasis under salinity stress. en-copyright= kn-copyright= en-aut-name=ImranShahin en-aut-sei=Imran en-aut-mei=Shahin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OnoShuntaro en-aut-sei=Ono en-aut-mei=Shuntaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HorieRie en-aut-sei=Horie en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatsuharaMaki en-aut-sei=Katsuhara en-aut-mei=Maki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HorieTomoaki en-aut-sei=Horie en-aut-mei=Tomoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=Institute of Plant Science and Resources, Okayama University, Kurashiki 710-0046, Okayama, Japan kn-affil= affil-num=3 en-affil=Division of Applied Biology, Faculty of Textile Science and Technology, Shinshu University kn-affil= affil-num=4 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=5 en-affil=Division of Applied Biology, Faculty of Textile Science and Technology, Shinshu University kn-affil= en-keyword=heterologous expression systems kn-keyword=heterologous expression systems en-keyword=Na+ selectivity kn-keyword=Na+ selectivity en-keyword=Cl? selectivity kn-keyword=Cl? selectivity en-keyword=rice kn-keyword=rice END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=3 article-no= start-page=e70101 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260826 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Critical role of cellular communication network factor 1 in early osteogenesis of mesenchymal stem cells primed by low]intensity pulsed ultrasound and bone morphogenetic protein 2 en-subtitle= kn-subtitle= en-abstract= kn-abstract=There is a known reciprocal inhibitory relationship between adipogenesis and osteogenesis in mesenchymal stem cells (MSCs). Our previous study showed that low-intensity pulsed ultrasound (LIPUS) did not promote osteogenesis of a murine MSC line C3H10T1/2, although LIPUS treatment suppressed adipogenesis. Therefore, we investigated the effect of a combination of an osteoinductive factor such as bone morphogenic protein-2 (BMP-2) and LIPUS treatment on osteogenesis. This combination significantly upregulated the gene expressions of BMP receptors and RUNX2, which is a key early osteogenic transcription factor. Interestingly, cellular communication network factor 1 (CCN1) was significantly increased at the mRNA and protein levels. Additionally, Runx2 expression was increased by a recombinant CCN1 protein and decreased in CRISPR-Cas9-generated Ccn1 knockout (KO) cells treated with the combination of LIPUS treatment and BMP-2. Moreover, Runx2 expression was recovered through the transfection of a Ccn1 expression plasmid into Ccn1 KO cells. These findings indicate that treatment with the combination of LIPUS treatment and BMP-2 promoted CCN1 production, and the CCN1 regulates the Runx2 expression in C3H10T1/2 cells, thus suggesting that CCN1 induced by mechanical stimulation and an osteoinductive factor plays a pivotal role in osteogenesis of MSCs. en-copyright= kn-copyright= en-aut-name=PaingHsu Myat en-aut-sei=Paing en-aut-mei=Hsu Myat 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=KubokiTakuo en-aut-sei=Kuboki en-aut-mei=Takuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 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 kn-affil= affil-num=4 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=BMP]2 kn-keyword=BMP]2 en-keyword=CCN1 kn-keyword=CCN1 en-keyword=low]intensity pulsed ultrasound (LIPUS) kn-keyword=low]intensity pulsed ultrasound (LIPUS) en-keyword=mesenchymal stem cells kn-keyword=mesenchymal stem cells en-keyword=osteogenic differentiation kn-keyword=osteogenic differentiation END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=2 article-no= start-page=e70089 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=Species]specific roles of cellular communication network proteins in cartilage development: A comparative study using in vitro chondrogenic models en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cellular communication network (CCN) proteins are key matricellular regulators of cartilage development, yet their species-specific roles and network-level context remain unclear. This study integrated bulk RNA sequencing from chicken and mouse embryonic limb bud micromass cultures and human mesenchymal stem cell chondrogenesis with co-expression, protein?protein interaction, and ortholog analyses to construct CCN-centered regulatory networks across models. CCN1 and CCN2 emerged as dominant, conserved hubs enriched in collagen-containing extracellular matrix, cartilage development, and growth factor signaling modules, whereas CCN3?CCN6 showed lower context-dependent expression and connectivity. Functional and ortholog analyses revealed moderate pathway conservation, with high conservation of IGF, EGFR, and HIF-1 signaling, but reduced overlap in hypoxia and mechanosensing/Hippo categories, indicating species-specific tuning of environmental sensing. A focused ortholog screen identified multifunctional conserved hubs, including COL2A1, TGFBR1, SMAD3, RUNX2, HIF1A, IGF1, SPP1, and CD44. Single-cell RNA-seq meta-analysis of human iPSC-derived chondrogenesis and embryonic limb datasets showed CCN1/2 expression and homologous network activity peaking in mesenchymal and early chondrocyte populations, consistent with model-dependent persistence into hypertrophic and ossification stages in vivo. Overall, this work defines a conserved CCN1/2-centered axis integrating extracellular matrix formation with growth factor and mechanical cues, providing a framework for model selection and CCN-targeted cartilage regeneration strategies. en-copyright= kn-copyright= en-aut-name=WangZhangzheng en-aut-sei=Wang en-aut-mei=Zhangzheng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=V?g?Judit en-aut-sei=V?g? en-aut-mei=Judit kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Tak?csRoland en-aut-sei=Tak?cs en-aut-mei=Roland kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=P?liskaSzil?rd en-aut-sei=P?liska en-aut-mei=Szil?rd kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KimEe Hyun en-aut-sei=Kim en-aut-mei=Ee Hyun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=JinEun]Jung en-aut-sei=Jin en-aut-mei=Eun]Jung kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 ORCID= en-aut-name=KleerCelina G en-aut-sei=Kleer en-aut-mei=Celina G kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=PerbalBernard en-aut-sei=Perbal en-aut-mei=Bernard kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MattaCsaba en-aut-sei=Matta en-aut-mei=Csaba kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Anatomy, Histology and Embryology Faculty of Medicine, University of Debrecen kn-affil= affil-num=2 en-affil=Department of Anatomy, Histology and Embryology Faculty of Medicine, University of Debrecen kn-affil= affil-num=3 en-affil=Department of Anatomy, Histology and Embryology Faculty of Medicine, University of Debrecen kn-affil= affil-num=4 en-affil=Genomic Medicine and Bioinformatics Core Facility Department of Biochemistry and Molecular Biology Faculty of Medicine, University of Debrecen kn-affil= affil-num=5 en-affil=Department of Biomedical Materials Science Graduate School of JABA, Wonkwang University kn-affil= affil-num=6 en-affil=Department of Biomedical Materials Science Graduate School of JABA, Wonkwang University kn-affil= affil-num=7 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University, Faculty of Medicine, Dentistry and Pharmaceutical Science kn-affil= affil-num=8 en-affil=Department of Pathology, University of Michigan Medical School kn-affil= affil-num=9 en-affil=International CCN Society kn-affil= affil-num=10 en-affil=Department of Anatomy, Histology and Embryology Faculty of Medicine, University of Debrecen kn-affil= en-keyword=cartilage regeneration kn-keyword=cartilage regeneration en-keyword=CCN kn-keyword=CCN en-keyword=chondrogenesis kn-keyword=chondrogenesis en-keyword=osteoarthritis kn-keyword=osteoarthritis en-keyword=regulatory network kn-keyword=regulatory network en-keyword=transcriptomics kn-keyword=transcriptomics END start-ver=1.4 cd-journal=joma no-vol=137 cd-vols= no-issue= article-no= start-page=103183 end-page= 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=Activation phosphorylation and dephosphorylation dynamics of Ca2+/Calmodulin-dependent protein kinase Iƒ¿ in HeLa cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Ca??/calmodulin-dependent protein kinase I (CaMKI), a multifunctional CaM-activated protein kinase, is involved in various Ca?? signaling pathways including neuronal development. Here, we characterize the phosphorylation at Thr177 (an activation Thr residue) and subsequent dephosphorylation dynamics of CaMKIƒ¿ in HeLa cells upon physiological stimulation that elevates intracellular Ca??. ATP induced CaMKIƒ¿ phosphorylation within 5?10 min; phosphorylation was then blocked by CaMKK inhibitor TIM-063, or by the depletion of extracellular Ca??. This was followed by gradual dephosphorylation to basal levels within 30?60 min. Histamine induced CaMKIƒ¿ phosphorylation, peaking within 3?4 min; this process was abolished by treatment with either TIM-063 or intracellular Ca?? chelation using BAPTA-AM and thapsigargin; however, not by extracellular Ca?? depletion. CaMKIƒ¿ was then rapidly dephosphorylated to basal levels within 10 min. Consistently, histamine-induced (but not ATP-induced) CaMKIƒ¿ phosphorylation was absent in triple IP? receptor-knockout HeLa cells. Dephosphorylation of CaMKIƒ¿ after ATP-induced phosphorylation was unaffected by okadaic acid or CaMK phosphatase (CaMKP, known as PPM1F) inhibitors (ANS and ANDS). We found that HeLa cell extracts contained Mg2+/Mn2+-dependent CaMKIƒ¿ dephosphorylation activity that was insensitive to ANS and ANDS. Furthermore, co-expression of PP2Cƒ¿ fully abolished ATP-, histamine-, or ionomycin-stimulated CaMKIƒ¿ phosphorylation, which is consistent with in vitro dephosphorylation of CaMKIƒ¿ at Thr177 by recombinant PP2Cƒ¿. Taken together, these results reveal that agonist-induced Ca?? influx from the extracellular space or release from intracellular stores transiently activates CaMKK-CaMKIƒ¿ signaling in HeLa cells, which is shut off by dephosphorylation catalyzed by PP2Cƒ¿ as a promising candidate for CaMKIƒ¿ phosphatase. en-copyright= kn-copyright= en-aut-name=ChenYerun en-aut-sei=Chen en-aut-mei=Yerun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MikiMasao en-aut-sei=Miki en-aut-mei=Masao 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=OhtsukaSatomi en-aut-sei=Ohtsuka en-aut-mei=Satomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=EtoMasumi en-aut-sei=Eto en-aut-mei=Masumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IshidaAtsuhiko en-aut-sei=Ishida en-aut-mei=Atsuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 ORCID= en-aut-name=MizutaniAkihiro en-aut-sei=Mizutani en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AndoHideaki en-aut-sei=Ando en-aut-mei=Hideaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MikoshibaKatsuhiko en-aut-sei=Mikoshiba en-aut-mei=Katsuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 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=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Veterinary Science, Okayama University of Science kn-affil= affil-num=6 en-affil=Laboratory of Molecular Brain Science, Graduate School of Integrated Sciences for Life, Hiroshima University kn-affil= affil-num=7 en-affil=Clinical Examination Department, Kagawa Prefectural University of Health Sciences kn-affil= affil-num=8 en-affil=Department of Pharmacotherapeutics, Showa Pharmaceutical University kn-affil= affil-num=9 en-affil=Laboratory for Developmental Neurobiology, RIKEN Center for Brain Science kn-affil= affil-num=10 en-affil=Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University kn-affil= affil-num=11 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=CaMKIƒ¿ kn-keyword=CaMKIƒ¿ en-keyword=CaMKK kn-keyword=CaMKK en-keyword=PP2Cƒ¿ kn-keyword=PP2Cƒ¿ en-keyword=Phosphorylation kn-keyword=Phosphorylation en-keyword=Dephosphorylation kn-keyword=Dephosphorylation en-keyword=Ca2+-signaling kn-keyword=Ca2+-signaling END start-ver=1.4 cd-journal=joma no-vol=139 cd-vols= no-issue=2 article-no= start-page=255 end-page=265 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=Knockout of a single aquaporin, OsPIP2;4, decreases root water permeability in rice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aquaporins (AQPs) are membrane proteins that facilitate water transport and are present in nearly all bacterial, animal, and plant cells. In plants, AQPs are classified into four or more subfamilies, with plasma membrane intrinsic proteins (PIPs) playing a key role in root water uptake and cellular water regulation. Previous studies have demonstrated that PIPs contribute to root hydraulic conductivity (Lpr) in various plant species. In this study, we examined the specific role of OsPIP2;4, one of the PIP-type aquaporins among 11 rice (Oryza sativa) PIP2s, in regulating Lpr. Transgenic rice plants, including OsPIP2;4-knockout (KO) and overexpressing (Ox) lines, were used for this investigation. Two independent KO lines, generated via the CRISPR-Cas9 system and T-DNA insertion mutagenesis, respectively, showed significantly lower Lpr compared to wild-type rice plants. The decrease in Lpr in the T-DNA KO line was associated with reduced OsPIP2;4 transcript levels, measured by real-time PCR, and lower OsPIP2;4 protein levels, as shown by immunohistochemical analysis. Conversely, no notable increase in Lpr was observed in the Ox lines. These results suggest that OsPIP2;4 is expressed in appropriate tissues in rice roots and is a key factor influencing Lpr. This research represents a significant step toward further understanding the physiological functions of OsPIP2;4 in rice. en-copyright= kn-copyright= en-aut-name=OnishiAya en-aut-sei=Onishi en-aut-mei=Aya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HorieTomoaki en-aut-sei=Horie en-aut-mei=Tomoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IshitsukaRyo en-aut-sei=Ishitsuka en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SasanoShizuka en-aut-sei=Sasano en-aut-mei=Shizuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HorieRie en-aut-sei=Horie en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MitoYunosuke en-aut-sei=Mito en-aut-mei=Yunosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UtsugiShigeko en-aut-sei=Utsugi en-aut-mei=Shigeko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IshikawaJunko en-aut-sei=Ishikawa en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MahdiehMajid en-aut-sei=Mahdieh en-aut-mei=Majid kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KatsuharaMaki en-aut-sei=Katsuhara en-aut-mei=Maki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=Division of Applied Biology, Faculty of Textile Science and Technology, Shinshu University kn-affil= affil-num=3 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=4 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=5 en-affil=Division of Applied Biology, Faculty of Textile Science and Technology, Shinshu University kn-affil= affil-num=6 en-affil=Division of Applied Biology, Faculty of Textile Science and Technology, Shinshu University kn-affil= affil-num=7 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=8 en-affil=Institute of Crop Science, NARO kn-affil= affil-num=9 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=10 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=PIP aquaporin kn-keyword=PIP aquaporin en-keyword=Rice kn-keyword=Rice en-keyword=Root hydraulic conductivity kn-keyword=Root hydraulic conductivity en-keyword=Root pressure chamber kn-keyword=Root pressure chamber END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue= article-no= start-page=100639 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=Interbacterial antagonism mediates plant growth modulation by rhizosphere synthetic communities in barley en-subtitle= kn-subtitle= en-abstract= kn-abstract=Microbial communities in plant roots are shaped by complex interbacterial interactions, yet how these interactions translate into plant fitness remains poorly understood. In this study, 127 bacterial isolates were obtained from barley (Hordeum vulgare L.) roots of two cultivars grown in a non-fertilized field, representing 45 genera and 72 species. Screening identified isolates with growth-promoting, growth-reducing, and neutral phenotypes. Co-inoculation experiments using synthetic communities (SynComs) demonstrated that growth-promoting isolates effectively cancelled the inhibitory effects of growth-reducing isolates on barley seedling growth. Mechanistic investigation revealed that growth-promoting isolates Variovorax sp. 14F-2.1 and Pseudomonas sp. 37A kill growth-reducing isolates Flavobacterium sp. 2D-1 through direct cell-to-cell contact. Deletion of the Type VI secretion system (T6SS) gene tssA in Variovorax sp. 14F-2.1 substantially reduced this activity, implicating T6SS as a key antagonistic mechanism. Phytohormone profiling revealed that growth-promoting and neutral isolates, but not growth-reducing isolates, produce cytokinins, and only Variovorax sp. 14F-2.1 could degrade IAA, suggesting a potential hormonal basis for differential growth effects. A two-year field microbiome study showed that fertilization regimen and seasonal sampling times were dominant drivers of rhizosphere community composition, while bacterial inoculation had limited and inconsistent effects on microbial diversity and plant growth under field conditions. These results demonstrate that interbacterial antagonism is a key determinant of community-level plant growth outcomes and highlight the complexity of translating laboratory inoculant effects to field settings. en-copyright= kn-copyright= en-aut-name=MahamudMd Asif en-aut-sei=Mahamud en-aut-mei=Md Asif kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=PichaikarnRungnapa en-aut-sei=Pichaikarn en-aut-mei=Rungnapa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=LatifMuhammad Ammar en-aut-sei=Latif en-aut-mei=Muhammad Ammar kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsuuraTakakazu en-aut-sei=Matsuura en-aut-mei=Takakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= 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=5 ORCID= en-aut-name=SaishoDaisuke en-aut-sei=Saisho en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UngcharoenwiwatPakpimol en-aut-sei=Ungcharoenwiwat en-aut-mei=Pakpimol kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TaniAkio en-aut-sei=Tani en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=2 en-affil=School of Science, Walailak University kn-affil= affil-num=3 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=4 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=5 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=6 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=7 en-affil=School of Science, Walailak University kn-affil= affil-num=8 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= en-keyword=Barley kn-keyword=Barley en-keyword=Rhizosphere microbiome kn-keyword=Rhizosphere microbiome en-keyword=SynCom kn-keyword=SynCom en-keyword=Bacterial antagonism kn-keyword=Bacterial antagonism en-keyword=Type VI secretion system kn-keyword=Type VI secretion system en-keyword=Phytohormone kn-keyword=Phytohormone END start-ver=1.4 cd-journal=joma no-vol=138 cd-vols= no-issue=2 article-no= start-page=58 end-page=61 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260803 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=A case of autoamputated primary uterine diffuse large B-cell lymphoma treated with Pola-R-CHP therapy and CNS recurrence prophylaxis kn-title=Ž©‘R’E—Ž‚µ‚½Žq‹{Œ´”­ DLBCL ‚ɑ΂µ‚Ä Pola-R-CHP —Ö@‚Æ CNS Ä”­—\–h‚ðs‚Á‚½‚P—á en-subtitle= kn-subtitle= en-abstract= kn-abstract=@A 55-year-old woman presented to her local physician with the chief complaint of genital bleeding. A 22~19-mm mass was noted on the patient's cervix, and during the internal examination the mass auto-amputated. The pathological examination of the auto-amputated mass revealed diffuse large B-cell lymphoma (DLBCL). An examination by F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET-CT) showed FDG uptake at physiological levels in the cervix, with no abnormal uptake in other organs. Cervical tissue was sampled after the spontaneous detachment of the cervical mass, and the biopsy of the cervical mass did not reveal findings suggestive of lymphoma. Six courses of chemotherapy with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisolone (Pola-R-CHP) plus an intramedually injection of methotrexate, cytarabine, and predonisolone (IT-triple), followed by two courses of high-dose intrathecal methotrexate (HD-MTX) were adiministered, and the patient has remained recurrence-free for the more than 8 months since the completion of this treatment. Primary uterine DLBCL is an extremely rare disease with a high rate of recurrence in the central nervous system and a poor prognosis. Our search of the relevant literature identified very few reports describing the prognoses of cases with spontaneous tumor detachment. en-copyright= kn-copyright= en-aut-name=OsadaHikaru en-aut-sei=Osada en-aut-mei=Hikaru kn-aut-name=’·“cW kn-aut-sei=’·“c kn-aut-mei=W aut-affil-num=1 ORCID= en-aut-name=KimuraMaiko en-aut-sei=Kimura en-aut-mei=Maiko kn-aut-name=–Ø‘º^ˆßŽq kn-aut-sei=–Ø‘º kn-aut-mei=^ˆßŽq aut-affil-num=2 ORCID= en-aut-name=MuneishiManaka en-aut-sei=Muneishi en-aut-mei=Manaka kn-aut-name=@Έ¤‰Ô kn-aut-sei=@Î kn-aut-mei=ˆ¤‰Ô aut-affil-num=3 ORCID= en-aut-name=MurayamaKozo en-aut-sei=Murayama en-aut-mei=Kozo kn-aut-name=‘ºŽRWŽO kn-aut-sei=‘ºŽR kn-aut-mei=WŽO aut-affil-num=4 ORCID= en-aut-name=NiiyaDaigo en-aut-sei=Niiya en-aut-mei=Daigo kn-aut-name=V’J‘åŒå kn-aut-sei=V’J kn-aut-mei=‘åŒå aut-affil-num=5 ORCID= en-aut-name=TakeuchiMakoto en-aut-sei=Takeuchi en-aut-mei=Makoto kn-aut-name=’|“འkn-aut-sei=’|“à kn-aut-mei=½ aut-affil-num=6 ORCID= en-aut-name=FujiiSoichiro en-aut-sei=Fujii en-aut-mei=Soichiro kn-aut-name=“¡ˆä‘ˆê˜Y kn-aut-sei=“¡ˆä kn-aut-mei=‘ˆê˜Y aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Hematology, Japanese Red Cross Okayama Hospital kn-affil=‰ªŽRÔ\Žš•a‰@@ŒŒ‰t“à‰È affil-num=2 en-affil=Department of Hematology, Japanese Red Cross Okayama Hospital kn-affil=‰ªŽRÔ\Žš•a‰@@ŒŒ‰t“à‰È affil-num=3 en-affil=Department of Hematology, Japanese Red Cross Okayama Hospital kn-affil=‰ªŽRÔ\Žš•a‰@@ŒŒ‰t“à‰È affil-num=4 en-affil=Department of Hematology, Japanese Red Cross Okayama Hospital kn-affil=‰ªŽRÔ\Žš•a‰@@ŒŒ‰t“à‰È affil-num=5 en-affil=Department of Hematology, Japanese Red Cross Okayama Hospital kn-affil=‰ªŽRÔ\Žš•a‰@@ŒŒ‰t“à‰È affil-num=6 en-affil=Department of Hematology, Japanese Red Cross Okayama Hospital kn-affil=‰ªŽRÔ\Žš•a‰@@ŒŒ‰t“à‰È affil-num=7 en-affil=Department of Hematology, Japanese Red Cross Okayama Hospital kn-affil=‰ªŽRÔ\Žš•a‰@@ŒŒ‰t“à‰È en-keyword=‚Ñ‚Ü‚ñ«‘å×–EŒ^‚a×–EƒŠƒ“ƒpŽî (diffuse large B-cell lymphoma) kn-keyword=‚Ñ‚Ü‚ñ«‘å×–EŒ^‚a×–EƒŠƒ“ƒpŽî (diffuse large B-cell lymphoma) en-keyword=Žq‹{Œ´”­ƒŠƒ“ƒpŽî (primary uterine lymphoma) kn-keyword=Žq‹{Œ´”­ƒŠƒ“ƒpŽî (primary uterine lymphoma) en-keyword=Pola-R-CHP—Ö@ (Pola-R-CHP regimen) kn-keyword=Pola-R-CHP—Ö@ (Pola-R-CHP regimen) en-keyword=HD-MTX—Ö@ (HD-MTX regimen) kn-keyword=HD-MTX—Ö@ (HD-MTX regimen) END start-ver=1.4 cd-journal=joma no-vol=138 cd-vols= no-issue=2 article-no= start-page=35 end-page=37 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260803 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=The 2025 Incentive Award of the Okayama Medical Association in Cardiovascular and Pulmonary Research (2025 Sunada Prize) kn-title=—ߘa‚V”N“x‰ªŽRˆãŠw‰ïÜ@‹¹•”EzŠÂŒ¤‹†§—ãÜi»“cÜj en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=ItohYoshihiko en-aut-sei=Itoh en-aut-mei=Yoshihiko kn-aut-name=ˆÉ“¡Œc•F kn-aut-sei=ˆÉ“¡ kn-aut-mei=Œc•F aut-affil-num=1 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È@tE–ƉuE“à•ª”å‘ãŽÓ“à‰ÈŠw END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue= article-no= start-page=1842408 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260820 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=New mechanistic insight into SARM1 activation: TRIM32-mediated ubiquitination is a key lever that actuates SARM1fs catalytic action, leading to axon degeneration and cell death en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sterile alpha and TIR motif-containing protein 1 (SARM1) is an enzyme that cleaves nicotinamide adenine dinucleotide (NAD+) and plays a role in disrupting neural circuits through axon degeneration and cell death. SARM1 is activated by changes in the nicotinamide mononucleotide (NMN)/NAD+ ratio and by various post-translational modifications, but its complete regulatory mechanism remains poorly understood. Here, we report that tripartite motif-containing protein 32 (TRIM32) activates SARM1 through specific ubiquitination triggered by anticancer drug treatment. TRIM32 promotes the attachment of Lys27-linked ubiquitin chains to Lys173 and Lys375 within the ARM domain, which is an autoinhibitory region of SARM1. This ubiquitination by TRIM32 increases SARM1fs NAD+-cleaving catalytic activity and enhances its ability to induce neurite degeneration and cell death. A mutant form of TRIM32 lacking the enzymatically active RING domain fails to promote SARM1 ubiquitination, and reducing TRIM32 levels decreases SARM1 ubiquitination. Additionally, ubiquitin-specific peptidase 13 (USP13), a known negative regulator of SARM1, can deubiquitinate SARM1. These findings suggest that TRIM32 is a key regulator of axon degeneration and cell death through its ubiquitination of SARM1. en-copyright= kn-copyright= en-aut-name=MurataHitoshi en-aut-sei=Murata en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=YamamotoKen-ichi en-aut-sei=Yamamoto en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 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=5 ORCID= affil-num=1 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=axon degeneration kn-keyword=axon degeneration en-keyword=NAD?+ kn-keyword=NAD?+ en-keyword=SARM1 kn-keyword=SARM1 en-keyword=TRIM32 kn-keyword=TRIM32 en-keyword=ubiquitination kn-keyword=ubiquitination END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=15 article-no= start-page=2302 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260724 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Impact of Cold Storage and Seasonality on Raw Cow Milk Microbiota, Assessed by Conventional and Viability PCR en-subtitle= kn-subtitle= en-abstract= kn-abstract=The microbiota of healthy Holstein cowfs milk was analyzed to evaluate the effects of immediate (freezing at the farm: on-site workflow) and delayed processing (freezing after cool transport: laboratory workflow) and to investigate seasonal changes in September, November, and January. Propidium monoazide (PMA) was also used to distinguish between viable and non-viable cells. Microbiota composition differed between the laboratory and the on-site workflow. After cool transport, the abundances of Lactobacillus and Turicibacter increased, while those of Streptococcus, Bradyrhizobium, and Acinetobacter decreased. Based on the ƒÀ-diversity assessment, the difference between viable and non-viable cells was marginal compared with the difference between on-site and laboratory workflows. In the subsequent on-site workflow experiment, seasonal variation was clearly demonstrated. The relative abundances of Lactobacillus, Turicibacter, and Bacillus were high in September; Staphylococcus, Phenylobacterium, and Bradyrhizobium in November; and Phyllobacterium in January. The seasonal effect was greater than the PMA treatment effect. Despite the studyfs limitations, such as a limited number of milk samples and data from only one farm with a single management system, our findings indicate that storage and transport at low temperatures could lead to inaccurate assessments, particularly of opportunistic environmental microbiota. Viability PCR could help improve our understanding of the factors involved but would not substantially alter the raw milk microbiota. en-copyright= kn-copyright= en-aut-name=TranPhong Dinh en-aut-sei=Tran en-aut-mei=Phong Dinh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TsurutaTakeshi en-aut-sei=Tsuruta en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 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= en-keyword=cow milk kn-keyword=cow milk en-keyword=cold storage kn-keyword=cold storage en-keyword=microbiota kn-keyword=microbiota en-keyword=seasonal variation kn-keyword=seasonal variation en-keyword=viability kn-keyword=viability END start-ver=1.4 cd-journal=joma no-vol=359 cd-vols= no-issue= article-no= start-page=127928 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20261015 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Discrimination of nanovesicles using two-color laser-induced fluorescence detection en-subtitle= kn-subtitle= en-abstract= kn-abstract=A two-color fluorescence-detection system was developed to distinguish between two types of nanovesicles labeled with different fluorescent dyes. This system employs two lasers emitting at distinct wavelengths (488 and 635 nm). These lasers are reshaped into sheet-like beams and focused at separate positions within a square capillary. As vesicles flow through the capillary, they pass through the laser beams and emit fluorescence when excited by the corresponding wavelength. This technique allows for the counting of vesicles and identification of the specific fluorophores on the vesicles based on their emission positions. The system was validated using liposomes labeled with fluorophores excited by the 488 and 635 nm lasers. It was then applied to differentiate CD63-positive extracellular vesicles (EVs) from other types of EVs in a culture media consisting of HeLa and A549 cells. Additionally, the system was used to study the effect of the anticancer drug doxorubicin on EV secretion in these cancer cells. en-copyright= kn-copyright= en-aut-name=AsahiShunsuke en-aut-sei=Asahi en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KanetaTakashi en-aut-sei=Kaneta en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Chemistry, Okayama University kn-affil= affil-num=2 en-affil=Department of Chemistry, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=31 cd-vols= no-issue=5 article-no= start-page=e70145 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260821 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Transforming Life Science Through Chromosome]Level Genome Assemblies en-subtitle= kn-subtitle= en-abstract= kn-abstract=Advances in long-read sequencing and Hi?C scaffolding have made chromosome-level genome assembly increasingly accessible to individual laboratories, shifting genome research from large consortium-led projects toward investigator-driven studies across diverse taxa. This transition allows researchers to select organisms based on biological questions rather than the prior availability of genomic resources. In this review, we summarize the core experimental and computational steps for generating, evaluating, and annotating chromosome-level assemblies, and examine how they have advanced research in non-model organisms and genetically complex systems. Representative case studies illustrate four major contributions: resolving structural variation and lineage-specific genome architecture, linking genome organization to phenotypic innovation and plasticity, reconstructing deep chromosome evolution and macrosynteny, and distinguishing homologous and homoeologous chromosomes in polyploid genomes. These examples show that chromosome-level assemblies provide more than complete reference sequences. They establish a continuous genomic coordinate system through which genes, regulatory elements, transposable element insertions, sequence variants, and cellular states can be interpreted within broader chromosomal, population, and evolutionary contexts. We describe this integrative perspective as gglocal biology.h Future progress will require pangenomic, population-scale, and haplotype-resolved resources integrated with multi-omics and functional analyses. Collectively, chromosome-level genomics is reshaping life science by embedding molecular functions within chromosomal and evolutionary contexts. en-copyright= kn-copyright= en-aut-name=KonTetsuo en-aut-sei=Kon en-aut-mei=Tetsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KataokaKosuke en-aut-sei=Kataoka en-aut-mei=Kosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=LuoYi]Jyun en-aut-sei=Luo en-aut-mei=Yi]Jyun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WibisanaJohannes Nicolaus en-aut-sei=Wibisana en-aut-mei=Johannes Nicolaus kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TogaKouhei en-aut-sei=Toga en-aut-mei=Kouhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=MondenYuki en-aut-sei=Monden en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 ORCID= affil-num=1 en-affil=Department of Neurosciences and Developmental Biology, University of Vienna kn-affil= affil-num=2 en-affil=Graduate School of Engineering, Tokyo University of Agriculture and Technology kn-affil= affil-num=3 en-affil=Biodiversity Research Center, Academia Sinica kn-affil= affil-num=4 en-affil=Genomics and Regulatory Systems Unit, Okinawa Institute of Science and Technology Graduate University kn-affil= affil-num=5 en-affil=Laboratory of BioDX, PtBio Co]Creation Research Center, Genome Editing Innovation Center, Hiroshima University kn-affil= affil-num=6 en-affil=Laboratory of Bioengineering, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences 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=Ushimado Marine Institute, Okayama University kn-affil= en-keyword=chromosome-level genome assembly kn-keyword=chromosome-level genome assembly en-keyword=genome evolution kn-keyword=genome evolution en-keyword=Hi?C scaffolding kn-keyword=Hi?C scaffolding en-keyword=long-read sequencing kn-keyword=long-read sequencing en-keyword=non-model animals kn-keyword=non-model animals END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=6 article-no= start-page=e202500237 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=NUAK2 Inhibition Enhances Macromolecular Drug Delivery in a 3D Fibrotic Model of the Pancreatic Tumor Microenvironment en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pancreatic ductal adenocarcinoma (PDAC) features a fibrotic tumor microenvironment that impedes drug delivery and significantly limits the successful clinical application of nanomedicines. Targeting signaling in pancreatic stellate cells (PSCs), which drive fibrosis via excessive secretion of extracellular matrix proteins such as collagen I, may be useful in overcoming this fibrotic barrier. The AMPK-related kinases NUAK1/2 have recently gained interest as promoters of fibrosis, but whether they play a profibrotic role in PSCs remains unknown. Here, patient PSCs are used to assess NUAK1/2 involvement in the PDAC fibrotic barrier. Leveraging a 3D cell culture model of PDAC fibrosis, the effect of targeting NUAK1/2 on the permeability of macromolecular dextrans of various sizes, as well as physiologically relevant macromolecules, albumin and IgG, and clinical nanomedicines, Doxil and Abraxane, is investigated. NUAK1/2 inhibition is shown to diminish collagen I to enhance macromolecular permeability, via a mechanism independent of established pathways involving transforming growth factor-ƒÀ (TGFƒÀ) and yes-associated protein (YAP). Through isoform-specific knockdown, predominant NUAK2 involvement is demonstrated. Mechanistically, actin stress fiber regulation by NUAK2 is shown to be important. Altogether, these results show in?vitro that NUAK2 promotes fibrotic signaling in PSCs and may be targeted to enhance macromolecular drug delivery in PDAC. en-copyright= kn-copyright= en-aut-name=NakamuraMisaki en-aut-sei=Nakamura en-aut-mei=Misaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=OhiraMayu en-aut-sei=Ohira en-aut-mei=Mayu 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=NakamuraReika en-aut-sei=Nakamura en-aut-mei=Reika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SenoYu en-aut-sei=Seno en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YaraSaaya en-aut-sei=Yara en-aut-mei=Saaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujitaSakura en-aut-sei=Fujita en-aut-mei=Sakura kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ShibataDaichi en-aut-sei=Shibata en-aut-mei=Daichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=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=OsadaKensuke en-aut-sei=Osada en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=13 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=14 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=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 Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Pharmaceutical Biomedicine Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Pharmaceutical Biomedicine Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Materials Processing Graduate School of Engineering, Tohoku University 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 Molecular Imaging and Theranostics Institute for Quantum Medical Science, National Institutes for Quantum Sciences and Technology (QST) kn-affil= affil-num=13 en-affil=Department of Bioengineering Graduate School of Engineering, The University of Tokyo kn-affil= affil-num=14 en-affil=Division of Gastroenterology Graduate School of Medicine, Tohoku University kn-affil= affil-num=15 en-affil=Department of Pharmaceutical Biomedicine Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=fibrosis kn-keyword=fibrosis en-keyword=nanomedicine kn-keyword=nanomedicine en-keyword=NUAK kinase kn-keyword=NUAK kinase en-keyword=pancreatic cancer kn-keyword=pancreatic cancer en-keyword=tumor microenvironment kn-keyword=tumor microenvironment END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=1 article-no= start-page=12 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=Knockout analysis of period and timeless and EGFP-based visualization of per-expressing clock cells in the cricket circadian clock en-subtitle= kn-subtitle= en-abstract= kn-abstract=In the present study, we generated crickets with knockout of either period (per) or timeless (tim) gene by CRISPR/Cas9-based genome editing. We also identified a naturally occurring per- mutant lacking a large coding region including PAS domains. To examine possible synergistic effects, a per- and timKO double mutant was generated by applying genome editing to the per- crickets. Under constant darkness (DD), timKO crickets exhibited a locomotor rhythm with a free-running period of 23.06?}?0.20?h (mean?}?SD), which was significantly shorter than that of the parental strain (23.78?}?0.12?h). By contrast, perKO and per- crickets showed basically similar phenotype of locomotor rhythm: they exhibited an arrhythmic pattern during the first two to three weeks after transfer to DD but subsequently showed a complex rhythmic pattern with one or multiple components with significantly longer free-running periods (33.35?}?10.72?h). In the per-;timKO double mutants, approximately 60% of individuals became arrhythmic, while the remaining 40% exhibited complex rhythms with extremely longer free-running periods (37.0?}?9.17?h) under DD. These results suggest the existence of an underlying oscillatory mechanism that is responsible for regulating locomotor rhythms independently of the canonical per/tim feedback loop. Furthermore, we generated a reporter line on a per? background by knocking egfp into exon 1 of the per gene, allowing egfp expression to report per transcription. EGFP expression was detected in three distinct clusters of cells within the optic lobe: two located along the dorsal and ventral boundaries between the lamina and medulla neuropils, and one situated near the accessory medulla. These findings raise the possibility that these form part of the circadian clock network that governs circadian locomotor rhythms. en-copyright= kn-copyright= en-aut-name=TomiokaKenji en-aut-sei=Tomioka en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InoueShintaro en-aut-sei=Inoue en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MitoTaro en-aut-sei=Mito en-aut-mei=Taro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MoriyamaYoshiyuki en-aut-sei=Moriyama en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YoshiiTaishi en-aut-sei=Yoshii en-aut-mei=Taishi 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=Bio-Innovation Research Center, Tokushima University kn-affil= affil-num=3 en-affil=Bio-Innovation Research Center, Tokushima University kn-affil= affil-num=4 en-affil=Department of Natural Sciences, Kawasaki Medical School kn-affil= affil-num=5 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=Circadian clock kn-keyword=Circadian clock en-keyword=Cricket kn-keyword=Cricket en-keyword=Genome editing kn-keyword=Genome editing en-keyword=Locomotor rhythm kn-keyword=Locomotor rhythm en-keyword=period kn-keyword=period en-keyword=per-less oscillation kn-keyword=per-less oscillation en-keyword=timeless kn-keyword=timeless END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=3 article-no= start-page=e70025 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202505 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Polished Rice Regulates Maturation but Not Survival of Secondary Cells in Drosophila Male Accessory Gland en-subtitle= kn-subtitle= en-abstract= kn-abstract=In Drosophila males, the accessory gland is responsive to nutrient signal-dependent regulation of fertility/fecundity. The accessory gland is composed of two types of binucleated epithelial cells, about 1000 main cells and 60 secondary cells (SCs). The transcription factors Defective proventriculus (Dve), Abdominal-B, and Ecdysone receptors (EcRs) are strongly expressed in adult SCs. In response to nutrient conditions during development, coordinated action between Dve and ecdysone signaling determines the optimal number of SCs and regulates their maturation. A downstream effector of ecdysone signaling, Ftz-F1, is crucial in this process. Another downstream effector, Polished rice (Pri), is small peptides of 11 or 32 amino acids. Here we show that pri is required for maturation of SCs and for male fecundity, whereas it is not involved in determination of the number of SCs. We provide evidence that Pri acts downstream of Ftz-F1 to regulate maturation but not survival of SCs. en-copyright= kn-copyright= en-aut-name=OtsuneShinichi en-aut-sei=Otsune en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsukaMirai en-aut-sei=Matsuka en-aut-mei=Mirai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShirakashiChisato en-aut-sei=Shirakashi en-aut-mei=Chisato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZhangXuanshuo en-aut-sei=Zhang en-aut-mei=Xuanshuo 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=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= affil-num=5 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=Drosophila kn-keyword=Drosophila en-keyword=ecdysone kn-keyword=ecdysone en-keyword=fecundity kn-keyword=fecundity en-keyword=fertility kn-keyword=fertility en-keyword=nutrition kn-keyword=nutrition en-keyword=steroid kn-keyword=steroid END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue= article-no= start-page=1680076 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260306 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Prolonged TNF-ƒ¿ stimulation induces a PD-1?associated exhaustion-like phenotype in mesenchymal stromal cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Mesenchymal stromal cells (MSCs) have emerged as promising therapeutic agents for inflammatory diseases because of their potent immunomodulatory properties. Although acute inflammation transiently enhances MSC functionality, the impact of chronic inflammatory exposure remains poorly defined. In this study, we investigated the effects of sustained TNF-ƒ¿ stimulation and indirect co-culture with M1 macrophages on MSC behavior. Comprehensive gene expression profiling was performed to assess the changes in immunoregulatory, apoptotic, and metabolic pathways. To determine functional reversibility, we also evaluated MSCs following the withdrawal of TNF-ƒ¿. Short-term exposure led to upregulation of Tgf-ƒÀ, Il-10, and Fasl, whereas prolonged stimulation suppressed these genes and significantly increased the expression of immune checkpoint genes Pd-1 and Ctla-4, indicative of an exhaustion-like phenotype. This phenotypic shift was associated with sustained NF-ƒÈB activation, upregulation of Stat3 and Ap-1, suppression of mTORC1/2 components, decreased Pd-l1 expression, and increased Pd-1 expression, raising the possibility that PD-1 upregulation is associated with MSC dysfunction under chronic inflammatory stress. These findings revealed that prolonged stimulation (48 h) induces an exhaustion-like dysfunction state in MSCs, characterized by checkpoint activation, transcriptional repression, and metabolic dysfunction. PD-1 may serve as a biomarker associated with inflammation-induced MSC impairment. en-copyright= kn-copyright= en-aut-name=MatsunagaNaoya en-aut-sei=Matsunaga en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AkiyamaKentaro en-aut-sei=Akiyama en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MunAung Ye en-aut-sei=Mun en-aut-mei=Aung Ye kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZouTinling en-aut-sei=Zou en-aut-mei=Tinling kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ItoKazuki en-aut-sei=Ito en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TagashiraRuji en-aut-sei=Tagashira en-aut-mei=Ruji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 ORCID= affil-num=1 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Occlusal and Oral Functional Rehabilitation, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=immune checkpoint kn-keyword=immune checkpoint en-keyword=immunoregulatory dysfunction kn-keyword=immunoregulatory dysfunction en-keyword=mesenchymal stromal cells (MSCs) kn-keyword=mesenchymal stromal cells (MSCs) en-keyword=prolonged inflammatory stimulation kn-keyword=prolonged inflammatory stimulation en-keyword=TNF-ƒ¿ (tumor necrosis factor-alpha) kn-keyword=TNF-ƒ¿ (tumor necrosis factor-alpha) END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue=10 article-no= start-page=101308 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202510 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Inhibition of Scarb1 on Endothelial Cells Attenuates Pressure Overload-Induced Heart Failure Progression en-subtitle= kn-subtitle= en-abstract= kn-abstract=Inappropriate endothelial cell (EC) interactions contribute to heart failure; however, their precise mechanisms remain poorly understood. This study investigated EC-fibroblast interactions mediated by Scarb1 using single-cell RNA-sequencing analysis in a mouse heart failure model. ECs exhibited inflammatory and fibrotic gene expression, with Scarb1-mediated fibroblast-EC interactions driving disease progression. EC-specific Scarb1 knockout and systemic SCARB1 inhibition attenuated heart failure progression. In vitro and spatial omics analyses confirmed the role of SCARB1 in ECs and cell-cell interaction during heart failure progression. These findings highlight SCARB1 as a promising therapeutic target for EC-focused interventions. en-copyright= kn-copyright= en-aut-name=KatsukiToshiomi en-aut-sei=Katsuki en-aut-mei=Toshiomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KusumotoDai en-aut-sei=Kusumoto en-aut-mei=Dai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AkibaYohei en-aut-sei=Akiba en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KimuraMai en-aut-sei=Kimura en-aut-mei=Mai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KomuroJin en-aut-sei=Komuro en-aut-mei=Jin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakamuraTakahiro en-aut-sei=Nakamura en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HashimotoHisayuki en-aut-sei=Hashimoto en-aut-mei=Hisayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KoukaThukaa en-aut-sei=Kouka en-aut-mei=Thukaa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SugaiKazuhisa en-aut-sei=Sugai en-aut-mei=Kazuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KatsumataYoshinori en-aut-sei=Katsumata en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MiyasakaMasaki en-aut-sei=Miyasaka en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 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=12 ORCID= en-aut-name=KuramotoJunko en-aut-sei=Kuramoto en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KubotaYoshiaki en-aut-sei=Kubota en-aut-mei=Yoshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FukudaKeiichi en-aut-sei=Fukuda en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=YuasaShinsuke en-aut-sei=Yuasa en-aut-mei=Shinsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=IedaMasaki en-aut-sei=Ieda en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= affil-num=1 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=2 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=3 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=4 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=5 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=6 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=7 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=8 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=9 en-affil=Institute for Integrated Sports Medicine, School of Medicine, Keio University kn-affil= affil-num=10 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=11 en-affil=Department of Computational Biology and Medical Sciences, the University of Tokyo kn-affil= affil-num=12 en-affil=Department of Computational Biology and Medical Sciences, the University of Tokyo kn-affil= affil-num=13 en-affil=Department of Pathology, Keio University School of Medicine kn-affil= affil-num=14 en-affil=Department of Anatomy, Keio University School of Medicine kn-affil= affil-num=15 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=16 en-affil=Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=17 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= en-keyword=endothelial cells kn-keyword=endothelial cells en-keyword=fibroblasts kn-keyword=fibroblasts en-keyword=heart failure kn-keyword=heart failure en-keyword=SCARB1 kn-keyword=SCARB1 END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=4 article-no= start-page=233 end-page=240 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=Regional Prevalence of Carbapenemase-Producing Enterobacterales and Extended-Spectrum Beta-Lactamase-Producing Enterobacterales in Okayama and Neighboring Prefectures, Japan en-subtitle= kn-subtitle= en-abstract= kn-abstract=Carbapenemase-producing Enterobacterales (CPE) and extended-spectrum ƒÀ-lactamase (ESBL)-producing Enterobacterales (ESBL-E) are representative antimicrobial-resistant pathogens. We investigated the prevalence of CPE and ESBL-E in Okayama, Japan to clarify their current epidemiology and potential clinical burden. Active surveillance for CPE and ESBL-E was performed first, using stool samples submitted to the Okayama Medical Laboratory (Japan) in the years 2024-2025. Screening was performed using a selective agar (CHROMagar mSuper CARBA/ESBL). Phenotypic identification was conducted with the use of a modified carbapenem inactivation method and double-disk phenotypic confirmatory tests. Clinical information including patient age, sex, sampling date, and hospital address were collected, and the data were analyzed according to specimen origin (hospitals, clinics, and health checkups). A total of 2,000 stool samples were screened, of which two CPE isolates (0.1%) and 285 ESBL-E isolates (14.3%) were identified. By specimen origin, the ESBL-E positivity rate was significantly higher in hospitals (17.4%) than in clinics (11.8%). By age category, the late elderly (> 75 years) exhibited the highest ESBL-E positivity rate (22.6%) compared to other age groups. In the clinics and health checkups, infants (0 years) demonstrated high ESBL-E positivity rates (18.2% and 14.3%, respectively). Escherichia coli was the most common ESBL-E organism in the hospitals (77.2%), clinics (88.8%), and health checkups (87.5%). Our active screening demonstrated that the prevalences of CPE and ESBL-E were within the reported ranges; however, in this era of increasing internationalization, continuous surveillance of these notifiable pathogens is warranted. en-copyright= kn-copyright= en-aut-name=OgawaSakura en-aut-sei=Ogawa en-aut-mei=Sakura 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=AkazawaHidemasa en-aut-sei=Akazawa en-aut-mei=Hidemasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NambaSachie en-aut-sei=Namba en-aut-mei=Sachie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HirotaChiyoko en-aut-sei=Hirota en-aut-mei=Chiyoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KishiueTomoyoshi en-aut-sei=Kishiue en-aut-mei=Tomoyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IbaraShohei en-aut-sei=Ibara en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KondoTakayuki en-aut-sei=Kondo en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FukudaGenshi en-aut-sei=Fukuda en-aut-mei=Genshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=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=GotohKazuyoshi en-aut-sei=Gotoh en-aut-mei=Kazuyoshi 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= en-aut-name=HagiyaHideharu en-aut-sei=Hagiya en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Infectious Diseases, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Infectious Diseases, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Infectious Diseases, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Laboratory Testing, Okayama Medical Laboratory Center kn-affil= affil-num=5 en-affil=Department of Laboratory Testing, Okayama Medical Laboratory Center kn-affil= affil-num=6 en-affil=Department of Laboratory Testing, Okayama Medical Laboratory Center kn-affil= affil-num=7 en-affil=Department of Laboratory Testing, Okayama Medical Laboratory Center kn-affil= affil-num=8 en-affil=Department of Laboratory Testing, Okayama Medical Laboratory Center kn-affil= affil-num=9 en-affil=Department of Sales Promotion, Okayama Medical Laboratory Center kn-affil= affil-num=10 en-affil=Microbiology Division, Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences kn-affil= affil-num=12 en-affil=Department of Medical Laboratory Science, Okayama University Graduate School of Health 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 Infectious Diseases, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=antimicrobial resistance kn-keyword=antimicrobial resistance en-keyword=carbapenem-resistant Enterobacteriaceae kn-keyword=carbapenem-resistant Enterobacteriaceae en-keyword=extended-spectrum ƒÀ-lactamase kn-keyword=extended-spectrum ƒÀ-lactamase en-keyword=infection prevention and control kn-keyword=infection prevention and control en-keyword=Okayama Medical Laboratory kn-keyword=Okayama Medical Laboratory END start-ver=1.4 cd-journal=joma no-vol=131 cd-vols= no-issue=8 article-no= start-page=e2026JB034225 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260816 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Spin Transition of Ferric Iron in Silicate Glasses Inferred by High]Pressure Electrical Conductivity Measurements en-subtitle= kn-subtitle= en-abstract= kn-abstract=Silicate melt has been proposed to exist near the base of the mantle and has been invoked to explain seismic and electrical conductivity anomalies observed near the core-mantle boundary; however, its presence and stability under lowermost-mantle conditions remain uncertain. Here we report high-pressure electrical conductivity measurements of Fe2+- and Fe3+-bearing pyroxene glasses (Fe3+/ƒ°Fe ? 0.5), used as analogs of silicate melts, up to megabar pressures at room temperature. At lower pressures, conductivity increases with pressure and iron content, consistent with electron-hole hopping between Fe2+ and Fe3+. Above 77?85 GPa, all samples show a marked conductivity decrease, suggesting a pressure-induced spin transition of Fe3+. Previous studies have suggested that lower-mantle silicate melts may be enriched in Fe3+, and iron spin-state changes may modify iron partitioning between silicate melts and coexisting crystalline phases. Therefore, the Fe3+ spin transition inferred here may affect the evolution of deep-mantle melts through pressure-dependent changes in iron partitioning behavior. 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=YoshinoTakashi en-aut-sei=Yoshino en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KitaoShinji en-aut-sei=Kitao en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MitsuiTakaya en-aut-sei=Mitsui en-aut-mei=Takaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MasudaRyo en-aut-sei=Masuda en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SetoMakoto en-aut-sei=Seto en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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 Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=4 en-affil=Synchrotron Radiation Research Center, Kansai Photon Science Institute, Quantum Beam Science Research Directorate, National Institutes for Quantum Science and Technology kn-affil= affil-num=5 en-affil=Graduate School of Science and Technology, Hirosaki University kn-affil= affil-num=6 en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= en-keyword=high pressure kn-keyword=high pressure en-keyword=electrical conductivity kn-keyword=electrical conductivity en-keyword=silicate glass kn-keyword=silicate glass en-keyword=diamond anvil cell kn-keyword=diamond anvil cell en-keyword=the Earth's mantle kn-keyword=the Earth's mantle en-keyword=ferric iron kn-keyword=ferric iron 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=20260711 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical utility of diagnosing Lynch syndrome in gynecologic oncology: a joint statement from four Japanese academic societies en-subtitle= kn-subtitle= en-abstract= kn-abstract=Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome, associated with substantially increased risks of colorectal and gynecologic malignancies. Endometrial cancer may serve as a sentinel cancer for LS, placing gynecologists and gynecologic oncologists in a key position for early recognition and long-term management. This joint statement was developed through a multidisciplinary process involving the Japan Society of Gynecologic Oncology, the Japan Society of Clinical Oncology, the Japanese Society of Hereditary Tumors, and the Japanese Society for Cancer of the Colon and Rectum. It aims to clarify the clinical utility of diagnosing LS in gynecologic oncology within the Japanese healthcare system. We outline a tumor-first paradigm in which universal mismatch repair immunohistochemistry and/or microsatellite instability testing for endometrial cancer facilitates LS detection and provides actionable biomarkers for systemic therapy. This statement summarizes the clinical impact of LS diagnosis across gynecologic oncology. We highlight patterns of synchronous and metachronous malignancies and the prevalence of LS in ovarian cancer, particularly in endometrioid and clear?cell subtypes. We discuss surgical implications, including risk-reducing hysterectomy with bilateral salpingo-oophorectomy, consideration of concomitant gynecologic risk-reducing surgery during colorectal cancer resection, and individualized ovarian preservation in selected early-stage endometrial cancer or atypical endometrial hyperplasia. We also review the treatment relevance of deficient mismatch repair/microsatellite instability-high status for immune checkpoint inhibitors and emerging fertility-preserving approaches, and address surveillance, cascade testing for relatives, implementation barriers, and the need for multidisciplinary pathways and healthcare system?level support to ensure equitable access to genetic counseling and testing. en-copyright= kn-copyright= en-aut-name=SatoShinya en-aut-sei=Sato en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MasudaKenta en-aut-sei=Masuda en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OdaKatsutoshi en-aut-sei=Oda en-aut-mei=Katsutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KuwataTakeshi en-aut-sei=Kuwata en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakajimaTakeshi en-aut-sei=Nakajima en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YamadaMasayoshi en-aut-sei=Yamada en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YamaguchiTatsuro en-aut-sei=Yamaguchi en-aut-mei=Tatsuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HirasawaAkira en-aut-sei=Hirasawa en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MandaiMasaki en-aut-sei=Mandai en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TanakayaKohji en-aut-sei=Tanakaya en-aut-mei=Kohji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=IshidaHideyuki en-aut-sei=Ishida en-aut-mei=Hideyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=YoshinoTakayuki en-aut-sei=Yoshino en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OkamotoAikou en-aut-sei=Okamoto en-aut-mei=Aikou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Obstetrics and Gynecology, Faculty of Medicine, Tottori University kn-affil= affil-num=2 en-affil=Department of Obstetrics and Gynecology, Keio University School of Medicine kn-affil= affil-num=3 en-affil=Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=4 en-affil=Department of Genetic Medicine and Services, National Cancer Center Hospital East kn-affil= affil-num=5 en-affil=Division of Hereditary Tumors, Department of Genetic Oncology, Osaka International Cancer Institute kn-affil= affil-num=6 en-affil=Endoscopy Division, National Cancer Center Hospital kn-affil= affil-num=7 en-affil=Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital kn-affil= affil-num=8 en-affil=Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Surgery, National Hospital Organization Iwakuni Medical Center kn-affil= affil-num=11 en-affil=Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University kn-affil= affil-num=12 en-affil=Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East kn-affil= affil-num=13 en-affil=Department of Obstetrics and Gynecology, Sanno Hospital, International University of Health and Welfare kn-affil= en-keyword=Lynch syndrome kn-keyword=Lynch syndrome en-keyword=Endometrial cancer kn-keyword=Endometrial cancer en-keyword=Ovarian cancer kn-keyword=Ovarian cancer en-keyword=Mismatch repair kn-keyword=Mismatch repair en-keyword=Microsatellite instability kn-keyword=Microsatellite instability en-keyword=Immune checkpoint inhibitor kn-keyword=Immune checkpoint inhibitor END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=8 article-no= start-page=e0356180 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260813 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Study protocol: Effect of inulin supplementation on gut microbiota in patients with oral lichen planus ? A double-blind, randomised, placebo-controlled parallel-group trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Oral lichen planus is a chronic inflammatory disease of the oral mucosa characterised by immune dysregulation, but its pathogenesis remains incompletely understood and no curative treatment has been established. Our previous work showed that patients with oral lichen planus exhibit gut dysbiosis, including reduced microbial diversity and depletion of butyrate-producing bacteria. Because butyrate promotes regulatory T-cell differentiation and supports immune homeostasis, targeting this dysbiosis may represent a microbiota-directed approach for immune modulation in oral lichen planus. This study aims to investigate the effects of inulin supplementation on the gut microbiota and related immune markers in patients with oral lichen planus. This multicentre, double-blind, randomised, placebo-controlled parallel-group trial will enrol 80 patients with oral lichen planus. Participants will be randomly assigned in a 1:1 ratio to receive either inulin (8 g/day) or a maltose placebo for 4 weeks, in addition to standard care. The primary outcome is the change in the relative abundance of prespecified butyrate-producing gut bacteria from baseline to the end of intervention at Week 6. Secondary outcomes include changes in gut microbiota diversity, salivary microbiota composition, faecal short-chain fatty acid concentrations, peripheral blood regulatory T-cell counts, blood test parameters, and clinical symptoms of oral lichen planus. Analyses will follow the intention-to-treat principle, and between-group differences will be assessed using appropriate statistical methods. This trial is designed to evaluate, in a randomised placebo-controlled setting, whether a microbiota-directed intervention can modify gut microbial profiles and related immune markers in patients with oral lichen planus. The findings are expected to clarify whether inulin supplementation can modify gut microbial profiles and related immunological markers in patients with oral lichen planus. Trial registration: UMIN Clinical Trials Registry (UMIN-CTR), UMIN000060840, registered on 1 April 2026 (https://rctportal.mhlw.go.jp/detail/um?trial_id=UMIN000060840#). en-copyright= kn-copyright= en-aut-name=NambuKoki en-aut-sei=Nambu en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KanekoNaoki en-aut-sei=Kaneko en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YokomizoShiho en-aut-sei=Yokomizo en-aut-mei=Shiho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ChenHu en-aut-sei=Chen en-aut-mei=Hu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YanLijing en-aut-sei=Yan en-aut-mei=Lijing kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShiyaoWang en-aut-sei=Shiyao en-aut-mei=Wang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ShizumaRyusei en-aut-sei=Shizuma en-aut-mei=Ryusei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IwataEiji en-aut-sei=Iwata en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OhyamaYukiko en-aut-sei=Ohyama en-aut-mei=Yukiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AkagawaShohei en-aut-sei=Akagawa en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 ORCID= en-aut-name=KawanoShintaro en-aut-sei=Kawano en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MoriyamaMasafumi en-aut-sei=Moriyama en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=2 en-affil=Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=3 en-affil=Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=4 en-affil=Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=5 en-affil=Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=6 en-affil=Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=7 en-affil=Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=8 en-affil=Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=10 en-affil=Department of Pediatrics, Kansai Medical University kn-affil= affil-num=11 en-affil=Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=12 en-affil=Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= affil-num=13 en-affil=Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=61 cd-vols= no-issue=9 article-no= start-page=1988 end-page=1991 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=Stomatal Traits in Strawberry Cultivars: Variation among Plant Parts and Associations with Growth and Yield en-subtitle= kn-subtitle= en-abstract= kn-abstract=Stomatal traits are important determinants of photosynthesis and water use; however, their variation among plant parts and cultivars and their relationships with growth and yield in strawberry remain unclear. This study characterized stomatal density and guard cell length among plant parts and across 34 cultivars and examined their associations with growth and yield. Stomata were found not only on the abaxial leaf surface but also on petioles and calyces and occasionally on the adaxial surface of leaves. Both traits varied widely among cultivars and decreased between November and May. Stomatal density was significantly negatively correlated with plant height, estimated leaf area, and total yield in both seasons, whereas guard cell length showed no significant association with these traits. These results suggest that stomatal density may be a more relevant indicator of growth and yield in strawberries and that characterizing stomatal traits across plant parts and cultivars may support breeding and cultivation research. en-copyright= kn-copyright= en-aut-name=Hikawa-EndoMinori en-aut-sei=Hikawa-Endo en-aut-mei=Minori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamanakaRyosuke en-aut-sei=Yamanaka en-aut-mei=Ryosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YanoTakayoshi en-aut-sei=Yano en-aut-mei=Takayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=2 en-affil=Western Region Agricultural Research Center, NARO kn-affil= affil-num=3 en-affil=Western Region Agricultural Research Center, NARO kn-affil= en-keyword=stomatal density kn-keyword=stomatal density en-keyword=guard cell length kn-keyword=guard cell length en-keyword=plant growth kn-keyword=plant growth en-keyword=yield kn-keyword=yield END start-ver=1.4 cd-journal=joma no-vol=66 cd-vols= no-issue=2 article-no= start-page=122 end-page=129 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=RHOA G17V mutation analysis redirecting diagnosis: nodal T-follicular helper cell lymphoma with classic Hodgkin lymphoma feature en-subtitle= kn-subtitle= en-abstract= kn-abstract=Nodal T-follicular helper cell lymphoma (nTFHL) may present with Hodgkin/Reed?Sternberg (HRS)-like cells and can morphologically mimic classic Hodgkin lymphoma (CHL), although these entities are usually distinguishable. We report an unusual case showing marked morphologic and molecular overlap with CHL, creating a diagnostic challenge but ultimately considered biologically consistent with nTFHL.
An 81-year-old woman presented with stage IV disease involving the bone marrow and markedly elevated serum soluble interleukin-2 receptor levels. Excisional lymph node biopsy revealed scattered HRS cells in a T-cell?rich background, with strong CD30 and PD-L1 expression and weak PAX5 positivity, findings consistent with CHL. Fluorescence in situ hybridization demonstrated copy-number alterations at the 9p24.1 locus in HRS cells, further supporting molecular features characteristic of CHL.
However, the presence of two T-follicular helper markers, detection of the RHOA p.Gly17Val (G17V) mutation, and oligoclonal T-cell receptor rearrangements with shared peaks in lymph node and bone marrow indicated an underlying nTFHL. The differential therapeutic response also supported a diagnosis of nTFHL, which could not have been established on morphology alone.
In this case, although the HRS cells displayed morphological, immunophenotypic, and molecular features highly suggestive of CHL, the biological nature of the lesion was consistent with nTFHL. Compared with previously reported cases of nTFHL with HRS-like cells, this case more closely resembled CHL and may represent a distinct subset best described as gnTFHL with CHL features,h a concept warranting greater recognition among pathologists and clinicians. en-copyright= kn-copyright= en-aut-name=YamadaRio en-aut-sei=Yamada en-aut-mei=Rio 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=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=FukumiTakuya en-aut-sei=Fukumi en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OhsawaKumiko en-aut-sei=Ohsawa en-aut-mei=Kumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 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=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=4 en-affil=Department of Hematology, Okayama City Hospital kn-affil= affil-num=5 en-affil=Department of Pathology, Saitama Medical Center, Saitama Medical University kn-affil= affil-num=6 en-affil=Department of Pathology, Saitama Medical Center, Saitama Medical University kn-affil= affil-num=7 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= en-keyword=classic Hodgkin lymphoma kn-keyword=classic Hodgkin lymphoma en-keyword=nodal T-follicular helper cell lymphoma kn-keyword=nodal T-follicular helper cell lymphoma en-keyword=RHOA mutation kn-keyword=RHOA mutation END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=9 article-no= start-page=e70066 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240924 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Decreased CD3+CD56+ Natural Killer T Lymphocytes and Increased Human Leukocyte Antigen-DR+ Cells in the Inflamed Area of Pouchitis in Ulcerative Colitis Patients en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Pouchitis is an inflammatory condition that affects the ileal pouch during ileal pouch-anal anastomosis surgery. Despite its clinical significance, precise immunological mechanisms underlying pouchitis remain unclear. This study aimed to investigate the lymphocyte profile in the ileal pouch of patients with pouchitis compared to those with familial adenomatous polyposis (FAP) and ulcerative colitis without pouchitis using flow cytometry and immunohistochemical techniques.
Methods: We prospectively analyzed endoscopic biopsy specimens from the ileal pouches of 15 patients and categorized them into three groups: FAP, ulcerative colitis with an inflammation-free pouch (UC-I), and ulcerative colitis with ulcers and/or erosions in the pouch (UC-UE). Flow cytometry was used to assess various T-lymphocyte markers, including cluster of differentiation (CD) 4, CD8, CD56, and human leukocyte antigen (HLA)-DR. Immunohistochemistry was performed to visualize the spatial distribution of CD3+, CD56+, and HLA-DR+ cells in the pouch mucosa.
Results: We observed significantly reduced CD56+/CD3+ and CD8+/CD3+ ratios in the UC-UE group compared to those in the FAP group, indicating a disruption in natural killer T-cell populations. Immunohistochemical analysis revealed that the spatial distribution of lymphocytes differed among the non-inflamed mucosa, dense lymphocyte infiltration, and lymphoid follicles, with these components frequently intermingling. CD56 + cells were less abundant in areas with dense lymphocyte infiltration, whereas HLA-DR+ cells were more abundant.
Conclusion: Our study revealed a decrease in CD56+ natural killer T cells and an increase in HLA-DR+-activated T cells in areas with dense lymphocyte infiltration, suggesting an association between these cells and pouchitis in ulcerative colitis. The distinct patterns observed in non-inflamed mucosa, areas with dense lymphocyte infiltration, and lymphoid follicles underscore the need for further analyses of these three segments to elucidate the immunological mechanisms underlying pouchitis. 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=TakaharaMasahiro en-aut-sei=Takahara en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=InokuchiToshihiro en-aut-sei=Inokuchi en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HiraokaSakiko en-aut-sei=Hiraoka en-aut-mei=Sakiko 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 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= en-keyword=flow cytometry kn-keyword=flow cytometry en-keyword=immunohistochemistry kn-keyword=immunohistochemistry en-keyword=lymphocytes, pouchitis kn-keyword=lymphocytes, pouchitis en-keyword=ulcerative colitis kn-keyword=ulcerative colitis END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=1 article-no= start-page=88 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260731 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Early-Stage Oral Squamous Cell Carcinoma in Adolescents and Young Adults Compared with Older Patients Exhibits Distinct Clinicopathological Features en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose This study aimed to compare the clinicopathological features of stage I?II oral squamous cell carcinoma (OSCC) between adolescents and young adults (AYAs) and older patients, and to identify prognostic factors in AYA OSCC.
Methods Forty-eight AYA patients aged 15?39 years and 69 older patients aged???65 years with surgically treated stage I?II OSCC were retrospectively analyzed. Histological evaluation, survival analysis, immunohistochemistry for p53, p16, and MTAP, high-risk HPV RNA in situ hybridization, and fluorescence in situ hybridization for CDKN2A and MTAP were performed.
Results Compared with older patients, OSCCs in AYAs were more frequently located on the tongue (93.7% vs. 47.8%) and more often exhibited a superficial spreading growth pattern (60.4% vs. 31.8%). AYA tumors more frequently showed modified WPOI-1, high tumor budding, and abnormal p53 immunophenotypes (85.4% vs. 68.1%). AYA patients showed significantly better overall and disease-free survival than older patients. Within the AYA group, depth of invasion (DOI)?>?5 mm was associated with distant metastasis and poorer overall and disease-free survival. Postoperative lymph node metastasis occurred in 31.2% of AYAs. Univariable analysis suggested that clinical stage II, tumor thickness?>?5 mm, DOI?>?5 mm, and tumor budding scores 1?2 were associated with postoperative lymph node metastasis. Molecular status, including p53, p16/CDKN2A, and MTAP, did not provide robust prognostic stratification.
Conclusion Early-stage AYA OSCC exhibits distinct clinicopathological features. DOI was the strongest prognostic indicator, whereas clinical stage, tumor thickness, and tumor budding may provide additional prognostic information regarding the risk of late nodal metastasis. en-copyright= kn-copyright= en-aut-name=OnoSawako en-aut-sei=Ono en-aut-mei=Sawako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HiroseKatsutoshi en-aut-sei=Hirose en-aut-mei=Katsutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=AbeTatsuya en-aut-sei=Abe en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SukegawaShintaro en-aut-sei=Sukegawa en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MasuiMasanori en-aut-sei=Masui en-aut-mei=Masanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IkedaChihoko en-aut-sei=Ikeda en-aut-mei=Chihoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IsomuraMadoka en-aut-sei=Isomura en-aut-mei=Madoka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TachibanaYuri en-aut-sei=Tachibana en-aut-mei=Yuri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OnoJunya en-aut-sei=Ono en-aut-mei=Junya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ShimadaKatsumitsu en-aut-sei=Shimada en-aut-mei=Katsumitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 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=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 Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Oral and Maxillofacial Pathology, Osaka University Graduate School of Dentistry kn-affil= affil-num=3 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Division of Oral Pathology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=5 en-affil=Department of Oral and Maxillofacial Surgery, Kagawa University Faculty of Medicine kn-affil= affil-num=6 en-affil=Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Oral Pathology, Osaka Dental University kn-affil= affil-num=8 en-affil=Department of Diagnostic Pathology, School of Medicine, Fujita Health University kn-affil= affil-num=9 en-affil=Department of Pathology Informatics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University Faculty of Medicine kn-affil= affil-num=10 en-affil=Department of Pathology, The Nippon Dental University School of Life Dentistry at Niigata kn-affil= affil-num=11 en-affil=Department of Clinical Pathophysiology, School of Dentistry, Matsumoto Dental University kn-affil= affil-num=12 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=13 en-affil=Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Squamous cell carcinoma of head and neck kn-keyword=Squamous cell carcinoma of head and neck en-keyword=Mouth neoplasms kn-keyword=Mouth neoplasms en-keyword=Adolescent kn-keyword=Adolescent en-keyword=Young adult kn-keyword=Young adult en-keyword=Prognosis kn-keyword=Prognosis en-keyword=Immunohistochemistry kn-keyword=Immunohistochemistry en-keyword=Tumor suppressor protein p53 kn-keyword=Tumor suppressor protein p53 END start-ver=1.4 cd-journal=joma no-vol=66 cd-vols= no-issue=12 article-no= start-page=1811 end-page=1822 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250828 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=ABA receptor isoforms differently regulate stomatal movements and generation of reactive oxygen species in ABA signaling in Arabidopsis guard cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=ABA signaling in stomatal guard cells is crucial for plants to cope with abiotic stress condition. Pyrabactin is a synthetic agonist of ABA that has a selective affinity to limited isoforms of ABA receptors. Here, we investigated the differential utilization of downstream signaling events in guard cell ABA signaling under specific receptor isoforms taking advantage of pyrabactin affinity. Pyrabactin-induced stomatal closure as well as ABA, while it did not inhibit stomatal opening. Plasma membrane inwardly rectifying K+ channel was not regulated by pyrabactin, while H+-ATPase activation was negatively regulated by pyrabactin. Pharmacological and molecular genetic evidence supported that reactive oxygen species production occurred differentially between the closure-inducing and opening-inhibiting signals in guard cells. These findings offer a previously unidentified mechanism for ABA signaling events promoting closure induction and opening inhibition of stomata, which were distinct from each other and governed by different ABA receptor isoforms discriminable by their affinity for pyrabactin. en-copyright= kn-copyright= en-aut-name=YinYe en-aut-sei=Yin en-aut-mei=Ye kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HayashiYuki en-aut-sei=Hayashi en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SirajamMonira en-aut-sei=Sirajam en-aut-mei=Monira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ShaiekOumayma en-aut-sei=Shaiek en-aut-mei=Oumayma 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=NakamuraYoshimasa en-aut-sei=Nakamura en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KinoshitaToshinori en-aut-sei=Kinoshita en-aut-mei=Toshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 ORCID= 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=9 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 Science, Nagoya 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 Science, Nagoya University kn-affil= affil-num=8 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=9 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=302 cd-vols= no-issue=8 article-no= start-page=113318 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=Proton pump rhodopsins for optogenetic manipulation of biological activities and beyond en-subtitle= kn-subtitle= en-abstract= kn-abstract=Water (H2O), the principal component of living organisms including humans, dissociates into H+ and OH- in aqueous environments, and the resulting H+ concentration determines both cellular pH and the proton motive force (PMF) across cellular membranes. These physicochemical parameters are fundamental regulators of a wide range of biological processes. Optogenetics enables the manipulation of biological and cellular functions using light, typically through the ectopic expression of microbial rhodopsins as photoreceptive proteins in target cells or organs. This review provides a comprehensive overview of optogenetic studies employing H+ pump rhodopsins in diverse biological systems and highlights their growing relevance to neuroscience, cell biology, bioengineering, and therapeutic research. Notably, optical control of H+ concentration allows the precise modulation of neural and non-neural activities in animals and bacteria, highlighting the broad applicability and significant potential of H+ pump rhodopsins for optogenetics. Based on previous and current studies, we discuss how further expansion of the molecular toolkit of H+ pump rhodopsins could enable increasingly fine-tuned manipulation of intracellular pH dynamics and PMF for probing cellular physiology and designing next-generation therapeutic strategies and consider emerging directions that extend beyond classical optogenetics toward the optical control of bioenergetic and chemical processes. en-copyright= kn-copyright= en-aut-name=KojimaKeiichi en-aut-sei=Kojima en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InokuchiMiyu en-aut-sei=Inokuchi en-aut-mei=Miyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SudoYuki en-aut-sei=Sudo en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Faculty 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=Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=H+ pump kn-keyword=H+ pump en-keyword=optogenetics kn-keyword=optogenetics en-keyword=pH kn-keyword=pH en-keyword=proton motive force kn-keyword=proton motive force en-keyword=retinal kn-keyword=retinal en-keyword=rhodopsin kn-keyword=rhodopsin END start-ver=1.4 cd-journal=joma no-vol=229 cd-vols= no-issue= article-no= start-page=105080 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=Enhanced calcium activity and transcriptomic alterations in iPSC-derived neurons from BAFME patients with repeat expansions en-subtitle= kn-subtitle= en-abstract= kn-abstract=Benign adult familial myoclonus epilepsy (BAFME) is caused by intronic TTTCA and TTTTA repeat expansions in SAMD12 and other genes; the neuronal basis of cortical hyperexcitability, however, remains unclear. We generated induced pluripotent stem cell (iPSC)-derived glutamatergic and GABAergic neurons from three BAFME1 patients and examined functional and transcriptomic phenotypes. Patient-derived neurons retained the pathogenic repeat expansions and showed a tendency toward upstream intronic RNA accumulation. Calcium imaging revealed increased spontaneous Ca2?+ transient frequency in both neuronal subtypes, indicating heightened activity. Pharmacological profiling demonstrated attenuated responses to calcium-permeable ƒ¿-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor (CP-AMPAR) blockade and GABAA receptor antagonism in GABAergic neurons, suggesting altered inhibitory signaling. RNA sequencing revealed transcriptomic alterations without differential expression of ion channels and neurotransmitter receptors. In glutamatergic neurons, ATF4-regulated genes, including SLC7A5 encoding LAT1, a Kv1.2 channel modulator, were downregulated. Reduced SLC7A5 expression was validated at both mRNA and protein levels. In GABAergic neurons, synapse-associated genes PTPRD and GPC6 were upregulated. TCERG1L and NLRP2 were suppressed across both neuronal subtypes. These findings suggest subtype-specific alterations may contribute to neuronal hyperexcitability in BAFME and provide a platform for mechanistic studies of repeat expansion-associated epilepsies. en-copyright= kn-copyright= en-aut-name=NagasakoYuki en-aut-sei=Nagasako en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IshikawaMitsuru en-aut-sei=Ishikawa en-aut-mei=Mitsuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=SupakulSopak en-aut-sei=Supakul en-aut-mei=Sopak kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MaedaSumihiro en-aut-sei=Maeda en-aut-mei=Sumihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 ORCID= en-aut-name=OkanoHideyuki en-aut-sei=Okano en-aut-mei=Hideyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=2 en-affil=Department of Physiology, Keio University School of Medicine kn-affil= affil-num=3 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Physiology, Keio University School of Medicine kn-affil= affil-num=5 en-affil=Department of Physiology, Keio University School of Medicine kn-affil= affil-num=6 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=7 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=8 en-affil=Department of Physiology, Keio University School of Medicine kn-affil= en-keyword=Induced pluripotent stem cells kn-keyword=Induced pluripotent stem cells en-keyword=Glutamatergic neurons kn-keyword=Glutamatergic neurons en-keyword=GABAergic neurons kn-keyword=GABAergic neurons en-keyword=Calcium imaging kn-keyword=Calcium imaging en-keyword=BAFME kn-keyword=BAFME en-keyword=Repeat expansion kn-keyword=Repeat expansion en-keyword=Epilepsy kn-keyword=Epilepsy END start-ver=1.4 cd-journal=joma no-vol=65 cd-vols= no-issue=5 article-no= start-page=104504 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202610 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Association of initial interface formation time with CD34+ collection efficiency in continuous mononuclear cell collection: A retrospective study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Factors influencing CD34+ cell collection efficiency (CE) during peripheral blood stem cell harvesting have been investigated; however, the impact of procedural management remains unclear. In continuous mononuclear cell (CMNC) collection, a stable cell?plasma interface (IF) is formed through channel priming, initial IF establishment, and mononuclear cell (MNC) collection. Although IF instability is known to impair CE, the adequacy of initial IF formation has not been examined as an independent factor. Therefore, we focused on the time required for initial IF formation and its association with CE.
Methods: We retrospectively analyzed 291 Spectra Optia CMNC procedures (52 autologous and 239 allogeneic) performed between 2016 and 2025. Initial interface formation time (IFT) was defined as the interval from the start of the procedure to transition to MNC collection. CE2 was defined as the ratio of collected CD34+ cells to the product of pre-apheresis peripheral blood CD34+ cell concentration and processed blood volume. Results: CE2 was lower in autologous than in allogeneic collections (41.3% vs. 59.2%) and was associated with longer IFT (median, 18 vs. 15?min). CE2 correlated with white blood cell count (r?=??0.24), hematocrit (r?=?0.36), and IFT (r?=??0.23; all p? Conclusion: IFT is independently associated with CE2 and provides insight into the early dynamics of IF formation during leukapheresis, highlighting an underexplored procedural aspect of CE. en-copyright= kn-copyright= en-aut-name=MurakamiHiroyuki en-aut-sei=Murakami en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=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=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=8 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 Hematology, 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=Division of Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology, Okayama University Hospital kn-affil= en-keyword=CD34+CE2 kn-keyword=CD34+CE2 en-keyword=Continuous mononuclear cell collection kn-keyword=Continuous mononuclear cell collection en-keyword=Spectra Optia kn-keyword=Spectra Optia en-keyword=Interface formation time kn-keyword=Interface formation time en-keyword=Leukapheresis kn-keyword=Leukapheresis END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=7 article-no= start-page=1527 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260713 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Upregulation of the Outer Membrane Protein OmpV and Its Role in Polymyxin B Stress Adaptation in Vibrio mimicus en-subtitle= kn-subtitle= en-abstract= kn-abstract=OmpV is an outer membrane protein found in a variety of Gram-negative bacteria. In this study, we demonstrated that V. mimicus strain CS-66, isolated from a patient with diarrhea, was resistant to polymyxin B (PL-B) and colistin (CL) but susceptible to chloramphenicol and ciprofloxacin. When strain CS-66 was cultured in Luria?Bertani broth containing a sub-minimal inhibitory concentration of each antibiotic used for the susceptibility tests, ompV expression as assayed by reverse transcription-qPCR, significantly increased regardless of the antibiotic tested. In contrast, cell aggregation during the early log phase was observed only when the strain was grown in the broth supplemented with PL-B or CL. A space-filling model of V. mimicus OmpV was generated. The model showed that, although OmpV adopted a ƒÀ-barrel conformation, it had closed top and bottom ends and possessed a lateral cavity. Structural analysis further indicated that the interior of this lateral cavity was negatively charged and sufficiently large to accommodate PL-B. These results suggest that V. mimicus may adapt to PL-B stress through physical sequestration within the negatively charged cavity of OmpV. 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=OnoderaYuta en-aut-sei=Onodera en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AnnoiShunki en-aut-sei=Annoi en-aut-mei=Shunki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=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=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=Research Center for Intestinal Health Science, Okayama University kn-affil= affil-num=5 en-affil=Research Institute of Nursing Care for People and Community, University of Hyogo kn-affil= en-keyword=Vibrio mimicus kn-keyword=Vibrio mimicus en-keyword=polymyxin B kn-keyword=polymyxin B en-keyword=OmpV kn-keyword=OmpV en-keyword=ƒÀ-barrel protein kn-keyword=ƒÀ-barrel protein en-keyword=antibiotic sequestration kn-keyword=antibiotic sequestration 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=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/ƒÊL), 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-4Rƒ¿. 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-ƒÀ 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 ƒ¿-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 ƒ¿-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-ƒÀ 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 ƒÀ-tubulin and ƒÁ-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 Womenfs 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-ƒ¿?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 ƒÂ-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 ƒÂ-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 ƒÂ-toxin triggers degranulation, we investigated ƒÂ-toxin-induced changes in murine bone marrow-derived cultured mast cells in this study. We found that ƒÂ-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 ƒÂ-toxin is involved in the Ca2+-independent phase. However, Ca2+-independent degranulation remains unchanged although Ca2+-influx and degranulation induced by ƒÂ-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 ƒÂ-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, ƒÂ-toxin-induced degranulation remained unchanged in Mrgprb2?/? mast cells. Our findings pave the way for identification of the target receptors of ƒÂ-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=ƒÂ-toxin kn-keyword=ƒÂ-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 ƒ¿ 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) ƒÊg/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-1ƒÀ, interleukin-6, and interferon-ƒÁ 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 physiciansf 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 physiciansf 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 physiciansf 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: ƒÏ=0.046, p=0.845; TRB: ƒÏ=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=Br?gelmannJohannes en-aut-sei=Br?gelmann 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„Ÿchemotherapy 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 ?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? 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-ƒÀ 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-ƒÀ (TGF-ƒÀ), in Egfr-mutant lung cancer. Here, we investigate whether TGF-ƒÀ 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-ƒÀ inhibitor) or vactosertib (a specific TGF-ƒÀ 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-ƒÀ 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-ƒÀ 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-ƒÀ 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-ƒÀ kn-keyword=TGF-ƒÀ 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 ƒÀ-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 5Œ 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 5Œ 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 ƒÂ-(Al,Fe)OOH and Implication for Mid-Lower Mantle Seismic Heterogeneities en-subtitle= kn-subtitle= en-abstract= kn-abstract=ƒÂ-(Al,Fe)OOH is an important water carrier and plays a critical role on Earth's deep water cycle. Lattice parameters of ƒÂ-(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 Vƒ³ of ƒÂ-(Al0.89Fe0.11)OOH occur significant elastic softening, with maximum reductions of 50% on KT and 29% on Vƒ³ at 33 GPa and 300 K to 37% on KT and 23% on Vƒ³ at 41 GPa and 700 K. The anomalous elastic properties of ƒÂ-(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=ƒÂ-(Al,Fe)OOH kn-keyword=ƒÂ-(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 ƒÃ-FeOOH: toward a better understanding of pressure-induced hydrogen-bond symmetrization en-subtitle= kn-subtitle= en-abstract= kn-abstract=High-pressure spectroscopic measurements of ƒÃ-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 ƒÃ-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 ƒÃ?FeOOH preserves a disordered hydrogen?bond configuration up to at least 45 GPa, whereas ƒÂ-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=ƒÃ-FeOOH kn-keyword=ƒÃ-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-ƒÀ1—U“±«ŠÖ߃ŠƒEƒ}ƒ`ŠŠ–ŒüˆÛ‰è×–E‚Ì‘B‚É‚¨‚¯‚éADAM12‚ÌŠÖ—^ kn-title=Involvement of ADAM12 in TGF-ƒÀ1-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=—Ñúº? 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en-aut-name=OKUMURAMisa en-aut-sei=OKUMURA en-aut-mei=Misa kn-aut-name=‰œ‘º”üŽÑ kn-aut-sei=‰œ‘º kn-aut-mei=”üŽÑ aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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“‹ÚŽîᇗn‰ðƒAƒfƒmƒEƒCƒ‹ƒX‚ÍAƒ}ƒNƒƒsƒmƒTƒCƒg[ƒVƒX‚ð‰î‚µ‚ÄäXŠàŠÖ˜AäX¯×–E‚ɃAƒ|ƒg[ƒVƒX‚ð—U“±‚·‚é@ 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=¼ŽRŠx–F kn-aut-sei=¼ŽR kn-aut-mei=Šx–F aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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=”ñ¬×–E”xŠà‚É”º‚¤œ“]ˆÚŠ³ŽÒ‚É‚¨‚¯‚霊֘AŽ–Û—\‘ª‚Ì‚½‚߂̃ŠƒXƒN‘w•Ê‰»‚ÌŒŸ“¢ 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=â–{‹gG kn-aut-sei=â–{ kn-aut-mei=‹gG aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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‚ð”­Œ»‚·‚邃ŠƒXƒNƒqƒg_Œo‰èŽî×–E‚ð•W“I‚Æ‚µ‚½‹ßÔŠOüŒõü–Ɖu—Ö@ 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=”[Š—m kn-aut-sei=”[Š kn-aut-mei=—m aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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=ƒ‰ƒbƒgŠŒF×–EŽî×–EŠ”PC1‚Q‚É‚¨‚¯‚éƒoƒ“ƒfƒ^ƒjƒu‚̃JƒeƒR[ƒ‹ƒAƒ~ƒ“‡¬‘jŠQì—p 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=ˆÉ“¡Œc•F kn-aut-sei=ˆÉ“¡ kn-aut-mei=Œc•F aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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=ƒqƒgŽ•“÷üˆÛ‰è×–E‚Æ‚Ì‹¤”|—{‚É‚¨‚¯‚é‹@ŠB“IL“WŽhŒƒ‚ªƒqƒgiPS×–E—R—ˆS‹Ø×–E‚̬n‚ɑ΂·‚é‰e‹¿ 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=‰¤šëá kn-aut-sei=‰¤ kn-aut-mei=šëá aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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=ŽîᇗZ‰ðƒEƒCƒ‹ƒX‚É‚æ‚ép53Šˆ«‰»‚ÍRŽîᇖƉu‰ž“š‚Ì‘£i‚É‚æ‚Á‚Ä‘å’°Šà‚É‚¨‚¯‚ép53“±“üŽ÷ó×–EƒƒNƒ`ƒ“‚ÌŒø‰Ê‚ð‘‹­‚·‚é 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=ŽR“cŒ³•F kn-aut-sei=ŽR“c kn-aut-mei=Œ³•F aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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=äXŠàŠ³ŽÒ‚É‚¨‚¯‚ép‘OŒã‚̃Qƒmƒ€î•ñ‚ÉŠî‚­—\Œã‘w•Ê‰» 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=‹{–{k‹g kn-aut-sei=‹{–{ kn-aut-mei=k‹g aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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=Œ`Ž¿×–Eœ‘Žî‚É‚¨‚¯‚éCD56”­Œ»‚Ìf’f“I—L—p«‚Æ•p“x 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=¡ˆä‚Ý‚Ç‚è kn-aut-sei=¡ˆä kn-aut-mei=‚Ý‚Ç‚è aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Health Sciences, Okayama University kn-affil=‰ªŽR‘åŠw‘åŠw‰@•ÛŒ’ŠwŒ¤‹†‰È 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=ŽîᇎüˆÍ‘gD‚ªŽîᇊ֘Aƒ}ƒNƒƒtƒ@[ƒW‚ÌWâÆ‚Æ•ª‰»‚É—^‚¦‚é‰e‹¿‚ɂ‚¢‚Ä 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=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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‘jŠQ‚ÍAŒûoG•½ã”çŠà‚É‚¨‚¢‚Ä‘B’†‚ÌŒŒŠÇ‚ð‘I‘ð“I‚É•W“I‰»‚µŽîᇉ󎀂ð—U“±‚·‚é 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=‰ªŽR‘åŠw‘åŠw‰@ˆãŽ•–òŠw‘‡Œ¤‹†‰È 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 ƒ¿,ƒÀ-unsaturated carbonyl moieties. The optimal hit 15 inhibited hepatitis B surface antigen (HBsAg) production with an IC50 of 2.48 ƒÊM 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 ƒÐE is initially produced as an inactive precursor protein pro-ƒÐE 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-ƒÐE 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-ƒÐE. 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-ƒÐE 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 ƒÊm 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), Link?ping 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), Link?ping 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), Link?ping 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 gEREG/EGFR/CSF axish 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/ƒÀ-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 SLbfs 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) ƒ¿-particles and 7Li ions generated through the 10B(n, ƒ¿)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-ƒÀ1, 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-ƒÀ1-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-ƒ¿, TGF-ƒÀ1, 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-ƒÀ1 upregulated the expression of ADAM12 and cell proliferation of RASFs. ADAM12 siRNA suppressed TGF-ƒÀ1-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-ƒÀ1-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-ƒÀ1 kn-keyword=TGF-ƒÀ1 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 ƒ¿-melanocyte-stimulating hormone (ƒ¿-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 ƒÊM and 15.13 nmol/min/mg protein, and those of pH-independent Zn2+ transport were 0.52 ƒÊM and 8.88 nmol/min/mg protein (low concentrations of Zn2+), 3.02 ƒÊM 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 ƒ¢pH of 0.5?1.5. The Zn2+ transport activity decreased at an outside pH of 8.0, despite an increase in ƒ¢pH. 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 ƒ¢pH. 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 (Mƒ³) in the presence of receptor activator of nuclear factor-ƒÈB 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/Mƒ³ 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/Mƒ³ 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/Mƒ³ unit kn-keyword=OC/Mƒ³ 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, CaMK2ƒÁ, 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 ?M), 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 PP2Cƒ¿-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=”MŠÔÃ…ˆ³‰Áˆ³–@‚ð—p‚¢‚½ƒCƒbƒgƒŠƒAˆÀ’艻ƒWƒ‹ƒRƒjƒAãk–§‘w‚̒ቷŒ`¬ 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=^“ç‹•½ kn-aut-sei=^“ç kn-aut-mei=‹•½ aut-affil-num=1 ORCID= en-aut-name=ECHIGOMitsuaki en-aut-sei=ECHIGO en-aut-mei=Mitsuaki kn-aut-name=‰zŒã–žH kn-aut-sei=‰zŒã kn-aut-mei=–žH aut-affil-num=2 ORCID= en-aut-name=KISHIMOTOAkira en-aut-sei=KISHIMOTO en-aut-mei=Akira kn-aut-name=ŠÝ–{º kn-aut-sei=ŠÝ–{ kn-aut-mei=º aut-affil-num=3 ORCID= affil-num=1 en-affil=Osaka Gas Co. Ltd. kn-affil=‘åãƒKƒXiŠ”j affil-num=2 en-affil=Osaka Gas Co. Ltd. kn-affil=‘åãƒKƒXiŠ”j affil-num=3 en-affil=Institute of Academic and Research, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil=‰ªŽR‘åŠwŠwpŒ¤‹†‰@ŠÂ‹«¶–½Ž©‘R‰ÈŠwŠwˆæ 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 Beh?etfs disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Beh?etfs 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=Beh?etfs disease kn-keyword=Beh?etfs 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??m 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=Mart?nezJose G. en-aut-sei=Mart?nez 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), Link?ping 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), Link?ping 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), Link?ping 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)-ƒ¿ are reportedly key effectors of psoriasis. Additionally, gamma delta (ƒÁƒÂ) T cells exacerbate inflammation by producing inflammatory cytokines such as IL-17 and TNF-ƒ¿. 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 ƒÁƒÂ 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-ƒ¿ 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 ƒÁƒÂ T cell infiltration and upregulated IL-17 and IL-23 expression in the skin, as well as enhanced ƒÁƒÂ 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-ƒ¿ 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-ƒ¿ 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