start-ver=1.4 cd-journal=joma no-vol=49 cd-vols= no-issue=2 article-no= start-page=364 end-page=370 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260221 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Functional Transport Properties of Human Zinc Transporter 1: Kinetics and pH-Dependency en-subtitle= kn-subtitle= en-abstract= kn-abstract=Intracellular zinc (Zn2+) homeostasis is essential for physiological and pathological processes and is strictly regulated by Zn2+ transporters. Zinc transporter 1 (ZnT1) is a ubiquitously expressed plasma membrane-localized Zn transporter that exports Zn2+ from the cytoplasm to the extracellular space. However, the functional transport properties regarding kinetics and driving forces of ZnT1 remain debatable. In this study, we established a cell-free proteoliposome assay system and demonstrated that ZnT1 transports Zn2+ with high affinity in pH-dependent and pH-independent manners. The Km and Vmax of pH-dependent Zn2+ transport were 0.40 μM and 15.13 nmol/min/mg protein, and those of pH-independent Zn2+ transport were 0.52 μM and 8.88 nmol/min/mg protein (low concentrations of Zn2+), 3.02 μM and 17.59 nmol/min/mg protein (high concentrations of Zn2+), respectively, suggesting biphasic kinetic components of Zn2+ transport. Even without pH gradient formation, ZnT1 exhibits potent Zn2+ transport activity. In pH dependency, Zn2+ transport activity was higher at an inside pH of 6.0 than at 6.5–7.5 for proteoliposomes, despite the same ΔpH of 0.5–1.5. The Zn2+ transport activity decreased at an outside pH of 8.0, despite an increase in ΔpH. Although previous studies have proposed that ZnT1-mediated Zn2+ transport activity is driven by a calcium (Ca2+) gradient and not by a pH gradient, Ca2+ does not enhance Zn2+ transport activity in the presence or absence of a pH gradient. These results strongly suggest that ZnT1 protein transports Zn2+ optimally at a specific pH and exports excess intracellular Zn2+ even without ΔpH. en-copyright= kn-copyright= en-aut-name=YoshiokaYuma en-aut-sei=Yoshioka en-aut-mei=Yuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyajiTakaaki en-aut-sei=Miyaji en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= affil-num=1 en-affil=Department of Molecular Membrane Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Molecular Membrane Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=zinc transporter 1 kn-keyword=zinc transporter 1 en-keyword=SLC30A1 kn-keyword=SLC30A1 en-keyword=zinc kn-keyword=zinc en-keyword=pH kn-keyword=pH en-keyword=proteoliposome kn-keyword=proteoliposome END start-ver=1.4 cd-journal=joma no-vol=25 cd-vols= no-issue= article-no= start-page=103265 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202606 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Peptide nanomicelles for NIR light-dependent siRNA delivery en-subtitle= kn-subtitle= en-abstract= kn-abstract=The peptide amphiphile PA8, derived from the GAVILRR peptide, was developed as a carrier for small interfering RNA (siRNA) delivery; however, its RNA interference (RNAi) efficacy was limited owing to predominant endocytotic uptake. In this study, the RNAi efficiency of PA8 nanomicelle/siRNA complexes was enhanced by modifying the nanomicelles with the photosensitizer DY750 and the tumor-homing peptide iRGD. The conjugation of DY750 to the nanomicelles facilitated endosomal escape of the nanomicelle/siRNA complexes, enabling the cytosolic release of siRNA. Additionally, the incorporation of iRGD improved RNAi delivery efficiency in the AsPC-1 pancreatic ductal adenocarcinoma cell line. PA8-DY750-iRGD nanomicelle complexes loaded with siRNA against polo-like kinase 1 (PLK1) achieved an 80% reduction in PLK1 mRNA levels in AsPC-1 cells and a moderate 28% knockdown in NCI-N87 gastric cancer cells. Notably, no RNAi effect was observed in noncancerous 1C3D3 pancreatic cells or HEK293T kidney cells, underscoring the selectivity of this system for AsPC-1 cells. These findings highlight the potential of PA8-DY750-iRGD nanomicelle complexes as a targeted therapeutic platform for specific cancers, particularly pancreatic cancer. en-copyright= kn-copyright= en-aut-name=HakimTaufik Fatwa Nur en-aut-sei=Hakim en-aut-mei=Taufik Fatwa Nur kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KitamatsuMizuki en-aut-sei=Kitamatsu en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FujimotoShoumu en-aut-sei=Fujimoto en-aut-mei=Shoumu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeKazunori en-aut-sei=Watanabe en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OhtsukiTakashi en-aut-sei=Ohtsuki en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Applied Chemistry, Kindai University kn-affil= affil-num=3 en-affil=Department of Applied Chemistry, Kindai University kn-affil= affil-num=4 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=Peptide nanomicelles kn-keyword=Peptide nanomicelles en-keyword=siRNA kn-keyword=siRNA en-keyword=Near infrared light kn-keyword=Near infrared light en-keyword=Targeted delivery kn-keyword=Targeted delivery en-keyword=Photosensitizer kn-keyword=Photosensitizer END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=2 article-no= start-page=831 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260114 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Porphyromonas gingivalis Vesicles Control Osteoclast–Macrophage Lineage Fate en-subtitle= kn-subtitle= en-abstract= kn-abstract=Porphyromonas gingivalis (Pg), a keystone pathogen of chronic periodontitis, releases outer membrane vesicles (OMVs) that act as nanoscale vehicles to disseminate virulence factors within periodontal tissues and systemically beyond the oral cavity. Although Pg-OMVs are increasingly recognized as critical mediators of host–pathogen interactions, their effects on the differentiation and function of monocyte–macrophage/osteoclast lineage cells remain unclear. Here, we examined the impact of Pg-OMVs on the differentiation of RAW264.7 monocyte/macrophage-like cells into osteoclasts (OC) and/or macrophages (MΦ) in the presence of receptor activator of nuclear factor-κB ligand (RANKL). OMVs were isolated from Pg W83 and applied to RANKL-primed RAW264.7 cells using three distinct stimulation schedules: (1) simultaneous treatment with Pg-OMVs and RANKL at Day 0; (2) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 1; and (3) RANKL priming at Day 0 followed by Pg-OMV stimulation at Day 3. In all schedules, cells were cultured for 7 days from the initial RANKL exposure. Remarkably, simultaneous exposure to Pg-OMVs and RANKL (Schedule 1) markedly suppressed osteoclastogenesis (OC-genesis) while promoting M1 macrophage polarization. In contrast, delayed Pg-OMV stimulation of RANKL-primed cells (Schedules 2 and 3) significantly enhanced OC-genesis while reducing M1 polarization. These schedule-dependent effects were consistent with altered expression of osteoclastogenic markers, including dc-stamp, oc-stamp, nfatc1, and acp5. Importantly, a monoclonal antibody against OC-STAMP counteracted the Pg-OMV-induced upregulation of OC-genesis in Schedules 2 and 3. Furthermore, levels of Pg-OMV phagocytosis were inversely correlated with osteoclast formation. Finally, co-stimulation with RANKL and Pg-OMVs (Schedule 1) enhanced macrophage migratory capacity, whereas delayed stimulation with Pg-OMVs (Schedules 2 and 3) did not. Collectively, these findings indicate that Pg-OMVs exert stage-specific effects on the OC/MΦ lineage: stimulation at early stages of RANKL priming suppresses OC-genesis and promotes M1 polarization, whereas stimulation at later stages enhances OC-genesis without inducing M1 differentiation. Thus, Pg-OMVs may critically influence the fate of the OC/MΦ unit in periodontal lesions, contributing to disease progression and tissue destruction. en-copyright= kn-copyright= en-aut-name=LeonElizabeth en-aut-sei=Leon en-aut-mei=Elizabeth kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakamuraShin en-aut-sei=Nakamura en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShindoSatoru en-aut-sei=Shindo en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=PastoreMaria Rita en-aut-sei=Pastore en-aut-mei=Maria Rita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KumagaiTomoki en-aut-sei=Kumagai en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HeidariAlireza en-aut-sei=Heidari en-aut-mei=Alireza kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AbdolahiniaElaheh Dalir en-aut-sei=Abdolahinia en-aut-mei=Elaheh Dalir kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UedaTomoya en-aut-sei=Ueda en-aut-mei=Tomoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MemidaTakumi en-aut-sei=Memida en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=Duran-PinedoAna en-aut-sei=Duran-Pinedo en-aut-mei=Ana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=Frias-LopezJorge en-aut-sei=Frias-Lopez en-aut-mei=Jorge kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HanXiaozhe en-aut-sei=Han en-aut-mei=Xiaozhe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=ChenXin en-aut-sei=Chen en-aut-mei=Xin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HuangShengyuan en-aut-sei=Huang en-aut-mei=Shengyuan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=CaoGuoqin en-aut-sei=Cao en-aut-mei=Guoqin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=RuizSunniva en-aut-sei=Ruiz en-aut-mei=Sunniva kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=PotempaJan en-aut-sei=Potempa en-aut-mei=Jan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KawaiToshihisa en-aut-sei=Kawai en-aut-mei=Toshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=2 en-affil=Department of Periodontics and Endodontics, Division of Dentistry, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=4 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=5 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=6 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=7 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=8 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=9 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=10 en-affil=Department of Oral Biology, College of Dentistry, University of Florida kn-affil= affil-num=11 en-affil=Department of Oral Biology, College of Dentistry, University of Florida kn-affil= affil-num=12 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=13 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=14 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=15 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=16 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University kn-affil= affil-num=17 en-affil=Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville kn-affil= affil-num=18 en-affil=Department of Oral Science and Translational Research, College of Dental Medicine, Nova Southeastern University, Fort Lauderdale, FL 33314, USA kn-affil= en-keyword=Porphyromonas gingivalis kn-keyword=Porphyromonas gingivalis en-keyword=outer membrane vesicle kn-keyword=outer membrane vesicle en-keyword=periodontitis pathogenesis kn-keyword=periodontitis pathogenesis en-keyword=macrophage polarization kn-keyword=macrophage polarization en-keyword=osteoclastogenesis kn-keyword=osteoclastogenesis en-keyword=OC/MΦ unit kn-keyword=OC/MΦ unit END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=7 article-no= start-page=3143 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260330 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=CXCR2-Dependent Infiltration of Tumor-Associated Neutrophils Is Linked to Enhanced CD8+ T Cell Effector Function and Reduced Lung Metastasis in 4T1 Breast Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Triple-negative breast cancer (TNBC) is characterized by prominent neutrophil infiltration; however, its significance remains controversial. Here, we investigated the role of neutrophil chemoattractant receptors in TNBC progression and metastasis. In contrast to wild-type (WT), Fpr1−/−, and Fpr2−/− mice, neutrophils were almost completely absent in 4T1 tumors from Cxcr2−/− mice, indicating a dominant role for CXCR2 in the recruitment of tumor-associated neutrophils, leading us to use Cxcr2−/− mice for further studies. Primary tumor growth was comparable between WT and Cxcr2−/− mice, whereas lung metastasis was significantly increased in Cxcr2−/− mice, with reduced expression of inflammatory cytokines, chemokines and cytotoxic molecules, including granzyme B and perforin, in primary tumors and metastatic lungs of Cxcr2−/− mice. In vitro, WT, but not Cxcr2−/−, neutrophils enhanced CD8+ T cell activation, partly via ICAM-1, and directly induced tumor cell death, supporting their anti-tumor function. To assess clinical relevance, transcriptomic data were analyzed. High neutrophil infiltration combined with elevated CXCR2 expression, and to a lesser extent CXCR1 expression, was associated with improved prognosis in patients with basal-like BC that largely overlaps with TNBC. Collectively, these findings suggest that CXCR2-mediated neutrophil recruitment exerts protective, anti-tumor effects and may represent a new prognostic marker for TNBC patients. en-copyright= kn-copyright= en-aut-name=LiTiantian en-aut-sei=Li en-aut-mei=Tiantian kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoshimuraTeizo en-aut-sei=Yoshimura en-aut-mei=Teizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TianMiao en-aut-sei=Tian en-aut-mei=Miao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishidaGakushi en-aut-sei=Nishida en-aut-mei=Gakushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LiChunning en-aut-sei=Li en-aut-mei=Chunning kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujisawaMasayoshi en-aut-sei=Fujisawa en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=breast cancer kn-keyword=breast cancer en-keyword=neutrophils kn-keyword=neutrophils en-keyword=CD8+ T cells kn-keyword=CD8+ T cells en-keyword=chemokines kn-keyword=chemokines en-keyword=chemokine receptors kn-keyword=chemokine receptors en-keyword=tumor microenvironment kn-keyword=tumor microenvironment END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=4 article-no= start-page=760 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260327 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Role of Nitrate-Reducing Bacteria Isolated from Helicobacter pylori-Infected Individuals in Gastric Cancer Development en-subtitle= kn-subtitle= en-abstract= kn-abstract=Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric mucosa, with a global prevalence in humans of approximately 40%. It is likely the cause of 90% of gastric cancer (GC) cases and thus considered the most prominent driver of GC development. However, during gastric mucosal atrophy, other bacteria such as nitrate-reducing bacteria (NRB) also proliferate. In this study, we isolated NRB from patients with gastritis and GC to examine their effects on the epithelial cell cycle and production of various cytokines in monocytic cell lines. Bacterial counts (excluding H. pylori and NRB) increased with the progression of gastric mucosal atrophy and were significantly higher in patients with GC. Gastric epithelial cell lines were stimulated with isolated NRB, and the proportion of cells in each cell cycle was measured. Strains from patients with open-type gastritis progressed more rapidly through cell cycles than those from patients with GC. NRB isolated from gastric cancer had high nitrate-reducing activity. Thus, NRB may contribute to GC progression during H. pylori-induced carcinogenesis. Therefore, evaluating gastric atrophy and microbiota may be important for managing the risk of GC. en-copyright= kn-copyright= en-aut-name=KuwagiSerika en-aut-sei=Kuwagi en-aut-mei=Serika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=GotohKazuyoshi en-aut-sei=Gotoh en-aut-mei=Kazuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KomatsubaraMarina en-aut-sei=Komatsubara en-aut-mei=Marina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TsujiShuma en-aut-sei=Tsuji en-aut-mei=Shuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OkanoueShyoutarou en-aut-sei=Okanoue en-aut-mei=Shyoutarou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OkadaHiroyuki en-aut-sei=Okada en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UchiyamaJumpei en-aut-sei=Uchiyama en-aut-mei=Jumpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=WatanabeAkari en-aut-sei=Watanabe en-aut-mei=Akari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YokotaKenji en-aut-sei=Yokota en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Academic Field of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Himeji Red Cross Hospital kn-affil= affil-num=7 en-affil=Department of Bacteriology, Academic Field of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Oral Health Care and Rehabilitation, Institute of Biomedical Sciences, Graduate School, Tokushima University kn-affil= affil-num=9 en-affil=Department of Bacteriology, Academic Field of Health Sciences, Okayama University kn-affil= en-keyword=Helicobacter pylori infection kn-keyword=Helicobacter pylori infection en-keyword=gastric cancer kn-keyword=gastric cancer en-keyword=nitrate-reducing bacteria kn-keyword=nitrate-reducing bacteria en-keyword=gastritis kn-keyword=gastritis END start-ver=1.4 cd-journal=joma no-vol=135 cd-vols= no-issue= article-no= start-page=103134 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202605 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Regulation of brain-specific kinases 1 and 2 (BRSK1/2) by Ca2+/calmodulin en-subtitle= kn-subtitle= en-abstract= kn-abstract=We conducted a genome-wide calmodulin (CaM) interaction screening of 462 GST-fused human protein kinases to identify novel CaM-dependent protein kinases (CaMKs). In addition to known CaMKs, including myosin light chain kinases, CaMK2γ, and death-associated kinase 2, we identified the brain-specific protein kinase 2 (BRSK2, also known as SAD-A) as a novel CaM interactant. Proximity biotinylation and CaM–sepharose chromatography assays revealed that rat BRSK isoforms (BRSK1/2) interact with CaM in a Ca2+-dependent manner in vitro. We found that CaM suppresses the activation-loop phosphorylation of BRSK1 (at Thr189) and BRSK2 (at Thr175) by liver kinase B1 (LKB1), an activating kinase, in a Ca2+-dependent manner (IC50 of ∼7 µM), thereby inhibiting BRSK activation. LKB1-catalyzed phosphorylation of the catalytic domain mutant of BRSK1 (residues 1–294) at Thr189 was suppressed by the addition of Ca2+/CaM, consistent with direct CaM binding of the kinase domain, as well as wild-type BRSK1. We confirmed that the LKB1 activity was not directly suppressed by Ca2+/CaM, supporting the hypothesis that the direct interaction of Ca2+/CaM with the kinase domain blocks the phosphorylation/activation of BRSK1/2 by LKB1. The kinase activity and PP2Cα-catalyzed dephosphorylation of LKB1-phosphorylated BRSK1 were not altered by Ca2+/CaM, although it was demonstrated to bind to Ca2+/CaM like that of unphosphorylated BRSK1. This unrecognized mechanism of BRSK1/2 regulation, involving the direct role of Ca2+/CaM binding, which inhibits phosphorylation/activation by LKB1, may open a new Ca2+ signal transduction pathway in neurons. en-copyright= kn-copyright= en-aut-name=WashidaNaoyuki en-aut-sei=Washida en-aut-mei=Naoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KataokaMoe en-aut-sei=Kataoka en-aut-mei=Moe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=BrunAnna R. en-aut-sei=Brun en-aut-mei=Anna R. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakezakiUryu en-aut-sei=Takezaki en-aut-mei=Uryu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HijikawaKo en-aut-sei=Hijikawa en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YamauchiHaruki en-aut-sei=Yamauchi en-aut-mei=Haruki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OhtsukaSatomi en-aut-sei=Ohtsuka en-aut-mei=Satomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MagariMasaki en-aut-sei=Magari en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MorishitaRyo en-aut-sei=Morishita en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TokumitsuHiroshi en-aut-sei=Tokumitsu en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil= kn-affil= affil-num=2 en-affil=Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University kn-affil= affil-num=3 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University kn-affil= affil-num=6 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=9 en-affil=CellFree Sciences Co., Ltd. kn-affil= affil-num=10 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=BRSK1 kn-keyword=BRSK1 en-keyword=BRSK2 kn-keyword=BRSK2 en-keyword=calmodulin kn-keyword=calmodulin en-keyword=LKB1 kn-keyword=LKB1 en-keyword=phosphorylation kn-keyword=phosphorylation en-keyword=Ca2+ kn-keyword=Ca2+ en-keyword=CaM-dependent protein kinase kn-keyword=CaM-dependent protein kinase END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260325 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinicopathological and transcriptomic profiles of 101 patients with diffuse large B-cell lymphoma/high-grade B-cell lymphoma with double-hit MYC and BCL2 or BCL6 and triple hit en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aims: Diffuse large B-cell lymphoma/high-grade B-cell lymphoma (DLBCL/HGBCL) with MYC and BCL2 rearrangements (double-hit lymphoma with BCL2, DHL-BCL2) is a mature aggressive B-cell lymphoma that also includes concurrent triple hit with BCL6 translocation (TH). DHL with MYC and BCL6 (DH-BCL6) can also occur. The differences among these three DLBCL/HGBCL subtypes have not yet been definitively determined.
Methods and Results: This study characterized the clinicopathological features and transcriptomic profiles of a series of 101 cases of DLBCL/HGBCL that were subclassified according to MYC, BCL2 and BCL6 FISH data, including cell-of-origin (COO)-like, molecular high-grade (MHG)-like and double-hit/dark-zone (DHIT/DZsig)-like signatures. DLBCL/HGBCL-DH-BCL2 was characterized by higher HGBCL morphology, CD10 positivity, GCB Hans's, GCB COO and MHG molecular subtype. DLBCL/HGBCL-TH had higher LDH levels and worse overall survival. DLBCL/HGBCL-DH-BCL6 had higher MUM1 expression, non-GCB Hans', ABC/Unclassified COO, non-MHG and low DHIT/DZ signatures. Transcriptomic analysis showed that DLBCL/HGBCL-DH-BCL2 and DLBCL/HGBCL-TH were close but separated from DLBCL/HGBCL-DH-BCL6. Gene set enrichment analysis (GSEA) revealed different levels of enrichment between the subtypes.
Conclusions: DLBCL/HGBCL-DH-BCL6 differs from the DLBCL/HGBCL-DH-BCL2, and the DLBCL/HGBCL-TH is associated with the worst survival. Analysis of all three genes of MYC, BCL2 and BCL6 is recommended in the context of DLBCL/HGBCL diagnosis. en-copyright= kn-copyright= en-aut-name=MiyaokaMasashi en-aut-sei=Miyaoka en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=CarrerasJoaquim en-aut-sei=Carreras en-aut-mei=Joaquim kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KikutiYara Yukie en-aut-sei=Kikuti en-aut-mei=Yara Yukie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IkomaHaruka en-aut-sei=Ikoma en-aut-mei=Haruka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NagaseShunsuke en-aut-sei=Nagase en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ItoAtsushi en-aut-sei=Ito en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OritaMakoto en-aut-sei=Orita en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawadaHiroshi en-aut-sei=Kawada en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SakaiRika en-aut-sei=Sakai en-aut-mei=Rika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SatoYasuharu en-aut-sei=Sato en-aut-mei=Yasuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NishimuraMidori Filiz en-aut-sei=Nishimura en-aut-mei=Midori Filiz kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TsukasakiKunihiro en-aut-sei=Tsukasaki en-aut-mei=Kunihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MomoseShuji en-aut-sei=Momose en-aut-mei=Shuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KameokaYoshihiro en-aut-sei=Kameoka en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=YoshidaMasahiro en-aut-sei=Yoshida en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SatouAkira en-aut-sei=Satou en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KatoSeiichi en-aut-sei=Kato en-aut-mei=Seiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=OishiNaoki en-aut-sei=Oishi en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=SaitoAkio en-aut-sei=Saito en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=SadahiraKen en-aut-sei=Sadahira en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=MasugiYohei en-aut-sei=Masugi en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=NakamuraNaoya en-aut-sei=Nakamura en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=2 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=3 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=4 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=5 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=6 en-affil=Department of Pathology, School of Medicine Tokai University Isehara Japan kn-affil= affil-num=7 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=8 en-affil=Department of Hematology, School of Medicine, Tokai University kn-affil= affil-num=9 en-affil=Department of Medical Oncology, Kanagawa Cancer Center kn-affil= affil-num=10 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=11 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=12 en-affil=Department of Hematology, International Medical Center, Saitama Medical University kn-affil= affil-num=13 en-affil=Department of Pathology, Saitama Medical Center, Saitama Medical University kn-affil= affil-num=14 en-affil=Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine kn-affil= affil-num=15 en-affil=Department of Hematology, Osaka City General Hospital kn-affil= affil-num=16 en-affil=Department of Surgical Pathology, Aichi Medical University Hospital kn-affil= affil-num=17 en-affil=Center for Clinical Pathology, Fujita Health University Hospital kn-affil= affil-num=18 en-affil=Department of Pathology, University of Yamanashi kn-affil= affil-num=19 en-affil=Department of Hematology, NHO Shibukawa Medical Center kn-affil= affil-num=20 en-affil=Division of Hematology, Kawasaki Municipal Kawasaki Hospital kn-affil= affil-num=21 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= affil-num=22 en-affil=Department of Pathology, School of Medicine, Tokai University kn-affil= en-keyword=BCL2 kn-keyword=BCL2 en-keyword=BCL6 kn-keyword=BCL6 en-keyword=high-grade B-cell lymphoma kn-keyword=high-grade B-cell lymphoma en-keyword=molecular profile kn-keyword=molecular profile en-keyword=MYC kn-keyword=MYC en-keyword=rearrangements kn-keyword=rearrangements END start-ver=1.4 cd-journal=joma no-vol=75 cd-vols= no-issue=3 article-no= start-page=84 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260225 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A real-world comparison of nivolumab plus cabozantinib and pembrolizumab plus lenvatinib focusing on safety outcomes in metastatic renal cell carcinoma: results from the JK-FOOT consortium en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose Immune checkpoint inhibitor (ICI)-based combination therapy is a standard first-line treatment for metastatic renal cell carcinoma (mRCC), with combinations such as nivolumab plus cabozantinib (Nivo + Cabo) and pembrolizumab plus lenvatinib (Pem + Len) demonstrating favorable oncologic outcomes. However, no direct comparisons between these two regimens have been conducted. This study aimed to compare the safety and oncologic outcomes of Nivo + Cabo and Pem + Len in patients with mRCC.
Methods This retrospective study included 185 patients with mRCC treated with Nivo + Cabo (n = 81) or Pem + Len (n = 104) between January 2018 and June 2025 across multiple institutions. The primary outcome was a comparison of treatment-related adverse events (TrAEs). Oncologic outcomes, including objective response rate (ORR), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS), were compared using one-to-one propensity score matching.
Results Any-grade TrAEs occurred in 90% of patients in the Nivo + Cabo group and 92% in the Pem + Len group (p = 0.6). Severe TrAEs (grade ≥ 3) were more frequent in the Pem + Len group (44%) than in the Nivo + Cabo group (30%, p = 0.048). Tyrosine kinase inhibitor dose reduction and treatment discontinuation rates were similar between groups. In the matched cohort (Nivo + Cabo: n = 74; Pem + Len: n = 74), ORRs were comparable (66% vs. 71%, p = 0.6). With a median follow-up of 17 months, no significant differences were observed in PFS (p = 0.4), CSS (p = 0.9), or OS (p = 0.5).
Conclusions Nivo + Cabo and Pem + Len demonstrated similar oncologic efficacy as first-line treatments for mRCC. However, Pem + Len was associated with more severe TrAEs. Careful toxicity management and shared decision-making are essential when selecting ICI-based combinations. en-copyright= kn-copyright= en-aut-name=YanagisawaTakafumi en-aut-sei=Yanagisawa en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MoriKeiichiro en-aut-sei=Mori en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KawadaTatsushi en-aut-sei=Kawada en-aut-mei=Tatsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatayamaSatoshi en-aut-sei=Katayama en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TsujinoTakuya en-aut-sei=Tsujino en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MaenosonoRyoichi en-aut-sei=Maenosono en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyodaShingo en-aut-sei=Toyoda en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NukayaTakuhisa en-aut-sei=Nukaya en-aut-mei=Takuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MorinakaHirofumi en-aut-sei=Morinaka en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TamuraKeita en-aut-sei=Tamura en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FukuokayaWataru en-aut-sei=Fukuokaya en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=UrabeFumihiko en-aut-sei=Urabe en-aut-mei=Fumihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MurakamiMasaya en-aut-sei=Murakami en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=BekkuKensuke en-aut-sei=Bekku en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TakaharaKiyoshi en-aut-sei=Takahara en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=FujitaKazutoshi en-aut-sei=Fujita en-aut-mei=Kazutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AzumaHaruhito en-aut-sei=Azuma en-aut-mei=Haruhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=ArakiMotoo en-aut-sei=Araki en-aut-mei=Motoo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=InamotoTeruo en-aut-sei=Inamoto en-aut-mei=Teruo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KomuraKazumasa en-aut-sei=Komura en-aut-mei=Kazumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KimuraTakahiro en-aut-sei=Kimura en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= affil-num=1 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=2 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=3 en-affil=Department of Urology, Comprehensive Cancer Center, Medical University of Vienna kn-affil= affil-num=4 en-affil=Department of Urology, Comprehensive Cancer Center, Medical University of Vienna kn-affil= affil-num=5 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=6 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=7 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=8 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=9 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=10 en-affil=Department of Urology, Hamamatsu Medical University kn-affil= affil-num=11 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=12 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=13 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=14 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=16 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=17 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=18 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=19 en-affil=Department of Urology, Hamamatsu Medical University kn-affil= affil-num=20 en-affil=Department of Urology, Kawasaki Medical School kn-affil= affil-num=21 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= en-keyword=Metastatic renal cell carcinoma kn-keyword=Metastatic renal cell carcinoma en-keyword=Immune checkpoint inhibitor kn-keyword=Immune checkpoint inhibitor en-keyword=Pembrolizumab kn-keyword=Pembrolizumab en-keyword=Lenvatinib kn-keyword=Lenvatinib en-keyword=Nivolumab kn-keyword=Nivolumab en-keyword=Cabozantinib kn-keyword=Cabozantinib END start-ver=1.4 cd-journal=joma no-vol=73 cd-vols= no-issue=3 article-no= start-page=55 end-page=59 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260315 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Low Temperature Formation of Dense Yttria-Stabilized Zirconia Layer Using Hot Isostatic Pressing kn-title=熱間静水圧加圧法を用いたイットリア安定化ジルコニア緻密層の低温形成 en-subtitle= kn-subtitle= en-abstract= kn-abstract=The sintering conditions using hot isostatic press (HIP) of yttria-stabilized zirconia (YSZ) were investigated to obtain a dense YSZ layer at low sintering temperature such as 1000°C for an electrolyte of metal-supported solid oxide fuel cell. It was found that a dense YSZ pellet with relative density of 93% could be obtained under a sintering condition of 1000°C-10 hours with HIP in 195 MPa. On the other hand, in X-ray diffraction analysis of the dense YSZ pellet, peaks of the monoclinic phase were slightly detected in addition to peaks of the cubic phase. From energy dispersive X-ray spectroscopy analysis, a small amount of boron was detected in the dense YSZ pellet. It is considered that the YSZ crystalline phase transformation of cubic to monoclinic phase was occurred by the boron diffusion from the diffusion barrier coating of metal foil capsule used for the HIP. en-copyright= kn-copyright= en-aut-name=MANABEKyohei en-aut-sei=MANABE en-aut-mei=Kyohei kn-aut-name=真鍋享平 kn-aut-sei=真鍋 kn-aut-mei=享平 aut-affil-num=1 ORCID= en-aut-name=ECHIGOMitsuaki en-aut-sei=ECHIGO en-aut-mei=Mitsuaki kn-aut-name=越後満秋 kn-aut-sei=越後 kn-aut-mei=満秋 aut-affil-num=2 ORCID= en-aut-name=KISHIMOTOAkira en-aut-sei=KISHIMOTO en-aut-mei=Akira kn-aut-name=岸本昭 kn-aut-sei=岸本 kn-aut-mei=昭 aut-affil-num=3 ORCID= affil-num=1 en-affil=Osaka Gas Co. Ltd. kn-affil=大阪ガス（株） affil-num=2 en-affil=Osaka Gas Co. Ltd. kn-affil=大阪ガス（株） affil-num=3 en-affil=Institute of Academic and Research, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil=岡山大学学術研究院環境生命自然科学学域 en-keyword=dense yttria-stabilized zirconia kn-keyword=dense yttria-stabilized zirconia en-keyword=hot isostatic press kn-keyword=hot isostatic press en-keyword=low sintering temperature kn-keyword=low sintering temperature en-keyword=electrolyte kn-keyword=electrolyte en-keyword=metal-supported solid oxide fuel cell kn-keyword=metal-supported solid oxide fuel cell END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=35 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260124 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A case of tubulointerstitial nephritis with infiltration of neutrophils and interleukin-17-positive cells associated with Behçet’s disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Behçet’s disease (BD) is a non-infectious inflammatory condition characterized by neutrophilic infiltration. In addition to primary symptoms, including oral and genital ulcers, ocular involvement, and skin lesions, BD can also affect various organs. However, renal involvement, particularly in tubulointerstitial nephritis, has rarely been described. Herein, a rare case of acute tubulointerstitial nephritis in a patient clinically diagnosed with BD is reported. The renal lesion presented with other symptoms of BD and fever, and was considered to be BD-related due to the presence of neutrophilic infiltration and its responsiveness to BD-directed therapy. Alterations in T-helper (Th) 1, Th2, and Th17 cytokine profiles are associated with BD activity. Interleukin (IL)-17 plays a central role in neutrophil activation, and recent studies have demonstrated a strong correlation between IL-17A levels and BD activity. In the present case, elevated serum IL-17A levels and infiltration of IL-17A-positive cells into the renal tissue reflected an active phase of BD and a BD-associated renal lesion. en-copyright= kn-copyright= en-aut-name=UchidaNaruhiko en-aut-sei=Uchida en-aut-mei=Naruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanakaKeiko en-aut-sei=Tanaka en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KubotaNatsuki en-aut-sei=Kubota en-aut-mei=Natsuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatsuyamaTakayuki en-aut-sei=Katsuyama en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TanabeKatsuyuki en-aut-sei=Tanabe en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UchidaHaruhito A. en-aut-sei=Uchida en-aut-mei=Haruhito A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Tubulointerstitial nephritis kn-keyword=Tubulointerstitial nephritis en-keyword=Behçet’s disease kn-keyword=Behçet’s disease en-keyword=Neutrophils kn-keyword=Neutrophils en-keyword=Interleukin-17 kn-keyword=Interleukin-17 en-keyword=T-helper (Th) 1/Th2/Th17 cytokines kn-keyword=T-helper (Th) 1/Th2/Th17 cytokines END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=3 article-no= start-page=e202500639 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=PPy‐Coated Wire Actuators for the Micromechanostimulation of Cells: Fabrication and Characterization en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cellular mechanotransduction signals play a crucial role in physiological and pathological conditions, including skeletal disorders. Although various systems exist to mechanically stimulate cultured cells, most are constrained by incubator incompatibility, limited physiological relevance, nonuniform stimulation, or complexity. The objective of this article is to develop and validate a compact, incubator-compatible tool capable of delivering localized and physiologically relevant mechanical stimulation to small cell populations. Here, we introduce a polypyrrole-based wire-shaped microactuator designed to induce localized mechanical stress to adjacent cells. These wire-shaped microactuators are biocompatible, easy-to-use, and compact for use within standard in vitro cell culture systems. Using a noncontact optical method, we characterize the actuation of polypyrrole-coated wires in an aqueous NaDBS electrolyte, showing radial expansion of 1.5–8 µm depending on the deposited polypyrrole film thickness, comparable to cellular dimensions. Next, the actuation is confirmed to be robust and stable to use in cell culture media at physiological temperature. To evaluate biological relevance, osteoblastic KUSA-A1 cells are mechanically stimulated inside the incubator and transcriptomic changes are assessed. Mechanical stimulation resulted in upregulation of genes previously associated with mechanotransduction, including Fos and Fosb. Additionally, several uncharacterized long noncoding RNAs are differentially expressed, suggesting potential novel players in the mechanotransduction pathway. en-copyright= kn-copyright= en-aut-name=Ortega‐SantosAmaia B. en-aut-sei=Ortega‐Santos en-aut-mei=Amaia B. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HayanoSatoru en-aut-sei=Hayano en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HaraEmilio Satoshi en-aut-sei=Hara en-aut-mei=Emilio Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MartínezJose G. en-aut-sei=Martínez en-aut-mei=Jose G. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=JagerEdwin W. H. en-aut-sei=Jager en-aut-mei=Edwin W. H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Sensor and Actuator Systems, Department of Physics Chemistry and Biology (IFM), Linköping University kn-affil= affil-num=2 en-affil=Department of Orthodontics, Okayama University Hospital kn-affil= affil-num=3 en-affil=Advanced Research Center for Oral and Craniofacial Sciences Dental School, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Sensor and Actuator Systems, Department of Physics Chemistry and Biology (IFM), Linköping University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Sensor and Actuator Systems, Department of Physics Chemistry and Biology (IFM), Linköping University kn-affil= en-keyword=conducting polymers kn-keyword=conducting polymers en-keyword=mechanotransduction kn-keyword=mechanotransduction en-keyword=osteoblasts kn-keyword=osteoblasts en-keyword=polypyrrole kn-keyword=polypyrrole en-keyword=RNA sequencing kn-keyword=RNA sequencing en-keyword=soft-microactuators kn-keyword=soft-microactuators END start-ver=1.4 cd-journal=joma no-vol=2025 cd-vols= no-issue= article-no= start-page=9884345 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251120 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparing the Activity of Peripheral Blood Mononuclear Cells Frozen Under Electromagnetic Field Freezing and Standard Slow-Freezing en-subtitle= kn-subtitle= en-abstract= kn-abstract=Peripheral blood mononuclear cells (PBMCs) are cells obtained from the blood that are used not only in clinical tests but also in various research applications. The slow-freezing (SLF) method, currently the standard for PBMC cryopreservation, involves extended storage at −80°C before transfer to liquid nitrogen. Delays in this transfer, such as overnight or weekend holds, risk a gradual decline in cell viability. Additionally, variability in freezing duration can lead to inconsistent cell quality, emphasizing the need for an alternative freezing method that allows for more timely transfer to liquid nitrogen. This study is aimed at clarifying whether the method of using a freezer with an applied electromagnetic field (EMF) is superior to the currently used standard SLF method for PBMC cryopreservation. A comparison of the number of viable cells, cell viability, and cell activity showed that the EMF method was equivalent to the SLF method. However, the shortest time required for freezing was significantly shorter with the EMF method than the SLF method (0.25 vs. 3 h), allowing for earlier transfer of PBMC to liquid nitrogen. This demonstrates that the EMF method offers an advantage in operational efficiency, particularly for facilities that routinely process and store PBMCs, such as biobanks and other storage-focused departments. en-copyright= kn-copyright= en-aut-name=MatsubaraTakehiro en-aut-sei=Matsubara en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TakagiMina en-aut-sei=Takagi en-aut-mei=Mina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UwaboTakahiro en-aut-sei=Uwabo en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SohJunichi en-aut-sei=Soh en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MoritaMizuki en-aut-sei=Morita en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Okayama University Hospital Biobank kn-affil= affil-num=2 en-affil=Faculty of Health Sciences, Okayama University Medical School kn-affil= affil-num=3 en-affil=Department of Biorepository Research and Networking, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Thoracic Surgery, Osaka Metropolitan University Graduate School of Medicine kn-affil= affil-num=5 en-affil=Okayama University Hospital Biobank kn-affil= affil-num=6 en-affil=Okayama University Hospital Biobank kn-affil= END start-ver=1.4 cd-journal=joma no-vol=19 cd-vols= no-issue=2 article-no= start-page=dmm052605 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260201 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A genetic model of congenital intestinal atresia implicates Mypt1 in epithelial organisation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Congenital intestinal atresia (IA) is a birth defect characterised by the absence or closure of part of the intestine. Although genetic factors are implicated, mechanistic understanding has been hindered by the lack of suitable animal models. Here, we describe a medaka (Oryzias latipes) mutant, generated by N-ethyl-N-nitrosourea (ENU) mutagenesis, that develops IA during embryogenesis. Positional cloning identified a nonsense mutation in mypt1, encoding myosin phosphatase target subunit 1. Mutant embryos exhibited ectopic accumulation of F-actin and phosphorylated myosin regulatory light chain (Mrlc) in the intestinal epithelium, consistent with disrupted actomyosin regulation. These cytoskeletal abnormalities were accompanied by epithelial disorganisation, without notable alterations in cell proliferation, motility or apoptosis. Inhibition of myh11a, encoding smooth muscle (SM) myosin heavy chain, ameliorated the IA phenotype, whereas blebbistatin treatment completely rescued the defect, suggesting a non-contractile role prior to SM maturation. Together, these findings demonstrate that mypt1 loss disrupts intestinal morphogenesis through actomyosin dysregulation. Given the recent clinical identification of IA associated with MYPT1 variants, this medaka model offers a valuable platform to investigate the developmental and molecular basis of MYPT1-associated IA in humans. en-copyright= kn-copyright= en-aut-name=KobayashiDaisuke en-aut-sei=Kobayashi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=UrasakiAkihiro en-aut-sei=Urasaki en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KimuraTetsuaki en-aut-sei=Kimura en-aut-mei=Tetsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AnsaiSatoshi en-aut-sei=Ansai en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsuoKazuhiko en-aut-sei=Matsuo en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YokoiHayato en-aut-sei=Yokoi en-aut-mei=Hayato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakashimaShigeo en-aut-sei=Takashima en-aut-mei=Shigeo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KitagawaTadao en-aut-sei=Kitagawa en-aut-mei=Tadao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KageTakahiro en-aut-sei=Kage en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NaritaTakanori en-aut-sei=Narita en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=JindoTomoko en-aut-sei=Jindo en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KinoshitaMasato en-aut-sei=Kinoshita en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=NaruseKiyoshi en-aut-sei=Naruse en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NakajimaYoshiro en-aut-sei=Nakajima en-aut-mei=Yoshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=ShigetaMasaki en-aut-sei=Shigeta en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=SakakiShinichiro en-aut-sei=Sakaki en-aut-mei=Shinichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=InoueSatoshi en-aut-sei=Inoue en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SabaRie en-aut-sei=Saba en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=YamadaKei en-aut-sei=Yamada en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=YokoyamaTakahiko en-aut-sei=Yokoyama en-aut-mei=Takahiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=IshikawaYuji en-aut-sei=Ishikawa en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=ArakiKazuo en-aut-sei=Araki en-aut-mei=Kazuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=SagaYumiko en-aut-sei=Saga en-aut-mei=Yumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=TakedaHiroyuki en-aut-sei=Takeda en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=YashiroKenta en-aut-sei=Yashiro en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= affil-num=1 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=2 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=3 en-affil=Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology kn-affil= affil-num=4 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=5 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=6 en-affil=Graduate School of Agricultural Science, Tohoku University kn-affil= affil-num=7 en-affil=Institute for Glyco-core Research (iGCORE)/Life Science Research Centre, Gifu University kn-affil= affil-num=8 en-affil=Program in Environmental Management, Graduate School of Agriculture, Kindai University kn-affil= affil-num=9 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=10 en-affil=Laboratory of Molecular Biology, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University kn-affil= affil-num=11 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=12 en-affil=Department of Applied Biosciences, Graduate School of Agriculture, Kyoto University kn-affil= affil-num=13 en-affil=Laboratory of Bioresources, National Institute for Basic Biology kn-affil= affil-num=14 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=15 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=16 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=17 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=18 en-affil=Department of Radiology, Kyoto Prefectural University of Medicine kn-affil= affil-num=19 en-affil=Department of Radiology, Kyoto Prefectural University of Medicine kn-affil= affil-num=20 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= affil-num=21 en-affil=Research Centre for Radiation Protection, National Institute of Radiological Sciences kn-affil= affil-num=22 en-affil=Research Center for Aquatic Breeding, National Research Institute of Aquaculture, Fisheries Research Agency kn-affil= affil-num=23 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=24 en-affil=Department of Biological Sciences, Graduate School of Science, The University of Tokyo kn-affil= affil-num=25 en-affil=Department of Anatomy and Developmental Biology, Kyoto Prefectural University of Medicine kn-affil= en-keyword=Intestinal atresia kn-keyword=Intestinal atresia en-keyword=Mypt1 kn-keyword=Mypt1 en-keyword=Disease model kn-keyword=Disease model en-keyword=Actomyosin regulation kn-keyword=Actomyosin regulation en-keyword=Intestinal development kn-keyword=Intestinal development END start-ver=1.4 cd-journal=joma no-vol=68 cd-vols= no-issue=3 article-no= start-page=e70044 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260310 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Simple Method for RNA-Seq of Manually Isolated Chromatophores in Oryzias Fishes en-subtitle= kn-subtitle= en-abstract= kn-abstract=RNA sequencing (RNA-seq) has become an essential tool for analyzing gene expression and exploring cell type–specific transcriptomes. However, sample preparation and quality control remain challenging, as current approaches typically rely on dissecting tissues containing mixed cell populations or using flow cytometry to isolate fluorescently labeled cells. Here we present a simple and reliable method for RNA-seq of chromatophores (pigment cells) by manually isolating cells based on their natural pigmentation. We analyzed four chromatophore types—melanophores, xanthophores, iridophores, and leucophores—in medaka (Oryzias latipes). Remarkably, as few as 100 cells per type yielded reasonably high-quality transcriptomes sufficient to identify differentially expressed genes (DEGs). Furthermore, this method was successfully applied to a non-model medaka species, O. woworae, which shares the same four chromatophore types. Our approach enables efficient, low-cost, and cross-species transcriptome analysis of chromatophores without requiring transgenic markers or flow cytometry. en-copyright= kn-copyright= en-aut-name=GodaMakoto en-aut-sei=Goda en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyagiAsuka en-aut-sei=Miyagi en-aut-mei=Asuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SugiwakaKeisuke en-aut-sei=Sugiwaka en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeMasakatsu en-aut-sei=Watanabe en-aut-mei=Masakatsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=Bessho‐UeharaManabu en-aut-sei=Bessho‐Uehara en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HibiMasahiko en-aut-sei=Hibi en-aut-mei=Masahiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyodaAtsushi en-aut-sei=Toyoda en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanakaRieko en-aut-sei=Tanaka en-aut-mei=Rieko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MasengiKawilarang W. A. en-aut-sei=Masengi en-aut-mei=Kawilarang W. A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YamahiraKazunori en-aut-sei=Yamahira en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AnsaiSatoshi en-aut-sei=Ansai en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HashimotoHisashi en-aut-sei=Hashimoto en-aut-mei=Hisashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Institute of Photonics Medicine, Hamamatsu University School of Medicine kn-affil= affil-num=2 en-affil=Institute of Photonics Medicine, Hamamatsu University School of Medicine kn-affil= affil-num=3 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= affil-num=4 en-affil=Cellular and Structural Physiology Institute (CeSPI) and Graduate School of Pharmaceutical Sciences, Nagoya University kn-affil= affil-num=5 en-affil=Frontier Research Institute for Interdisciplinary Science, Tohoku University kn-affil= affil-num=6 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= affil-num=7 en-affil=Comparative Genomics Laboratory, National Institute of Genetics kn-affil= affil-num=8 en-affil=World Medaka Aquarium, Nagoya Higashiyama Zoo and Botanical Gardens kn-affil= affil-num=9 en-affil=Faculty of Fisheries and Marine Science, Sam Ratulangi University kn-affil= affil-num=10 en-affil=Tropical Biosphere Research Center, University of the Ryukyus kn-affil= affil-num=11 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=12 en-affil=Department of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=3 article-no= start-page=e72040 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effects of Overload on Imiquimod‐Induced Psoriasis Model Mice: A Basic Experimental Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Aim: Psoriasis is a skin disorder complicated by arthritis and enthesitis. The cytokines interleukin (IL)-17, IL-23, and tumor necrosis factor (TNF)-α are reportedly key effectors of psoriasis. Additionally, gamma delta (γδ) T cells exacerbate inflammation by producing inflammatory cytokines such as IL-17 and TNF-α. However, details regarding the mechanisms linking pathogenesis and mechanical stress remain unclear. This study aimed to investigate the effect of strenuous exercise on the pathology of psoriasis using mouse models of imiquimod (IMQ)-induced psoriasis.
Methods: Twenty mice were randomly assigned to four groups: IMQ − TRED− (control), IMQ − TRED+ (treadmill running mice), IMQ + TRED− group (IMQ treated mice), and IMQ + TRED+ group (IMQ treated and treadmill running mice). The tissue sections from back skin and thymus were immunostained with antibodies against IL-17, IL-23, and γδ T cells. Shoulder sections were stained using hematoxylin and eosin, and Toluidine Blue and Picrosirius Red. Additionally, the shoulder tissue sections were immunostained with antibodies against TNF-α and matrix metalloproteinase (MMP)-13. Serum cytokine level was measured to evaluate systemic inflammation.
Results: Strenuous exercise exacerbated pathological changes associated with psoriasis, including increased γδ T cell infiltration and upregulated IL-17 and IL-23 expression in the skin, as well as enhanced γδ T cell development and IL-17 expression in the thymus. Although strenuous exercise did not further worsen the modified PASI scores, histological and immunological markers of inflammation were significantly enhanced. Serum levels of TNF-α and IL-17 were significantly elevated in IMQ-induced psoriasis model mice. Moreover, pathological changes induced by strenuous exercise were observed in the enthesis, including angiogenesis and upregulated expression of TNF-α and MMP-13.
Conclusion: This study revealed that strenuous exercise exacerbates pathological changes in IMQ-induced psoriasis model mice. en-copyright= kn-copyright= en-aut-name=FurutaniTomoki en-aut-sei=Furutani en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SaitoTaichi en-aut-sei=Saito en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IkedaAsahi en-aut-sei=Ikeda en-aut-mei=Asahi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MashimaKenta en-aut-sei=Mashima en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YukihiroNatsumi en-aut-sei=Yukihiro en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KusakabeSatoki en-aut-sei=Kusakabe en-aut-mei=Satoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakamichiRyo en-aut-sei=Nakamichi en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YoshidaAki en-aut-sei=Yoshida en-aut-mei=Aki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NishidaKeiichiro en-aut-sei=Nishida en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Section of Medicine, Division of Medicine, Dentistry, and Pharmaceutical Sciences, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Okayama University Medical School Faculty of Medicine kn-affil= affil-num=4 en-affil=Okayama University Medical School Faculty of Medicine kn-affil= affil-num=5 en-affil=Okayama University Medical School Faculty of Medicine kn-affil= affil-num=6 en-affil=Okayama University Medical School Faculty of Medicine Okayama Japan kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Locomotive Pain Center, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=enthesis kn-keyword=enthesis en-keyword=psoriasis kn-keyword=psoriasis en-keyword=strenuous exercise kn-keyword=strenuous exercise END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=1 article-no= start-page=e70168 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Mechanosensitive Ion Channel PIEZO1 Suppresses BMP2-Induced Ossification of the Annulus Fibrosus Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective: Major cause of low-back pain is intervertebral disc degeneration (IVDD), with mechanical stress playing a crucial role in its progression. A mechanosensitive ion channel, PIEZO1, is involved in various musculoskeletal tissues, but its role in the annulus fibrosus (AF) remains unclear. This study aimed to elucidate the function of PIEZO1 in AF cells under mechanical stimulation.
Methods: Primary rat AF cells were subjected to cyclic tensile strain (CTS) at low (2%) and high (12%) strain levels to investigate strain-dependent effects on osteogenic gene expression. We evaluated the effects of Piezo1, Piezo2, and Trpv4 knockdown by RNA interference to identify the upstream mechanotransducer. Furthermore, PIEZO1 was activated using the agonist Yoda1, followed by RNA-sequencing analysis and evaluation of its effects on BMP2-induced osteogenesis in rat AF cells. We also examined the effects of Yoda1 in primary human AF cells.
Results: Low-strain CTS significantly suppressed osteogenic marker expression, which was not observed with high strain. Piezo1 knockdown reversed this suppression, whereas Piezo2 and Trpv4 had no effect. Piezo1 activation by Yoda1 produced similar anti-osteogenic effects in both rat and human AF cells. RNA sequencing revealed the enrichment of ossification and calcineurin signaling pathways in rat cells. Furthermore, Piezo1 activation inhibited BMP2-induced osteogenesis and nuclear translocation of p-Smad1/5/9.
Conclusions: Piezo1 maintains AF cell homeostasis under mechanical stress by suppressing osteogenic changes via calcineurin-mediated inhibition of BMP signaling, which may represent a novel therapeutic target for IVDD. en-copyright= kn-copyright= en-aut-name=ShitozawaHisakazu en-aut-sei=Shitozawa en-aut-mei=Hisakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakamichiRyo en-aut-sei=Nakamichi en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshidaAki en-aut-sei=Yoshida en-aut-mei=Aki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UedaMasataka en-aut-sei=Ueda en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SaitoTaichi en-aut-sei=Saito en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UotaniKoji en-aut-sei=Uotani en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OdaYoshiaki en-aut-sei=Oda en-aut-mei=Yoshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakatoriRyo en-aut-sei=Takatori en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YamashitaKazutaka en-aut-sei=Yamashita en-aut-mei=Kazutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OzakiToshifumi en-aut-sei=Ozaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Orthopaedic Surgery, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Orthopaedic Surgery, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=annulus fibrosus kn-keyword=annulus fibrosus en-keyword=calcification kn-keyword=calcification en-keyword=ossification kn-keyword=ossification en-keyword=PIEZO1 kn-keyword=PIEZO1 END start-ver=1.4 cd-journal=joma no-vol=67 cd-vols= no-issue= article-no= start-page=101798 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Alcohol consumption, smoking, and the implications of their cessations for field carcinogenesis in the esophagus: a 10-year prospective cohort study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Alcohol and tobacco are established carcinogens, which promote field carcinogenesis for esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the long-term effects of alcohol and tobacco cessations, and background mucosal status, on risk for metachronous ESCC (mESCC) after endoscopic resection (ER).
Methods This was a multicentre prospective cohort study of patients with intramucosal ESCC treated by ER. All participants received structured education on cessation, and underwent regular endoscopic surveillance. Patients were stratified by Lugol-voiding lesion (LVL) grade (A: none, B: 1–9, C: ≥10). The impacts of alcohol and smoking cessation on field carcinogenesis were assessed.
Findings Among 331 enrolled patients, the median follow-up was 120 months (range: 1.3–176.9). The cumulative incidences of mESCC were 10.4%, 27.2%, and 61.8% in grades A, B, and C, respectively. An increment of 1 unit (22 g ethanol) of alcohol consumption and higher LVL grade independently increased the risk for mESCC. Alcohol or smoking cessation reduced this risk (hazard ratio [HR] 0.52, 95% confidence interval [CI]: 0.31–0.88; HR 0.44, 95% CI: 0.25–0.78, respectively), and combined cessation had the greatest impact (HR 0.21, 95% CI: 0.07–0.65). Complete cessation, rather than partial reduction, was necessary to achieve meaningful risk reduction.
Interpretation Alcohol and tobacco exposure, and a large number of LVL, are major determinants of mESCC. Complete cessation markedly reduces risk, underscoring the importance of behavioural interventions for secondary prevention of field carcinogenesis after ER. en-copyright= kn-copyright= en-aut-name=KatadaChikatoshi en-aut-sei=Katada en-aut-mei=Chikatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YokoyamaTetsuji en-aut-sei=Yokoyama en-aut-mei=Tetsuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YanoTomonori en-aut-sei=Yano en-aut-mei=Tomonori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FurueYasuaki en-aut-sei=Furue en-aut-mei=Yasuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SuzukiHaruhisa en-aut-sei=Suzuki en-aut-mei=Haruhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IshidoKenji en-aut-sei=Ishido en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YamamotoKeiko en-aut-sei=Yamamoto en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakanishiHiroyoshi en-aut-sei=Nakanishi en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KoikeTomoyuki en-aut-sei=Koike en-aut-mei=Tomoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TamaokiMasashi en-aut-sei=Tamaoki en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KawataNoboru en-aut-sei=Kawata en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HiraoMotohiro en-aut-sei=Hirao en-aut-mei=Motohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KawaharaYoshiro en-aut-sei=Kawahara en-aut-mei=Yoshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OgataTakashi en-aut-sei=Ogata en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KatagiriAtsushi en-aut-sei=Katagiri en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=YamanouchiTakenori en-aut-sei=Yamanouchi en-aut-mei=Takenori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KiyokawaHirofumi en-aut-sei=Kiyokawa en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KawakuboHirofumi en-aut-sei=Kawakubo en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KonnoMaki en-aut-sei=Konno en-aut-mei=Maki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=YokoyamaAkira en-aut-sei=Yokoyama en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=OhashiShinya en-aut-sei=Ohashi en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=OmoriTai en-aut-sei=Omori en-aut-mei=Tai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=ShimodaTadakazu en-aut-sei=Shimoda en-aut-mei=Tadakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=OchiaiAtsushi en-aut-sei=Ochiai en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=IshikawaHideki en-aut-sei=Ishikawa en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=YokoyamaAkira en-aut-sei=Yokoyama en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=MutoManabu en-aut-sei=Muto en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= affil-num=1 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Health Promotion, National Institute of Public Health kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East kn-affil= affil-num=4 en-affil=Department of Endoscopy, Saitama Cancer Center kn-affil= affil-num=5 en-affil=Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine kn-affil= affil-num=6 en-affil=Department of Gastroenterology, Kitasato University School of Medicine kn-affil= affil-num=7 en-affil=Division of Endoscopy, Hokkaido University Hospital kn-affil= affil-num=8 en-affil=Department of Gastroenterology, Ishikawa Prefectural Central Hospital kn-affil= affil-num=9 en-affil=Division of Gastroenterology, Tohoku University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Division of Endoscopy, Shizuoka Cancer Center kn-affil= affil-num=12 en-affil=Department of Surgery, NHO Osaka National Hospital kn-affil= affil-num=13 en-affil=Department of Practical Gastrointestinal Endoscopy, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=14 en-affil=Department of Gastrointestinal Surgery, Kanagawa Cancer Center kn-affil= affil-num=15 en-affil=Division of Gastroenterology, Department of Medicine, Showa Medical University Hospital kn-affil= affil-num=16 en-affil=Department of Gastroenterology, Kumamoto Regional Medical Center kn-affil= affil-num=17 en-affil=Department of Gastroenterology, St. Marianna University School of Medicine kn-affil= affil-num=18 en-affil= kn-affil= affil-num=19 en-affil=Department of Gastroenterology, Tochigi Cancer Center kn-affil= affil-num=20 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=21 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= affil-num=22 en-affil=Department of Surgery, Kawasaki Municipal Kawasaki Hospital kn-affil= affil-num=23 en-affil=Department of Diagnostic Pathology, Shizuoka Cancer Center kn-affil= affil-num=24 en-affil=Exploratory Oncology Research and Clinicai Trial Center, National Cancer Center kn-affil= affil-num=25 en-affil=Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine kn-affil= affil-num=26 en-affil=Clinical Research Unit, National Hospital Organization Kurihama Medical and Addiction Center kn-affil= affil-num=27 en-affil=Department of Medical Oncology, Kyoto University Graduate School of Medicine kn-affil= en-keyword=Esophageal squamous cell carcinoma kn-keyword=Esophageal squamous cell carcinoma en-keyword=Field carcinogenesis kn-keyword=Field carcinogenesis en-keyword=Metachronous cancer kn-keyword=Metachronous cancer en-keyword=Alcohol kn-keyword=Alcohol en-keyword=Tobacco kn-keyword=Tobacco en-keyword=Lugol-voiding lesion kn-keyword=Lugol-voiding lesion END start-ver=1.4 cd-journal=joma no-vol=24 cd-vols= no-issue=1 article-no= start-page=146 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260115 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=MMP-3 cleavage of Lamin A induces pro-migratory nuclear deformity, nucleophagy, and their autophagic secretion with extracellular vesicles in metastatic cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that cleave a plethora of substrates, including components of the extracellular matrix and cell-surface-associated proteins, as well as intracellular targets. MMPs have also been found in extracellular vesicles (EVs), such as exosomes. MMP-3 promotes tumor growth, epithelial-to-mesenchymal transition, genome instability, migration, invasion, and metastasis of cancer cells, and nuclear MMP-3 controls gene transcription. Intranuclear proteolysis by MMPs may significantly alter cancer progression. However, the nuclear substrates of MMP-3 have not been well investigated. In this study, we performed proteomic analyses to identify the nuclear substrates and EV proteins regulated by MMP-3. While rabidly metastatic colon cancer (LuM1) three-dimensionally cultured tumoroids secreted EVs containing 30 protein types, including Lamin A (LMNA), MMP-3, fibronectin (FN1), HSPA8 (Hsc70), β-actin (ACTB), and vimentin (VIM), CRISPR/Cas9-based knockout of MMP-3 reduced the secretion of these proteins in EVs. Notably, EV-bound cleaved Lamin secretion was confirmed by immunoelectron microscopy. Also, MMP-3 formed proteolytic dimers via its hemopexin-like repeat domains in nuclei. Many nuclear MMP-3-binding proteins, including Lamin A/C, histones, topoisomerases, and hnRNPs, were screened by co-immunoprecipitation followed by proteomics. Proteolytic MMP-3 overexpression generated a C-terminal 30-kDa fragment of Lamin A, whose cleavage site was defined via structural analysis. MMP-3 digestion of Lamin A induced nuclear deformity (atypia) required for cell migration in confined space. The cleaved Lamin A and MMP-3 were transported with autophagosomes (LC3B+), nucleophagosomes, and amphisomes (CD63 + LC3B+) and co-secreted with EVs. Proteolytic MMP-3 also induced nuclear speckles of Lamin A, suggesting their roles in transcription and splicing. Clinical analysis revealed that high expressions of MMP3 and LMNA were significantly seen in head and neck squamous cell carcinoma (HNSC) than in the other 16 cancer types, and predicted poor prognosis of patients suffering from HNSC, pancreatic, rectum and lung adenocarcinomas at specific stages. Immunohistochemistry revealed that nuclear MMP-3 and cleaved Lamin were significantly higher expressed in stage IV metastatic HNSC cases than in stage I non-metastatic cases. Taken together, MMP3-cleavage of Lamin A induces nuclear deformity, nucleophagy, and their autophagic co-secretion with EVs in metastatic cancer. Also, high expression of MMP-3 and secretion of Lamin A can predict poor prognosis in multiple cancer types at specific stages. en-copyright= kn-copyright= en-aut-name=EguchiTakanori en-aut-sei=Eguchi en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TahaEman A. en-aut-sei=Taha en-aut-mei=Eman A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakanoKeisuke en-aut-sei=Nakano en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TiwariVikas en-aut-sei=Tiwari en-aut-mei=Vikas kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakebeKatsuki en-aut-sei=Takebe en-aut-mei=Katsuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=InoueTomohiro en-aut-sei=Inoue en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=XingLizi en-aut-sei=Xing en-aut-mei=Lizi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SogawaChiharu en-aut-sei=Sogawa en-aut-mei=Chiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OkamotoKuniaki en-aut-sei=Okamoto en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=CalderwoodStuart K. en-aut-sei=Calderwood en-aut-mei=Stuart K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Biochemistry, Faculty of Science, Ain Shams University kn-affil= affil-num=3 en-affil=Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Council of Scientific & Industrial Research-Indian Institute of Toxicological Research kn-affil= affil-num=5 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Food and Health Sciences, Faculty of Environmental Studies, Hiroshima Institute of Technology kn-affil= affil-num=9 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Division of Molecular and Cellular Biology, Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= en-keyword=Lamin A (LMNA) kn-keyword=Lamin A (LMNA) en-keyword=Matrix metalloprotease (MMP) kn-keyword=Matrix metalloprotease (MMP) en-keyword=Proteolysis kn-keyword=Proteolysis en-keyword=Extracellular vesicle (EV) kn-keyword=Extracellular vesicle (EV) en-keyword=Exosome kn-keyword=Exosome en-keyword=Autophagy kn-keyword=Autophagy en-keyword=Amphisome kn-keyword=Amphisome en-keyword=Proteome kn-keyword=Proteome en-keyword=Nuclear deformity kn-keyword=Nuclear deformity en-keyword=Migration kn-keyword=Migration en-keyword=Metastatic cancer kn-keyword=Metastatic cancer en-keyword=Head and neck squamous cell carcinoma kn-keyword=Head and neck squamous cell carcinoma en-keyword=Colorectal cancer kn-keyword=Colorectal cancer END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=2 article-no= start-page=199 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260128 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Targeting the Gut in Sepsis: Therapeutic Potential of Medical Gases en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, often resulting in multiorgan dysfunction. Among affected systems, the gastrointestinal tract plays a central role in sepsis progression by promoting systemic inflammation through impaired barrier function, immune imbalance, and microbiome alterations. Recent research has identified selected medical gases and gasotransmitters as promising therapeutic candidates for preserving gut integrity in sepsis. In particular, hydrogen, carbon monoxide, and hydrogen sulfide exhibit antioxidative, anti-inflammatory, and cytoprotective properties. These gases act through defined molecular pathways, including activation of Nrf2, inhibition of NF-κB, and preservation of tight junction integrity, thereby supporting intestinal barrier function. In addition, they influence immune cell phenotypes and autophagy, with indirect effects on the gut microbiome. Although most supporting evidence derives from preclinical models, translational findings and emerging safety data highlight the potential of gut-targeted gas-based strategies. This review summarizes current mechanistic and translational evidence for gut-protective medical gases in sepsis and discusses their integration into future organ-specific and mechanism-based therapeutic approaches. en-copyright= kn-copyright= en-aut-name=YumotoTetsuya en-aut-sei=Yumoto en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ObaraTakafumi en-aut-sei=Obara en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NaitoHiromichi en-aut-sei=Naito en-aut-mei=Hiromichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakaoAtsunori en-aut-sei=Nakao en-aut-mei=Atsunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Emergency, Critical Care, and Disaster Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=carbon monoxide kn-keyword=carbon monoxide en-keyword=gastrointestinal tract kn-keyword=gastrointestinal tract en-keyword=gut kn-keyword=gut en-keyword=hydrogen kn-keyword=hydrogen en-keyword=hydrogen sulfide kn-keyword=hydrogen sulfide en-keyword=sepsis kn-keyword=sepsis en-keyword=septic shock kn-keyword=septic shock END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=888 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251215 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=TRPV2 in muscle satellite cells is crucial for skeletal muscle remodelling en-subtitle= kn-subtitle= en-abstract= kn-abstract=Skeletal muscle remodelling relies on muscle stem cells (MuSCs) for regeneration after injury and hypertrophy in response to mechanical loading. However, the mechanisms that trigger MuSC activation and proliferation remain unclear. Transient receptor potential vanilloid 2 (TRPV2) ion channels respond to insulin-like growth factor-1 and mechanical stimuli to regulate the biological characteristics of various cells. Using a temporally inducible MuSC-specific conditional knockout (cKO) mouse, we show that TRPV2 regulates MuSC function and is essential for muscle remodelling. In cultured myofibre, MuSCs express TRPV2 and exhibit Ca2+ responses to the TRPV2 agonists 2-aminoethoxydiphenyl borate and probenecid, which are abolished upon TRPV2 deletion. TRPV2-deficient MuSCs exhibit reduced paired box 7 (Pax7) expression and impaired proliferation, suggesting TRPV2 is a factor that regulates the early stage of MuSC function. Myotube formation in MuSCs was enhanced by overexpression of TRPV2 and suppressed by TRPV2 deficiency, suggesting that TRPV2 is a factor that promotes myogenesis. Muscle-administered cardiotoxin promoted muscle regeneration and resulted in the appearance of numerous Pax7-positive MuSCs between myofibres. MuSC-specific TRPV2 cKO mice exhibit substantially impaired muscle regeneration after cardiotoxin-induced injury, drastically reducing Pax7-positive MuSCs between myofibres. In floxed mice, mechanical loading via synergist ablation induces hypertrophy and greatly increases the number of myonuclei per myofibre. In contrast, MuSC-specific TRPV2 cKO mice show no changes in myofibre thickness or nuclear number, either at baseline or after mechanical loading. Mechanical loading of floxed mice increased TRPV2+/Pax7+ double-positive MuSCs, but MuSC-specific TRPV2 cKO mice showed no change. Additionally, MuSCs exhibit Ca2+ responses to hypo-osmotic stimuli, which are suppressed by TRPV2 inhibitors and TRPV2 deletion, suggesting that MuSCs exhibit TRPV2-dependent mechanical responses. These results establish TRPV2 as a critical regulator of MuSC-mediated muscle remodelling, an important finding that may lead to therapeutic strategies for muscle repair and adaptation. en-copyright= kn-copyright= en-aut-name=ChenYanzhu en-aut-sei=Chen en-aut-mei=Yanzhu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatanosakaKimiaki en-aut-sei=Katanosaka en-aut-mei=Kimiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShibuyaMakoto en-aut-sei=Shibuya en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=DongYubing en-aut-sei=Dong en-aut-mei=Yubing kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZhangLidan en-aut-sei=Zhang en-aut-mei=Lidan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KanagawaMotoi en-aut-sei=Kanagawa en-aut-mei=Motoi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FukadaSo-ichiro en-aut-sei=Fukada en-aut-mei=So-ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NaruseKeiji en-aut-sei=Naruse en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KatanosakaYuki en-aut-sei=Katanosaka en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University kn-affil= affil-num=3 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka kn-affil= affil-num=6 en-affil=Department of Cell Biology and Molecular Medicine, Ehime University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, The University of Osaka kn-affil= affil-num=8 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=3303 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260113 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparative efficacy of immune checkpoint inhibitor combination therapies by metastatic site in metastatic renal cell carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Few studies have investigated the efficacy of immuno-oncology (IO) combinations at different metastatic sites in renal cell carcinoma (RCC). We evaluated the differential efficacy of IO–IO and IO–tyrosine kinase inhibitor (TKI) combinations by metastatic site in metastatic RCC (mRCC). This retrospective multicenter study by the JK-FOOT Study Group included 579 patients with intermediate- or poor-risk mRCC (per International Metastatic RCC Database Consortium criteria) treated with first-line IO combinations between September 2018 and December 2024. Metastatic sites were lymph nodes, lungs, bones, liver, brain, and others. The primary endpoints were progression-free survival (PFS) and overall survival (OS); the secondary endpoint was objective response rate. Efficacy was compared between IO–IO and IO–TKI for each site. For lymph node (n = 36), lung (n = 132), or brain (n = 16) metastases, OS or PFS was not significantly different between IO–IO and IO–TKI. In bone metastases (n = 80), OS tended to favor IO–TKI (P = 0.053). In liver metastases (n = 22), OS was significantly longer with IO–TKI (P = 0.011). IO–TKI may be a more appropriate first-line option than IO–IO for mRCC with bone or liver metastases, while efficacy is similar for other sites. en-copyright= kn-copyright= en-aut-name=ToyodaShingo en-aut-sei=Toyoda en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InokiLan en-aut-sei=Inoki en-aut-mei=Lan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HashimotoMamoru en-aut-sei=Hashimoto en-aut-mei=Mamoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FukuokayaWataru en-aut-sei=Fukuokaya en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MoriKeiichiro en-aut-sei=Mori en-aut-mei=Keiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NishimuraShingo en-aut-sei=Nishimura en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MaenosonoRyoichi en-aut-sei=Maenosono en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IwataTakehiro en-aut-sei=Iwata en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BekkuKensuke en-aut-sei=Bekku en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NukayaTakuhisa en-aut-sei=Nukaya en-aut-mei=Takuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YanagisawaTakafumi en-aut-sei=Yanagisawa en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TsujinoTakuya en-aut-sei=Tsujino en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KomuraKazumasa en-aut-sei=Komura en-aut-mei=Kazumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TakaharaKiyoshi en-aut-sei=Takahara en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=InamotoTeruo en-aut-sei=Inamoto en-aut-mei=Teruo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=AzumaHaruhito en-aut-sei=Azuma en-aut-mei=Haruhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=FujitaKazutoshi en-aut-sei=Fujita en-aut-mei=Kazutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=JK-FOOT study group en-aut-sei=JK-FOOT study group en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=2 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=3 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=4 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=5 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=6 en-affil=Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=8 en-affil=Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=11 en-affil=Department of Urology, The Jikei University School of Medicine kn-affil= affil-num=12 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=13 en-affil=Department of Urology, Kawasaki University School of Medicine kn-affil= affil-num=14 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=15 en-affil=Department of Urology, Hamamatsu University School of Medicine kn-affil= affil-num=16 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=17 en-affil=Department of Urology, Faculty of Medicine, Kindai University kn-affil= affil-num=18 en-affil= kn-affil= en-keyword=Metastatic renal cell carcinoma kn-keyword=Metastatic renal cell carcinoma en-keyword=Bone metastasis kn-keyword=Bone metastasis en-keyword=liver metastasis kn-keyword=liver metastasis en-keyword=Immuno-oncology kn-keyword=Immuno-oncology END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=RP99825 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250618 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Stimulatory and inhibitory G-protein signaling relays drive cAMP accumulation for timely metamorphosis in the chordate Ciona en-subtitle= kn-subtitle= en-abstract= kn-abstract=Larvae of the ascidian Ciona initiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowing Ciona to maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator of Ciona metamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation. en-copyright= kn-copyright= en-aut-name=HozumiAkiko en-aut-sei=Hozumi en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TotsukaNozomu M en-aut-sei=Totsuka en-aut-mei=Nozomu M kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OnoderaArata en-aut-sei=Onodera en-aut-mei=Arata kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangYanbin en-aut-sei=Wang en-aut-mei=Yanbin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HamadaMayuko en-aut-sei=Hamada en-aut-mei=Mayuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShiraishiAkira en-aut-sei=Shiraishi en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SatakeHonoo en-aut-sei=Satake en-aut-mei=Honoo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HorieTakeo en-aut-sei=Horie en-aut-mei=Takeo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HottaKohji en-aut-sei=Hotta en-aut-mei=Kohji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SasakuraYasunori en-aut-sei=Sasakura en-aut-mei=Yasunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=2 en-affil=Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University kn-affil= affil-num=3 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=4 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= affil-num=5 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=6 en-affil=Bioorganic Research Institute, Suntory Foundation for Life Sciences kn-affil= affil-num=7 en-affil=Bioorganic Research Institute, Suntory Foundation for Life Sciences kn-affil= affil-num=8 en-affil=Laboratory for Single-cell Neurobiology, Graduate School of Frontier Biosciences, Osaka University kn-affil= affil-num=9 en-affil=Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University kn-affil= affil-num=10 en-affil=Shimoda Marine Research Center, University of Tsukuba kn-affil= END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=1 article-no= start-page=16 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260221 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Compound heterozygosity of a novel missense variant and exonic deletion in hypomyelinating leukodystrophy 15 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Hypomyelinating leukodystrophy 15 (HLD15) results from biallelic pathogenic variants in EPRS1, but exonic deletions have not been reported. We describe a 40-year-old woman with mild intellectual disability, ataxia, dystonia, and MRI showing hypomyelination. Whole-exome sequencing identified a heterozygous missense variant in the prolyl-tRNA synthetase domain of EPRS1 (c.3430 C > G; p.Leu1144Val, NM_004446.3), without second variant. Whole-genome sequencing revealed a heterozygous 220-bp deletion spanning exon 15 (c.1743-30_1932del), and segregation analysis confirmed compound heterozygosity. RT-PCR from lymphoblastoid cells demonstrated exon-15 skipping leading to a frameshift (p.Asn582Serfs*10) and nonsense-mediated decay, leaving predominant expression of the paternally inherited missense allele. These findings support loss-of-function for the deletion and classify c.3430 C > G as likely pathogenic under ACMG/AMP criteria (PM1, PM2, PM3, PP3). This case represents the first exonic deletion reported in EPRS1. The relatively mild, adult-onset phenotype broadens both mutational and clinical spectra of HLD15 and highlights the importance of structural-variant anal en-copyright= kn-copyright= en-aut-name=MitsutakeAkihiko en-aut-sei=Mitsutake en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsukawaTakashi en-aut-sei=Matsukawa en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OrimoKenta en-aut-sei=Orimo en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UedaKunihiro en-aut-sei=Ueda en-aut-mei=Kunihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SekiTomonari en-aut-sei=Seki en-aut-mei=Tomonari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShiioYasushi en-aut-sei=Shiio en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MitsuiJun en-aut-sei=Mitsui en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IshiuraHiroyuki en-aut-sei=Ishiura en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MoriHarushi en-aut-sei=Mori en-aut-mei=Harushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TsujiShoji en-aut-sei=Tsuji en-aut-mei=Shoji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TodaTatsushi en-aut-sei=Toda en-aut-mei=Tatsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=2 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=3 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=4 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= affil-num=5 en-affil=Department of Neurology, Tokyo Teishin Hospital kn-affil= affil-num=6 en-affil=Department of Neurology, Tokyo Teishin Hospital kn-affil= affil-num=7 en-affil=Department of Precision Medicine Neurology, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=8 en-affil=Department of Neurology, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Radiology, School of Medicine, Jichi Medical University, kn-affil= affil-num=10 en-affil=Institute of Medical Genomics, International University of Health and Welfare kn-affil= affil-num=11 en-affil=Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan Department of Neurology kn-affil= en-keyword=Hypomyelinating leukodystrophy kn-keyword=Hypomyelinating leukodystrophy en-keyword=EPRS1 kn-keyword=EPRS1 en-keyword=Structural variant kn-keyword=Structural variant en-keyword=Exon deletion kn-keyword=Exon deletion en-keyword=Nonsense‑mediated decay kn-keyword=Nonsense‑mediated decay en-keyword=Whole‑genome sequencing kn-keyword=Whole‑genome sequencing END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=50 article-no= start-page=e06926 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251031 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Collagen Signaling via DDR1 Exacerbates Barriers to Macromolecular Drug Delivery in a 3D Model of Pancreatic Cancer Fibrosis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Fibrosis is a significant barrier to drug delivery in pancreatic ductal adenocarcinoma (PDAC) and contributes to its dismal prognosis. Pancreatic stellate cells (PSCs) drive fibrosis by excessively secreting extracellular matrix proteins such as collagen I. Collagen I is thought to physically obstruct the delivery of macromolecules, such as albumin, antibodies, and nanomedicines. Apart from its structural role, collagen signals through dedicated cell surface receptors, such as the discoidin domain receptors (DDR) 1/2. However, whether and how collagen signaling contributes to fibrotic barrier generation remains uncharacterized. Here, a 3D culture model of PDAC fibrosis constructed from patient PSCs is used to assess the contribution of DDR1/2-mediated collagen signaling. DDR1/2 inhibition diminishes collagen I expression in PSCs to enhance macromolecular delivery. Moreover, MEK inhibitors exacerbate the fibrotic barrier by up-regulating collagen I, an effect reversed by inhibiting DDR1/2. Through isoform-specific targeting, inhibiting DDR1, but not DDR2, is shown to be effective. Downstream of DDR, the involvement of the PI3K/AKT/mTOR pathway is demonstrated, particularly alternative mTOR complexes involving MEAK7 and GIT1. Altogether, the results show in vitro that DDR1-mediated collagen signaling exacerbates the fibrotic barrier and may be targeted to enhance macromolecular drug delivery in PDAC. en-copyright= kn-copyright= en-aut-name=OhiraMayu en-aut-sei=Ohira en-aut-mei=Mayu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KitamuraMoe en-aut-sei=Kitamura en-aut-mei=Moe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IwasakiHiroyo en-aut-sei=Iwasaki en-aut-mei=Hiroyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=Ohta‐OkanoHaruko en-aut-sei=Ohta‐Okano en-aut-mei=Haruko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TsujiiHiyori en-aut-sei=Tsujii en-aut-mei=Hiyori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakamuraReika en-aut-sei=Nakamura en-aut-mei=Reika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakazawaTakuya en-aut-sei=Nakazawa en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NishiguchiAkihiro en-aut-sei=Nishiguchi en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YamamotoMasaya en-aut-sei=Yamamoto en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OsadaKensuke en-aut-sei=Osada en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=CabralHoracio en-aut-sei=Cabral en-aut-mei=Horacio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MasamuneAtsushi en-aut-sei=Masamune en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KanoMitsunobu R. en-aut-sei=Kano en-aut-mei=Mitsunobu R. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=TanakaHiroyoshi Y. en-aut-sei=Tanaka en-aut-mei=Hiroyoshi Y. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Biomaterials Field, Research Center for Macromolecules and Biomaterials, National Institute for Materials Science kn-affil= affil-num=9 en-affil=Department of Materials Processing, Graduate School of Engineering, Tohoku University kn-affil= affil-num=10 en-affil=Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum Sciences and Technology (QST) kn-affil= affil-num=11 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=12 en-affil=Department of Bioengineering, Graduate School of Engineering, The University of Tokyo kn-affil= affil-num=13 en-affil=Division of Gastroenterology, Graduate School of Medicine, Tohoku University kn-affil= affil-num=14 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=15 en-affil=Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=collagen kn-keyword=collagen en-keyword=fibrosis kn-keyword=fibrosis en-keyword=nanomedicine kn-keyword=nanomedicine en-keyword=pancreatic cancer kn-keyword=pancreatic cancer en-keyword=pancreatic stellate cell kn-keyword=pancreatic stellate cell END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue=11 article-no= start-page=e2543107 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251112 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Trastuzumab Deruxtecan for ERBB2-Mutant Metastatic Non–Small Cell Lung Cancer With or Without Brain Metastases: A Secondary Analysis of Randomized Clinical Trials en-subtitle= kn-subtitle= en-abstract= kn-abstract=Importance Brain metastases reduce overall survival rates of patients with non–small cell lung cancer (NSCLC); patients with epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–mutant NSCLC are more likely to have baseline brain metastases. Trastuzumab deruxtecan (T-DXd) is an approved ERBB2-directed treatment for previously treated unresectable or metastatic ERBB2-mutant NSCLC.
Objective To assess the clinical effectiveness and safety of T-DXd 5.4 mg/kg and 6.4 mg/kg doses in patients with previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases.
Design, Setting, and Participants This post hoc secondary analysis pooled patients from the DESTINY-Lung01 (data cutoff date: December 3, 2021) and DESTINY-Lung02 (data cutoff date: December 23, 2022) clinical trials by T-DXd dose (5.4 mg/kg and 6.4 mg/kg). DESTINY-Lung01 was a multicenter, open-label, 2-cohort, nonrandomized phase 2 study, while DESTINY-Lung02 was a dose-blinded, multicenter, 2-cohort, randomized phase 2 study. Participants had a previously treated ERBB2-mutant metastatic NSCLC with or without untreated or previously treated stable brain metastases at baseline. All statistical analyses were performed from April 2023 to October 2024.
Intervention Patients received a T-DXd dose of either 5.4 mg/kg or 6.4 mg/kg intravenously every 3 weeks.
Main Outcome and Measure Systemic and intracranial effectiveness by blinded independent central review using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1, sites of progression, and safety.
Results This analysis included 102 patients in the T-DXd 5.4-mg/kg dose group (65 females [64%]; median [range] age, 57.5 [37.0-83.0] years and 59.5 [30.0-79.0] years in patients with and without brain metastases, respectively) and 141 patients in the T-DXd 6.4-mg/kg dose group (94 females [67%]; median [range] age, 62.5 [29.0-88.0] years and 59.0 [27.0-83.0] years in patients with and without brain metastases, respectively). In each group, 31% (32 of 102) and 38% (54 of 141) of patients, respectively, had baseline brain metastases and 53% (17 of 32) and 44% (24 of 54), respectively, received prior brain metastasis treatment. In patients with and without brain metastases, systemic confirmed objective response rates (ORRs) were 47% (15 of 32; 95% CI, 29%-65%) and 50% (35 of 70; 95% CI, 38%-62%), respectively, with the T-DXd 5.4-mg/kg dose, and 50% (27 of 54; 95% CI, 36%-64%) and 59% (51 of 87; 95% CI, 48%-69%) with the T-DXd 6.4-mg/kg dose. Median progression-free survival was 7.1 (95% CI, 5.5-9.7) months in the T-DXd 5.4-mg/kg dose group and 7.1 (95% CI, 4.5-9.6) months in the T-DXd 6.4-mg/kg dose group of patients with baseline brain metastases. Among patients with measurable baseline brain metastases, intracranial confirmed ORRs were 50% (7 of 14; 95% CI, 23%-77%) with the T-DXd 5.4-mg/kg dose and 30% (9 of 30; 95% CI, 15%-49%) with the T-DXd 6.4-mg/kg dose. At both doses, the safety profile of T-DXd was generally manageable, regardless of baseline brain metastases, favoring the T-DXd 5.4 mg/kg dose.
Conclusions and Relevance In this secondary analysis, T-DXd at the approved dose of 5.4 mg/kg showed antitumor activity in patients with previously treated ERBB2-mutant metastatic NSCLC with or without brain metastases. This finding supports T-DXd 5.4 mg/kg use in this population. en-copyright= kn-copyright= en-aut-name=JännePasi A. en-aut-sei=Jänne en-aut-mei=Pasi A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=PlanchardDavid en-aut-sei=Planchard en-aut-mei=David kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GotoKoichi en-aut-sei=Goto en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SmitEgbert F. en-aut-sei=Smit en-aut-mei=Egbert F. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=de LangenAdrianus Johannes en-aut-sei=de Langen en-aut-mei=Adrianus Johannes kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KuboToshio en-aut-sei=Kubo en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=PérolMaurice en-aut-sei=Pérol en-aut-mei=Maurice kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FelipEnriqueta en-aut-sei=Felip en-aut-mei=Enriqueta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HayashiHidetoshi en-aut-sei=Hayashi en-aut-mei=Hidetoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NakagawaKazuhiko en-aut-sei=Nakagawa en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NagasakaMisako en-aut-sei=Nagasaka en-aut-mei=Misako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=PereiraKaline en-aut-sei=Pereira en-aut-mei=Kaline kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TaguchiAyumi en-aut-sei=Taguchi en-aut-mei=Ayumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=AliAhmed en-aut-sei=Ali en-aut-mei=Ahmed kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KarnoubMaha en-aut-sei=Karnoub en-aut-mei=Maha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=YonemochiRie en-aut-sei=Yonemochi en-aut-mei=Rie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=LeungDavid en-aut-sei=Leung en-aut-mei=David kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=LiBob T. en-aut-sei=Li en-aut-mei=Bob T. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= affil-num=1 en-affil=Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute kn-affil= affil-num=2 en-affil=Department of Medical Oncology, Thoracic Cancer Group, Gustave Roussy, Medical Oncology kn-affil= affil-num=3 en-affil=Department of Thoracic Oncology, Nation Cancer Center Hospital East kn-affil= affil-num=4 en-affil=Department of Pulmonary Diseases, Leiden University Medical Center kn-affil= affil-num=5 en-affil=Department of Thoracic Oncology, Netherlands Cancer Institute kn-affil= affil-num=6 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=7 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=8 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Medical Oncology, Centre Léon Bérard kn-affil= affil-num=10 en-affil=Department of Medical Oncology, Vall d’Hebron University and Vall d’Hebron Institute of Oncology kn-affil= affil-num=11 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=12 en-affil=Department of Medical Oncology, Kindai University Faculty of Medicine kn-affil= affil-num=13 en-affil=Department of Thoracic Oncology, Aichi Cancer Center kn-affil= affil-num=14 en-affil=Division of Hematology-Oncology, Department of Medicine, University of California Irvine kn-affil= affil-num=15 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=16 en-affil=Daiichi Sankyo Co Ltd kn-affil= affil-num=17 en-affil=Daiichi Sankyo Europe GmbH kn-affil= affil-num=18 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=19 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=20 en-affil=Daiichi Sankyo Inc kn-affil= affil-num=21 en-affil=Thoracic Oncology and Early Drug Development Service, Global Research Program, Memorial Sloan Kettering Cancer Center kn-affil= END start-ver=1.4 cd-journal=joma no-vol=20 cd-vols= no-issue=12 article-no= start-page=1814 end-page=1828 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02—A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Trastuzumab deruxtecan (T-DXd) demonstrated strong and durable responses in patients with previously treated HER2 (ERBB2) mutant (HER2m) metastatic NSCLC (mNSCLC) in the DESTINY-Lung02 primary analysis (December 23, 2022, data cutoff). This final analysis evaluated T-DXd efficacy and safety after 8 additional months of follow-up, including clinically relevant subgroups and patient-reported outcomes.
Methods: DESTINY-Lung02 was a randomized, dose-blinded, multicenter, phase 2 trial. Patients with previously treated HER2m mNSCLC were randomized 2:1 to receive T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. Primary end point was confirmed objective response rate by blinded independent central review.
Results: As of August 25, 2023, 102 and 50 patients had received T-DXd 5.4 or 6.4 mg/kg, respectively. Median follow-up (Q1–Q3) was 15.8 (8.2–20.7) months and 16.5 (9.4–20.8) months, respectively. Confirmed objective response rate (95% confidence interval) was 50.0% (51/102; 39.9%–60.1%) and 56.0% (28/50; 41.3%–70.0%), respectively. Safety profile was acceptable and generally manageable. Accordingly, median treatment duration (Q1–Q3) was 7.7 (3.7–14.4) months and 8.3 (2.8–13.1) months; drug-related grade 3 or higher treatment-emergent adverse events occurred in 39.6% (40/101) and 60.0% (30/50), with nausea most common (67.3% [68/101], 82.0% [41/50]). Adjudicated drug-related interstitial lung disease occurred in 14.9% (15/101) and 32.0% (16/50), mostly grade 1 or 2 with one grade 5 in each arm. Health-related quality of life was preserved for the duration of T-DXd treatment while sample size was sufficient for analysis, with no adverse effects on health-related quality of life observed at either dose.
Conclusions: T-DXd demonstrated strong and durable responses at both doses, with no clinically significant changes in toxicity. The approved 5.4-mg/kg dose demonstrated a more favorable benefit-risk profile, including lower adjudicated drug-related interstitial lung disease incidence.
ClinicalTrials.gov identifier: NCT04644237 en-copyright= kn-copyright= en-aut-name=JännePasi A. en-aut-sei=Jänne en-aut-mei=Pasi A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuboToshio en-aut-sei=Kubo en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KimSang-We en-aut-sei=Kim en-aut-mei=Sang-We kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=PlanchardDavid en-aut-sei=Planchard en-aut-mei=David kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AhnMyung-Ju en-aut-sei=Ahn en-aut-mei=Myung-Ju kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SmitEgbert en-aut-sei=Smit en-aut-mei=Egbert kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=Johannes de LangenAdrianus en-aut-sei=Johannes de Langen en-aut-mei=Adrianus kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=PérolMaurice en-aut-sei=Pérol en-aut-mei=Maurice kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=Pons-TostivintElvire en-aut-sei=Pons-Tostivint en-aut-mei=Elvire kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NovelloSilvia en-aut-sei=Novello en-aut-mei=Silvia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=HayashiHidetoshi en-aut-sei=Hayashi en-aut-mei=Hidetoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KimDong-Wan en-aut-sei=Kim en-aut-mei=Dong-Wan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=PereiraKaline en-aut-sei=Pereira en-aut-mei=Kaline kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=ChengFu-Chih en-aut-sei=Cheng en-aut-mei=Fu-Chih kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=TaguchiAyumi en-aut-sei=Taguchi en-aut-mei=Ayumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=ChengYingkai en-aut-sei=Cheng en-aut-mei=Yingkai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=DuntonKyle en-aut-sei=Dunton en-aut-mei=Kyle kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=AliAhmed en-aut-sei=Ali en-aut-mei=Ahmed kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=GotoKoichi en-aut-sei=Goto en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute kn-affil= affil-num=2 en-affil=Department of Thoracic Oncology, National Cancer Central Hospital kn-affil= affil-num=3 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=4 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Oncology Department, Asan Medical Center, Seoul, and University of Ulsan College of Medicine, Ulsan kn-affil= affil-num=6 en-affil=Department of Medical Oncology, Thoracic Cancer Group, Gustave Roussy, and Faculty of Medicine, Paris-Saclay University kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Samsung Medical Center Sungkyunkwan, and University School of Medicine kn-affil= affil-num=8 en-affil=Department of Pulmonary Diseases, Leiden University Medical Center kn-affil= affil-num=9 en-affil=Department of Thoracic Oncology, Netherlands Cancer Institute kn-affil= affil-num=10 en-affil=Department of Medical Oncology, Léon Berard Centre kn-affil= affil-num=11 en-affil=Centre Hospitalier Universitaire Nantes, Nantes University kn-affil= affil-num=12 en-affil=Department of Oncology, University of Turin, Turin, and Azienda Ospedaliero-Universitaria San Luigi Gonzaga kn-affil= affil-num=13 en-affil=Department of Medical Oncology, Kindai University Hospital kn-affil= affil-num=14 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=15 en-affil=Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital kn-affil= affil-num=16 en-affil=Daiichi Sankyo kn-affil= affil-num=17 en-affil=Daiichi Sankyo kn-affil= affil-num=18 en-affil=Daiichi Sankyo kn-affil= affil-num=19 en-affil=Daiichi Sankyo kn-affil= affil-num=20 en-affil=Daiichi Sankyo UK kn-affil= affil-num=21 en-affil=Daiichi Sankyo Europe GmbH kn-affil= affil-num=22 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital East kn-affil= en-keyword=HER2-directed therapy kn-keyword=HER2-directed therapy en-keyword=HER2-mutant kn-keyword=HER2-mutant en-keyword=HER2-targeted kn-keyword=HER2-targeted en-keyword=Non–small cell lung cancer kn-keyword=Non–small cell lung cancer en-keyword=Trastuzumab deruxtecan kn-keyword=Trastuzumab deruxtecan END start-ver=1.4 cd-journal=joma no-vol=88 cd-vols= no-issue=5 article-no= start-page=1003 end-page=1015 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251222 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Claudin-18 expression in gastric type adenocarcinoma and HPV-associated adenocarcinoma of the uterine cervix en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aims: Claudin-18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using the clone 43-14A antibody, or about the gene expression of its isoforms in ECAs.
Methods and results: We examined CLDN18, HIK1083, p16 and Rb expression by immunohistochemistry and high-risk human papillomavirus (HR-HPV) mRNA by in situ hybridization (ISH) in 121 ECAs, including 35 HPV-independent adenocarcinomas (gastric type [GAS], n = 24; non-GAS, n = 11) and 86 HPV-associated ECAs. We also analysed mRNA expression of the CLDN18.1 (lung type) and CLDN18.2 (gastric type) isoforms by quantitative polymerase chain reaction (qPCR) in selected cases. CLDN18 positivity was detected in 8/24 (33%) GASs, 0/11 (0%) non-GASs and 2/86 (2%) HPV-associated ECAs, with positivity defined as staining in ≥75% of tumour cells, as in gastric cancer. When a 5% cut-off was used, CLDN18 positivity was detected in 22/24 (92%) GASs, 0/11 (0%) non-GASs and 6/86 (7%) HPV-associated ECAs; CLDN18 expression was thus significantly associated with GAS histology (P < 0.0001). Among the 6 cases of HPV-associated ECAs with CLDN18 expression (ranging from 5% to 80%), the histological patterns included a mix of usual and mucinous features in 4 cases, pure usual type in 1 and villoglandular variant in 1. Otherwise features such as p16 overexpression and the Rb partial loss pattern were consistent with those of HPV-associated ECAs. Six of 22 (27%) CLDN18-positive GASs were also positive for p16, but their other features—such as CLDN18 expression and the Rb preserved pattern—were the same as in p16 negative GASs. Expression of CLDN18.2 mRNA but not CLDN18.1 mRNA was confirmed in both GASs and HPV-associated ECAs.
Conclusions: CLDN18 (43-14A) emerged as a potential diagnostic and therapeutic marker for GAS. A minor subset of HPV-associated ECAs also can be immunoreactive for CLDN18 and express CLDN18.2 mRNA, suggesting divergent gastric phenotypic differentiation. The caution is that GAS and HPV-associated ECAs can share overlapping histological features and similar expression of CLDN18 and p16. en-copyright= kn-copyright= en-aut-name=YasutakeNobuko en-aut-sei=Yasutake en-aut-mei=Nobuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YokawaYuki en-aut-sei=Yokawa en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MishimaRiri en-aut-sei=Mishima en-aut-mei=Riri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KomamizuMisato en-aut-sei=Komamizu en-aut-mei=Misato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KugaRyosuke en-aut-sei=Kuga en-aut-mei=Ryosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=JiromaruRina en-aut-sei=Jiromaru en-aut-mei=Rina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawatokoShinichiro en-aut-sei=Kawatoko en-aut-mei=Shinichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SonodaKenzo en-aut-sei=Sonoda en-aut-mei=Kenzo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YahataHideaki en-aut-sei=Yahata en-aut-mei=Hideaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KatoKiyoko en-aut-sei=Kato en-aut-mei=Kiyoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OdaYoshinao en-aut-sei=Oda en-aut-mei=Yoshinao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YamamotoHidetaka en-aut-sei=Yamamoto en-aut-mei=Hidetaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=2 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= affil-num=3 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= affil-num=5 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences Kyushu University Fukuoka Japan kn-affil= affil-num=6 en-affil=Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=7 en-affil=Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=8 en-affil=Department of Medicine and Clinical Science, Kyushu University Beppu Hospital kn-affil= affil-num=9 en-affil=Department of Gynecology, Kyushu University Beppu Hospital kn-affil= affil-num=10 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=11 en-affil=Department of Gynecology and Obstetrics, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=12 en-affil=Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=13 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry & Pharmaceutical Science, Okayama University kn-affil= en-keyword=claudin-18 kn-keyword=claudin-18 en-keyword=endocervical adenocarcinoma kn-keyword=endocervical adenocarcinoma en-keyword=gastric type kn-keyword=gastric type en-keyword=human papillomavirus kn-keyword=human papillomavirus en-keyword=p16 kn-keyword=p16 END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=7 article-no= start-page=e87334 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250705 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Challenge of Diagnosing Scirrhous Gastric Cancer by Endoscopic Biopsy: A Case Report en-subtitle= kn-subtitle= en-abstract= kn-abstract=Scirrhous gastric cancer, also known as linitis plastica, is a rare and aggressive subtype of gastric carcinoma that poses significant diagnostic challenges due to its submucosal infiltration and often normal-appearing mucosa. We report a case involving a 30-year-old Japanese woman who presented with a six-month history of epigastric pain and postprandial vomiting. Initial endoscopic examination revealed erythema and mucosal swelling, with limited antral distensibility and resistance during duodenal intubation. Despite 12 mucosal biopsies, histopathological examination revealed no evidence of malignancy. Given the strong clinical and endoscopic suspicion of scirrhous gastric cancer, additional deep sections and immunohistochemical staining were performed. These revealed scattered signet-ring cell carcinoma and poorly differentiated adenocarcinoma, with positive immunostaining for p53 and Ki67. The patient underwent total gastrectomy, and the diagnosis of scirrhous gastric cancer was confirmed on the resected specimen. This case highlights the importance of a high index of clinical suspicion, close collaboration between endoscopists and pathologists, and the utility of ancillary diagnostic tools, such as immunohistochemistry, in identifying subepithelial gastric malignancies that may be missed on conventional biopsy. en-copyright= kn-copyright= en-aut-name=IkedaYuka en-aut-sei=Ikeda en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshinoTadashi en-aut-sei=Yoshino en-aut-mei=Tadashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IkedaNobumasa en-aut-sei=Ikeda en-aut-mei=Nobumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Internal Medicine, Clinic IkedaDepartment of Internal Medicine, Clinic Ikeda kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pathology, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Internal Medicine, Clinic Ikeda kn-affil= affil-num=6 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=endoscopic biopsy kn-keyword=endoscopic biopsy en-keyword=esophagogastroduodenoscopy kn-keyword=esophagogastroduodenoscopy en-keyword=immunohistochemistry kn-keyword=immunohistochemistry en-keyword=linitis plastica kn-keyword=linitis plastica en-keyword=scirrhous gastric cancer kn-keyword=scirrhous gastric cancer END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=2 article-no= start-page=284 end-page=293 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260201 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical Characteristics and Spatial Transcriptome Analysis of Non–Small Cell Lung Cancers Exhibiting Early Alectinib Resistance: A Retrospective OLCSG Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Some anaplastic lymphoma kinase (ALK) gene rearrangement–positive lung cancers show early resistance, within 3 months, to alectinib. This study investigated the clinical and molecular characteristics of these patients. We analyzed patients with unresectable stage III/IV disease without indications for radical radiotherapy and recurrent ALK-positive lung cancer who received alectinib as the primary ALK tyrosine kinase inhibitor between 2013 and 2021 at nine hospitals. In total, 103 patients were included. The median age was 65 years; 44 were male and 22 had brain metastases. The median progression-free survival and overall survival (OS) were 28.7 and 80.6 months. Nineteen patients treated for ≤3 months and 84 treated for >3 months were categorized into the early resistance and responder groups, respectively. The early resistance group had significantly shorter OS (8.4 months vs. not estimable, P < 0.001) and was significantly more likely to have brain metastases (42% vs. 17%, P = 0.027). They also showed elevated inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR). Univariate analysis identified brain metastases and high NLR as significant predictors of early resistance. Spatial transcriptome analysis and immunohistochemical staining revealed upregulation of annexin A1 (ANXA1), a calcium-dependent phospholipid-binding protein involved in inflammation and cancer progression, in the early resistance group. Interleukin 6 stimulation, prompted by elevated inflammatory markers, increased ANXA1 expression and reduced alectinib sensitivity. Knockdown of ANXA1 improved alectinib sensitivity in alectinib-resistant cells. In conclusion, brain metastases and high NLR are associated with early resistance. ANXA1 may play an important role in mediating early resistance. New treatment options for the early resistance group are required. en-copyright= kn-copyright= en-aut-name=KuribayashiTadahiro en-aut-sei=Kuribayashi en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MakimotoGo en-aut-sei=Makimoto en-aut-mei=Go kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TomidaShuta en-aut-sei=Tomida en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=InoueHirofumi en-aut-sei=Inoue en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YokoyamaToshihide en-aut-sei=Yokoyama en-aut-mei=Toshihide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KuyamaShoichi en-aut-sei=Kuyama en-aut-mei=Shoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KatoYuka en-aut-sei=Kato en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KudoKenichiro en-aut-sei=Kudo en-aut-mei=Kenichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HoritaNaokatsu en-aut-sei=Horita en-aut-mei=Naokatsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KayataniHiroe en-aut-sei=Kayatani en-aut-mei=Hiroe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=InoueMasaaki en-aut-sei=Inoue en-aut-mei=Masaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SugimotoKeisuke en-aut-sei=Sugimoto en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NinomiyaKiichiro en-aut-sei=Ninomiya en-aut-mei=Kiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Ohara Healthcare Foundation, Kurashiki Central Hospital kn-affil= affil-num=7 en-affil=Department of Respiratory Medicine, NHO Iwakuni Clinical Center kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, National Hospital Organization Okayama Medical Center kn-affil= affil-num=10 en-affil=Department of Respiratory Medicine, Kure Kyosai Hospital kn-affil= affil-num=11 en-affil=Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital kn-affil= affil-num=12 en-affil=Department of Chest Surgery, Shimonoseki City Hospital kn-affil= affil-num=13 en-affil=Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital kn-affil= affil-num=14 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=15 en-affil=Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=17 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= END start-ver=1.4 cd-journal=joma no-vol=95 cd-vols= no-issue=1 article-no= start-page=10 end-page=20 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparison of Fruit Development, Ripening, and Transcriptome Dynamics in Taiwanese and Japanese Cultivars of Japanese Apricot (Prunus mume Sieb. et Zucc.) en-subtitle= kn-subtitle= en-abstract= kn-abstract=In this study, we compared changes in traits associated with fruit development and ripening in Taiwanese and Japanese cultivars of Japanese apricot (Prunus mume Sieb. et Zucc.). We also analyzed transcriptome profiles to comprehensively examine different fruit development and ripening patterns between the two groups in terms of fruit characteristics and gene expression. Early fruit development in Taiwanese cultivars ‘ST’ and ‘Ellching’ and the Japanese cultivar ‘Hakuo’ was ahead of that in other three Japanese cultivars (P1). From late April to early May, around the stone-hardening stage, the developmental differences decreased to the same level. Thereafter, Japanese cultivars showed rapid growth, whereas Taiwanese cultivars showed slower growth, reversing the developmental differences between these lines (P2). Ethylene production was not detected until the full ripening stage and was detected for the first time at this stage in five cultivars, except for ‘Ellching’ (P3). In contrast, no ethylene production was observed during the entire duration of fruit development in ‘Ellching’. A multidimensional scaling plot showed that the overall transcriptome profile changed according to the three stages (P1–P3) of fruit development and ripening. At P1, gene ontologies (GOs) related to cell division, such as the cell cycle and regulation of cyclin-dependent protein serine/threonine kinase activity, were enriched for differentially expressed genes downregulated in Taiwanese cultivars as compared with their expression in Japanese cultivars. At P2, GOs related to fruit development were not enriched, but some genes related to phytohormones, such as auxin, abscisic acid, and cytokinin, which are associated with fruit development and ripening, were differentially expressed. At P3, the expression of genes such as ACS, ACO, and PG, which are involved in ethylene biosynthesis, increased in response to increased ethylene production, but not in ‘Ellching’, which showed no ethylene production. Expression analysis of 115 NAC (NAM-ATAF1/2-CUC2) family genes, which are related to fruit ripening and ripening date in other fruit species, in the ‘Ellching’ genome revealed changes in expression of NAC056 and NAC073 corresponding to fruit development and ripening in Taiwanese and Japanese cultivars. We discuss the differences in fruit development and ripening behaviors between Taiwanese and Japanese cultivars in terms of physiological and transcriptome changes. en-copyright= kn-copyright= en-aut-name=KashiwamotoTomoaki en-aut-sei=Kashiwamoto en-aut-mei=Tomoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KawaiTakashi en-aut-sei=Kawai en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OeTakaaki en-aut-sei=Oe en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NumaguchiKoji en-aut-sei=Numaguchi en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KitamuraYuto en-aut-sei=Kitamura en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KuboYasutaka en-aut-sei=Kubo en-aut-mei=Yasutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FukudaFumio en-aut-sei=Fukuda en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UshijimaKoichiro en-aut-sei=Ushijima en-aut-mei=Koichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Japanese Apricot Laboratory, Wakayama Fruit Tree Experiment Station kn-affil= affil-num=4 en-affil=Japanese Apricot Laboratory, Wakayama Fruit Tree Experiment Station kn-affil= affil-num=5 en-affil=Faculty of Agriculture, Setsunan University kn-affil= affil-num=6 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=8 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=cell division kn-keyword=cell division en-keyword=ethylene production kn-keyword=ethylene production en-keyword=NAC kn-keyword=NAC en-keyword=phytohormone kn-keyword=phytohormone en-keyword=stone hardening kn-keyword=stone hardening END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=5 article-no= start-page=2113 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260224 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Fgf10 Gene Dosage from a Single Allele Is Insufficient for Forming Multilayered Epithelial Cells in the Murine Lacrimal Gland en-subtitle= kn-subtitle= en-abstract= kn-abstract=Mutations in the fibroblast growth factor 10 (FGF10) gene in humans cause aplasia of the lacrimal and salivary glands (ALSG). In patients with ALSG, heterozygous loss-of-function mutations are found, and FGF10 haploinsufficiency results in the absence of these secretory organs. Lacrimal glands (LGs) are formed through epithelial thickening, budding, and branching morphogenesis. To compare the variable phenotypes of the Fgf10+/− Harderian glands (HGs) previously reported, we examined the development of LGs in wild-type (WT), Fgf10+/−, and Fgf10-null mice. Pax6 immunostaining was performed to visualize the LG primordia from embryonic day 15.5 (E15.5) onwards. In situ hybridization of the genes encoding the epithelial receptor of FGF10, FGFR2b, and its other ligands was performed to determine their potential involvement in LG development. LG primordia were not observed in Fgf10+/− mice bilaterally at E16.5 or later stages. At E15.5, budding from the developing conjunctival epithelium (CE) was observed in a small fraction of the Fgf10+/− LG primordia. In contrast, the Fgf10-null CE failed to promote budding. Among Fgf1, Fgf3, Fgf7, Fgf10, and Fgf22, Fgf10 was expressed in the mesenchyme surrounding developing LG epithelial cells, whereas Fgf1 was expressed in the LG epithelium of WT mice. Fgf7 was initially expressed in the mesenchyme surrounding the nascent LG epithelium, but its expression subsequently became diffused. Thus, we conclude that among the FGFR2b ligands, initial LG formation is dependent on the mesenchymal factors FGF10 and FGF7, and FGF1 is likely to function as an epithelial factor in the LG primordia. A single allele of Fgf10 was found to be insufficient to support the budding process during LG morphogenesis. en-copyright= kn-copyright= en-aut-name=IkedaShiori en-aut-sei=Ikeda en-aut-mei=Shiori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SatoKeita en-aut-sei=Sato en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TajikaYuki en-aut-sei=Tajika en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FujitaHirofumi en-aut-sei=Fujita en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=BandoTetsuya en-aut-sei=Bando en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NohnoTsutomu en-aut-sei=Nohno en-aut-mei=Tsutomu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyaishiSatoru en-aut-sei=Miyaishi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OhuchiHideyo en-aut-sei=Ohuchi en-aut-mei=Hideyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Radiological Technology, Gumma Prefectural College of Health Sciences kn-affil= affil-num=4 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Legal Medicine, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Cytology and Histology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=fibroblast growth factor kn-keyword=fibroblast growth factor en-keyword=Fgf10 kn-keyword=Fgf10 en-keyword=Fgf1 kn-keyword=Fgf1 en-keyword=Fgf3 kn-keyword=Fgf3 en-keyword=Fgf7 kn-keyword=Fgf7 en-keyword=Fgf22 kn-keyword=Fgf22 en-keyword=Fgfr2b kn-keyword=Fgfr2b en-keyword=mouse kn-keyword=mouse en-keyword=lacrimal gland kn-keyword=lacrimal gland en-keyword=development kn-keyword=development END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue= article-no= start-page=1716939 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251127 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Structural analysis of PSI-ACPI and PSII-ACPII supercomplexes from a cryptophyte alga Rhodomonas sp. NIES-2332 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Light energy is converted to chemical energy by two photosystems (PSI and PSII) in complex with their light-harvesting complex proteins (LHCI and LHCII) in photosynthesis. Rhodomonas is a member of cryptophyte alga whose LHCs contain unique chlorophyll a/c proteins (ACPs) and phycobiliproteins. We purified PSI-ACPI and PSII-ACPII supercomplexes from a cryptophyte Rhodomonas sp. NIES-2332 and analyzed their structures at high resolutions of 2.08 Å and 2.17 Å, respectively, using cryo-electron microscopy. These structures are largely similar to those reported previously from two other species of cryptophytes, but exhibited some differences in both the pigment locations and subunit structures. A part of the antenna subunits of both photosystems is shifted compared with the previously reported structures from other species of cryptophytes, suggesting some differences in the energy transfer rates from the antenna to the PSI and PSII cores. Newly identified lipids are found to occupy the interfaces between the antennae and cores, which may be important for assembly and stabilization of the supercomplexes. Water molecules surrounding three iron-sulfur clusters of the PSI core are found in our high-resolution structure, some of which are conserved from cyanobacteria to higher plants but some are different. In addition, our structure of PSII-ACPII lacks the subunits of oxygen-evolving complex as well as the Mn4CaO5 cluster, suggesting that the cells are in the S-growth phase, yet the PSI-ACPI structure showed the binding of PsaQ, suggesting that it is in an L-phase. These results suggest that the S-phase and L-phase can co-exist in the cryptophytic cells. The high-resolution structures of both PSI-ACPIs and PSII-ACPIIs solved in this study provide a more solid structural basis for elucidating the energy transfer and quenching mechanisms in this group of the organisms. en-copyright= kn-copyright= en-aut-name=ZhangWenyue en-aut-sei=Zhang en-aut-mei=Wenyue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoneharaNozomi en-aut-sei=Yonehara en-aut-mei=Nozomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IshiiMizuki en-aut-sei=Ishii en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=JiangHaowei en-aut-sei=Jiang en-aut-mei=Haowei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=La RoccaRomain en-aut-sei=La Rocca en-aut-mei=Romain kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TsaiPi-Cheng en-aut-sei=Tsai en-aut-mei=Pi-Cheng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=LiHongjie en-aut-sei=Li en-aut-mei=Hongjie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AkitaFusamichi en-aut-sei=Akita en-aut-mei=Fusamichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=ShenJian-Ren en-aut-sei=Shen en-aut-mei=Jian-Ren kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Advanced Research Field, Research Institute for Interdisciplinary Science, and Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=cryptophytes kn-keyword=cryptophytes en-keyword=Rhodomonas kn-keyword=Rhodomonas en-keyword=photosystem I kn-keyword=photosystem I en-keyword=photosystem II kn-keyword=photosystem II en-keyword=light-harvesting complex kn-keyword=light-harvesting complex en-keyword=photosynthesis kn-keyword=photosynthesis END start-ver=1.4 cd-journal=joma no-vol=19 cd-vols= no-issue=1 article-no= start-page=13 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251208 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pan-cancer profiling links C1orf50 to DNA repair and immune modulation in ovarian cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background C1orf50 encodes a small, evolutionarily conserved protein, the function of which remains unclear. Its significance across various human cancers, particularly its specific role in ovarian cancer within an immunogenomic context, is not yet fully understood. Utilizing The Cancer Genome Atlas and single-cell RNA sequencing (scRNA-seq) public datasets, we conducted a comprehensive profiling of C1orf50 across multiple cancer types, with a particular focus on ovarian cancer, to investigate its associations with copy-number status, genomic instability, tumor programs, and the immune microenvironment.
Results Across cancer types, copy-number gain or amplification of C1orf50 was most frequent in ovarian cancer and closely tracked with higher messenger RNA levels. Higher C1orf50 expression was associated with a greater tumor mutational burden and homologous recombination deficiency, as indicated by gene-set patterns that suggested heightened cell-cycle and cellular stress responses accompanied by reduced oxidative phosphorylation, enrichment of regulatory T cells, and depletion of resting memory CD4 T cells. In ovarian cancer, focal events at chromosome 1p34.2 were accompanied by stepwise increases in C1orf50 expression by clinical stage and were linked to higher tumor mutational burden, homologous recombination deficiency, and greater loss of heterozygosity, together with more frequent gene alterations in BRCA1 or BRCA2. Immune composition clustered into profiles consistent with an immunosuppressive context in tumors with higher C1orf50 expression. The scRNA-seq data further revealed that cancer cells enhanced immune-suppressive interactions with various immune cell populations and diminished antigen-presentation signals. Analyses of genomic instability in ovarian cancer suggested mutational processes compatible with base-substitution patterns associated with cytidine deaminase activity and with insertion-deletion patterns characteristic of homologous recombination failure, while transcript-level patterns pointed to a broad downshift of canonical DNA repair activity with apparent compensatory adjustments in related pathways rather than a uniform change in any single pathway.
Conclusions The overexpression of C1orf50 characterizes an aggressive immunogenomic phenotype in ovarian cancer, distinguished by genomic instability, impaired DNA repair mechanisms, and extensive immunosuppression. These findings indicate that C1orf50 warrants consideration as a potential biomarker and a prospective target for therapeutic investigation. Furthermore, they advocate for the progression to prospective validation and functional studies to ascertain its clinical significance. en-copyright= kn-copyright= en-aut-name=RogachevskayaAnna en-aut-sei=Rogachevskaya en-aut-mei=Anna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OtaniYusuke en-aut-sei=Otani en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhtsuAkira en-aut-sei=Ohtsu en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ChinVanessa D. en-aut-sei=Chin en-aut-mei=Vanessa D. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=PeñaTirso en-aut-sei=Peña en-aut-mei=Tirso kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AraiSeiji en-aut-sei=Arai en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujimuraAtsushi en-aut-sei=Fujimura en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaAtsushi en-aut-sei=Tanaka en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= affil-num=2 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Harvard Medical School kn-affil= affil-num=4 en-affil=UMass Chan Medical School, UMass Memorial Medical Center kn-affil= affil-num=5 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= affil-num=6 en-affil=Department of Urology, Gunma University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=8 en-affil=Department of Molecular Physiology, Faculty of Medicine, Graduate School of Medicine, Kagawa University kn-affil= affil-num=9 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School kn-affil= en-keyword=C1orf50 kn-keyword=C1orf50 en-keyword=Pan-cancer analysis kn-keyword=Pan-cancer analysis en-keyword=DNA repair kn-keyword=DNA repair en-keyword=Gene expression kn-keyword=Gene expression en-keyword=Tumor microenvironment kn-keyword=Tumor microenvironment en-keyword=Immune evasion kn-keyword=Immune evasion en-keyword=Single-cell RNA-seq kn-keyword=Single-cell RNA-seq END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=9 article-no= start-page=4363 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gaseous CO2 electrolysis: latest advances in electrode and electrolyzer technologies toward abating CO2 emissions en-subtitle= kn-subtitle= en-abstract= kn-abstract=The conversion of CO2 into multicarbon (C2+) products via electrochemical reduction is considered a key technology for the sustainable production of fuels and chemicals. The performance of high-rate gaseous CO2 electrolysis is governed by interrelated factors such as the electrocatalysts, electrodes, electrolytes, and cell architectures. Despite the intensive focus on catalyst research, systematic studies addressing the other components remain scarce, leaving critical gaps in our understanding toward achieving higher performance in CO2 electrolysis systems. The nanoscale design of catalyst surface electronic structures and the macroscale design of electrodes and electrolyzer architectures both influence the overall activity of the electrochemical system. In designing macroscale components, it is necessary to establish benchmarks based on a comprehensive evaluation of CO2 emissions for the entire electrolysis process, because these parameters are directly linked to output metrics such as current density and cell voltage under practical operating conditions. This review summarizes recent advances in electrodes and electrolyzers, and through life-cycle assessment (LCA), evaluates key performance indicators (KPIs) for achieving negative emissions and assesses the current technology readiness of CO2 electrolysis. en-copyright= kn-copyright= en-aut-name=KamiyaKazuhide en-aut-sei=Kamiya en-aut-mei=Kazuhide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakasoneSora en-aut-sei=Nakasone en-aut-mei=Sora kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuriharaRyo en-aut-sei=Kurihara en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=InoueAsato en-aut-sei=Inoue en-aut-mei=Asato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IrieHazuki en-aut-sei=Irie en-aut-mei=Hazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakahataShoko en-aut-sei=Nakahata en-aut-mei=Shoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishinaYuta en-aut-sei=Nishina en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TaniguchiSatoshi en-aut-sei=Taniguchi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NguyenThuy T. H. en-aut-sei=Nguyen en-aut-mei=Thuy T. H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KataokaSho en-aut-sei=Kataoka en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=2 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=3 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=4 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=5 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=6 en-affil=Research Center for Solar Energy Chemistry, Graduate School of Engineering Science, The University of Osaka kn-affil= affil-num=7 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= affil-num=8 en-affil=Research Institute for Chemical Process Technology, National Institute of Advanced Industrial Science and Technology (AIST), Central 5 kn-affil= affil-num=9 en-affil=Research Institute for Chemical Process Technology, National Institute of Advanced Industrial Science and Technology (AIST), Central 5 kn-affil= affil-num=10 en-affil=Research Institute for Chemical Process Technology, National Institute of Advanced Industrial Science and Technology (AIST), Central 5 kn-affil= END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue= article-no= start-page=103078 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202502 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): long-term results of a multicentre, single-arm, phase 2 trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi).
Methods We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165).
Findings With a median follow-up of 7.1 years (interquartile range 5.6–8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%–80%) and OS was 78% (95% CI 61%–89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1).
Interpretation Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients.
Funding This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center. en-copyright= kn-copyright= en-aut-name=ShimadaKazuyuki en-aut-sei=Shimada en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamaguchiMotoko en-aut-sei=Yamaguchi en-aut-mei=Motoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuwatsukaYachiyo en-aut-sei=Kuwatsuka en-aut-mei=Yachiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsueKosei en-aut-sei=Matsue en-aut-mei=Kosei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SatoKeijiro en-aut-sei=Sato en-aut-mei=Keijiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KusumotoShigeru en-aut-sei=Kusumoto en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NagaiHirokazu en-aut-sei=Nagai en-aut-mei=Hirokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TakizawaJun en-aut-sei=Takizawa en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FukuharaNoriko en-aut-sei=Fukuhara en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NagafujiKoji en-aut-sei=Nagafuji en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MiyazakiKana en-aut-sei=Miyazaki en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OhtsukaEiichi en-aut-sei=Ohtsuka en-aut-mei=Eiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OkamotoAkinao en-aut-sei=Okamoto en-aut-mei=Akinao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SugitaYasumasa en-aut-sei=Sugita en-aut-mei=Yasumasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=UchidaToshiki en-aut-sei=Uchida en-aut-mei=Toshiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KayukawaSatoshi en-aut-sei=Kayukawa en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=WakeAtsushi en-aut-sei=Wake en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KondoYukio en-aut-sei=Kondo en-aut-mei=Yukio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=MeguroAkiko en-aut-sei=Meguro en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=KinYoshihiro en-aut-sei=Kin en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=MinamiYosuke en-aut-sei=Minami en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=HashimotoDaigo en-aut-sei=Hashimoto en-aut-mei=Daigo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=NishiyamaTakahiro en-aut-sei=Nishiyama en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=ShimadaSatoko en-aut-sei=Shimada en-aut-mei=Satoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=MasakiYasufumi en-aut-sei=Masaki en-aut-mei=Yasufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=OkamotoMasataka en-aut-sei=Okamoto en-aut-mei=Masataka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=KiyoiHitoshi en-aut-sei=Kiyoi en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=SuzukiRitsuro en-aut-sei=Suzuki en-aut-mei=Ritsuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=NakamuraShigeo en-aut-sei=Nakamura en-aut-mei=Shigeo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=KinoshitaTomohiro en-aut-sei=Kinoshita en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Nagoya University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Hematological Malignancies, Mie University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Advanced Medicine, Nagoya University Hospital kn-affil= affil-num=4 en-affil=Division of Hematology/Oncology, Internal Medicine, Kameda Medical Center kn-affil= affil-num=5 en-affil=Department of Hematology, Nagano Red Cross Hospital kn-affil= affil-num=6 en-affil=Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences kn-affil= affil-num=7 en-affil=Department of Hematology, National Hospital Organization Nagoya Medical Center kn-affil= affil-num=8 en-affil=Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine kn-affil= affil-num=9 en-affil=Department of Hematology and Rheumatology, Tohoku University Hospital kn-affil= affil-num=10 en-affil=Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Mie University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Hematology, Oita Prefectural Hospital kn-affil= affil-num=13 en-affil=Department of Hematology, Fujita Health University School of Medicine kn-affil= affil-num=14 en-affil=Department of Hematology, Oami Municipal Hospital kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital kn-affil= affil-num=16 en-affil=Department of Clinical Oncology, Nagoya Memorial Hospital kn-affil= affil-num=17 en-affil=Department of Hematology, Toranomon Hospital Kajigaya kn-affil= affil-num=18 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=19 en-affil=Department of Internal Medicine, Toyama Prefectural Central Hospital kn-affil= affil-num=20 en-affil=Division of Hematology, Tochigi Cancer Center kn-affil= affil-num=21 en-affil=Department of Hematology, Daini Osaka Police Hospital kn-affil= affil-num=22 en-affil=Department of Hematology, National Cancer Center Hospital East kn-affil= affil-num=23 en-affil=Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine kn-affil= affil-num=24 en-affil=Division of Hematology, Ichinomiya Municipal Hospital kn-affil= affil-num=25 en-affil=Department of Pathology and Clinical Laboratories, Nagoya University Hospital kn-affil= affil-num=26 en-affil=Department of Hematology and Immunology, Kanazawa Medical University kn-affil= affil-num=27 en-affil=Department of Hematology, Fujita Health University School of Medicine kn-affil= affil-num=28 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=29 en-affil=Department of Hematology and Oncology, Nagoya University Graduate School of Medicine kn-affil= affil-num=30 en-affil=Department of HSCT Data Management and Biostatistics, Nagoya University School of Medicine kn-affil= affil-num=31 en-affil=Department of Pathology and Clinical Laboratories, Nagoya University Hospital kn-affil= affil-num=32 en-affil=Department of Hematology and Cell Therapy, Aichi Cancer Center kn-affil= en-keyword=Central nervous system-directed therapy kn-keyword=Central nervous system-directed therapy en-keyword=Intravascular large B-Cell lymphoma kn-keyword=Intravascular large B-Cell lymphoma en-keyword=R-CHOP kn-keyword=R-CHOP en-keyword=Secondary central nervous system involvement kn-keyword=Secondary central nervous system involvement END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=6 article-no= start-page=e86575 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250623 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Retreatment With EGFR-Tyrosine Kinase Inhibitor After Disease Progression Following Gefitinib Induction and Chemoradiotherapy in EGFR-Mutant Stage III Non-small Lung Cancer: An Efficacy and Safety Analysis of the LOGIK0902/OLCSG0905 Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and objective: We had previously conducted a phase II study (LOGIK0902/OLCSG0905 study) involving the eight-week administration of gefitinib, followed by cisplatin-based chemoradiotherapy, to treat locally advanced, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC). Despite favorable overall survival outcomes, more than half of the patients relapsed after the protocol therapy, highlighting the need to clarify the clinical significance of retreatment with EGFR-tyrosine kinase inhibitors (TKIs). We investigated the efficacy and safety of EGFR-TKI retreatment after disease progression.
Materials and methods: We included 14 patients who relapsed after the protocol treatment and received any type of EGFR-TKI as post-progression treatment in this sub-analysis. We evaluated the efficacy and safety of retreatment with EGFR-TKI in these patients.
Results: Among the 14 patients, 11 (78.6%) responded to the induction of gefitinib in the treatment protocol. After relapse, 9/14 patients (64.3%) received gefitinib, 3/14 (21.4%) received afatinib, and 2/14 (14.3%) received erlotinib monotherapy, respectively. The median duration of post-progression EGFR-TKI treatment was 17.9 (0.7-45.5) months. The overall response rate (ORR) and disease control rate were 64.3% [9/14 patients; 95% confidence interval (CI): 35.1%-87.2%] and 85.7% (12/14 patients; 95% CI: 57.2%-98.2%), respectively. The median progression-free survival (PFS) and median survival durations after the initiation of EGFR-TKI retreatment were 11.8 months (95% CI: 5.7-20.7 months) and 47.4 months (95% CI: 31.8 months to not estimable), respectively. Adverse events were comparable to those previously reported.
Conclusions: Patients with disease progression after protocol therapy demonstrated sensitivity to retreatment with an EGFR-TKI, with acceptable safety. en-copyright= kn-copyright= en-aut-name=SaekiSho en-aut-sei=Saeki en-aut-mei=Sho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HottaKatsuyuki en-aut-sei=Hotta en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SakataShinya en-aut-sei=Sakata en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OdaNaohiro en-aut-sei=Oda en-aut-mei=Naohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=InoueKoji en-aut-sei=Inoue en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TamuraTomoki en-aut-sei=Tamura en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ToyozawaRyo en-aut-sei=Toyozawa en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HaradaDaijiro en-aut-sei=Harada en-aut-mei=Daijiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaKentaro en-aut-sei=Tanaka en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=InoueKoji en-aut-sei=Inoue en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ShioyamaYoshiyuki en-aut-sei=Shioyama en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=GembaKenichi en-aut-sei=Gemba en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SasakiTomonari en-aut-sei=Sasaki en-aut-mei=Tomonari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=BesshoAkihiro en-aut-sei=Bessho en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KishimotoJunji en-aut-sei=Kishimoto en-aut-mei=Junji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=KatsuiKuniaki en-aut-sei=Katsui en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KiuraKatsuyuki en-aut-sei=Kiura en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=SugioKenji en-aut-sei=Sugio en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Respiratory Medicine, Kumamoto University Hospital kn-affil= affil-num=2 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Kumamoto University Hospital kn-affil= affil-num=4 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Kitakyushu Municipal Medical Center kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=10 en-affil=Department of Respiratory Medicine, Ehime Prefectural Central Hospital kn-affil= affil-num=11 en-affil=Radiation Oncology, Ion Beam Therapy Center, SAGA HIMAT Foundation kn-affil= affil-num=12 en-affil=Department of Respiratory Medicine, Chugoku Central Hospital kn-affil= affil-num=13 en-affil=Department of Radiation Oncology, Iizuka Hospital kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital kn-affil= affil-num=15 en-affil=Center for Clinical and Translational Research, Kyushu University Hospital kn-affil= affil-num=16 en-affil=Department of Radiology, Division of Radiation Oncology, Kawasaki Medical School kn-affil= affil-num=17 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=18 en-affil=Thoracic and Breast Surgery, Oita University kn-affil= en-keyword=chemoradiotherapy kn-keyword=chemoradiotherapy en-keyword=egfr kn-keyword=egfr en-keyword=locally advanced setting kn-keyword=locally advanced setting en-keyword=non-small cell lung cancer kn-keyword=non-small cell lung cancer en-keyword=progression kn-keyword=progression en-keyword=retreatment kn-keyword=retreatment en-keyword=safety kn-keyword=safety en-keyword=targeted therapy kn-keyword=targeted therapy END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=14 article-no= start-page=2155 end-page=2159 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250715 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Myeloid Sarcoma in the Small Intestine en-subtitle= kn-subtitle= en-abstract= kn-abstract=Myeloid sarcoma is a rare extramedullary tumor of immature myeloid cells that is often associated with acute myeloid leukemia (AML). We herein report an 81-year-old man who presented with intestinal obstruction due to myeloid sarcoma of the small intestine. Diagnostic challenges were overcome using double-balloon enteroscopy and a biopsy, which confirmed the diagnosis of myeloid sarcoma. The patient subsequently developed AML but responded well to chemotherapy. This case underscores the importance of considering myeloid sarcoma in the differential diagnosis of small-bowel tumors. Highlighting the significance of a histological analysis, even in patients presenting with small bowel obstruction, the early diagnosis and treatment are crucial for improving outcomes, particularly in patients without a history of hematologic malignancies. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KamioTomohiro en-aut-sei=Kamio en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HirataShoichiro en-aut-sei=Hirata en-aut-mei=Shoichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsuedaKatsunori en-aut-sei=Matsueda en-aut-mei=Katsunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KametakaDaisuke en-aut-sei=Kametaka en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KawanoSeiji en-aut-sei=Kawano en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=acute myeloid leukemia kn-keyword=acute myeloid leukemia en-keyword=double-balloon enteroscopy kn-keyword=double-balloon enteroscopy en-keyword=myeloid sarcoma kn-keyword=myeloid sarcoma en-keyword=small intestine kn-keyword=small intestine END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=2 article-no= start-page=363 end-page=368 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250304 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Microsatellite-high intrahepatic cholangiocarcinoma with favorable treatment outcome using pembrolizumab en-subtitle= kn-subtitle= en-abstract= kn-abstract=Intrahepatic cholangiocarcinoma has a poor prognosis. In unresectable cases, the survival period is short despite combination therapy with cytotoxic anticancer agents and immune checkpoint inhibitors. The usefulness of immune checkpoint inhibitors against malignant tumors with microsatellite instability-high (MSI-H) mutations was shown in the KEYNOTE158 study; however, data for intrahepatic cholangiocarcinoma are insufficient. In the present case, a 65-year-old man with intrahepatic cholangiocarcinoma and lymph node metastasis could not be treated with a combination of gemcitabine, CDDP, and S-1. A comprehensive cancer genomic profiling (CGP) test showed MLH1 pathogenic mutation and MSI-H. When pembrolizumab was administered, the tumor shrinkage effect was rapidly observed, which was sustained even after 30 months. No pathogenic mutations were observed in the germline test, and MSI-high was considered to be due to the MLH1 pathogenic mutation occurring sporadically in somatic cells. MSI-H intrahepatic cholangiocarcinoma is extremely rare. However, because pembrolizumab is expected to be effective, CGP testing should be actively performed. en-copyright= kn-copyright= en-aut-name=HoriguchiShigeru en-aut-sei=Horiguchi en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatoHironari en-aut-sei=Kato en-aut-mei=Hironari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MiyamotoKazuya en-aut-sei=Miyamoto en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MorimotoKosaku en-aut-sei=Morimoto en-aut-mei=Kosaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsumiAkihiro en-aut-sei=Matsumi en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TerasawaHiroyuki en-aut-sei=Terasawa en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FujiiYuki en-aut-sei=Fujii en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsumotoKazuyuki en-aut-sei=Matsumoto en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Gastroenterology and Hepatology, Okayama University Hospital kn-affil= en-keyword=Microsatellite instability (MSI)-high kn-keyword=Microsatellite instability (MSI)-high en-keyword=Tumor mutation burden (TMB)-high kn-keyword=Tumor mutation burden (TMB)-high en-keyword=Intrahepatic cholangiocarcinoma kn-keyword=Intrahepatic cholangiocarcinoma en-keyword=Comprehensive genome profiling kn-keyword=Comprehensive genome profiling END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=2 article-no= start-page=e79651 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250225 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gastric Metastasis of Renal Cell Carcinoma Initially Diagnosed by Esophagogastroduodenoscopy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Here, we report a rare case of renal cell carcinoma (RCC) initially detected as a gastric metastasis. A 58-year-old man with epigastric discomfort underwent esophagogastroduodenoscopy, which revealed a reddish semi-pedunculated lesion with a whitish coating. Biopsy and imaging confirmed clear cell RCC metastasis. Contrast-enhanced computed tomography (CT) revealed a primary renal tumor with pancreatic and lymph node metastases. Despite chemotherapy treatment, the patient died after 10 months. Gastric metastases from RCC, although rare, should be considered in highly vascular gastric lesions with white coatings. Clinicians must be vigilant for metastatic diseases with atypical gastric findings. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KamioTomohiro en-aut-sei=Kamio en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HirataShoichiro en-aut-sei=Hirata en-aut-mei=Shoichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=clear renal cell carcinoma kn-keyword=clear renal cell carcinoma en-keyword=esophagogastroduodenoscopy (egd) kn-keyword=esophagogastroduodenoscopy (egd) en-keyword=gastric metastasis kn-keyword=gastric metastasis en-keyword=metastatic tumor, renal cell carcinoma (rcc) kn-keyword=metastatic tumor, renal cell carcinoma (rcc) END start-ver=1.4 cd-journal=joma no-vol=21 cd-vols= no-issue=1 article-no= start-page=57 end-page=66 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Piezo1-mediated mechanotransduction in cementocytes via protein kinase B and p38 mitogen-activated protein kinase signaling en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/purpose: Cementocytes, terminally differentiated cells embedded within cellular cementum, are morphologically similar to osteocytes; however, their mechanosensory function remains poorly understood. This study aimed to investigate whether Piezo1, a mechanosensitive ion channel, contributes to the regulation of osteo/cementogenic gene expression in murine cementocyte-like IDG-CM6 cells.
Materials and methods: IDG-CM6 cells were subjected to cyclic stretch or treated with Piezo1-specific agonist Yoda1 or antagonist GsMTx4. Expression levels of osteo/cementogenic genes (Wnt1, Sost, Opg) and protein levels were analyzed. The involvement of intracellular signaling pathways was assessed using pharmacological inhibitors targeting mitogen-activated protein kinase and protein kinase B (PKB/AKT) pathways.
Results: Cyclic stretch upregulated Wnt1 and Opg, and downregulated Sost expression, without altering Piezo1 expression, suggesting an enhanced osteo/cementogenic potential. These effects were abolished by GsMTx4 and closely mimicked by Yoda1 stimulation. The Yoda1-induced gene expression changes were transient and diminished after withdrawal. Inhibitor experiments confirmed that Piezo1-mediated gene expression is modulated primarily through the AKT and p38 signaling pathways. Phosphorylation of AKT and p38 was rapidly induced by cyclic stretch.
Conclusion: Our findings demonstrate that Piezo1 functions as a mechanosensor in cementocytes, modulating the expression of osteo/cementogenic genes via the AKT and p38 pathways. This study provides new insight into the molecular mechanisms of cementocyte mechanotransduction and may inform strategies for periodontal regeneration and orthodontic treatment. en-copyright= kn-copyright= en-aut-name=XiongKaixin en-aut-sei=Xiong en-aut-mei=Kaixin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakisakaYukihiko en-aut-sei=Sakisaka en-aut-mei=Yukihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TenkumoTaichi en-aut-sei=Tenkumo en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NemotoEiji en-aut-sei=Nemoto en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MaruyamaKentaro en-aut-sei=Maruyama en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MuhammadFaisal en-aut-sei=Muhammad en-aut-mei=Faisal kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SuzukiShigeki en-aut-sei=Suzuki en-aut-mei=Shigeki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TadaHiroyuki en-aut-sei=Tada en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YamadaSatoru en-aut-sei=Yamada en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Stomatology, Chengdu Integrated TCM and Western Medicine Hospital (Chengdu First People’s Hospital) kn-affil= affil-num=2 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=3 en-affil=Division of Advanced Prosthetic Dentistry, Tohoku University Graduate School of Dentistry kn-affil= affil-num=4 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=5 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=6 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=7 en-affil=Department of Operative Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Division of Oral Microbiology and Immunology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=9 en-affil=Division of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= en-keyword=Cementocytes kn-keyword=Cementocytes en-keyword=Mechanotransduction kn-keyword=Mechanotransduction en-keyword=Piezo1 kn-keyword=Piezo1 en-keyword=Signal transduction kn-keyword=Signal transduction END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=5 article-no= start-page=372 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260224 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Periodontal disease damages the tissues that support teeth and can ultimately lead to tooth loss, yet effective treatments to regenerate these tissues are still limited. Recent studies have shown that substances produced during normal cellular metabolism can influence how genes are regulated, but their role in periodontal regeneration has not been fully clarified. In this study, we investigated whether alpha-ketoglutarate, a naturally occurring metabolite involved in energy production, could promote periodontal tissue regeneration. We found that alpha-ketoglutarate enhanced bone-related and extracellular matrix-related gene expression in human periodontal ligament cells by reducing a repressive gene-regulatory signal that normally suppresses these genes. Importantly, alpha-ketoglutarate did not broadly alter chromatin accessibility, indicating that its effects were mediated through selective gene regulation. Furthermore, oral administration of alpha-ketoglutarate promoted alveolar bone regeneration and collagen-rich tissue formation in a mouse model of periodontal disease. Because alpha-ketoglutarate is a naturally occurring molecule in the body, these findings suggest that metabolite-based regulation of gene activity may represent a promising and safe approach for periodontal tissue regeneration. en-copyright= kn-copyright= en-aut-name=HasegawaRyu en-aut-sei=Hasegawa en-aut-mei=Ryu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SuzukiShigeki en-aut-sei=Suzuki en-aut-mei=Shigeki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FahrezaRahmad Rifqi en-aut-sei=Fahreza en-aut-mei=Rahmad Rifqi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TsaiShin-Ho en-aut-sei=Tsai en-aut-mei=Shin-Ho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=DaidoujiYoshino en-aut-sei=Daidouji en-aut-mei=Yoshino kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OmoriMasato en-aut-sei=Omori en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KajikawaTetsuhiro en-aut-sei=Kajikawa en-aut-mei=Tetsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamadaSatoru en-aut-sei=Yamada en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=2 en-affil=Department of Operative Dentistry, Okayama University Graduate School, Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=4 en-affil=Department of Operative Dentistry, Okayama University Graduate School, Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=6 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=7 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=8 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= en-keyword=alpha-ketoglutarate kn-keyword=alpha-ketoglutarate en-keyword=periodontal ligament kn-keyword=periodontal ligament en-keyword=extracellular matrix kn-keyword=extracellular matrix en-keyword=epigenetic regulation kn-keyword=epigenetic regulation en-keyword=H3K27me3 kn-keyword=H3K27me3 END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=4 article-no= start-page=715 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260223 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Antigen Remodeling in Colorectal Cancer: How Radiotherapy and Chemotherapy Enhance Immunotherapy Responsiveness en-subtitle= kn-subtitle= en-abstract= kn-abstract=Colorectal cancer (CRC) is traditionally considered a “cold tumor” characterized by low immunogenicity and limited responsiveness to immune checkpoint inhibitors (ICIs). However, recent findings reveal that cytotoxic modalities can reprogram this immunologically inert landscape. This review integrates these evolving concepts to guide the optimization of future treatments. Radiotherapy induces extensive DNA double-strand breaks, which may generate de novo mutations through error-prone repair while simultaneously exposing cryptic antigens via increased transcriptional instability, alternative splicing, and enhanced proteasomal processing. Chemoradiation also amplifies epigenetic and epitranscriptomic sources of neoepitope diversity, including RNA editing and stress-induced splicing alterations, expanding the immunopeptidome beyond canonical mutation-driven neoantigens. These changes collectively enhance antigen presentation and facilitate T-cell priming. Chemotherapy further reduces immunosuppressive cell populations and promotes dendritic cell activation, creating a permissive milieu for subsequent immune engagement. Clinically, the VOLTAGE studies demonstrated that long-course chemoradiotherapy can sensitize even mismatch repair–proficient rectal cancers to PD-1 blockade, yielding clinically meaningful pathological responses. In contrast, mismatch repair–deficient rectal tumors may respond completely to ICIs alone. Short-course radiotherapy combined with chemotherapy and ICIs has also shown encouraging activity in the setting of total neoadjuvant therapy. Collectively, these findings support a paradigm in which radiotherapy, chemotherapy, and epigenetic/epitranscriptomic alterations—including RNA editing—act as potent modulators of tumor antigenicity. By expanding the neoantigen repertoire and reshaping the tumor microenvironment, these strategies can transform CRC from a cold tumor into one that is increasingly responsive to immunotherapy. en-copyright= kn-copyright= en-aut-name=MatsumiYuki en-aut-sei=Matsumi en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakahashiToshiaki en-aut-sei=Takahashi en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MoriwakeKazuya en-aut-sei=Moriwake en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KayanoMasashi en-aut-sei=Kayano en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=colorectal cancer kn-keyword=colorectal cancer en-keyword=immunotherapy kn-keyword=immunotherapy en-keyword=radiotherapy kn-keyword=radiotherapy en-keyword=chemotherapy kn-keyword=chemotherapy en-keyword=neoantigens kn-keyword=neoantigens END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260221 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Turning pancreatic cancer from cold to hot: the promise of a p53-expressing oncolytic adenovirus (OBP-702) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pancreatic cancer remains one of the most lethal malignancies, with limited therapeutic options and poor responsiveness to immune checkpoint inhibitors (ICIs). This resistance is largely attributed to its profoundly immunosuppressive and desmoplastic tumor microenvironment (TME), characterized by low tumor mutational burden, dense stroma, and abundant immunosuppressive cell populations. Therefore, strategies capable of enhancing tumor immunogenicity and overcoming immune evasion are urgently needed. Oncolytic virotherapy is a promising approach, offering not only tumor-selective cytotoxicity, but also potent immunomodulatory effects. Of these agents, Telomelysin (OBP-301, Suratadenoturev), a telomerase-specific oncolytic adenovirus, demonstrated clinical safety but limited efficacy in refractory tumors. To address this challenge, we developed OBP-702, a next-generation, p53-armed, oncolytic adenovirus designed to augment antitumor activity. Preclinical studies have shown that OBP-702 exerts robust cytotoxicity through multiple mechanisms, including p53-mediated apoptosis and autophagy, E1A–E2F1-mediated p21 suppression, and inhibition of oncogenic KRAS pathways. Importantly, OBP-702 induces strong immunogenic cell death, activates dendritic cells, and promotes tumor-specific T-cell responses, effectively converting immunologically “cold” pancreatic tumors into “hot” tumors. OBP-702 also remodels the immunosuppressive TME by reducing granulocyte–macrophage colony-stimulating factor (GM-CSF) secretion, suppressing myeloid-derived suppressor cells (MDSCs), and targeting stromal components, such as cancer-associated fibroblasts (CAFs). These effects contribute to enhanced responses to ICIs and standard chemotherapies. Given its multifaceted antitumor functions and ability to overcome key barriers in pancreatic cancer, OBP-702 represents a highly promising therapeutic candidate. A first-in-human clinical trial evaluating endoscopic ultrasonography-guided intratumoral injection of OBP-702 is currently in preparation, expected to advance clinical translation of this novel virotherapeutic strategy. en-copyright= kn-copyright= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HashimotoMasashi en-aut-sei=Hashimoto en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KanayaNobuhiko en-aut-sei=Kanaya en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KakiuchiYoshihiko en-aut-sei=Kakiuchi en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Oncolys BioPharma Inc kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Oncolytic adenovirus kn-keyword=Oncolytic adenovirus en-keyword=p53 kn-keyword=p53 en-keyword=OBP-702 kn-keyword=OBP-702 en-keyword=Immunogenic cell death kn-keyword=Immunogenic cell death en-keyword=Tumor microenvironment kn-keyword=Tumor microenvironment en-keyword=Pancreatic cancer kn-keyword=Pancreatic cancer END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260219 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Induction of IL-9-producing CD8+ T cells by ascochlorin derivatives en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Purpose: Ascochlorin (ASC) is an antiviral antibiotic from the fermented broth of Ascochyta viciae which exerts an inhibitory effect to cancers. Its impact on immune cells has not been examined. In this study, we obtained ASC derivatives with less cytotoxicity and determined whether they affected T cells, indicating possible immune-mediated antitumour effects.
Experimental Approach: Newly synthesised ASC derivatives were screened for inhibitory effects on T-cell antigen receptor (TCR)-stimulated proliferative responses using murine CD4+ and CD8+ T cells. Two compounds were identified that exhibited >10-fold less toxicity compared with ASC. N184, the less toxic of the two, was analysed for its in vivo antitumour effects, and in vitro effects on CD8+ T-cell proliferation, survival, cytokine production and exhaustion, using microscopy, qPCR and flow cytometry.
Key Results: N184 induced limited IL-9 production in CD8+ T cells following TCR stimulation, thereby improving cell survival. It also enhanced cytokine production in the late phase of proliferation and suppressed the induction of exhaustion. N184 suppressed tumour growth in mice in a CD8+ T cell-dependent manner. The effect was partially prevented by an IL-9-neutralising antibody.
Conclusion and Implications: N184 induces differentiation of IL-9-producing CD8+ T cells in vitro and elicits antitumour immunity in an IL-9-dependent manner. en-copyright= kn-copyright= en-aut-name=ImanoNatsumi en-aut-sei=Imano en-aut-mei=Natsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishidaMikako en-aut-sei=Nishida en-aut-mei=Mikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TokumasuMiho en-aut-sei=Tokumasu en-aut-mei=Miho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZhaoWeiyang en-aut-sei=Zhao en-aut-mei=Weiyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamashitaNahoko en-aut-sei=Yamashita en-aut-mei=Nahoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UdonoHeiichiro en-aut-sei=Udono en-aut-mei=Heiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Immunology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Immunology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Immunology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=ascochlorin derivative kn-keyword=ascochlorin derivative en-keyword=CD8 positive T lymphocytes kn-keyword=CD8 positive T lymphocytes en-keyword=cell survival kn-keyword=cell survival en-keyword=IFN-γ kn-keyword=IFN-γ en-keyword=interleukin-9 kn-keyword=interleukin-9 en-keyword=Tc9 kn-keyword=Tc9 en-keyword=tumour immunity kn-keyword=tumour immunity END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue= article-no= start-page=1673581 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260107 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Binding of IgA1 and surface-expressed collagen-binding protein of Streptococcus mutans contributes to IgA nephropathy pathogenesis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: The present study was conducted to examine the interaction between collagen-binding protein (Cnm) of Streptococcus mutans and immunoglobulin (IgA) to clarify the possible involvement in IgA nephropathy (IgAN) development.
Methods: The binding of Cnm to human immunoglobulins was examined using an enzyme-linked immunosorbent assay. A nephritis-induced rat model was employed to confirm the localization of Cnm.
Results: IgA1 showed significantly greater binding ability to Cnm than to other bacterial surface proteins, and Cnm showed significantly greater binding ability to IgA1 than to other immunoglobulins. In rats administered Cnm, IgA deposition was observed in the glomerular mesangial region. Furthermore, biotin-labeled Cnm was observed in the same region as IgA deposition in the Cnm group.
Conclusions: Taken together, it is considered that following invasion into the bloodstream, Cnm binds to and forms a complex with IgA1, leading to deposition of IgA1 in renal glomeruli. en-copyright= kn-copyright= en-aut-name=MatsuokaDaiki en-aut-sei=Matsuoka en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SueharaKana en-aut-sei=Suehara en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakaShuhei en-aut-sei=Naka en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MisakiTaro en-aut-sei=Misaki en-aut-mei=Taro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NagasawaYasuyuki en-aut-sei=Nagasawa en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ItoSeigo en-aut-sei=Ito en-aut-mei=Seigo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SuehiroYuto en-aut-sei=Suehiro en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NomuraRyota en-aut-sei=Nomura en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NakanoKazuhiko en-aut-sei=Nakano en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=Matsumoto-NakanoMichiyo en-aut-sei=Matsumoto-Nakano en-aut-mei=Michiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Division of Nephrology, Seirei Hamamatsu General Hospital kn-affil= affil-num=5 en-affil=Department of General Internal Medicine, Hyogo Medical University kn-affil= affil-num=6 en-affil=Department of Internal Medicine, Japan Self-Defense Force Iruma Hospital kn-affil= affil-num=7 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=8 en-affil=Department of Pediatric Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=9 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=10 en-affil=Department of Pediatric Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=bacterial surface proteins kn-keyword=bacterial surface proteins en-keyword=collagen-binding protein kn-keyword=collagen-binding protein en-keyword=human immunoglobulins kn-keyword=human immunoglobulins en-keyword=IgA nephropathy kn-keyword=IgA nephropathy en-keyword=Streptococcus mutans kn-keyword=Streptococcus mutans END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=1 article-no= start-page=69 end-page=74 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effective Treatment of Advanced Hepatocellular Carcinoma with Extensive Peritoneal Dissemination Using Lenvatinib en-subtitle= kn-subtitle= en-abstract= kn-abstract=Patients with hepatocellular carcinoma (HCC) and extensive peritoneal dissemination generally have a poor prognosis and are often resistant to systemic therapy. We report the case of a 47-year-old woman with HCC and massive peritoneal dissemination who presented with malignant ascites requiring repeated cell-free and concentrated ascites reinfusion therapy and peritoneovenous shunt placement, as well as malignant pleural effusion requiring pleurodesis. Combined immunotherapy with durvalumab/tremelimumab was initiated;however, disease progression was observed after three treatment courses, prompting a switch to lenvatinib therapy. Two months after initiation of lenvatinib, CT imaging demonstrated complete disappearance of arterial enhancement in the primary hepatic lesion, along with reduction in the size of peritoneal dissemination nodules. Thirteen months after switching to lenvatinib (16 months after the initial diagnosis), the alpha-fetoprotein level continued to decrease, and the disease remained stable under treatment. Despite the extremely high tumor burden, lenvatinib achieved disease stabilization and symptomatic improvement. en-copyright= kn-copyright= en-aut-name=WakatsukiShinya en-aut-sei=Wakatsuki en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakamotoShinya en-aut-sei=Sakamoto en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UenoAkiko en-aut-sei=Ueno en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NambaTakaomi en-aut-sei=Namba en-aut-mei=Takaomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamamotoYorito en-aut-sei=Yamamoto en-aut-mei=Yorito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MatsumotoManabu en-aut-sei=Matsumoto en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=IwataJun en-aut-sei=Iwata en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OkabayashiTakehiro en-aut-sei=Okabayashi en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Kochi Health Sciences Center kn-affil= affil-num=3 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=4 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=5 en-affil=Department of Obstetrics and Gynecology, Kochi Health Sciences Center kn-affil= affil-num=6 en-affil=Department of Diagnostic Pathology, Kochi Health Sciences Center kn-affil= affil-num=7 en-affil=Department of Diagnostic Pathology, Kochi Health Sciences Center kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Kochi Health Sciences Center kn-affil= en-keyword=diagnostic laparoscopy kn-keyword=diagnostic laparoscopy en-keyword=hepatocellular carcinoma kn-keyword=hepatocellular carcinoma en-keyword=peritoneal dissemination kn-keyword=peritoneal dissemination en-keyword=lenvatinib kn-keyword=lenvatinib END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=1 article-no= start-page=63 end-page=67 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Metastatic Intraocular Tumor Likely from Hepatocellular Carcinoma Mimicking Panuveitis en-subtitle= kn-subtitle= en-abstract= kn-abstract=A 77-year-old man undergoing treatment for hepatocellular carcinoma (HCC) presented with blurred vision in his right eye, persisting for 2 months. Slit-lamp microscopy and fundus examination revealed inflammatory cells in the anterior chamber, severe vitreous opacities, and retinal vasculitis in the right eye. The patient underwent vitreous surgery with biopsy, and vitreous cytology confirmed a metastatic intraocular tumor originating from the HCC. Radiotherapy was administered to the right eye, with no recurrence of intraocular inflammation observed at 10 months post-irradiation. en-copyright= kn-copyright= en-aut-name=TakasuEri en-aut-sei=Takasu en-aut-mei=Eri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShiodeYusuke en-aut-sei=Shiode en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KindoHiroya en-aut-sei=Kindo en-aut-mei=Hiroya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KimuraShuhei en-aut-sei=Kimura en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HosokawaMio en-aut-sei=Hosokawa en-aut-mei=Mio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MatobaRyo en-aut-sei=Matoba en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KanzakiYuki en-aut-sei=Kanzaki en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MoritaTetsuro en-aut-sei=Morita en-aut-mei=Tetsuro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AdachiTakuya en-aut-sei=Adachi en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MorizaneYuki en-aut-sei=Morizane en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=metastatic intraocular tumor kn-keyword=metastatic intraocular tumor en-keyword=hepatocellular carcinoma kn-keyword=hepatocellular carcinoma en-keyword=panuveitis kn-keyword=panuveitis en-keyword=uveitis masquerade syndrome kn-keyword=uveitis masquerade syndrome END start-ver=1.4 cd-journal=joma no-vol=80 cd-vols= no-issue=1 article-no= start-page=55 end-page=62 dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202602 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Changes in Prescribing Patterns of Antiviral Drugs before and after Public Coverage Termination among Hospitalized COVID-19 Patients in Regional Hospitals in Japan: A Retrospective, Multicenter Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=In Japan, antiviral agents for COVID-19 were freely available until September 2023 as part of national policy. This study evaluated changes in these agents’ prescribing patterns and the patient outcomes following the policy shift. We conducted a multicenter retrospective study at four hospitals in Japan’s Okayama and Kagawa prefectures from January 2022 to March 2024. The study period was divided into the public-expenditure phase (January 2022 to September 2023) and the post-expenditure phase (October 2023 to March 2024). We extracted the hospitalized patients’ clinical data from the electronic database. The study’s primary outcome was the antiviral prescription rate; the secondary outcome was in-hospital mortality. Among the 302 hospitalized patients (median age 85 years), 52.0% were classified as having a mild condition. Of the patients with mild conditions, 37.7% were diagnosed in outpatient settings prior to hospitalization. During the public-expenditure phase, 47.4% of the patients received antivirals as outpatients, mainly molnupiravir (80.9%). In the post-expenditure period, 80.0% of the patients were prescribed antivirals, mostly molnupiravir (91.7%). The antiviral prescription rate was significantly higher after the policy change. The overall in-hospital mortality was 15.8%, with no significant difference between the two periods (17.0% vs. 10.5%). Despite the termination of government funding, antiviral prescriptions remained frequent at community hospitals located in highly aging regions of western Japan such as Okayama and Kagawa prefectures. Mortality remains high among the elderly, highlighting the need for continued antiviral therapy and booster vaccinations. en-copyright= kn-copyright= en-aut-name=AkazawaHidemasa en-aut-sei=Akazawa en-aut-mei=Hidemasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HagiyaHideharu en-aut-sei=Hagiya en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukushimaShinnosuke en-aut-sei=Fukushima en-aut-mei=Shinnosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamotoShohei en-aut-sei=Yamamoto en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NakanoYasuhiro en-aut-sei=Nakano en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= affil-num=2 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= affil-num=5 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= affil-num=6 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, kn-affil= en-keyword=coronavirus disease 2019 kn-keyword=coronavirus disease 2019 en-keyword=public expenditure kn-keyword=public expenditure en-keyword=prescribing pattern kn-keyword=prescribing pattern en-keyword=prognosis kn-keyword=prognosis en-keyword=Japan kn-keyword=Japan END start-ver=1.4 cd-journal=joma no-vol=33 cd-vols= no-issue=4 article-no= start-page=201045 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Collagen depletion by pirfenidone enhances antitumor effect of oncolytic adenovirus against peritoneal metastases of gastric cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cancer-associated fibroblasts (CAFs) play a crucial role in collagen accumulation, which develops and promotes peritoneal metastasis (PM) in gastric cancer (GC). In addition, the abundant stromal collagens in the tumor microenvironment function as a physical barrier against penetration of antitumor drugs and oncolytic viruses. This study investigated whether collagen depletion by pirfenidone (PFD), an antifibrotic drug, enhances the antitumor effects of oncolytic adenoviruses. Analysis of the clinical samples revealed a significant association of high expression of collagen 1 and α-smooth muscle actin (α-SMA) with PM development and poor prognosis of advanced GC. Human and murine GC cells enhanced collagen production by fibroblasts, which was suppressed by PFD. Abundant fibroblasts and collagen inhibited the penetration of OBP-702, which reduced the antitumor effects of OBP-702 in the spheroid model. Intraperitoneal co-injection of GC cells and fibroblasts promoted the development of collagen-rich PM and reduced the antitumor effects of OBP-702 in vivo model. PFD suppressed collagen production in PM and improved viral penetration into the tumors, which enhanced the antitumor effects of OBP-702 against PM of GC. Collagen depletion by PFD enhances the penetration of OBP-702 into PM of GC, in turn enhancing the antitumor effects of OBP-702 against PM of GC. en-copyright= kn-copyright= en-aut-name=OkuraTomohiro en-aut-sei=Okura en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KikuchiSatoru en-aut-sei=Kikuchi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MikaneYu en-aut-sei=Mikane en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KanayaNobuhiko en-aut-sei=Kanaya en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MitsuiEma en-aut-sei=Mitsui en-aut-mei=Ema kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UneYuta en-aut-sei=Une en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NomaKazuhiro en-aut-sei=Noma en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OhtsukaJunko en-aut-sei=Ohtsuka en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OhkiRieko en-aut-sei=Ohki en-aut-mei=Rieko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Laboratory of Fundamental Oncology, National Cancer Center Research Institute kn-affil= affil-num=13 en-affil=Laboratory of Fundamental Oncology, National Cancer Center Research Institute kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil= Oncolys BioPharma, Inc. kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=MT: Regular Issue kn-keyword=MT: Regular Issue en-keyword=oncolytic virotherapy kn-keyword=oncolytic virotherapy en-keyword=peritoneal metastasis kn-keyword=peritoneal metastasis en-keyword=gastric cancer kn-keyword=gastric cancer en-keyword=collagen kn-keyword=collagen en-keyword=pirfenidone kn-keyword=pirfenidone END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=1 article-no= start-page=9 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260212 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The Influence of Fluidic Flow Stress on the Development of the Secondary Palate en-subtitle= kn-subtitle= en-abstract= kn-abstract=Craniofacial development is orchestrated by a finely regulated interplay of numerous genes and signaling pathways. Palatogenesis proceeds through a complex, stepwise process, in which endogenous mechanical stresses within tissues have been implicated. However, the impact of exogenous fluidic flow mechanical stress derived from maternal movement on palatal development remains unclear. In this study, we investigated the effect of exogenous fluidic flow mechanical stress on palatal morphogenesis, focusing on the horizontal outgrowth of palatal shelves after elevation. Palatal tissues dissected from mouse embryos were subjected to organ culture with or without mechanical loading (loaded and unloaded groups, respectively). Stress magnitude was quantified by calculating wave energy, and morphometric and molecular analyses were performed. Compared with the unloaded group, palatal shelves in the loaded group showed significant increases in thickness and volume, accompanied by enhanced cell proliferation, nuclear translocation of YAP and β-catenin, and upregulation of the osteogenic markers Osterix and Osteocalcin. No significant difference in apoptosis was observed. These findings indicate that exogenous mechanical stress promotes cell proliferation and osteogenic differentiation through the Hippo and WNT/β-catenin pathways in palate explants. Our results suggest that moderate maternal movement-induced mechanical stress contributes to normal palatogenesis, providing new insights into the mechanisms underlying cleft palate. en-copyright= kn-copyright= en-aut-name=NagataMasayo en-aut-sei=Nagata en-aut-mei=Masayo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HayanoSatoru en-aut-sei=Hayano en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KosamiTakahiro en-aut-sei=Kosami en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Orthodontics, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Orthodontics, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=mechanical stress kn-keyword=mechanical stress en-keyword=palatal development kn-keyword=palatal development en-keyword=β-catenin kn-keyword=β-catenin en-keyword=YAP kn-keyword=YAP END start-ver=1.4 cd-journal=joma no-vol=178 cd-vols= no-issue=1 article-no= start-page=e70775 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Reactive Carbonyl Species Mediate Isothiocyanate Signaling Pathway in Arabidopsis thaliana Guard Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Our previous results demonstrated that depletion of glutathione (GSH) rather than elevation of levels of reactive oxygen species (ROS) is highly correlated with the decrease in stomatal aperture induced by isothiocyanates (ITCs), although ROS is considered a key second messenger in stomatal closure, suggesting that another signal component regulates stomatal apertures along with GSH depletion. This study, using Arabidopsis, clarified that reactive carbonyl species (RCS), especially acrolein and 4-hydroxy-(E)-2-nonenal, are determinants of stomatal aperture responses to ITCs. All tested ITCs, allyl isothiocyanate (AITC), sulforaphane (SFN), benzyl isothiocyanate (BITC), and phenethyl isothiocyanate (PEITC), significantly induced stomatal closure, which was inhibited by the RCS scavengers, carnosine and pyridoxamine. The RCS scavengers suppressed ITC-induced depletion of GSH but not elevation of ROS levels. All tested ITCs (AITC, SFN, BITC, and PEITC) increased levels of RCS and non-RCS aldehydes in the epidermal tissues. However, acrolein, 4-hydroxy-(E)-2-nonenal, crotonaldehyde, and (E)-2-pentenal induced stomatal closure at 10 and 100 μM, whereas propionaldehyde, butyraldehyde, and n-pentanal did not at concentrations up to 100 μM. Acrolein and 4-hydroxy-(E)-2-nonenal more effectively induced stomatal closure and GSH depletion than crotonaldehyde and (E)-2-pentenal did. The contents of RCS were more strongly correlated with GSH levels and stomatal closure than with ROS levels. These results suggest that RCS, especially acrolein and 4-hydroxy-(E)-2-nonenal, acts as key regulators of stomatal closure in guard cells in response to ITCs. en-copyright= kn-copyright= en-aut-name=FarzanaSumaiya en-aut-sei=Farzana en-aut-mei=Sumaiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IslamMd. Moshiul en-aut-sei=Islam en-aut-mei=Md. Moshiul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakamuraToshiyuki en-aut-sei=Nakamura en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakamuraYoshimasa en-aut-sei=Nakamura en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MunemasaShintaro en-aut-sei=Munemasa en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ManoJun'ichi en-aut-sei=Mano en-aut-mei=Jun'ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MurataYoshiyuki en-aut-sei=Murata en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=6 en-affil=Science Research Center, Yamaguchi University kn-affil= affil-num=7 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= en-keyword=arabidopsis kn-keyword=arabidopsis en-keyword=GSH depletion kn-keyword=GSH depletion en-keyword=isothiocyanate kn-keyword=isothiocyanate en-keyword=reactive carbonyl species kn-keyword=reactive carbonyl species en-keyword=reactive oxygen species kn-keyword=reactive oxygen species END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=1 article-no= start-page=9 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260105 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Sodium butyrate augments the antibacterial activity of tetracycline against clinical isolates of multidrug-resistant Vibrio cholerae en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Antibiotic resistance poses a major challenge in treating Vibrio cholerae infections. One promising method to counter resistance is the co-administration of antibiotics with non-antibiotic adjuvants to enhance their efficacy. This study investigated the combined action of sodium butyrate (SB) and tetracycline on tetracycline-resistant V. cholerae strains.
Results The combined activity of SB and antibiotics was assessed on eight V. cholerae clinical isolates using the Fractional Inhibitory Concentration Index (FICI), with SB-Tetracycline showing strong synergy (FICI: 0.09–0.5). Functional and mechanistic studies, including time-kill kinetics, live/dead staining, SEM-based morphological analysis, and fluorometric assays, demonstrated a synergistic antibacterial effect of SB and Tetracycline. This effect was associated with increased membrane permeability, disruption of membrane integrity, dissipation of the proton motive force, and suppression of efflux activity. These changes collectively led to membrane damage, enhanced intracellular accumulation of Tetracycline, decreased intracellular ATP levels, and ultimately, bacterial cell death. Moreover, GM1-CT ELISA and fluorescence microscopy revealed the synergistic anti-virulence activity of the SB- Tetracycline combination. Finally, the combination of SB and Tetracycline showed enhanced efficacy in animal models compared with monotherapy.
Conclusion: The observed SB-Tetracycline synergy provides a promising therapeutic approach to overcome tetracycline resistance in V. cholerae, offering a potential adjunct strategy for the management of antibiotic-resistant cholera infections. en-copyright= kn-copyright= en-aut-name=KunduSushmita en-aut-sei=Kundu en-aut-mei=Sushmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AluSourin en-aut-sei=Alu en-aut-mei=Sourin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SinghAbhishek en-aut-sei=Singh en-aut-mei=Abhishek kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=GopeAnimesh en-aut-sei=Gope en-aut-mei=Animesh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NandyRanjan Kumar en-aut-sei=Nandy en-aut-mei=Ranjan Kumar kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MukhopadhyayAsish K. en-aut-sei=Mukhopadhyay en-aut-mei=Asish K. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyoshiShin-ichi en-aut-sei=Miyoshi en-aut-mei=Shin-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ChatterjeeNabendu Sekhar en-aut-sei=Chatterjee en-aut-mei=Nabendu Sekhar kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BhattacharyaSushmita en-aut-sei=Bhattacharya en-aut-mei=Sushmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=2 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=3 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=4 en-affil=Division of General Medicine, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=5 en-affil=Division of Bacteriology, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=6 en-affil=Division of Bacteriology, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=7 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= affil-num=9 en-affil=Division of Biochemistry, ICMR- National Institute for Research in Bacterial Infections kn-affil= en-keyword=V. cholerae kn-keyword=V. cholerae en-keyword=Sodium butyrate kn-keyword=Sodium butyrate en-keyword=Tetracycline kn-keyword=Tetracycline en-keyword=Synergy kn-keyword=Synergy en-keyword=Antibiotic adjuvant kn-keyword=Antibiotic adjuvant END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue= article-no= start-page=RP106917 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260205 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Dorsoventral-mediated Shh induction is required for axolotl limb regeneration en-subtitle= kn-subtitle= en-abstract= kn-abstract=Axolotls (Ambystoma mexicanum) exhibit a remarkable ability to regenerate limbs. Classical experiments have suggested that contact between cells derived from distinct orientations—dorsal, ventral, anterior, and posterior—within the regenerating blastema is necessary for accurate limb pattern formation. However, the molecular basis for this requirement has remained largely unknown. Here, we demonstrate that both dorsal and ventral tissues are required for limb formation via induction of Shh expression, which plays a crucial role in limb patterning. Using the accessory limb model, we induced position-specific blastemas lacking cells derived from a single orientation (anterior, posterior, dorsal, or ventral). Limb patterning occurred only in blastemas containing both dorsal- and ventral-derived cells. We further observed that Shh expression requires dorsoventral contact within a blastema, highlighting the necessity of dorsoventral contact for inducing Shh expression. Additionally, we identified WNT10B and FGF2 as dorsal- and ventral-mediated signals, respectively, that create the inductive environment for Shh expression. Our findings clarify the role of dorsal and ventral cells in inducing Shh, a mechanism that has rarely been studied in the context of limb regeneration and pattern formation. This model provides new insights into how cells with different positional identities drive the regeneration process. en-copyright= kn-copyright= en-aut-name=YamamotoSakiya en-aut-sei=Yamamoto en-aut-mei=Sakiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FurukawaSaya en-aut-sei=Furukawa en-aut-mei=Saya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiAyaka en-aut-sei=Ohashi en-aut-mei=Ayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HamadaMayuko en-aut-sei=Hamada en-aut-mei=Mayuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SatohAkira en-aut-sei=Satoh en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=2 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=3 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=4 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=5 en-affil=Okayama University, Graduate School of Environmental, Life, Natural Science and Technology kn-affil= END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=12 article-no= start-page=5742 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250615 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Specific Heat-Killed Lactic Acid Bacteria Enhance Mucosal Aminopeptidase N Activity in the Small Intestine of Aged Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aminopeptidase N (APN), an enzyme expressed in the small intestinal mucosa, is involved in dietary protein digestion. Previous studies have shown that oral administration of fermented milk containing lactic acid bacteria (LAB) enhances mucosal APN activity in young mice. This study aimed to investigate whether LAB strains stimulate mucosal APN activity in aged mice and to evaluate its relevance to age-related changes in body composition. The underlying molecular mechanisms were also explored in vitro. Experiment 1: Aged C57BL/6J mice were fed diets supplemented with heat-killed LAB strains—Enterococcus faecalis OU-23 (EF), Leuconostoc mesenteroides OU-03 (LM), or Lactiplantibacillus plantarum SNK12 (LP). Compared to the aged Control group, the ileal APN activity was significantly higher in the LP group. LP administration also elevated serum Gla-osteocalcin levels and decreased serum CTX-1 levels. Experiment 2: IEC-6 cells were co-cultured with LP that had been treated with RNase, DNase, or lysozyme. APN activity was significantly lower in cells co-cultured with DNase- or lysozyme-treated LP compared to those co-cultured with untreated LP. A specific LAB strain may enhance mucosal APN activity in the aged intestine, potentially contributing to improved bone metabolism. This effect may be mediated by bacterial DNA and peptidoglycan. en-copyright= kn-copyright= en-aut-name=TsurutaTakeshi en-aut-sei=Tsuruta en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WakisakaMami en-aut-sei=Wakisaka en-aut-mei=Mami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WatanabeTakumi en-aut-sei=Watanabe en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishijimaAoi en-aut-sei=Nishijima en-aut-mei=Aoi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IkedaAkihito en-aut-sei=Ikeda en-aut-mei=Akihito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TeraokaMao en-aut-sei=Teraoka en-aut-mei=Mao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WangTianyang en-aut-sei=Wang en-aut-mei=Tianyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ChenKuiyi en-aut-sei=Chen en-aut-mei=Kuiyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NishinoNaoki en-aut-sei=Nishino en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Bio-Lab Co., Ltd. kn-affil= affil-num=4 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=aging kn-keyword=aging en-keyword=aminopeptidase N kn-keyword=aminopeptidase N en-keyword=bone metabolism kn-keyword=bone metabolism en-keyword=lactic acid bacteria kn-keyword=lactic acid bacteria en-keyword=small intestine kn-keyword=small intestine END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260202 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pediatric autologous peripheral blood stem cell collection without heparin using a highly concentrated sodium citrate anticoagulant: A retrospective comparison with standard ACD-A en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Heparin combined with sodium citrate has been used in leukocytapheresis for pediatric patients. Since 2022, we have performed leukocytapheresis using a highly concentrated sodium citrate solution (HSC, 5.32%) instead of acid citrate dextrose solution A (ACD-A). We conducted this study to determine whether HSC use reduces run time and the total amount of anticoagulant solution in children.
Study Design and Methods: We retrospectively analyzed data from consecutive autologous peripheral blood stem cell harvests (auto-PBSCHs) between June 2012 and May 2025, including patient characteristics, mobilization methods, protocol used, anticoagulant type, run time, total anticoagulant solution volume, and collection efficiency.
Results: Auto-PBSCH was performed using the mononuclear cell collection (MNC) protocol in 28 procedures and the continuous MNC protocol in 20 procedures. ACD-A was used in 35 procedures and HSC in 13. The run time was significantly shorter (204 [range, 117–302] vs. 157 min [range, 103–227], p = .02) in the HSC group and also confirmed in multivariable regression analysis (coefficient, −55.6; 95% confidence interval, −106.2 to −5.04; p = .03). In a subgroup analysis of cMNC procedures, CD34+ collection efficiency showed a strong negative correlation with the proportion of run time devoted to establishing the initial interface (r = −.73, p = .0003).
Conclusion: Delays in establishing the initial interface can reduce the duration of the effective MNC collection phase and may negatively affect collection efficiency. Careful attention to the initial interface phase is therefore warranted when using HSC. en-copyright= kn-copyright= en-aut-name=FujiiKeiko en-aut-sei=Fujii en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KitamuraWataru en-aut-sei=Kitamura en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WashioKana en-aut-sei=Washio en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IkeuchiKazuhiro en-aut-sei=Ikeuchi en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ShimonoJoji en-aut-sei=Shimono en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MurakamiHiroyuki en-aut-sei=Murakami en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Pediatrics, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Division of Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Hematology, Okayama University Hospital kn-affil= en-keyword=acid citrate dextrose solution kn-keyword=acid citrate dextrose solution en-keyword=autologous kn-keyword=autologous en-keyword=continuous mononuclear cell collection kn-keyword=continuous mononuclear cell collection en-keyword=highly concentrated sodium kn-keyword=highly concentrated sodium en-keyword=pediatric kn-keyword=pediatric en-keyword=peripheral blood stem cells kn-keyword=peripheral blood stem cells END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260120 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=SPRED2 suppresses the stemness of hepatocellular carcinoma through the p53/miR-506-3p/KLF4 pathway en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective: We previously reported that endogenous Sprouty-related, EVH1 domain-containing protein 2 (SPRED2), an inhibitor of the Ras/Raf/ERK-MAPK pathway, controls hepatocellular carcinoma (HCC) cell stemness by downregulating the expression of pluripotency factors, such as Nanog, c-Myc, and KLF4, in an ERK-dependent fashion. However, the exact mechanisms by which SPRED2 regulates HCC cell stemness have not been established.
Methods: Three human HCC cell lines [HepG2 (parental and SPRED2-deficient), HLE, and Hep3B] were used. Cells were transfected to downregulate or overexpress proteins. Western blot and RT-qPCR were used to evaluate the level of protein and mRNA expression. Co-immunoprecipitation and ChIP-qPCR were used to examine protein-protein interactions and the activation of gene transcription. Clinical HCC tissues were also used to validate in vitro data.
Results: KLF4 was identified as the major pluripotency factor responsible for SPRED2-mediated downregulation of HCC cell stemness and KLF4 expression was regulated by miR-506-3p. SPRED2 formed a protein complex with the tumor suppressor (p53) and upregulated miR-506 gene transcription by binding to the promoter region, resulting in subsequent downregulation of KLF4 mRNA expression. There was a negative correlation between KLF4 expression and miR-506-3p and a positive correlation between miR-506-3p expression and SPRED2 in human HCC samples, highlighting the relevance of the study findings.
Conclusions: The current study revealed a novel SPRED2/p53/miR-506-3p/KLF4 axis through which SPRED2 contributes to the suppression of HCC cell stemness and provides a potential new target to prevent HCC progression. en-copyright= kn-copyright= en-aut-name=GaoTong en-aut-sei=Gao en-aut-mei=Tong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ItoSachio en-aut-sei=Ito en-aut-mei=Sachio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Moh-Moh-AungAye en-aut-sei=Moh-Moh-Aung en-aut-mei=Aye kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangTianyi en-aut-sei=Wang en-aut-mei=Tianyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=FujisawaMasayoshi en-aut-sei=Fujisawa en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshimuraTeizo en-aut-sei=Yoshimura en-aut-mei=Teizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=SPRED2 kn-keyword=SPRED2 en-keyword=p53 kn-keyword=p53 en-keyword=KLF4 kn-keyword=KLF4 en-keyword=miR-506-3p kn-keyword=miR-506-3p en-keyword=stemness kn-keyword=stemness END start-ver=1.4 cd-journal=joma no-vol=45 cd-vols= no-issue=1 article-no= start-page=116781 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Immunopeptidomics combined with full-length transcriptomics uncovers diverse neoantigens en-subtitle= kn-subtitle= en-abstract= kn-abstract=Neoantigens are crucial for antitumor immunity and immune checkpoint inhibitor (ICI) efficacy by triggering strong immune responses. However, conventional methods for identifying neoantigens, such as whole-exon sequencing and short-read RNA sequencing (RNA-seq), appear to be insufficient, and the tumor mutational burden cannot sufficiently predict ICI efficacy. In this study, we employed a proteogenomic approach using long-read RNA-seq with Pacific Biosciences Single-Molecule Real-Time Sequencing technology to analyze full-length transcripts in combination with the human leukocyte antigen ligandome. As a result, many neoantigen candidates were identified, which were unregistered in a comprehensive database, including those from non-coding regions. Additionally, we validated the responses of specific T cell receptors (TCRs) to these candidates and identified several pairs of TCRs and neoantigens. These findings highlight the presence of more diverse neoantigens than expected that cannot be identified by conventional methods. en-copyright= kn-copyright= en-aut-name=IshinoTakamasa en-aut-sei=Ishino en-aut-mei=Takamasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WatanabeTomofumi en-aut-sei=Watanabe en-aut-mei=Tomofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TokitaSerina en-aut-sei=Tokita en-aut-mei=Serina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UedaYouki en-aut-sei=Ueda en-aut-mei=Youki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawaseKatsushige en-aut-sei=Kawase en-aut-mei=Katsushige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakanoYuka en-aut-sei=Takano en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ThuYin Min en-aut-sei=Thu en-aut-mei=Yin Min kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SuzukiYuta en-aut-sei=Suzuki en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OwaChie en-aut-sei=Owa en-aut-mei=Chie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=InozumeTakashi en-aut-sei=Inozume en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ZhouWenhao en-aut-sei=Zhou en-aut-mei=Wenhao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=NagasakiJoji en-aut-sei=Nagasaki en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KochinVitaly en-aut-sei=Kochin en-aut-mei=Vitaly kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=UenoToshihide en-aut-sei=Ueno en-aut-mei=Toshihide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KojimaShinya en-aut-sei=Kojima en-aut-mei=Shinya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=Honobe-TabuchiAkiko en-aut-sei=Honobe-Tabuchi en-aut-mei=Akiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KawamuraTatsuyoshi en-aut-sei=Kawamura en-aut-mei=Tatsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=OhnumaTakehiro en-aut-sei=Ohnuma en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=MatsuzawaTakamitsu en-aut-sei=Matsuzawa en-aut-mei=Takamitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=KawaharaYu en-aut-sei=Kawahara en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=YamashitaKazuo en-aut-sei=Yamashita en-aut-mei=Kazuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=LinJason en-aut-sei=Lin en-aut-mei=Jason kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=KosekiJun en-aut-sei=Koseki en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=NishikawaHiroyoshi en-aut-sei=Nishikawa en-aut-mei=Hiroyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=ArakiMotoo en-aut-sei=Araki en-aut-mei=Motoo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=KatoNaoya en-aut-sei=Kato en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=ShimamuraTeppei en-aut-sei=Shimamura en-aut-mei=Teppei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=MorishitaShinichi en-aut-sei=Morishita en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=SuzukiYutaka en-aut-sei=Suzuki en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=ManoHiroyuki en-aut-sei=Mano en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=TorigoeToshihiko en-aut-sei=Torigoe en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=KanasekiTakayuki en-aut-sei=Kanaseki en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= en-aut-name=KawazuMasahito en-aut-sei=Kawazu en-aut-mei=Masahito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=33 ORCID= en-aut-name=TogashiYosuke en-aut-sei=Togashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=34 ORCID= affil-num=1 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Division of Cancer Immunology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=4 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute kn-affil= affil-num=6 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo kn-affil= affil-num=9 en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo kn-affil= affil-num=10 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Immunology, Nagoya University Graduate School of Medicine kn-affil= affil-num=14 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=15 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=16 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=17 en-affil=Department of Dermatology, University of Yamanashi kn-affil= affil-num=18 en-affil=Department of Dermatology, Kumamoto Kenhoku Hospital kn-affil= affil-num=19 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=20 en-affil=Department of Dermatology, Chiba University Graduate School of Medicine kn-affil= affil-num=21 en-affil=KOTAI Biotechnologies, Inc kn-affil= affil-num=22 en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute kn-affil= affil-num=23 en-affil=Division of Systems Biology, Nagoya University Graduate School of Medicine kn-affil= affil-num=24 en-affil=Department of Immunology, Nagoya University Graduate School of Medicine kn-affil= affil-num=25 en-affil=Department of Urology, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=26 en-affil=Department of Gastroenterology, Graduate School of Medicine, Chiba University kn-affil= affil-num=27 en-affil=Division of Systems Biology, Nagoya University Graduate School of Medicine kn-affil= affil-num=28 en-affil=Department of Computational Biology and Medical Sciences, The University of Tokyo kn-affil= affil-num=29 en-affil=Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo kn-affil= affil-num=30 en-affil=Division of Cellular Signaling, National Cancer Center Research Institute kn-affil= affil-num=31 en-affil= kn-affil= affil-num=32 en-affil=Division of Cancer Immunology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=33 en-affil=Division of Cell Therapy, Chiba Cancer Center Research Institute kn-affil= affil-num=34 en-affil=Department of Tumor Microenvironment, Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=cancer immunology kn-keyword=cancer immunology en-keyword=neoantigen kn-keyword=neoantigen en-keyword=long-read RNA sequencing kn-keyword=long-read RNA sequencing en-keyword=HLA ligandome kn-keyword=HLA ligandome en-keyword=single-cell RNA sequencing kn-keyword=single-cell RNA sequencing en-keyword=single-cell TCR sequencing kn-keyword=single-cell TCR sequencing en-keyword=exhausted T cell kn-keyword=exhausted T cell END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=12 article-no= start-page=110594 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251216 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Endoscopic features of oral and pharyngolaryngeal papillomas and their role in distinguishing squamous cell carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=BACKGROUND
Oral and pharyngolaryngeal papillomas are occasionally detected during esophagogastroduodenoscopy. However, their endoscopic features have not been sufficiently investigated.
AIM
To distinguish oral and pharyngolaryngeal papillomas from elevated squamous carcinomas, this study examined their endoscopic features.
METHODS
Forty-seven patients with oral or pharyngeal papilloma participated in this study. The endoscopic characteristics of papillomas were identified by focusing on narrowband and blue laser imaging representations.
RESULTS
Papillomas were classified into three patterns based on their endoscopic features: Salmon roe-like polyps, polyps without capillary transparency, and pinecone-like polyps, with salmon roe-like polyps most prevalent (48.9%). We subsequently analyzed features differentiating papillomas and squamous cell carcinomas in the same region and found that squamous cell carcinomas exhibited at least one of the following three features: Uneven or absent lobulated structure, irregular morphology of capillaries, and coexistence of flat lesions. In contrast, papillomas displayed a uniform lobulated structure, homogeneous or non-visible capillaries, and an absence of flat components. When any of these characteristics were present, two endoscopic specialists evaluated the lesions for the diagnosis of squamous cell carcinoma, with sensitivities of 100% and 97.6% and specificities of 68.9% and 93.3%.
CONCLUSION
Understanding distinct endoscopic patterns of oropharyngeal papillomas and squamous cell carcinomas provides valuable guidance to endoscopists performing esophagogastroduodenoscopy. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HamadaKenta en-aut-sei=Hamada en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KonoYoshiyasu en-aut-sei=Kono en-aut-mei=Yoshiyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawanoSeiji en-aut-sei=Kawano en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KawaharaYoshiro en-aut-sei=Kawahara en-aut-mei=Yoshiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Practical Gastrointestinal Endoscopy, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Esophagogastroduodenoscopy kn-keyword=Esophagogastroduodenoscopy en-keyword=Human papillomavirus kn-keyword=Human papillomavirus en-keyword=Laryngeal polyp kn-keyword=Laryngeal polyp en-keyword=Papilloma kn-keyword=Papilloma en-keyword=Pharyngeal polyp kn-keyword=Pharyngeal polyp END start-ver=1.4 cd-journal=joma no-vol=145 cd-vols= no-issue= article-no= start-page=105021 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202603 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Assessing the role of folate syntrophy and folate cross-feeding in the pathobiology of infectious-inflamed milieu caused by Fusobacterium nucleatum en-subtitle= kn-subtitle= en-abstract= kn-abstract=Diet and nutrition affect almost every biological process, including multiple chronic diseases, diabetes, and some cancers. However, there are still significant gaps in our understanding of the importance of nutrition and healthy diets in syntrophy with respect to cross-feeding of the microbe-microbe and the microbe-host in the pathobiology of the infectious-inflamed intestinal milieu caused by anaerobic opportunistic bacteria such as Fusobacterium nucleatum (F. nucleatum). We examined the immune outcomes of three-member folate syntrophy and cross-feeding between F. nucleatum bacteria, endogenous folate-producing gut bacteria, and host cells at the host-pathogen interface using a triple co-culture model. T84, THP-1, and Huh7 cells were inoculated with F. nucleatum for 6 h in regular DMEM, DMEM with 9.5 μM folic acid, or with/without a mixture of Bifidobacterium longum subsp. infantis (B. infantis) and Escherichia coli Nissle 1917 (EcN). Cytokine secretion, cometabolite levels (ammonia, indoles), cell viability, and barrier integrity were assessed. F. nucleatum-induced folate depletion was associated with increased IL-1β and IL-6 and decreased IL-22, along with reduced transepithelial electrical resistance (TEER) and cell viability in T84 cells. Folate supplementation mitigated these effects. The mixture of B. infantis and EcN reduced F. nucleatum-induced pro-inflammatory cytokines, increased IL-22, and improved TEER and cell viability. These protective effects were enhanced by the addition of folate. F. nucleatum also elevated ammonia and reduced indoles, effects reversed by B. infantis and EcN. In addition to the intrinsic pathogenicity of harmful bacteria, folate deprivation, microbe–microbe folate syntrophy, and microbe–host folate cross-feeding contribute to the pathobiology of anaerobic opportunistic bacteria and influence the physiological fate of host cells. A combination of B. infantis and EcN modulates the infectious-inflamed interface through a cytoprotective effect and mechanical competitive extrusion of pathogenic F. nucleatum. These results provide potential insights into the mechanisms of early-onset colorectal cancer, and evidently, require future studies using patient-derived organoids and in vivo systems to improve clinical relevance. en-copyright= kn-copyright= en-aut-name=GhadimiDarab en-aut-sei=Ghadimi en-aut-mei=Darab kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=BlömerSophia en-aut-sei=Blömer en-aut-mei=Sophia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Şahin KayaAysel en-aut-sei=Şahin Kaya en-aut-mei=Aysel kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KrügerSandra en-aut-sei=Krüger en-aut-mei=Sandra kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=RöckenChristoph en-aut-sei=Röcken en-aut-mei=Christoph kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SchäferHeiner en-aut-sei=Schäfer en-aut-mei=Heiner kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UchiyamaJumpei en-aut-sei=Uchiyama en-aut-mei=Jumpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsuzakiShigenobu en-aut-sei=Matsuzaki en-aut-mei=Shigenobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BockelmannWilhelm en-aut-sei=Bockelmann en-aut-mei=Wilhelm kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= affil-num=2 en-affil=Faculty of Medicine, Christian-Albrechts-University of Kiel kn-affil= affil-num=3 en-affil=Department of Nutrition and Dietetics, Faculty of Health Sciences, Antalya Bilim University kn-affil= affil-num=4 en-affil=Institute of Pathology, Kiel University, University Hospital, Schleswig-Holstein kn-affil= affil-num=5 en-affil=Institute of Pathology, Kiel University, University Hospital, Schleswig-Holstein kn-affil= affil-num=6 en-affil=Laboratory of Molecular Gastroenterology & Hepatology, Christian-Albrechts-University & UKSH Campus Kiel kn-affil= affil-num=7 en-affil=Department of Bacteriology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Laboratory Science, Faculty of Health Sciences, Kochi Gakuen University kn-affil= affil-num=9 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= en-keyword=Nutrition kn-keyword=Nutrition en-keyword=Metaflammation kn-keyword=Metaflammation en-keyword=Folate kn-keyword=Folate en-keyword=Cytokines kn-keyword=Cytokines en-keyword=Infection kn-keyword=Infection en-keyword=Host cells kn-keyword=Host cells END start-ver=1.4 cd-journal=joma no-vol=35 cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=202601 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Addition of human platelet lysate to islet culture medium suppresses islet loss and improves transplantation outcomes en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NoguchiHirofumi en-aut-sei=Noguchi en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Miyagi-ShiohiraChika en-aut-sei=Miyagi-Shiohira en-aut-mei=Chika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SadahiraTakuya en-aut-sei=Sadahira en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WatanabeMasami en-aut-sei=Watanabe en-aut-mei=Masami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SaitohIssei en-aut-sei=Saitoh en-aut-mei=Issei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus kn-affil= affil-num=2 en-affil=Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus kn-affil= affil-num=3 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Pediatric Dentistry, Asahi University School of Dentistry kn-affil= END start-ver=1.4 cd-journal=joma no-vol=74 cd-vols= no-issue=11 article-no= start-page=1023 end-page=1032 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=2025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Bioconversion and Metabolic Fate of the n-1 Polyunsaturated Fatty Acids, 6,9,12,15- Hexadecatetraenoic (C16:4 n-1) and 8,11,14,17- Octadecatetraenoic (C18:4 n-1) Acids, in HepG2 Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Fish oil contains not only major fatty acids with double bonds at the n-3, n-6, n-7, and n-9 positions but also those with a double bond at the n-1 position, such as 6,9,12,15-hexadecatetraenoic acid (C16:4 n-1; HDTA). However, intracellular bioconversion and metabolic fate of n-1 polyunsaturated fatty acids (PUFA) remain unclear. Therefore, in this study, we aimed to assess the intracellular bioconversion and metabolic fate of HDTA and its metabolite, 8,11,14,17- octadecatetraenoic acid (C18:4 n-1; ODTA), using HepG2 cells. Based on the results of cell viability and cytotoxicity assays for HDTA and ODTA, the concentration of each fatty acid supplemented in the experiments was set at 10 μM. HepG2 cell culture with HDTA revealed C20:4 n-1 as a new HDTA metabolite, along with previously reported ODTA. Our findings suggest that the HDTA taken up by HepG2 cells undergoes elongation to form ODTA and C20:4 n-1. Following supplementation with HDTA, ODTA, and 5,8,11,14,17-eicosapentaenoic acid (C20:5 n-3; EPA), fatty acids disappeared from the culture medium within 24 h. Notably, the total relative level of HDTA and its metabolites, including ODTA and C20:4 n-1 in HDTA- and ODTA-supplemented cells were significantly lower than the total relative level of EPA and its metabolites, including 7,10,13,16,19-docosapentaenoic acid (C22:5 n-3), C24:6 n-3, and 4,7,10,13,16,19-docosahexaenoic acid (C22:6 n-3) in the EPA-supplemented cells. Except for a portion that was intracellularly elongated, most HDTA was taken up by HepG2 cells and may undergo rapid fatty acid β-oxidation. However, RNA-sequencing and real-time polymerase chain reaction analysis revealed no significant changes in fatty acid β-oxidation–related gene expression levels in HDTA-supplemented cells. Collectively, these results provide novel insights into the intracellular bioconversion mechanisms and metabolic fate of HDTA and ODTA in HepG2 cells, suggesting that the metabolic fate of n-1 PUFA is distinct from that of common PUFA. en-copyright= kn-copyright= en-aut-name=SugimotoKoki en-aut-sei=Sugimoto en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishiguchiHideto en-aut-sei=Nishiguchi en-aut-mei=Hideto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HosomiRyota en-aut-sei=Hosomi en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanizakiToshifumi en-aut-sei=Tanizaki en-aut-mei=Toshifumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TsushimaTadahiro en-aut-sei=Tsushima en-aut-mei=Tadahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=BabaNaomichi en-aut-sei=Baba en-aut-mei=Naomichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MisawaYoshihisa en-aut-sei=Misawa en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OnoMitsuaki en-aut-sei=Ono en-aut-mei=Mitsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MurakamiYuki en-aut-sei=Murakami en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KandaSeiji en-aut-sei=Kanda en-aut-mei=Seiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FukunagaKenji en-aut-sei=Fukunaga en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Faculty of Food and Nutritional Sciences, Toyo University kn-affil= affil-num=2 en-affil=Faculty of Chemistry, Materials, and Bioengineering, Kansai University kn-affil= affil-num=3 en-affil=Faculty of Chemistry, Materials, and Bioengineering, Kansai University kn-affil= affil-num=4 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=5 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=6 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=7 en-affil=Bizen Chemical Co., Ltd. kn-affil= affil-num=8 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Hygiene and Public Health, Kansai Medical University kn-affil= affil-num=11 en-affil=Department of Hygiene and Public Health, Kansai Medical University kn-affil= affil-num=12 en-affil=Faculty of Chemistry, Materials, and Bioengineering, Kansai University kn-affil= en-keyword=n-1 polyunsaturated fatty acids kn-keyword=n-1 polyunsaturated fatty acids en-keyword=hexadecatetraenoic acid kn-keyword=hexadecatetraenoic acid en-keyword=octadecatetraenoic acid kn-keyword=octadecatetraenoic acid en-keyword=HepG2 kn-keyword=HepG2 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251231 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Efficient resuscitation of early-stage viable but non-culturable cells of Vibrio cholerae using treatment with proteolytic enzymes en-subtitle= kn-subtitle= en-abstract= kn-abstract=Vibrio cholerae, the etiological agent of cholera, is ubiquitous in environmental brackish waters. Exposure to low water temperatures induces the bacterium to enter a viable but non-culturable (VBNC) state. In this study, a stepwise decrease in water temperature to 4°C was found to delay the transition to the non-culturable state compared to an abrupt temperature drop, suggesting that V. cholerae cells partially adapt to low temperatures. V. cholerae VBNC cells maintained at 4°C gradually lost their ability to revert to a culturable state. However, VBNC cells in the early stage of dormancy were efficiently resuscitated following treatment with proteolytic enzymes, including proteinase K. The abundance of culturable V. cholerae cells in brackish estuarine waters was quantified using the most probable number (MPN)–quantitative polymerase chain reaction (qPCR) method. Although culturable cells were undetectable in samples treated with bovine serum albumin, they were estimated at 93 and 1,500 MPN/mL in two water samples collected on different days and pre-incubated with proteinase K. Similarly, the abundance of Vibrio species increased markedly following treatment with this enzyme. Additionally, cells of Vibrio species were enumerated by the plating method using CHROMagar Vibrio plates. Consistent with the results of the MPN–qPCR method, treatment with proteinase K resulted in over a 100-fold increase in colony formation. Collectively, these findings suggest that treatment with proteinase K is effective for resuscitating and quantifying V. cholerae VBNC cells in environmental water samples. en-copyright= kn-copyright= en-aut-name=MiyoshiShin-ichi en-aut-sei=Miyoshi en-aut-mei=Shin-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OgasawaraMona en-aut-sei=Ogasawara en-aut-mei=Mona kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NiwakiShiho en-aut-sei=Niwaki en-aut-mei=Shiho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SugiharaRena en-aut-sei=Sugihara en-aut-mei=Rena kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MuzemboBasilua Andre en-aut-sei=Muzembo en-aut-mei=Basilua Andre kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ImamuraDaisuke en-aut-sei=Imamura en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Research Institute of Nursing Care for People and Community, University of Hyogo kn-affil= affil-num=6 en-affil=Research Center for Intestinal Health Science, Okayama University kn-affil= en-keyword=Vibrio cholerae kn-keyword=Vibrio cholerae en-keyword=viable but non-culturable kn-keyword=viable but non-culturable en-keyword=VBNC kn-keyword=VBNC en-keyword=protease kn-keyword=protease en-keyword=proteolytic enzyme kn-keyword=proteolytic enzyme END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=29639 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250813 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Single cell spatial transcriptomics links Wnt signaling disruption to extracellular matrix development in a cleft palate model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Despite advances in understanding the morphological disruptions that lead to defects in palate formation, the precise perturbations within the signaling microenvironment of palatal clefts remain poorly understood. To explore in greater depth the genomic basis of palatal clefts, we designed and implemented the first single cell spatial RNA-sequencing study in a cleft palate model, utilizing the Pax9−/− murine model at multiple developmental timepoints, which exhibits a consistent cleft palate defect. Visium HD, an emerging platform for true single-cell resolution spatially resolved transcriptomics, was employed using custom bins of 2 × 2 μm spatial gene expression data. Validation of spatial gene expression was then validated using custom designed Xenium In Situ mRNA spatial profiling and RNAscope Multiplex assays. Functional enrichment analysis revealed a palate cell-specific perturbation in Wnt signaling effector function in tandem with disrupted expression of extracellular matrix genes in developing mesenchyme. As a key step toward laying the framework for identifying key molecular targets these data can be used for translational studies aimed at developing effective therapies for human palatal clefts. en-copyright= kn-copyright= en-aut-name=PiñaJeremie Oliver en-aut-sei=Piña en-aut-mei=Jeremie Oliver kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=RajuResmi en-aut-sei=Raju en-aut-mei=Resmi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=StipanoEvan en-aut-sei=Stipano en-aut-mei=Evan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MyoAye Chan en-aut-sei=Myo en-aut-mei=Aye Chan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OnoMitsuaki en-aut-sei=Ono en-aut-mei=Mitsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ChattarajParna en-aut-sei=Chattaraj en-aut-mei=Parna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FurukawaMasae en-aut-sei=Furukawa en-aut-mei=Masae kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=D’SouzaRena N. en-aut-sei=D’Souza en-aut-mei=Rena N. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=2 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=3 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=4 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=5 en-affil=Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Department of Molecular Biology and Biochemistry, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Department of Molecular Biology and Biochemistry, Okayama University kn-affil= affil-num=7 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=8 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= affil-num=9 en-affil=Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) kn-affil= en-keyword=Spatial biology kn-keyword=Spatial biology en-keyword=Cleft palate kn-keyword=Cleft palate en-keyword=Genomics kn-keyword=Genomics en-keyword=Single cell kn-keyword=Single cell en-keyword=Gene expression kn-keyword=Gene expression en-keyword=Profiling kn-keyword=Profiling en-keyword=Extracellular matrix kn-keyword=Extracellular matrix en-keyword=Wnt kn-keyword=Wnt en-keyword=Transcriptome kn-keyword=Transcriptome END start-ver=1.4 cd-journal=joma no-vol=31 cd-vols= no-issue=12 article-no= start-page=102845 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Whole-genome sequencing and in vitro characterization of a disseminated ST398 Staphylococcus aureus infection: A case report en-subtitle= kn-subtitle= en-abstract= kn-abstract=Staphylococcus aureus potentially causes systemic infections such as disseminated abscesses and bloodstream infections, leading to high mortality rates. We herein describe a case of disseminated muscle abscesses caused by sequence type (ST) 398 methicillin-sensitive S. aureus (MSSA), along with in vitro investigation results for potential pathogenic factors. A 67-year-old healthy woman was admitted to our hospital with complaints of systemic body pain. Blood cultures identified MSSA and contrast-enhanced computed tomography revealed multiple muscle abscesses extending from her neck to her soles. She received antibiotic treatment with intravenous cephazolin and underwent repeated surgical drainage, and was finally discharged. Notably, the MSSA strain exclusively affected her muscle tissues, prompting us to perform genetic analysis to uncover the underlying reason. Short-read genome analysis revealed the isolate to be ST398, harboring chp and scn genes known for immune evasion from human immunity. However, no other known pathogenic factors were identified despite rigorous assays for biofilm formation, surface and cell wall proteins, protease production, and hyaluronidase activity. ST398 S. aureus is commonly isolated from livestock, and her prior experience of being flooded could be related to the disease onset. The present case underscores the possibility of severe ST398 MSSA infections in humans, even in the absence of direct animal exposure. en-copyright= kn-copyright= en-aut-name=SazumiYosuke en-aut-sei=Sazumi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FukushimaShinnosuke en-aut-sei=Fukushima en-aut-mei=Shinnosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HagiyaHideharu en-aut-sei=Hagiya en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatoAtsushi en-aut-sei=Kato en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SuyamaAtsuhito en-aut-sei=Suyama en-aut-mei=Atsuhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OguniKohei en-aut-sei=Oguni en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=GotohKazuyoshi en-aut-sei=Gotoh en-aut-mei=Kazuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KutsunoShoko en-aut-sei=Kutsuno en-aut-mei=Shoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HisatsuneJunzo en-aut-sei=Hisatsune en-aut-mei=Junzo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SugaiMotoyuki en-aut-sei=Sugai en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TsujiShuma en-aut-sei=Tsuji en-aut-mei=Shuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IioKoji en-aut-sei=Iio en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Bacteriology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences kn-affil= affil-num=8 en-affil=Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security kn-affil= affil-num=9 en-affil=Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security kn-affil= affil-num=10 en-affil=Antimicrobial Resistance Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security kn-affil= affil-num=11 en-affil=Department of Bacteriology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Microbiology Division, Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Staphylococcus aureus kn-keyword=Staphylococcus aureus en-keyword=Sequence type 398 kn-keyword=Sequence type 398 en-keyword=Disseminated infection kn-keyword=Disseminated infection en-keyword=Immune evasion cluster gene kn-keyword=Immune evasion cluster gene END start-ver=1.4 cd-journal=joma no-vol=35 cd-vols= no-issue=2 article-no= start-page=101548 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202506 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cerebellar abscess caused by Cladophialophora bantiana involving an elderly Japanese woman en-subtitle= kn-subtitle= en-abstract= kn-abstract=Phaeohyphomycosis is a rare fungal infection that presents significant challenges in diagnosis and treatment. Herein, we document a case of a cerebellar abscess caused by Cladophialophora bantiana. A 77-year-old woman with type 2 diabetes mellitus and a previous history of diffuse large B-cell lymphoma gradually developed ataxia and was transferred to an emergency department. Head imaging investigations indicated a cerebellar mass and the patient underwent an emergent endoscopic drainage. Although bacterial cultures of the drainage specimen yielded no growth, a dematiaceous fungus was isolated and subsequently identified as C. bantiana through ITS sequencing analysis. The patient received antifungal combination therapy, initially with liposomal amphotericin B and voriconazole, and finally posaconazole and 5-fluorocytosine. Brain abscesses caused by C. bantiana are rarely documented, and an optimal treatment strategy has yet to be established. Given the high fatality rate, an early surgical intervention is crucial for both diagnosis and treatment. The present case was successfully treated with minimally invasive surgical intervention alongside the antifungal combination therapy. en-copyright= kn-copyright= en-aut-name=NakamotoKenta en-aut-sei=Nakamoto en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HagiyaHideharu en-aut-sei=Hagiya en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukushimaShinnosuke en-aut-sei=Fukushima en-aut-mei=Shinnosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OguniKohei en-aut-sei=Oguni en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YokoyamaYukika en-aut-sei=Yokoyama en-aut-mei=Yukika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IioKoji en-aut-sei=Iio en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HiranoShuichiro en-aut-sei=Hirano en-aut-mei=Shuichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YaguchiTakashi en-aut-sei=Yaguchi en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BanSayaka en-aut-sei=Ban en-aut-mei=Sayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=WatanabeAkira en-aut-sei=Watanabe en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OkunobuHiroki en-aut-sei=Okunobu en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SuyamaAtsuhito en-aut-sei=Suyama en-aut-mei=Atsuhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KawaguchiMarina en-aut-sei=Kawaguchi en-aut-mei=Marina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SazumiYousuke en-aut-sei=Sazumi en-aut-mei=Yousuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Infectious Diseases, Okayama University Hospital kn-affil= affil-num=5 en-affil=Microbiology Division, Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=6 en-affil=Microbiology Division, Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Division of Clinical Research, Medical Mycology Research Center kn-affil= affil-num=9 en-affil=Division of Clinical Research, Medical Mycology Research Center kn-affil= affil-num=10 en-affil=Division of Clinical Research, Medical Mycology Research Center kn-affil= affil-num=11 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Brain abscess kn-keyword=Brain abscess en-keyword=Cladophialophora bantiana kn-keyword=Cladophialophora bantiana en-keyword=Black fungus kn-keyword=Black fungus en-keyword=Phaeohyphomycosis kn-keyword=Phaeohyphomycosis en-keyword=Posaconazole kn-keyword=Posaconazole END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=1 article-no= start-page=e70066 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Procedural Transhiatal Approach for the Thoracic Para‐Aortic Lymph Node: A Case Report en-subtitle= kn-subtitle= en-abstract= kn-abstract=The thoracic posterior para-aortic lymph node (TPAN) is classified as an extra-regional lymph node in esophageal cancer, with metastasis indicating poor prognosis. However, some cases with suspected TPAN metastasis may benefit from esophagectomy with lymph node dissection, including TPAN. This report presents the case of a 58-year-old man with upper thoracic esophageal squamous cell carcinoma and suspected simultaneous TPAN metastasis who underwent neoadjuvant chemotherapy followed by thoracoscopic subtotal esophagectomy and procedural transhiatal TPAN dissection. This transhiatal approach provided direct access to the lymph node without additional thoracic incisions, ensuring safe resection in coordination with the assistant and following anatomical landmarks systematically. Pathological examination showed a false-positive TPAN finding, though the patient later developed distant recurrence. Compared with conventional approaches, this transhiatal technique allows for procedural and reproducible lymphadenectomy while minimizing respiratory burden. This case highlights the feasibility of a transhiatal approach for TPAN dissection. en-copyright= kn-copyright= en-aut-name=HashimotoMasashi en-aut-sei=Hashimoto en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NomaKazuhiro en-aut-sei=Noma en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakedaYasushige en-aut-sei=Takeda en-aut-mei=Yasushige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsumotoHijiri en-aut-sei=Matsumoto en-aut-mei=Hijiri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawasakiKento en-aut-sei=Kawasaki en-aut-mei=Kento kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KunitomoTomoyoshi en-aut-sei=Kunitomo en-aut-mei=Tomoyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MaedaNaoaki en-aut-sei=Maeda en-aut-mei=Naoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanabeShunsuke en-aut-sei=Tanabe en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=112aoP kn-keyword=112aoP en-keyword=esophageal cancer kn-keyword=esophageal cancer en-keyword=thoracic posterior para-aortic lymph node kn-keyword=thoracic posterior para-aortic lymph node END start-ver=1.4 cd-journal=joma no-vol=23 cd-vols= no-issue=5 article-no= start-page=101 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250922 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Prolonged exposure to axitinib alters the molecular profile of Caki‑2 renal cell carcinoma cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Axitinib, an oral second‑generation multitargeted tyrosine kinase inhibitor, is used as a second‑line treatment for metastatic renal cell carcinoma (RCC). However, patients often develop resistance after initial responsiveness, necessitating the elucidation of the underlying resistance mechanisms. Therefore, the present study aimed to investigate the mechanisms underlying axitinib resistance using the Caki‑2 human papillary RCC model cells. Cells tolerating 0.1 µM axitinib were designated as Caki/AX cells. Cell viability was assessed using the water‑soluble tetrazolium salt assay. Notably, the 50% inhibitory concentration (IC50) values of axitinib and sunitinib were significantly higher in Caki/AX cells than those in Caki‑2 cells, indicating 2.83‑ and 1.2‑fold resistance, respectively. By contrast, the IC50 values of sorafenib and erlotinib were decreased in Caki/AX cells. Moreover, Caki/AX cells showed resistance to everolimus, temsirolimus and rapamycin, and decreased sensitivity to vinblastine, vincristine, paclitaxel, doxorubicin and SN‑38 compared with Caki‑2 cells. Notably, etoposide, 5‑fluorouracil, cisplatin and carboplatin sensitivities were comparable in both cell types. Reverse transcription‑quantitative polymerase chain reaction (PCR) analysis revealed that the mRNA levels of the ATP‑binding cassette subfamily B member 1 and subfamily G member 2 were significantly higher in Caki/AX cells than those in Caki‑2 cells. A PCR array related to vascular endothelial growth factor signalling showed that the mRNA levels of FIGF (also known as vascular endothelial growth factor D) and sphingosine kinase 1 were upregulated, whereas those of Rac family small GTPase 2 were downregulated in Caki/AX cells. Overall, these findings suggested that the upregulation of the ATP‑binding cassette subfamily B member 1, FIGF and sphingosine kinase 1 mRNA levels, and downregulation of the Rac family small GTPase 2 mRNA levels may contribute to acquired resistance in Caki/AX cells. en-copyright= kn-copyright= en-aut-name=NakayamaYuko en-aut-sei=Nakayama en-aut-mei=Yuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InoAya en-aut-sei=Ino en-aut-mei=Aya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamamotoKazuhiro en-aut-sei=Yamamoto en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TakaraKohji en-aut-sei=Takara en-aut-mei=Kohji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University kn-affil= affil-num=2 en-affil=Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Hyogo Medical University kn-affil= affil-num=3 en-affil=Department of Integrated Clinical and Basic Pharmaceutical Sciences, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Hyogo Medical University kn-affil= en-keyword=axitinib kn-keyword=axitinib en-keyword=renal cell carcinoma kn-keyword=renal cell carcinoma en-keyword=drug resistance kn-keyword=drug resistance en-keyword=ABC transporter kn-keyword=ABC transporter END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251211 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Atezolizumab + Chemotherapy for Advanced Non-Small Cell Lung Cancer in Japanese Clinical Practice (J-TAIL-2) en-subtitle= kn-subtitle= en-abstract= kn-abstract=First-line atezolizumab combination therapies were approved for the treatment of metastatic non-small cell lung cancer (NSCLC) based on results from the global phase 3 trials IMpower130, IMpower132, and IMpower150. These trials reported 12-month overall survival (OS) rates of 60%–67% with atezolizumab combination therapy. J-TAIL-2 (NCT04501497), a prospective, multicenter, observational study, evaluated atezolizumab combination therapy in routine clinical practice in Japan. Patients ≥ 20 years old with NSCLC received atezolizumab plus carboplatin and nab-paclitaxel (atezo + CnP), atezolizumab plus carboplatin or cisplatin plus pemetrexed (atezo + PP), or atezolizumab plus bevacizumab plus carboplatin and paclitaxel (atezo + bev + CP) in clinical practice. The primary endpoint was the 12-month OS rate. Secondary endpoints included OS, progression-free survival, and subgroup analyses, including IMpower-unlike (did not meet the main eligibility criteria of each IMpower trial) and IMpower-like patients. In total, 814 patients were enrolled (atezo + CnP, n = 217; atezo + PP, n = 211; atezo + bev + CP, n = 386). The IMpower-unlike group included patients with Eastern Cooperative Oncology Group performance status ≥ 2, autoimmune disease, or interstitial lung disease. Twelve-month OS rates (95% confidence interval [CI]) were 62.9% (55.8–69.2), 72.1% (65.2–77.9), and 68.3% (63.2–72.9) with atezo + CnP, atezo + PP, and atezo + bev + CP, respectively. OS hazard ratios (95% CI) in the IMpower-unlike vs. -like subgroups were 1.36 (0.91–2.05), 1.08 (0.70–1.68), and 1.49 (1.09–2.06), respectively. No new safety signals were observed. Real-world efficacy and safety for each atezolizumab combination were comparable to those in the relevant IMpower trials. en-copyright= kn-copyright= en-aut-name=YoshiokaHiroshige en-aut-sei=Yoshioka en-aut-mei=Hiroshige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishioMakoto en-aut-sei=Nishio en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OsoegawaAtsushi en-aut-sei=Osoegawa en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KikuchiEiki en-aut-sei=Kikuchi en-aut-mei=Eiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KimuraHideharu en-aut-sei=Kimura en-aut-mei=Hideharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=GotoYasushi en-aut-sei=Goto en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShimizuJunichi en-aut-sei=Shimizu en-aut-mei=Junichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MiyauchiEisaku en-aut-sei=Miyauchi en-aut-mei=Eisaku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YoshinoIchiro en-aut-sei=Yoshino en-aut-mei=Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MisumiToshihiro en-aut-sei=Misumi en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=WatanabeYasutaka en-aut-sei=Watanabe en-aut-mei=Yasutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=HataAkito en-aut-sei=Hata en-aut-mei=Akito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KisoharaAkira en-aut-sei=Kisohara en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KuyamaShoichi en-aut-sei=Kuyama en-aut-mei=Shoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=YamaguchiMasafumi en-aut-sei=Yamaguchi en-aut-mei=Masafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=MiwaAsako en-aut-sei=Miwa en-aut-mei=Asako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=IwasawaShunichiro en-aut-sei=Iwasawa en-aut-mei=Shunichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=TanakaMisa en-aut-sei=Tanaka en-aut-mei=Misa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=GemmaAkihiko en-aut-sei=Gemma en-aut-mei=Akihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Thoracic Oncology, Kansai Medical University kn-affil= affil-num=2 en-affil=Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine kn-affil= affil-num=5 en-affil=Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University kn-affil= affil-num=6 en-affil=Department of Respiratory Medicine, Kanazawa University Hospital kn-affil= affil-num=7 en-affil=Department of Thoracic Oncology, National Cancer Center Hospital kn-affil= affil-num=8 en-affil=Department of Thoracic Oncology, Aichi Cancer Center Hospital kn-affil= affil-num=9 en-affil=Department of Respiratory Medicine, Tohoku University Hospital kn-affil= affil-num=10 en-affil=International University of Health and Welfare, Narita Hospital kn-affil= affil-num=11 en-affil=Department of Data Science, National Cancer Center Hospital East kn-affil= affil-num=12 en-affil=Department of Thoracic Oncology, Saitama Cancer Center kn-affil= affil-num=13 en-affil=Division of Thoracic Oncology, Kobe Minimally Invasive Cancer Center kn-affil= affil-num=14 en-affil=Department of Respiratory Medicine, Kasukabe Medical Center kn-affil= affil-num=15 en-affil=Department of Respiratory Medicine, NHO Iwakuni Clinical Center kn-affil= affil-num=16 en-affil=Department of Thoracic Oncology, NHO Kyushu Cancer Center kn-affil= affil-num=17 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=18 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=19 en-affil=Chugai Pharmaceutical Co., Ltd. kn-affil= affil-num=20 en-affil=Nippon Medical School kn-affil= en-keyword=atezolizumab kn-keyword=atezolizumab en-keyword=chemotherapy kn-keyword=chemotherapy en-keyword=lung cancer kn-keyword=lung cancer en-keyword=non-small cell kn-keyword=non-small cell en-keyword=observational kn-keyword=observational END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue=4 article-no= start-page=1041 end-page=1054 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250904 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Asian Subgroup Analysis of Patients in the Phase 2 DeLLphi-301 Study of Tarlatamab for Previously Treated Small Cell Lung Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Tarlatamab is a bispecific T-cell engager (BiTE®) immunotherapy that binds delta-like ligand 3 on the surface of small cell lung cancer (SCLC) cells and CD3 on T cells, facilitating T cell-mediated cancer cell lysis. In the primary analysis of the phase 2 DeLLphi-301 study (NCT05060016), tarlatamab showed a favourable benefit-to-risk profile with durable objective responses and promising survival outcomes in patients with previously treated SCLC. Here, phase 2 data for the Asia region subgroup are presented.
Methods: Patients with previously treated, advanced SCLC received 10 mg tarlatamab every 2 weeks. The primary endpoint was objective response rate (ORR) by blinded independent central review (RECIST version 1.1). Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. The present analysis includes patients enrolled at sites in Asia.
Results: A total of 43 patients were enrolled at sites in Asia. ORR was 46.3% (95% confidence interval [CI], 30.7–62.6) and median DOR was 7.2 months (95% CI 3.9 to not estimable). The median follow-up was 16.6 months for PFS and 21.2 months for OS. Median PFS was 5.4 months (95% CI 3.0–8.1) and median OS was 19.0 months (95% CI 11.4 to not estimable). The most common treatment-emergent adverse event (AE) was cytokine release syndrome (48.8%), and all such events were grade 1 or 2. There were no discontinuations due to treatment-related AEs.
Conclusions: Tarlatamab demonstrated durable responses and promising survival outcomes with a manageable safety profile in this post hoc analysis of patients from Asia with previously treated SCLC.
Trial Registration: ClinicalTrials.gov, NCT05060016. en-copyright= kn-copyright= en-aut-name=AhnMyung-Ju en-aut-sei=Ahn en-aut-mei=Myung-Ju kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ChoByoung Chul en-aut-sei=Cho en-aut-mei=Byoung Chul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhashiKadoaki en-aut-sei=Ohashi en-aut-mei=Kadoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IzumiHiroki en-aut-sei=Izumi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LeeJong-Seok en-aut-sei=Lee en-aut-mei=Jong-Seok kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HanJi-Youn en-aut-sei=Han en-aut-mei=Ji-Youn kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ChiangChi-Lu en-aut-sei=Chiang en-aut-mei=Chi-Lu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HuangShuang en-aut-sei=Huang en-aut-mei=Shuang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HamidiAli en-aut-sei=Hamidi en-aut-mei=Ali kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MukherjeeSujoy en-aut-sei=Mukherjee en-aut-mei=Sujoy kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=XuKrista Lin en-aut-sei=Xu en-aut-mei=Krista Lin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=AkamatsuHiraoki en-aut-sei=Akamatsu en-aut-mei=Hiraoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Hematology-Oncology Department, Samsung Medical Center (SMC), Sungkyunkwan University School of Medicine kn-affil= affil-num=2 en-affil=Medical Oncology Department-501, ABMRC, Yonsei University kn-affil= affil-num=3 en-affil=Department of Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=4 en-affil=Thoracic Oncology, National Cancer Center Hospital East kn-affil= affil-num=5 en-affil=Hematology/Oncology, Seoul National University Bundang Hospital kn-affil= affil-num=6 en-affil=Center for Lung Cancer, National Cancer Center-Graduate School of Cancer Science and Policy kn-affil= affil-num=7 en-affil=Department of Chest Medicine, Taipei Veterans General Hospital kn-affil= affil-num=8 en-affil=Amgen Inc. kn-affil= affil-num=9 en-affil=Amgen Inc. kn-affil= affil-num=10 en-affil=Amgen Inc. kn-affil= affil-num=11 en-affil=Amgen Asia Pacific Pte. Ltd. kn-affil= affil-num=12 en-affil=Internal Medicine III, Wakayama Medical University kn-affil= en-keyword=Small cell lung cancer (SCLC) kn-keyword=Small cell lung cancer (SCLC) en-keyword=Tarlatamab kn-keyword=Tarlatamab en-keyword=DLL3 kn-keyword=DLL3 en-keyword=Bispecific T-cell engager kn-keyword=Bispecific T-cell engager en-keyword=Asian patients kn-keyword=Asian patients END start-ver=1.4 cd-journal=joma no-vol=193 cd-vols= no-issue= article-no= start-page=118724 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Deciphering the structural impact of norepinephrine analog radiopharmaceuticals on organic cation transporter affinity en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose: Previous studies have investigated the kinetics and affinities of norepinephrine transporter (NET)-targeting radiotracers, including [123I]MIBG, but the role of organic cation transporters (OCTs) remains unclear. This study aimed to evaluate how the structural design of selective NET-targeting tracers affects OCT-mediated non-specific uptake, identifying factors influencing both NET and OCT affinity.
Methods: Cellular uptake assays were conducted using SK-N-SH cells expressing human NET, and human OCT1-, OCT2-, and OCT3-expressing cells with [3H]norepinephrine, [3H]MPP+, and [131I]MIBG. Competitive uptake assays used non-radioactive reference compounds for several NET-targeting radiopharmaceuticals (MIBG, HED, EPI, PHEN, LMI1195, and PHPG), along with a new PET radiotracer [18F]AF78, and its two analogs with meta-iodide [18F]AF78(I) or hydroxyl group [18F]AF78(OH). Dynamic PET imaging in non-human primates assessed the in vivo uptake of [18F]AF78 after NET inhibition with desipramine.
Results: Monoamine-based tracers (EPI, PHEN, HED) exhibited high NET selectivity with minimal OCTs interaction, while guanidine-containing tracers (e.g., MIBG, LMI1195) displayed substantial OCTs affinity. Lower lipophilicity in guanidine-containing compounds, influenced by substitutions on the benzene ring (e.g., PHPG, AF78), correlated with weaker OCT interactions. PET imaging confirmed that cardiac uptake of [18F]AF78 is sensitive to desipramine pretreatment (***P < 0.0005), indicating its NET-specificity, while persistent hepatic retention suggests an OCT-mediated transport mechanism.
Conclusion: This study highlights the critical influence of the compounds’ chemical structure on NET and OCT affinities. Structural modifications that reduce OCT-mediated uptake while maintaining high NET affinity could improve the specificity and theranostic potential of NET-targeting ligands. These findings provide insights for designing next-generation radiotracers with enhanced selectivity and clinical utility. en-copyright= kn-copyright= en-aut-name=MühligSaskia en-aut-sei=Mühlig en-aut-mei=Saskia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ChenXinyu en-aut-sei=Chen en-aut-mei=Xinyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TutovAnna en-aut-sei=Tutov en-aut-mei=Anna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NoseNaoko en-aut-sei=Nose en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LapaConstantin en-aut-sei=Lapa en-aut-mei=Constantin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=WernerRudolf A. en-aut-sei=Werner en-aut-mei=Rudolf A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=DeckerMichael en-aut-sei=Decker en-aut-mei=Michael kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HiguchiTakahiro en-aut-sei=Higuchi en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital Würzburg kn-affil= affil-num=2 en-affil=Nuclear Medicine, Faculty of Medicine, University of Augsburg kn-affil= affil-num=3 en-affil=Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg kn-affil= affil-num=4 en-affil=Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Nuclear Medicine, Faculty of Medicine, University of Augsburg kn-affil= affil-num=6 en-affil=Department of Nuclear Medicine, LMU Hospital, Ludwig-Maximilians-University of Munich kn-affil= affil-num=7 en-affil=Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg kn-affil= affil-num=8 en-affil=Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Norepinephrine transporter kn-keyword=Norepinephrine transporter en-keyword=Organic cation transporter kn-keyword=Organic cation transporter en-keyword=Neuroendocrine tumor kn-keyword=Neuroendocrine tumor en-keyword=Competitive cell uptake kn-keyword=Competitive cell uptake en-keyword=PET radiotracer kn-keyword=PET radiotracer END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=7 article-no= start-page=oyaf201 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202507 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pharmacovigilance study for the identification of mogamulizumab-induced immune-related adverse events using a real-world database en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Mogamulizumab is a humanized anti-CCR4 monoclonal antibody used for relapsed/refractory adult T-cell leukemia, cutaneous T-cell lymphoma, and/or Sézary syndrome. Reports of immune-related adverse events (irAEs) in these patients are increasing, and the association between irAEs and mogamulizumab remains to be elucidated. This study aimed to evaluate the association between mogamulizumab and immune-related adverse events (irAEs), as well as to characterize the irAEs associated with mogamulizumab using data from a large-scale spontaneous reporting system.
Methods: We performed an exploratory hypothesis-generating analysis of patients from 1967 to September 2023 using VigiBase, a World Health Organization spontaneous adverse event reporting system database. We performed a disproportionality analysis and determined the reporting odds ratios and information components between the drugs of interest and each irAE.
Results: Mogamulizumab was associated with some irAEs, including myocarditis, severe cutaneous adverse reactions, hepatitis, and myositis. Mogamulizumab exhibited significantly higher reporting rates of these 4 irAEs compared to the anticancer agents other than mogamulizumab. Conversely, the reporting rate of other irAEs, including endocrine autoimmune diseases induced by immune checkpoint inhibitors, was not significant in patients who received mogamulizumab.
Conclusions: Mogamulizumab is associated with irAEs, including myocarditis, severe cutaneous adverse reactions, hepatitis, and myositis. en-copyright= kn-copyright= en-aut-name=MiyataKoji en-aut-sei=Miyata en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=Izawa-IshizawaYuki en-aut-sei=Izawa-Ishizawa en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NiimuraTakahiro en-aut-sei=Niimura en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YoshiokaToshihiko en-aut-sei=Yoshioka en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HyodoMizusa en-aut-sei=Hyodo en-aut-mei=Mizusa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ItokazuShuto en-aut-sei=Itokazu en-aut-mei=Shuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MiyataTatsumi en-aut-sei=Miyata en-aut-mei=Tatsumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AizawaFuka en-aut-sei=Aizawa en-aut-mei=Fuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YagiKenta en-aut-sei=Yagi en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KawadaKei en-aut-sei=Kawada en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HamanoHirofumi en-aut-sei=Hamano en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ZamamiYoshito en-aut-sei=Zamami en-aut-mei=Yoshito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=GodaMitsuhiro en-aut-sei=Goda en-aut-mei=Mitsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=IshizawaKeisuke en-aut-sei=Ishizawa en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=2 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=3 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=4 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=5 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=6 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=7 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=8 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=9 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=10 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=11 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= affil-num=14 en-affil=Department of Clinical Pharmacology and Therapeutics, Graduate School of Biomedical Sciences, Tokushima University kn-affil= en-keyword=irAEs kn-keyword=irAEs en-keyword=mogamulizumab kn-keyword=mogamulizumab en-keyword=VigiBase kn-keyword=VigiBase en-keyword=disproportionality analysis kn-keyword=disproportionality analysis en-keyword=sézary syndrome kn-keyword=sézary syndrome END start-ver=1.4 cd-journal=joma no-vol=5 cd-vols= no-issue=2 article-no= start-page=100820 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=2026 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Feasibility and Diagnostic Utility of Mucosal T-Cell Flow Cytometry for Intestinal Graft-Versus-Host Disease en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Aims: Timely diagnosis of intestinal complications after hematopoietic stem cell transplantation (HSCT), including graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy, and cytomegalovirus infection, is essential for appropriate management. This study evaluated whether mucosal T-cell profiling from endoscopic biopsies could support the diagnosis of these post-transplant conditions.
Methods: We prospectively analyzed 58 intestinal biopsy specimens from 21 post-HSCT patients. Paired samples were obtained from the stomach and duodenum during upper endoscopy and from the ileum and large intestine during colonoscopy. Lymphocytes were isolated from each specimen and analyzed using flow cytometry. These data were integrated with those of a previously collected cohort (35 patients, 51 samples) for comparative immunophenotypic analysis across histologically defined groups.
Results: Duodenal biopsies yielded more lymphocytes than did gastric biopsies (mean ± standard deviation: 532 ± 823 vs 233 ± 392 cells; P = .070), with comparable yields between the ileum and colon. Among 41 evaluable cases, the CD56+:CD3+ ratio was significantly lower in patients with GVHD (5.5 ± 2.2%) than in those with nonspecific or no inflammation (28.4 ± 16.3%; P = .006). A cutoff value of <11% provided 85.7% sensitivity and 83.3% specificity for diagnosing GVHD (area under the curve = 0.91).
Conclusion: Mucosal T-cell profiling using endoscopic biopsies is feasible and may aid in the diagnosis of GVHD after HSCT. A decreased CD56+:CD3+ ratio is a promising marker for distinguishing GVHD from other post-transplant intestinal conditions. en-copyright= kn-copyright= en-aut-name=IwamuroMasaya en-aut-sei=Iwamuro en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KondoTakumi en-aut-sei=Kondo en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HiramatsuMai en-aut-sei=Hiramatsu en-aut-mei=Mai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HirabataAraki en-aut-sei=Hirabata en-aut-mei=Araki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakahashiTakahide en-aut-sei=Takahashi en-aut-mei=Takahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TanakaTakehiro en-aut-sei=Tanaka en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Division of Medical Support, Okayama University Hospital kn-affil= affil-num=6 en-affil=Division of Medical Support, Okayama University Hospital kn-affil= affil-num=7 en-affil=Division of Medical Support, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=cytomegalovirus infection kn-keyword=cytomegalovirus infection en-keyword=flow cytometry kn-keyword=flow cytometry en-keyword=graft-versus-host disease kn-keyword=graft-versus-host disease en-keyword=hematopoietic stem cell transplantation kn-keyword=hematopoietic stem cell transplantation en-keyword=T lymphocytes kn-keyword=T lymphocytes END start-ver=1.4 cd-journal=joma no-vol=122 cd-vols= no-issue=5 article-no= start-page=733 end-page=743 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250715 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Intravenous umbilical cord-derived mesenchymal stromal cell therapy may improve overall survival in Japanese patients with idiopathic pneumonia syndrome after hematopoietic stem cell transplantation: a multicenter, single-arm, phase II trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Idiopathic pneumonia syndrome (IPS) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT) and has a poor prognosis. Although IPS is often treated with steroids, the disease can become resistant to or dependent on steroid treatment, and there is no effective cure for patients with refractory or steroid-dependent IPS. This multicenter, open-label, single-arm, phase II clinical trial investigated the efficacy and safety of HLC-001 (allogeneic umbilical cord-derived mesenchymal stromal cells) in patients with progressive steroid-dependent or refractory IPS after HSCT. Seven male patients (all male; mean age: 43.3 years) received HLC-001 and three completed the trial. The survival rate at day 56 (primary endpoint) was 71.4% (5/7 patients; 95% confidence interval: 29.0%–96.3%) and was sustained at day 100, suggesting that HLC-001 was more effective than previously reported treatment. Three of the five patients with ≥ 100 days of follow-up died. Five patients experienced at least one adverse drug reaction, none of which were serious. These findings indicate that HLC-001 was potentially effective and generally well tolerated in Japanese patients with steroid-dependent or refractory IPS after HSCT. Given there is no effective cure for steroid-dependent or refractory IPS, HLC-001 may be a promising treatment option and further clinical evaluation is warranted.
Trial registration: Japan Registry of Clinical Trials identifier: jRCT2063220014. en-copyright= kn-copyright= en-aut-name=DokiNoriko en-aut-sei=Doki en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KakoShinichi en-aut-sei=Kako en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakaidaEmiko en-aut-sei=Sakaida en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KandaYoshinobu en-aut-sei=Kanda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= affil-num=4 en-affil=Department of Hematology, Chiba University Hospital kn-affil= affil-num=5 en-affil=Division of Hematology, Department of Medicine, Jichi Medical University kn-affil= en-keyword=Graft-versus-host disease kn-keyword=Graft-versus-host disease en-keyword=Hematopoietic stem cell transplantation kn-keyword=Hematopoietic stem cell transplantation en-keyword=Idiopathic pneumonia syndrome kn-keyword=Idiopathic pneumonia syndrome en-keyword=Overall survival kn-keyword=Overall survival en-keyword=Umbilical cord-derived mesenchymal stromal cells kn-keyword=Umbilical cord-derived mesenchymal stromal cells END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=45 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2026 dt-pub=20260105 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Magnetic Detection of Cancer Cells Using Tumor-Homing Peptide-Modified Magnetic Nanoparticles en-subtitle= kn-subtitle= en-abstract= kn-abstract=Magnetic nanoparticles (MNPs) provide a platform for target detection because of their magnetic responsiveness to alternating magnetic fields (AMFs). We developed a detection method using MNPs modified with tumor-homing peptides (THPs), PL1 and PL3, which selectively bind to protein components enriched in malignant tissues. THP-MNPs were synthesized using maleimide-PEG-NHS linkers and characterized using transmission electron microscopy. Human glioblastoma cancer U87MG and normal tissue-derived HEK293 cells were incubated with THP-MNPs, and the magnetic signals were measured using a high-temperature superconducting quantum interference device (SQUID) magnetometer under an AMF (1.06 kHz). Dark-field microscopy confirmed the preferential binding of THP-MNPs to U87MG cells. In the absence of cells, THP-MNPs exhibited AMF-dependent signal enhancement, which correlated with particle size reduction due to THP release. This increase was completely suppressed in the presence of U87MG cells, indicating a strong THP-mediated interaction. PL3-MNPs exhibited superior discrimination between malignant and non-malignant cells. These results demonstrate that SQUID-based magnetic measurements using THP-MNPs enable rapid and label-free cancer cell detection. en-copyright= kn-copyright= en-aut-name=ZhouShengli en-aut-sei=Zhou en-aut-mei=Shengli kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FurutaniYuji en-aut-sei=Furutani en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamashitaKei en-aut-sei=Yamashita en-aut-mei=Kei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KakoSakuya en-aut-sei=Kako en-aut-mei=Sakuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WatanabeKazunori en-aut-sei=Watanabe en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KiwaToshihiko en-aut-sei=Kiwa en-aut-mei=Toshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OhtsukiTakashi en-aut-sei=Ohtsuki en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=magnetic nanoparticle kn-keyword=magnetic nanoparticle en-keyword=tumor-homing peptide kn-keyword=tumor-homing peptide en-keyword=superconducting quantum interference devices kn-keyword=superconducting quantum interference devices END start-ver=1.4 cd-journal=joma no-vol=74 cd-vols= no-issue= article-no= start-page=6009610 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=2025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Small Distance Increment Method for Measuring Complex Permittivity With mmWave Radar en-subtitle= kn-subtitle= en-abstract= kn-abstract=Measuring the complex permittivity of material is essential in many scenarios, such as quality checks in material manufacturing. Generally, measurement methods for characterizing the material are based on the use of a vector network analyzer (VNA), which is large and not easy for on-site measurement, especially in high-frequency range such as millimeter wave (mmWave). In addition, some measurement methods require the destruction of samples, which is not suitable for nondestructive inspection. In this work, a small distance increment (SDI) method is proposed to nondestructively measure the complex permittivity of a material. In SDI, the transmitter and receiver are formed as a monostatic radar, which is facing toward the material under test (MUT). During the measurement, the distance between the radar and the MUT changes with small increments, and the signals are recorded at each position. A mathematical model is formulated to depict the relationship among the complex permittivity, distance increment, and measured signals. By fitting the model, the complex permittivity of MUT is estimated. To implement and evaluate the proposed SDI method, a commercial off-the-shelf (COTS) mmWave radar is utilized, and the measurement system is developed. Then, the evaluation was carried out on the acrylic plate. With the proposed method, the estimated complex permittivity of the acrylic plate shows good agreement with the literature values, demonstrating the efficacy of the SDI method for characterizing the complex permittivity of the material. en-copyright= kn-copyright= en-aut-name=SongHang en-aut-sei=Song en-aut-mei=Hang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KimHyun Joon en-aut-sei=Kim en-aut-mei=Hyun Joon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WanMingxia en-aut-sei=Wan en-aut-mei=Mingxia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WeiBo en-aut-sei=Wei en-aut-mei=Bo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KikkawaTakamaro en-aut-sei=Kikkawa en-aut-mei=Takamaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TakadaJun-Ichi en-aut-sei=Takada en-aut-mei=Jun-Ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Research Institute for Semiconductor Engineering, Hiroshima University kn-affil= affil-num=2 en-affil=Department of Transdisciplinary Science and Engineering, Institute of Science Tokyo kn-affil= affil-num=3 en-affil=Department of Transdisciplinary Science and Engineering, Institute of Science Tokyo kn-affil= affil-num=4 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Research Institute for Semiconductor Engineering, Hiroshima University kn-affil= affil-num=6 en-affil=Department of Transdisciplinary Science and Engineering, Institute of Science Tokyo kn-affil= en-keyword=Complex permittivity measurement kn-keyword=Complex permittivity measurement en-keyword=material characterization kn-keyword=material characterization en-keyword=millimeter wave (mmWave) radar kn-keyword=millimeter wave (mmWave) radar en-keyword=nondestructive inspection kn-keyword=nondestructive inspection en-keyword=small distance increment (SDI) method kn-keyword=small distance increment (SDI) method END start-ver=1.4 cd-journal=joma no-vol=93 cd-vols= no-issue= article-no= start-page=102631 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202504 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Detection of the nuclear translocation of androgen receptor using quantitative and automatic cell imaging analysis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Testosterone signaling mediates diseases such as androgenetic alopecia and prostate cancer and is controlled by the activation of the androgen receptor (AR) and nuclear translocation of the ligand-receptor complex. This study established an immortalized dermal papilla cell line that stably expresses the AR labeled with a monomeric green fluorescence marker. The cells expressed the histone H2B protein as visualized using a red fluorescence marker, enabling the Detection of nuclear translocation under live cell conditions using image analysis. The AR was observed to be translocated from the cytoplasm to the nucleus of cells after stimulation with dihydrotestosterone (DHT). The signal intensity of the nuclear/cytoplasm ratio was analyzed using automatic image analysis and a newly developed algorithm. The quantitation method to detect nuclear translocation revealed that the AR nuclear signal plateaued approximately 20 min after DHT exposure. Our developed method has the potential to save human labor by the automatic process of the image. en-copyright= kn-copyright= en-aut-name=BaiLanlan en-aut-sei=Bai en-aut-mei=Lanlan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WuTao en-aut-sei=Wu en-aut-mei=Tao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukasawaMizuki en-aut-sei=Fukasawa en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KashiwagiSayo en-aut-sei=Kashiwagi en-aut-mei=Sayo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TateHaruka en-aut-sei=Tate en-aut-mei=Haruka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OzakiTaku en-aut-sei=Ozaki en-aut-mei=Taku kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SuganoEriko en-aut-sei=Sugano en-aut-mei=Eriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TomitaHiroshi en-aut-sei=Tomita en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IshiiTsuyoshi en-aut-sei=Ishii en-aut-mei=Tsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AkashiTakuya en-aut-sei=Akashi en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FukudaTomokazu en-aut-sei=Fukuda en-aut-mei=Tomokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=2 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=3 en-affil=Neuro-AI Integration Science Laboratory, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Rohto Pharmaceutical Co., Ltd., Basic Research Development Division kn-affil= affil-num=5 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=6 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=7 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=8 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= affil-num=9 en-affil=Rohto Pharmaceutical Co., Ltd., Basic Research Development Division kn-affil= affil-num=10 en-affil=Neuro-AI Integration Science Laboratory, Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=11 en-affil=Graduate School of Science and Engineering, Iwate University kn-affil= en-keyword=Dermal papilla cell kn-keyword=Dermal papilla cell en-keyword=Nuclear translocation kn-keyword=Nuclear translocation en-keyword=Androgen receptor kn-keyword=Androgen receptor en-keyword=Live cell imaging kn-keyword=Live cell imaging en-keyword=Digital image analysis kn-keyword=Digital image analysis en-keyword=Quantitation algorithm kn-keyword=Quantitation algorithm END start-ver=1.4 cd-journal=joma no-vol=75 cd-vols= no-issue=1 article-no= start-page=10 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251218 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gut microbial metabolite butyrate boosts p53-expressing telomerase-specific oncolytic adenovirus efficacy by enhancing infectivity and activating MHC-I/cGAS-STING en-subtitle= kn-subtitle= en-abstract= kn-abstract=The gut microbiota plays an essential role in regulating host immunity, and its metabolites such as butyrate exert immunomodulatory effects by acting as histone deacetylase inhibitors. Oncolytic virotherapy has emerged as a promising approach for cancer treatment, and we have developed OBP-702, a telomerase-specific oncolytic adenovirus that expresses p53 and elicits strong systemic antitumor responses. In this study, the potential synergy between butyrate and OBP-702 was investigated in colorectal cancer models. Using human and murine colorectal carcinoma cell lines, butyrate was found to directly enhance the infectivity of OBP-702 by upregulating CAR and integrins, thereby promoting apoptosis and autophagy in tumor cells. In addition, butyrate indirectly boosted systemic antitumor immunity by upregulating MHC-I expression through activation of the cGAS-STING pathway and enhancing CD8 + T cell recruitment via CXCL10 secretion. These findings were supported by in vivo experiments using CT26 subcutaneous, bilateral, and orthotopic tumor models, in which the combination of oral butyrate and intratumoral OBP-702 administration produced synergistic antitumor effects. These results highlight the therapeutic potential of integrating gut microbial metabolites with oncolytic virotherapy as a novel immunotherapeutic strategy for colorectal cancer. en-copyright= kn-copyright= en-aut-name=SakamotoMasaki en-aut-sei=Sakamoto en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KatayamaTetsuya en-aut-sei=Katayama en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MikaneYu en-aut-sei=Mikane en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HanzawaShunya en-aut-sei=Hanzawa en-aut-mei=Shunya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KadowakiDaisuke en-aut-sei=Kadowaki en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshidaYusuke en-aut-sei=Yoshida en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HamadaYuki en-aut-sei=Hamada en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SugimotoRyoma en-aut-sei=Sugimoto en-aut-mei=Ryoma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YagiChiaki en-aut-sei=Yagi en-aut-mei=Chiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HashimotoMasashi en-aut-sei=Hashimoto en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KanayaNobuhiko en-aut-sei=Kanaya en-aut-mei=Nobuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KakiuchiYoshihiko en-aut-sei=Kakiuchi en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=KikuchiSatoru en-aut-sei=Kikuchi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=18 en-affil=Oncolys BioPharma, Inc. kn-affil= affil-num=19 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Butyrate kn-keyword=Butyrate en-keyword=Oncolytic adenovirus kn-keyword=Oncolytic adenovirus en-keyword=MHC-I kn-keyword=MHC-I en-keyword=CD8 + T cells kn-keyword=CD8 + T cells en-keyword=Cancer immunotherapy kn-keyword=Cancer immunotherapy END start-ver=1.4 cd-journal=joma no-vol=137 cd-vols= no-issue=3 article-no= start-page=95 end-page=97 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251201 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=The 2024 Incentive Award of the Okayama Medical Association in Cardiovascular and Pulmonary Research (2024 Sunada Prize) kn-title=令和６年度岡山医学会賞　胸部・循環研究奨励賞（砂田賞） en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=KawanaShinichi en-aut-sei=Kawana en-aut-mei=Shinichi kn-aut-name=川名伸一 kn-aut-sei=川名 kn-aut-mei=伸一 aut-affil-num=1 ORCID= affil-num=1 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil=岡山大学大学院医歯薬学総合研究科 呼吸器・乳腺内分泌外科学 END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=20 article-no= start-page=4309 end-page=4317 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251009 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Characterization of Autonomous and Ca2+/Calmodulin-Dependent Activities of CaMKK Isoforms In Vitro and in Mouse Tissues en-subtitle= kn-subtitle= en-abstract= kn-abstract=Ca2+/CaM-dependent protein kinase kinase (CaMKK) phosphorylates and activates downstream kinases, including CaMKI, CaMKIV, PKB, and AMPK, regulating various cellular functions such as neuronal morphogenesis, metabolic control, and pathophysiological pathways, such as cancer progression. CaMKKα/1 is tightly regulated by an autoinhibitory mechanism. CaMKKβ/2 activity is highly Ca2+/CaM-independent (autonomous activity) in vitro and Ca2+/CaM-dependent in cultured cells. Whether these two activity states of CaMKKβ/2 exist in vivo and the detailed regulatory mechanisms for the transition of both activity states remain unclear due to the difficulty in distinguishing the two activity states. In this study, we detected Ca2+-dependent and autonomous CaMKK activity in HeLa cells and successfully separated both activity states of CaMKKβ/2 in mouse brain and testis extracts using a recently developed CaMKK inhibitor (TIM-063)-coupled sepharose, which binds to the catalytic domain in the active state but not in the autoinhibited state. Furthermore, lambda protein phosphatase treatment converted the Ca2+/CaM-dependent form to the autonomous form of CaMKKβ/2, which was not affected by Ala mutation of Ser128, Ser132, and Ser136. The two activity forms of CaMKKβ/2 had equivalent Ca2+/CaM-binding ability. The findings demonstrate the presence of autonomous and Ca2+/CaM-dependent forms of CaMKKβ/2 independently in mouse tissues and cultured cells. The transition of these states of CaMKKβ/2 may be dynamically regulated by the phosphorylation/dephosphorylation of serine residues in the N-terminal regulatory domain. en-copyright= kn-copyright= en-aut-name=OhtsukaSatomi en-aut-sei=Ohtsuka en-aut-mei=Satomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ChenYerun en-aut-sei=Chen en-aut-mei=Yerun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MagariMasaki en-aut-sei=Magari en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IshikawaTeruhiko en-aut-sei=Ishikawa en-aut-mei=Teruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SakagamiHiroyuki en-aut-sei=Sakagami en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SuizuFutoshi en-aut-sei=Suizu en-aut-mei=Futoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TokumitsuHiroshi en-aut-sei=Tokumitsu en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Science Education, Graduate School of Education, Okayama University kn-affil= affil-num=5 en-affil=Department of Anatomy, Kitasato University School of Medicine kn-affil= affil-num=6 en-affil=Clinical Examination Department, Kagawa Prefectural University of Health Sciences kn-affil= affil-num=7 en-affil=Applied Cell Biology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=8 article-no= start-page=938 end-page=943 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202508 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Clinical outcomes of Japanese patients treated with out-of-specification tisagenlecleucel in a phase 3b trial en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: The final manufactured tisagenlecleucel product should meet the commercial product release specifications to ensure the quality in terms of safety, purity, identity, and potency. However, it may occasionally fail to meet these specifications due to the nature of patient-derived cells with variable properties as starting material and the complex manufacturing process. The final product that does not meet at least one of the commercial release specifications is referred to as “out-of-specification” (OOS). However, the benefit-risk profile of OOS tisagenlecleucel has not yet been fully elucidated.
Aims: To evaluate the safety and efficacy of OOS tisagenlecleucel in Japanese patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).
Methods: This is a single-arm, open-label, multicenter phase 3b study (NCT04094311). Patients consistent with label indication were enrolled and followed-up for 3 months.
Results: Of the 29 patients enrolled between December 2019 and May 2022 across 13 qualified sites in Japan, 28 received tisagenlecleucel, and of these, 23 had r/r DLBCL and 5 had r/r B-ALL. The primary reasons for OOS were low cell viability (15 of 24 batches) and low dose (8 of 23 batches) tisagenlecleucel in the r/r DLBCL group, and high dose (4 of 5 batches) in the r/r B-ALL group. In patients with r/r DLBCL, the grade 3 or 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 3 and 1 patients, respectively. Response assessments were performed for 15 of 23 patients with r/r DLBCL: 6 achieved a complete response, and 1 achieved a partial response as the best response within 3 months.
Conclusions: Despite the limited patient sample size, our findings affirm that the infusion of OOS tisagenlecleucel is a viable option, with no observed increase in toxicity and outcomes comparable to those of in-specification products in clinical and real-world studies. en-copyright= kn-copyright= en-aut-name=KatoKoji en-aut-sei=Kato en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatoJun en-aut-sei=Kato en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GotoHideki en-aut-sei=Goto en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KobayashiTakeshi en-aut-sei=Kobayashi en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakahashiYoshiyuki en-aut-sei=Takahashi en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SakaidaEmiko en-aut-sei=Sakaida en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HiramatsuHidefumi en-aut-sei=Hiramatsu en-aut-mei=Hidefumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YamamotoMasahide en-aut-sei=Yamamoto en-aut-mei=Masahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YoshiharaSatoshi en-aut-sei=Yoshihara en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AndoJun en-aut-sei=Ando en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KohKatsuyoshi en-aut-sei=Koh en-aut-mei=Katsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FukushimaKentaro en-aut-sei=Fukushima en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=IwamotoFumiko en-aut-sei=Iwamoto en-aut-mei=Fumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TiwariRanjan en-aut-sei=Tiwari en-aut-mei=Ranjan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Hematology, Oncology, and Cardiovascular Medicine, Kyushu University Hospital kn-affil= affil-num=2 en-affil=Division of Hematology, Department of Medicine, Keio University School of Medicine kn-affil= affil-num=3 en-affil=Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital kn-affil= affil-num=4 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital kn-affil= affil-num=5 en-affil=Department of Pediatrics, Nagoya University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Hematology, Chiba University Hospital kn-affil= affil-num=7 en-affil=Department of Pediatrics, Graduate School of Medicine, Kyoto University kn-affil= affil-num=8 en-affil=Department of Hematology, Institute of Science Tokyo Hospital kn-affil= affil-num=9 en-affil=Department of Hematology, Hyogo Medical University Hospital kn-affil= affil-num=10 en-affil=Department of Cell Therapy and Transfusion Medicine, Juntendo University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Department of Hematology/Oncology, Saitama Children’s Medical Center kn-affil= affil-num=12 en-affil=Department of Hematology and Oncology, Osaka University Graduate School of Medicine kn-affil= affil-num=13 en-affil=Medical Affairs, Novartis Pharma K.K. kn-affil= affil-num=14 en-affil=Development Advance Quantitative Sciences, Novartis Healthcare Private Limited kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=CAR-T kn-keyword=CAR-T en-keyword=DLBCL kn-keyword=DLBCL en-keyword=Out-of-specification kn-keyword=Out-of-specification en-keyword=Safety kn-keyword=Safety en-keyword=Tisagenlecleucel kn-keyword=Tisagenlecleucel END start-ver=1.4 cd-journal=joma no-vol=46 cd-vols= no-issue=1 article-no= start-page=69 end-page=84 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251230 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=P53-Armed Oncolytic Virotherapy Promotes the Efficacy of PD1 Blockade in Murine Osteosarcoma Tumors en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: Osteosarcoma (OS) is refractory to immune checkpoint inhibitors targeting programmed cell death 1 (PD1)/PD ligand 1 (PD-L1) due to poor immune response. We previously developed telomerase-specific, replication-competent oncolytic adenoviruses non-armed OBP-301 and P53-armed OBP-702 that exert antitumor efficacy against human OS cells. Recently, we demonstrated that P53-armed OBP-702 induces more profound immunogenic cell death and antitumor immune response against human and murine OS cells than does non-armed OBP-301. In the present study, we assessed the combined efficacy of PD1 blockade and P53-armed OBP-702 against murine OS cells.
Materials and Methods: Three murine OS cell lines (K7M2, NHOS, NHOS-LM4) were used to assess the cytopathic effect of non-armed OBP-301 and P53-armed OBP-702 by XTT assay. Virus-induced immunogenic cell death was assessed by analyzing the levels of extracellular adenosine triphosphate and high-mobility group box protein B1. The expression of PD-L1 and PD-L2 was analyzed by flow cytometry. The malignant potential of NHOS-LM4 cells was analyzed by a migration and invasion assay. An orthotopic NHOS-LM4 tumor model was used to evaluate the antitumor efficacy of combination therapy with P53-armed OBP-702 and anti-PD1.
Results: P53-armed OBP-702 exhibited antitumor potential for the induction of immunogenic cell death, apoptosis, autophagy, and PD-L1/2 upregulation in K7M2 and NHOS cells. NHOS-LM4 cells showed increased migratory and invasive ability compared to NHOS cells. P53-armed OBP-702 significantly suppressed the malignant potential of NHOS-LM4 cells. Combination dosing showed that P53-armed OBP-702 significantly promoted the antitumor effect of PD1 blockade against NHOS-LM4 tumors.
Conclusion: Our results suggest that P53-armed OBP-702 is a promising agent for improving the antitumor effect of PD1 blockade in treating invasive OS. en-copyright= kn-copyright= en-aut-name=KUREMIHO en-aut-sei=KURE en-aut-mei=MIHO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TAZAWAHIROSHI en-aut-sei=TAZAWA en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=DEMIYAKOJI en-aut-sei=DEMIYA en-aut-mei=KOJI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KONDOHIROYA en-aut-sei=KONDO en-aut-mei=HIROYA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MOCHIZUKIYUSUKE en-aut-sei=MOCHIZUKI en-aut-mei=YUSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KOMATSUBARATADASHI en-aut-sei=KOMATSUBARA en-aut-mei=TADASHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YOSHIDAAKI en-aut-sei=YOSHIDA en-aut-mei=AKI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UOTANIKOJI en-aut-sei=UOTANI en-aut-mei=KOJI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HASEIJOE en-aut-sei=HASEI en-aut-mei=JOE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FUJIWARATOMOHIRO en-aut-sei=FUJIWARA en-aut-mei=TOMOHIRO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KUNISADATOSHIYUKI en-aut-sei=KUNISADA en-aut-mei=TOSHIYUKI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=URATAYASUO en-aut-sei=URATA en-aut-mei=YASUO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KAGAWASHUNSUKE en-aut-sei=KAGAWA en-aut-mei=SHUNSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=OZAKITOSHIFUMI en-aut-sei=OZAKI en-aut-mei=TOSHIFUMI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=FUJIWARATOSHIYOSHI en-aut-sei=FUJIWARA en-aut-mei=TOSHIYOSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Osteosarcoma kn-keyword=Osteosarcoma en-keyword=oncolytic adenovirus kn-keyword=oncolytic adenovirus en-keyword=P53 kn-keyword=P53 en-keyword=immunogenic cell death kn-keyword=immunogenic cell death en-keyword=PD1 kn-keyword=PD1 END start-ver=1.4 cd-journal=joma no-vol=46 cd-vols= no-issue=1 article-no= start-page=25 end-page=38 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251230 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Near-infrared Photoimmunotherapy Targeting High-risk Human Neuroblastoma Cells Expressing GD2 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system in infancy. Despite advances in treatment, the prognosis remains poor for high-risk NB patients. Although immunotherapy using anti-GD2 antibodies is available for high-risk NB, the therapeutic efficacy is insufficient. Near-infrared photoimmunotherapy (NIR-PIT) is an antitumor strategy that induces tumor-specific cytotoxicity by combining an antibody-photoabsorber conjugate (APC) with NIR light irradiation. In this study, we investigated the therapeutic efficacy of GD2-targeted NIR-PIT against human NB cells.
Materials and Methods: GD2 expression was analyzed on the surface of high-risk human NB cells (CHP-134, LA-N-5, IMR-32) and non-high-risk human NB cells (SK-N-SH) by flow cytometry. The APC was synthesized by incubating anti-GD2 antibody and IR700. The cytotoxic effect of GD2-targeted NIR-PIT was evaluated using the XTT assay. The distribution of dead cells within tumor spheres was evaluated using a live/dead assay. The in vivo antitumor effect of GD2-targeted NIR-PIT was assessed using a subcutaneous human NB xenograft tumor model.
Results: GD2 protein was expressed on the surface of CHP-134, LA-N-5, and IMR-32 cells but not SK-N-SH cells. GD2-targeted NIR-PIT significantly suppressed the viability of GD2-positive NB cells but not GD2-negative NB cells, compared to the control and monotherapy groups. GD2-targeted NIR-PIT significantly reduced the volume of GD2-positive CHP-134 tumor spheres by inducing the accumulation of dead cells. Subcutaneous CHP-134 xenograft tumor models demonstrated that GD2-targeted NIR-PIT significantly inhibited tumor growth compared with the control and monotherapy groups.
Conclusion: GD2-targeted NIR-PIT is a promising antitumor strategy for treating high-risk NB tumors expressing GD2. en-copyright= kn-copyright= en-aut-name=NOUSOHIROSHI en-aut-sei=NOUSO en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TAZAWAHIROSHI en-aut-sei=TAZAWA en-aut-mei=HIROSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TANIMOTOTERUTAKA en-aut-sei=TANIMOTO en-aut-mei=TERUTAKA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TANIMORIMICHI en-aut-sei=TANI en-aut-mei=MORIMICHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WATANABEHINAKO en-aut-sei=WATANABE en-aut-mei=HINAKO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OYAMATAKANORI en-aut-sei=OYAMA en-aut-mei=TAKANORI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NOMAKAZUHIRO en-aut-sei=NOMA en-aut-mei=KAZUHIRO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KAGAWASHUNSUKE en-aut-sei=KAGAWA en-aut-mei=SHUNSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KOBAYASHIHISATAKA en-aut-sei=KOBAYASHI en-aut-mei=HISATAKA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NODATAKUO en-aut-sei=NODA en-aut-mei=TAKUO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KURODASHINJI en-aut-sei=KURODA en-aut-mei=SHINJI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FUJIWARATOSHIYOSHI en-aut-sei=FUJIWARA en-aut-mei=TOSHIYOSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health kn-affil= affil-num=10 en-affil=Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Neuroblastoma kn-keyword=Neuroblastoma en-keyword=GD2 kn-keyword=GD2 en-keyword=near-infrared photoimmunotherapy kn-keyword=near-infrared photoimmunotherapy en-keyword=IR700 kn-keyword=IR700 END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue= article-no= start-page=RP99936 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250811 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Redistribution of fragmented mitochondria ensures symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes en-subtitle= kn-subtitle= en-abstract= kn-abstract=In cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Depletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2 cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+ levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensures proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage. en-copyright= kn-copyright= en-aut-name=GekkoHaruna en-aut-sei=Gekko en-aut-mei=Haruna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NomuraRuri en-aut-sei=Nomura en-aut-mei=Ruri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KuzuharaDaiki en-aut-sei=Kuzuhara en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KaneyasuMasato en-aut-sei=Kaneyasu en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KosekiGenpei en-aut-sei=Koseki en-aut-mei=Genpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AdhikariDeepak en-aut-sei=Adhikari en-aut-mei=Deepak kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MioYasuyuki en-aut-sei=Mio en-aut-mei=Yasuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=CarrollJohn en-aut-sei=Carroll en-aut-mei=John kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KonoTomohiro en-aut-sei=Kono en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FunahashiHiroaki en-aut-sei=Funahashi en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=WakaiTakuya en-aut-sei=Wakai en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=3 en-affil=Reproductive Centre, Mio Fertility Clinic kn-affil= affil-num=4 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=5 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=6 en-affil=Development and Stem Cell Program and Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University kn-affil= affil-num=7 en-affil=Reproductive Centre, Mio Fertility Clinic kn-affil= affil-num=8 en-affil=Development and Stem Cell Program and Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University kn-affil= affil-num=9 en-affil=Department of Bioscience, Tokyo University of Agriculture kn-affil= affil-num=10 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= affil-num=11 en-affil=Department of Animal Science, Graduate School of Environment and Life Science, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=53 cd-vols= no-issue=22 article-no= start-page=gkaf1322 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251126 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=eIF2D promotes 40S ribosomal subunit recycling during intrinsic ribosome destabilization en-subtitle= kn-subtitle= en-abstract= kn-abstract=Although eukaryotic initiation factor 2D (eIF2D) is implicated in translation initiation, reinitiation, and ribosome recycling, its precise role remains unclear. Here, we show that eIF2D promotes 40S ribosome recycling during intrinsic ribosome destabilization (IRD), a process in which ribosomes stochastically destabilize while translating proteins with consecutive acidic amino acids at their NH2-terminus. Unrecycled 40S ribosomes accumulate in eIF2D-deficient cells, leading to 80S ribosome stalling. Selective translation complex profiling (TCP-seq) reveals that eIF2D preferentially associates with IRD-prone regions. The winged helix domain, unique to eIF2D but absent in MCTS1–DENR, enhances its binding to 40S subunits, but likely clashes with ABCE1 during stop-codon-associated recycling. Loss of eIF2D reduces the expression of IRD-inducing proteins, including splicing factors. Together, these findings define a previously unappreciated role for eIF2D in 40S recycling and clarify its mechanistic divergence from the MCTS1–DENR complex. en-copyright= kn-copyright= en-aut-name=IchiharaKazuya en-aut-sei=Ichihara en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShiraishiTaichi en-aut-sei=Shiraishi en-aut-mei=Taichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ChadaniYuhei en-aut-sei=Chadani en-aut-mei=Yuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KitoYuki en-aut-sei=Kito en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ShiraishiChisa en-aut-sei=Shiraishi en-aut-mei=Chisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HirataMina en-aut-sei=Hirata en-aut-mei=Mina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakahashiYuta en-aut-sei=Takahashi en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KoboAkinao en-aut-sei=Kobo en-aut-mei=Akinao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HatanoAtsushi en-aut-sei=Hatano en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MatsumotoMasaki en-aut-sei=Matsumoto en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MachidaKodai en-aut-sei=Machida en-aut-mei=Kodai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ImatakaHiroaki en-aut-sei=Imataka en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=ToyodaAtsushi en-aut-sei=Toyoda en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=Mishiro-SatoEmi en-aut-sei=Mishiro-Sato en-aut-mei=Emi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NojimaTakayuki en-aut-sei=Nojima en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=ItoTakuhiro en-aut-sei=Ito en-aut-mei=Takuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TaguchiHideki en-aut-sei=Taguchi en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=NakayamaKeiichi I en-aut-sei=Nakayama en-aut-mei=Keiichi I kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=MatsumotoAkinobu en-aut-sei=Matsumoto en-aut-mei=Akinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=2 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=3 en-affil=Faculty of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University kn-affil= affil-num=5 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=6 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=7 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= affil-num=8 en-affil=School of Life Science and Technology, Institute of Science Tokyo kn-affil= affil-num=9 en-affil=Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=10 en-affil=Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University kn-affil= affil-num=11 en-affil=Graduate School of Engineering, University of Hyogo kn-affil= affil-num=12 en-affil=Graduate School of Engineering, University of Hyogo kn-affil= affil-num=13 en-affil=Advanced Genomics Center, National Institute of Genetics kn-affil= affil-num=14 en-affil=Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University kn-affil= affil-num=15 en-affil=Medical Institute of Bioregulation, Kyushu University kn-affil= affil-num=16 en-affil=Laboratory for Translation Structural Biology, RIKEN Center for Integrative Medical Sciences kn-affil= affil-num=17 en-affil=School of Life Science and Technology, Institute of Science Tokyo kn-affil= affil-num=18 en-affil=Division of Cell Biology, Medical Institute of Bioregulation, Kyushu University kn-affil= affil-num=19 en-affil=Division of Biological Science, Graduate School of Science, Nagoya University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=63 cd-vols= no-issue=13 article-no= start-page=1863 end-page=1872 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240701 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Activated CD4+ T Cell Proportion in the Peripheral Blood Correlates with the Duration of Cytokine Release Syndrome and Predicts Clinical Outcome after Chimeric Antigen Receptor T Cell Therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective Chimeric antigen receptor (CAR) T cell therapy is an emerging and effective therapy for relapsed or refractory diffuse large B cell lymphoma (R/R DLBCL). The characteristic toxicities of CAR T cell therapy include cytokine release syndrome (CRS) and prolonged cytopenia. We investigated the factors associated with these complications after CAR T cell therapy by analyzing lymphocyte subsets following CAR T cell infusion.
Methods We retrospectively analyzed peripheral blood samples on days 7, 14, and 28 after tisagenlecleucel (tisa-cel) infusion by flow cytometry at our institution between June 2020 and September 2022.
Patients Thirty-five patients with R/R DLBCL who received tisa-cel therapy were included.
Results A flow cytometry-based analysis of blood samples from these patients revealed that the proportion of CD4+CD25+CD127+ T cells (hereafter referred to as "activated CD4+ T cells" ) among the total CD4+ T cells on day 7 after tisa-cel infusion correlated with the duration of CRS (r=0.79, p<0.01). In addition, a prognostic analysis of the overall survival (OS) using time-dependent receiver operating characteristic curves indicated a significantly more favorable OS and progression-free survival of patients with a proportion of activated CD4+ T cells among the total CD4+ T cells <0.73 (p=0.01, and p<0.01, respectively).
Conclusion These results suggest that the proportion of activated CD4+ T cells on day 7 after tisa-cel infusion correlates with the CRS duration and predicts clinical outcomes after CAR T cell therapy. Further studies with a larger number of patients are required to validate these observations. en-copyright= kn-copyright= en-aut-name=KitamuraWataru en-aut-sei=Kitamura en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IkegawaShuntaro en-aut-sei=Ikegawa en-aut-mei=Shuntaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FujiwaraHideaki en-aut-sei=Fujiwara en-aut-mei=Hideaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KamoiChihiro en-aut-sei=Kamoi en-aut-mei=Chihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NishimoriHisakazu en-aut-sei=Nishimori en-aut-mei=Hisakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujiiKeiko en-aut-sei=Fujii en-aut-mei=Keiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MatsuokaKen-ichi en-aut-sei=Matsuoka en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Hematology and Oncology, Okayama University Hospital, Japan kn-affil= affil-num=4 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Division of Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=9 en-affil=Division of Blood Transfusion, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=chimeric antigen receptor T cell therapy kn-keyword=chimeric antigen receptor T cell therapy en-keyword=diffuse large B cell lymphoma kn-keyword=diffuse large B cell lymphoma en-keyword=flow cytometry kn-keyword=flow cytometry en-keyword=cytokine release syndrome kn-keyword=cytokine release syndrome en-keyword=prolonged cytopenia kn-keyword=prolonged cytopenia END start-ver=1.4 cd-journal=joma no-vol=19 cd-vols= no-issue=4 article-no= start-page=e70051 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Interaction between nuclear‐translocated cellular communication network factor 2 and purine‐rich box 1 regulates the expression of fibrosis‐related genes en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cellular communication network factor 2 (CCN2) with a nuclear localization signal-like peptide is known to promote fibrosis. However, translocation of CCN2 into the nucleus and its role in fibrosis remain unclear. We hypothesized that nuclear-translocated CCN2 is associated with purine-rich box 1 (PU.1), which is a transcription factor regulating the differentiation of myofibroblasts. Western blot analysis of the cytoplasmic and nuclear fractions of cell lysate and immunofluorescence analysis revealed that CCN2 was detectable in both the cytoplasm and nuclei of murine fibroblastic NIH3T3 cells. Additionally, chromatin immunoprecipitation (IP)-PCR and an electrophoretic mobility shift assay revealed that recombinant CCN2 protein bound to the regulatory region of Spi1, which encodes PU.1. Furthermore, IP-Western blot analysis showed that CCN2 interacted with PU.1. Finally, the forced expression of both Ccn2 and Spi1 significantly promoted the production of angiotensin II, and increased fibrosis-related molecules, such as Col1a1 and Acta2, at the gene and protein levels. These findings indicate that CCN2 translocated to the nucleus interacts with PU.1 and that the complex promotes the markers of myofibroblast differentiation, suggesting that CCN2 plays an important role in fibrosis via cooperation with PU.1, as a transcription co-factor. en-copyright= kn-copyright= en-aut-name=NguyenXuan Thi en-aut-sei=Nguyen en-aut-mei=Xuan Thi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KubotaSatoshi en-aut-sei=Kubota en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakigawaMasaharu en-aut-sei=Takigawa en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishidaTakashi en-aut-sei=Nishida en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Advanced Research Center for Oral and Craniofacial Sciences, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan kn-affil= affil-num=4 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=cellular communication network factor 2 (CCN2) kn-keyword=cellular communication network factor 2 (CCN2) en-keyword=fibrosis kn-keyword=fibrosis en-keyword=myofibroblast kn-keyword=myofibroblast en-keyword=purine‐rich box 1 (PU.1) kn-keyword=purine‐rich box 1 (PU.1) en-keyword=transcription co‐factor kn-keyword=transcription co‐factor END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=4 article-no= start-page=e70082 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A Case of Retinopathy–Sensory Neuropathy Syndrome With a Novel Compound Heterozygous FLVCR1 Variant en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background and Aims: Retinopathy–sensory neuropathy syndrome (RETSNS), also known as posterior column ataxia with retinitis pigmentosa (PCARP), is a rare neurodegenerative disorder that is caused by biallelic pathogenic variants in FLVCR1. Here, we report a case of a Japanese patient with RETSNS.
Methods: Clinical, neuroradiological, and electrophysiological findings were documented. Whole-genome sequencing was performed. Subcloning was carried out to confirm compound heterozygosity. A functional assay was performed to assess the pathogenicity of the variants.
Results: The patient showed retinitis pigmentosa and sensory ataxia. Over the course of the disease, autonomic dysfunction has become increasingly evident. Despite consanguinity in the family, whole-genome sequencing identified two heterozygous variants in FLVCR1 (c.369T>G, p.Phe123Leu and c.733A>G, p.Asn245Asp). Cloning of the PCR product followed by Sanger sequencing indicated compound heterozygosity of the variants. Immunocytochemistry of HEK293FT cells transfected with plasmids containing wild-type or variant FLVCR1 cDNA demonstrated altered subcellular localization of the variant FLVCR1 proteins, characterized by reduced membrane localization.
Interpretation: We report a novel variant in FLVCR1 causing RETSNS. The functional assay supports the pathogenicity of the variants. en-copyright= kn-copyright= en-aut-name=NakanoYumiko en-aut-sei=Nakano en-aut-mei=Yumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FukuiYusuke en-aut-sei=Fukui en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=DeguchiKentaro en-aut-sei=Deguchi en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MatsuokaChika en-aut-sei=Matsuoka en-aut-mei=Chika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawanoTomohito en-aut-sei=Kawano en-aut-mei=Tomohito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TairaYuki en-aut-sei=Taira en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MatsuoAyaka en-aut-sei=Matsuo en-aut-mei=Ayaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=OsakadaYosuke en-aut-sei=Osakada en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YunokiTaijun en-aut-sei=Yunoki en-aut-mei=Taijun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NomuraEmi en-aut-sei=Nomura en-aut-mei=Emi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=TakemotoMami en-aut-sei=Takemoto en-aut-mei=Mami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MoriharaRyuta en-aut-sei=Morihara en-aut-mei=Ryuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YamashitaToru en-aut-sei=Yamashita en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=IshiuraHiroyuki en-aut-sei=Ishiura en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Neurology, Okayama City General Medical Center kn-affil= affil-num=4 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=FLCVR1 kn-keyword=FLCVR1 en-keyword=functional analysis kn-keyword=functional analysis en-keyword=posterior column ataxia with retinitis pigmentosa kn-keyword=posterior column ataxia with retinitis pigmentosa en-keyword=subcellular localization kn-keyword=subcellular localization END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=6 article-no= start-page=469 end-page=474 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Ileus Tube-Related Intussusception: A Case Report and Review of 80 Previously Reported Cases en-subtitle= kn-subtitle= en-abstract= kn-abstract=We report a rare case of ileus tube-related intussusception in an adult. A 56-year-old man with adhesive bowel obstruction was treated with a nasointestinal ileus tube. Although his condition initially improved, persistent abdominal pain led to the diagnosis of intussusception via CT imaging. Manual repositioning of the tube resolved the intussusception without the need for bowel resection. A review of 80 previously reported cases of ileus tube-associated intussusception (total 81 cases, 95 lesions) highlighted the timing of onset, treatment strategies, and precautions. Early detection and diagnosis are crucial to prevent severe complications and preserve bowel function. en-copyright= kn-copyright= en-aut-name=TsujiiTeruyuki en-aut-sei=Tsujii en-aut-mei=Teruyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsudaTatsuo en-aut-sei=Matsuda en-aut-mei=Tatsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KimuraYuji en-aut-sei=Kimura en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatsubeRyoichi en-aut-sei=Katsube en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IwadouHironori en-aut-sei=Iwadou en-aut-mei=Hironori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FunabikiSadami en-aut-sei=Funabiki en-aut-mei=Sadami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KamikawaYasuaki en-aut-sei=Kamikawa en-aut-mei=Yasuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsudaTadakazu en-aut-sei=Matsuda en-aut-mei=Tadakazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Surgery, Matsuda Hospital kn-affil= affil-num=2 en-affil=Department of Surgery, Matsuda Hospital kn-affil= affil-num=3 en-affil=Department of Surgery, Matsuda Hospital kn-affil= affil-num=4 en-affil=Department of Surgery, Matsuda Hospital kn-affil= affil-num=5 en-affil=Department of Surgery, Matsuda Hospital kn-affil= affil-num=6 en-affil=Department of Surgery, Matsuda Hospital kn-affil= affil-num=7 en-affil=Department of Surgery, Matsuda Hospital kn-affil= affil-num=8 en-affil=Department of Surgery, Matsuda Hospital kn-affil= en-keyword=nasointestinal ileus tube kn-keyword=nasointestinal ileus tube en-keyword=intussusception kn-keyword=intussusception en-keyword=small bowel obstruction kn-keyword=small bowel obstruction en-keyword=enterectomy kn-keyword=enterectomy en-keyword=conservative treatment kn-keyword=conservative treatment END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=6 article-no= start-page=463 end-page=468 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=MRI Images of a Case of Adenocarcinoma, Human Papillomavirus-Independent, Mesonephric Type, of the Uterine Cervix en-subtitle= kn-subtitle= en-abstract= kn-abstract=We present a case of a woman in her 70s who was diagnosed with mesonephric adenocarcinoma of the uterine cervix, following biopsy and surgery. Preoperative MRI revealed a 7-cm, well-defined circumferential cervical mass with left lateral wall predominance, bulging into the uterine cavity and vagina. The lesion showed intermediate signal intensity on T2-weighted images, diffusion restriction, and early contrast enhancement weaker than that of the myometrium, followed by washout on contrast-enhanced imaging. The circumferential growth pattern with the lateral wall predominance and its imaging characteristics may suggest this rare entity be routinely included in the differential diagnosis of cervical cancers. en-copyright= kn-copyright= en-aut-name=AsanoYudai en-aut-sei=Asano en-aut-mei=Yudai kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishiharaChika en-aut-sei=Nishihara en-aut-mei=Chika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KitayamaTakahiro en-aut-sei=Kitayama en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OkawaNanako en-aut-sei=Okawa en-aut-mei=Nanako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 ORCID= en-aut-name=HigakiFumiyo en-aut-sei=Higaki en-aut-mei=Fumiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KojimaKatsuhide en-aut-sei=Kojima en-aut-mei=Katsuhide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SugiharaHanako en-aut-sei=Sugihara en-aut-mei=Hanako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=IdaNaoyuki en-aut-sei=Ida en-aut-mei=Naoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YanaiHiroyuki en-aut-sei=Yanai en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HirakiTakao en-aut-sei=Hiraki en-aut-mei=Takao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Radiology, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Radiology, 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 Radiology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Radiology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Radiology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Radiology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Obstetrics and Gynecology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Obstetrics and Gynecology, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=mesonephric adenocarcinoma kn-keyword=mesonephric adenocarcinoma en-keyword=cervical cancer kn-keyword=cervical cancer en-keyword=MRI imaging characteristics kn-keyword=MRI imaging characteristics en-keyword=HPV-independent adenocarcinoma kn-keyword=HPV-independent adenocarcinoma END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=6 article-no= start-page=451 end-page=455 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Recurrence of FVIII Inhibitor during Surgery in a Patient with Severe Hemophilia A Receiving Emicizumab Prophylaxis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Emicizumab, a bispecific monoclonal antibody, benefits patients with severe hemophilia A. It alters laboratory assessments of coagulation activity, requiring anti-idiotype monoclonal antibodies for accurate monitoring. A 64-year-old man, receiving emicizumab regularly, was admitted for laminoplasty. We planned to use FVIII replacement during the perioperative period after confirming the disappearance of inhibitors, monitoring coagulation activity with anti-idiotype monoclonal antibodies. Activated partial thromboplastin time was prolonged on postoperative day 2, prompting an immediate switch to eptacog alfa. The patient recovered without bleeding. This case underscores the necessity of anti-idiotype monoclonal antibodies for accurate monitoring. en-copyright= kn-copyright= en-aut-name=HagiharaMoe en-aut-sei=Hagihara en-aut-mei=Moe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=HayashinoKenta en-aut-sei=Hayashino en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YasuharaTakao en-aut-sei=Yasuhara en-aut-mei=Takao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KinKyohei en-aut-sei=Kin en-aut-mei=Kyohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HirataYuichi en-aut-sei=Hirata en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=8 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=9 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=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=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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 Neurological Surgery, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Neurological Surgery, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Neurological Surgery, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=11 en-affil=Division of Transfusion and Cell Therapy, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=emicizumab kn-keyword=emicizumab en-keyword=eptacog alfa kn-keyword=eptacog alfa en-keyword=hemophilia A kn-keyword=hemophilia A en-keyword=inhibitor kn-keyword=inhibitor en-keyword=anti-idiotype monoclonal antibodies to emicizumab kn-keyword=anti-idiotype monoclonal antibodies to emicizumab END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=6 article-no= start-page=421 end-page=429 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effects of Thoron Inhalation and Cyclosporin A Treatment on Dextran Sulfate Sodium-Induced Oxidative Damage in Mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Radon (222Rn; Rn) and thoron (220Rn; Tn) inhalation have been reported to enhance antioxidant activity in various organs. However, the effects of Tn on the colon have not been investigated. This study aimed to clarify the effects of Tn inhalation, alone and in combination with cyclosporin A (CsA), on dextran sulfate sodium (DSS)-induced colitis, and the accompanying oxidative stress, in mice. Male BALB/c mice were subjected to continuous 8-day Tn inhalation (c-Tn, 533±128 Bq/m3) or alternate-day Tn inhalation over the same period (f-Tn, 577±63Bq/m3), followed by treatment with 3% DSS and either CsA or vehicle for 7 days. Although the disease activity index (DAI) decreased significantly by day 2 in the c-Tn group, scores remained significantly higher than those in the f-Tn group. In the c-Tn group, superoxide dismutase and catalase activity in the colon were significantly elevated compared with those in sham controls. Thus, DSS-induced damage was effectively inhibited in the earlier stages by the c-Tn mode of inhalation than by the f-Tn mode. These findings suggest that continuous Tn inhalation more effectively attenuated early colitis symptoms than alternate-day inhalation, potentially through upregulation of antioxidant defenses. Tn and CsA showed no combined effects. en-copyright= kn-copyright= en-aut-name=TanakaAyumi en-aut-sei=Tanaka en-aut-mei=Ayumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NaoeShota en-aut-sei=Naoe en-aut-mei=Shota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakenakaReiju en-aut-sei=Takenaka en-aut-mei=Reiju kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KanzakiNorie en-aut-sei=Kanzaki en-aut-mei=Norie kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SakodaAkihiro en-aut-sei=Sakoda en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YamaokaKiyonori en-aut-sei=Yamaoka en-aut-mei=Kiyonori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KataokaTakahiro en-aut-sei=Kataoka en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Graduate School of Health Sciences, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Health Sciences, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Health Sciences, Okayama University kn-affil= affil-num=4 en-affil=Ningyo-toge Environmental Engineering Center, Japan Atomic Energy Agency kn-affil= affil-num=5 en-affil=Ningyo-toge Environmental Engineering Center, Japan Atomic Energy Agency kn-affil= affil-num=6 en-affil=Faculty of Health Sciences, Okayama University kn-affil= affil-num=7 en-affil=Faculty of Health Sciences, Okayama University kn-affil= en-keyword=thoron kn-keyword=thoron en-keyword=DSS kn-keyword=DSS en-keyword=antioxidant activity kn-keyword=antioxidant activity en-keyword=CsA kn-keyword=CsA en-keyword=colon kn-keyword=colon END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=18 article-no= start-page=9127 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250918 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Interaction Between Thyroid Hormones and Bone Morphogenetic Proteins in the Regulation of Steroidogenesis by Granulosa Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Thyroid hormones are fundamental regulators of cellular differentiation, development, and metabolism. Their receptors are expressed in reproductive tissues, including the ovary, and dysregulation of thyroid hormone homeostasis has been associated with menstrual disturbances, infertility, and adverse pregnancy outcomes. Bone morphogenetic protein (BMP) ligands and their receptors are functionally involved in gonadotropin-induced ovarian steroidogenesis in an autocrine or paracrine manner. In this study, we examined the effects of thyroid hormones on steroidogenesis and their interplay with BMP signaling by using human granulosa-like KGN cells and primary rat granulosa cells (GCs). In KGN cells, triiodothyronine (T3) enhanced forskolin-induced expression of key steroidogenic enzymes involved in both estradiol biosynthesis and progesterone synthesis/metabolism, whereas thyroxine (T4) exerted minimal effects. In rat GCs, T3 treatment increased follicle-stimulating hormone (FSH)-stimulated estradiol production without altering progesterone output. T3 pretreatment attenuated BMP-6-induced phosphorylation of Smad1/5/9 in KGN cells, accompanied by upregulation of inhibitory Smad6 and downregulation of the BMP type II receptor. Conversely, BMP-6 stimulation elevated thyroid hormone receptor β expression, indicating reciprocal regulatory interactions between thyroid hormone and BMP pathways. Collectively, these findings suggest that thyroid hormones modulate steroidogenesis, at least in part, through suppression of endogenous BMP-6 signaling in granulosa cells. en-copyright= kn-copyright= en-aut-name=MotohashiKanon en-aut-sei=Motohashi en-aut-mei=Kanon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SoejimaYoshiaki en-aut-sei=Soejima en-aut-mei=Yoshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamamotoKoichiro en-aut-sei=Yamamoto en-aut-mei=Koichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IwataNahoko en-aut-sei=Iwata en-aut-mei=Nahoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SuyamaAtsuhito en-aut-sei=Suyama en-aut-mei=Atsuhito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakanoYasuhiro en-aut-sei=Nakano en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=bone morphogenetic protein (BMP) kn-keyword=bone morphogenetic protein (BMP) en-keyword=thyroid hormone kn-keyword=thyroid hormone en-keyword=steroidogenesis kn-keyword=steroidogenesis en-keyword=ovary kn-keyword=ovary END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=4 article-no= start-page=104195 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202508 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Factors affecting the development of hypokalemia during apheresis in healthy donors en-subtitle= kn-subtitle= en-abstract= kn-abstract=Despite being generally safe, apheresis for peripheral blood stem cell collection potentially disrupts electrolyte balance owing to the use of citric acid as an anticoagulant. As prior research has primarily studied hypocalcemia, information on the kinetics of potassium levels during apheresis in healthy donors is scarce. We investigated the fluctuation in potassium levels during apheresis and the risk factors for hypokalemia. This subanalysis used data from an open-label, randomized controlled trial of “oral calcium supplementation versus placebo in mitigating citrate toxicity” conducted between January 2021 and July 2022, at Okayama University Hospital. Potassium levels were significantly reduced after 5-day granulocyte colony-stimulating factor (G-CSF) administration (p < 0.0001), with seven patients (16.7 %) given oral potassium administration before apheresis because the treating physician deemed potassium levels potentially unsafe and three (7.1 %) presenting with hypokalemia at apheresis. Potassium levels after apheresis were significantly lower than those before apheresis (baseline; p < 0.0001), and 28 of 42 donors (66.7 %) experienced biochemical, clinically unapparent hypokalemia immediately after the completion of apheresis. A > 15 % reduction in potassium levels from baseline was associated with age and the acid citrate dextrose solution A (ACD-A) volume in univariate analysis. In the multivariable analysis, both factors were associated (hazard ratio [HR], 11.60; 95 % confidence interval [CI], 1.60–83.70; p = 0.02 and HR, 17.50; 95 % CI, 1.07–136.00; p = 0.04). In conclusion, G-CSF administration and apheresis ultimately induced hypokalemia in two-thirds of the donors. Older age and higher ACD-A volume may affect potassium levels during apheresis in healthy donors. en-copyright= kn-copyright= en-aut-name=KitamuraWataru en-aut-sei=Kitamura en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=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=KobayashiHiroki en-aut-sei=Kobayashi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AbeMasaya en-aut-sei=Abe en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 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=6 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Hematology 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 Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Division of Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=Allogeneic kn-keyword=Allogeneic en-keyword=Peripheral blood stem cells kn-keyword=Peripheral blood stem cells en-keyword=Hypokalemia kn-keyword=Hypokalemia en-keyword=Acid citrate dextrose solution A kn-keyword=Acid citrate dextrose solution A en-keyword=Healthy donors kn-keyword=Healthy donors END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=8 article-no= start-page=1537 end-page=1544 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250528 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Phase-Ib dose-finding and pharmacokinetic trial of metformin combined with nivolumab for refractory/recurrent solid tumors en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Our previous findings showed that the addition of metformin to nivolumab resulted in remarkable tumor regression and increased the number of tumor-infiltrating T cells in mouse models. Therefore, we conducted a phase Ib study using combination therapy with nivolumab and metformin in patients with refractory/recurrent solid tumors.
Methods This study consisted of two parts: 1, evaluating the maximum tolerated dose (MTD), safety, pharmacokinetics in solid tumors, and 2, principally investigating the safety at the recommended dose limited to thoracic and pancreatic cancers. Metformin and nivolumab were administered orally at doses of 750–2,250 mg/day and biweekly at a fixed intravenous dose of 3 mg/kg, respectively. Dose-limiting toxicity was evaluated within the first 4 weeks. Both metformin and nivolumab were continued until disease progression or discontinued because of toxicity.
Results In total, 17 and 24 patients were enrolled in parts 1 and 2, respectively. One patient experienced increased pancreatic enzyme levels (grade 4) and lactic acidosis (grade 3). No Grade 5 adverse events were observed. MTD was not reached up to 2,250 mg/day of metformin, 2,250 mg/day was selected for part 2. An objective response was observed in 4 of 41 patients. One-year progression-free and overall survival rates were 9.8% and 56.8%, respectively. Two patients remained alive without disease progression for more than three years.
Conclusions Nivolumab and metformin combination therapy was well-tolerated and showed preliminary signals of efficacy in a subset of patients. Further verification of the underlying mechanism in cases where treatment is effective is required.
Trial registration numbers UMIN registration number 000028405 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000031915. en-copyright= kn-copyright= en-aut-name=KuboToshio en-aut-sei=Kubo en-aut-mei=Toshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KatoHironari en-aut-sei=Kato en-aut-mei=Hironari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HoriguchiShigeru en-aut-sei=Horiguchi en-aut-mei=Shigeru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=AsagiAkinori en-aut-sei=Asagi en-aut-mei=Akinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YoshidaMichihiro en-aut-sei=Yoshida en-aut-mei=Michihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UdonoHeiichiro en-aut-sei=Udono en-aut-mei=Heiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 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=9 ORCID= affil-num=1 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Gastroenterology, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Gastroenterology, Okayama University Hospital kn-affil= affil-num=4 en-affil=Department of Thoracic Oncology and Medicine, NHO Shikoku Cancer Center kn-affil= affil-num=5 en-affil=Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center kn-affil= affil-num=6 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Allergy and Respiratory Medicine, Okayama University Hospital kn-affil= en-keyword=Pancreatic cancer kn-keyword=Pancreatic cancer en-keyword=Thoracic tumors kn-keyword=Thoracic tumors en-keyword=Phase Ib kn-keyword=Phase Ib en-keyword=Anti-PD-1 antibody kn-keyword=Anti-PD-1 antibody en-keyword=Nivolumab kn-keyword=Nivolumab en-keyword=Metformin kn-keyword=Metformin END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue=1 article-no= start-page=1773 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251216 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Single-cell and spatial transcriptomic characterization of pulmonary pleomorphic carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung cancer that comprises both epithelial and sarcomatoid components. The molecular basis of PPC, including the cellular dynamics of its components, remains largely unknown. To elucidate potential therapeutic targets for PPC, we perform a multi-omics analysis incorporating digital spatial profiling and single-cell RNA sequencing (scRNA-seq). PPC exhibits diverse driver gene alterations, including MET exon 14 skipping mutation (METex14) and ALK fusion. In spatial transcriptomics, MET gene and protein are overexpressed exclusively within the epithelial component and not in the sarcomatoid component, even in patients harboring METex14. Epithelial-mesenchymal transition (EMT)-related transcriptional changes, along with extracellular matrix (ECM) remodeling between the epithelial and sarcomatoid components, are observed. scRNA-seq identifies cell populations within the epithelial component that contribute to the malignant transformation and differentiation of the sarcomatoid component. They are characterized by an intermediate EMT state with ECM remodeling signature, suggesting their potential as novel therapeutic targets for PPC. 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=HisamatsuKazuya en-aut-sei=Hisamatsu en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 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=8 ORCID= en-aut-name=HigashiharaTomoaki en-aut-sei=Higashihara en-aut-mei=Tomoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=HayashiNaohiro en-aut-sei=Hayashi en-aut-mei=Naohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 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=12 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=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=SuzawaKen en-aut-sei=Suzawa en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TomiokaYasuaki en-aut-sei=Tomioka en-aut-mei=Yasuaki 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=MiyoshiKentaroh en-aut-sei=Miyoshi en-aut-mei=Kentaroh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 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=20 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=21 ORCID= en-aut-name=OtaniYusuke en-aut-sei=Otani en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=TanakaAtsushi en-aut-sei=Tanaka en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 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=24 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=25 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=26 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=27 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=28 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= 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 Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=23 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=24 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=25 en-affil=Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=26 en-affil=Department of Pathology and Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=27 en-affil=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=28 en-affil=Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=32 cd-vols= no-issue=6 article-no= start-page=dsaf030 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251022 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=MedakaBase as a unified genomic resource platform for medaka fish biology en-subtitle= kn-subtitle= en-abstract= kn-abstract=Medaka, a group of small, mostly freshwater fishes in the teleost order Beloniformes, includes the rice fish Oryzias latipes, a useful model organism studied in diverse biological fields. Chromosome-scale genome sequences of the Hd-rR strain of this species were obtained in 2007, and its improved version has facilitated various genome-wide studies. However, despite its widespread utility, omics data for O. latipes are dispersed across various public databases and lack a unified platform. To address this, the medaka section of the National Bioresource Project (NBRP) of Japan established a genome informatics team in 2022 tasked with providing various in silico solutions for bench biologists. This initiative led to the launch of MedakaBase (https://medakabase.nbrp.jp), a web server that enables gene-oriented analysis including exhaustive sequence similarity searches. MedakaBase also provides on-demand browsing of diverse genome-wide datasets, including tissue-specific transcriptomes and intraspecific genomic variations, integrated with gene models from different sources. Additionally, the platform offers gene models optimized for single-cell transcriptome analysis, which often requires coverage of the 3′ untranslated region (UTR) of transcripts. Currently, MedakaBase provides genome-wide data for seven Oryzias species, including original data for O. mekongensis and O. luzonensis produced by the NBRP team. This article outlines technical details behind the data provided by MedakaBase. en-copyright= kn-copyright= en-aut-name=MorikamiKenji en-aut-sei=Morikami en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanizawaYasuhiro en-aut-sei=Tanizawa en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YaguraMasaru en-aut-sei=Yagura en-aut-mei=Masaru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SakamotoMika en-aut-sei=Sakamoto en-aut-mei=Mika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawamotoShoko en-aut-sei=Kawamoto en-aut-mei=Shoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakamuraYasukazu en-aut-sei=Nakamura en-aut-mei=Yasukazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YamaguchiKatsushi en-aut-sei=Yamaguchi en-aut-mei=Katsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShigenobuShuji en-aut-sei=Shigenobu en-aut-mei=Shuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 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=10 ORCID= en-aut-name=KurakuShigehiro en-aut-sei=Kuraku en-aut-mei=Shigehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Molecular Life History Laboratory, Department of Genomics and Evolutionary Biology, National Institute of Genetics, Research Organization of Information and Systems kn-affil= affil-num=2 en-affil=Genome Informatics Laboratory, National Institute of Genetics, Research Organization of Information and Systems kn-affil= affil-num=3 en-affil=Molecular Life History Laboratory, Department of Genomics and Evolutionary Biology, National Institute of Genetics, Research Organization of Information and Systems kn-affil= affil-num=4 en-affil=Genome Informatics Laboratory, National Institute of Genetics, Research Organization of Information and Systems kn-affil= affil-num=5 en-affil=Department of Genetics, Sokendai (Graduate University for Advanced Studies) kn-affil= affil-num=6 en-affil=Genome Informatics Laboratory, National Institute of Genetics, Research Organization of Information and Systems kn-affil= affil-num=7 en-affil=Trans-Omics Facility, National Institute for Basic Biology kn-affil= affil-num=8 en-affil=Trans-Omics Facility, National Institute for Basic Biology kn-affil= affil-num=9 en-affil=Laboratory of Bioresources, National Institute for Basic Biology, National Institutes of Natural Sciences kn-affil= affil-num=10 en-affil=Ushimado Marine Institute, Okayama University kn-affil= affil-num=11 en-affil=Molecular Life History Laboratory, Department of Genomics and Evolutionary Biology, National Institute of Genetics, Research Organization of Information and Systems kn-affil= en-keyword=medaka kn-keyword=medaka en-keyword=comparative genomics kn-keyword=comparative genomics en-keyword=genome browser kn-keyword=genome browser en-keyword=MedakaBase kn-keyword=MedakaBase en-keyword=Beloniformes kn-keyword=Beloniformes END start-ver=1.4 cd-journal=joma no-vol=23 cd-vols= no-issue=1 article-no= start-page=1387 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251208 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tumor marker–guided precision BNCT for CA19-9–positive cancers: a new paradigm in molecularly targeted chemoradiation therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Boron neutron capture therapy (BNCT) is a molecularly targeted chemoradiation modality that relies on boron delivery agents such as p-borophenylalanine (BPA), which require LAT1 (L-type amino acid transporter 1) for tumor uptake. However, the limited efficacy of BPA in LAT1-low tumors restricts its therapeutic scope. To address this limitation, we developed a tumor marker–guided BNCT strategy targeting cancers overexpressing the clinically validated glycan biomarker CA19-9.
Methods: We conducted transcriptomic analyses using The Cancer Genome Atlas (TCGA) datasets to identify LAT1-low cancers with high CA19-9 expression. These analyses revealed elevated expression of fucosyltransferase 3 (FUT3), which underlies CA19-9 biosynthesis, in pancreatic, biliary, and ovarian malignancies. Based on this, we synthesized a novel boron compound, fucose-BSH, designed to selectively accumulate in CA19-9–positive tumors. We evaluated its physicochemical properties, pharmacokinetics, biodistribution, and antitumor efficacy in cell lines and xenograft models, comparing its performance to that of BPA.
Results: Fucose-BSH demonstrated significantly greater boron uptake in CA19-9–positive cell lines (AsPC-1, Panc 04.03, HuCCT-1, HSKTC, OVISE) compared to CA19-9–negative PANC-1. In HuCCT-1 xenografts, boron accumulation reached 36.2 ppm with a tumor/normal tissue ratio of 2.1, outperforming BPA. Upon neutron irradiation, fucose-BSH–mediated BNCT achieved > 80% tumor growth inhibition. Notably, fucose-BSH retained therapeutic efficacy in LAT1-deficient models where BPA was ineffective, confirming LAT1-independent targeting.
Conclusions: This study establishes a novel precision BNCT approach by leveraging CA19-9 as a tumor-selective glycan marker for boron delivery. Fucose-BSH offers a promising platform for expanding BNCT to previously inaccessible LAT1-low malignancies, including pancreatic, biliary, and ovarian cancers. These findings provide a clinically actionable strategy for tumor marker–driven chemoradiation and lay the foundation for translational application in BNCT. This strategy has the potential to support companion diagnostic development and precision stratification in ongoing and future BNCT clinical trials.
Translational Relevance: Malignancies with elevated CA19-9 expression, such as pancreatic, biliary, and ovarian cancers, are associated with poor prognosis and limited response to current therapies. This study presents a tumor marker–guided strategy for boron neutron capture therapy (BNCT) by leveraging CA19-9 glycan biology to enable selective tumor targeting via fucose-BSH, a novel boron compound. Through transcriptomic data mining and preclinical validation, fucose-BSH demonstrated LAT1-independent boron delivery, potent BNCT-mediated cytotoxicity, and tumor-specific accumulation in CA19-9–positive models. These findings support a precision chemoradiation approach that addresses a critical gap in BNCT applicability, offering a clinically actionable pathway for patient stratification and therapeutic development in CA19-9–expressing cancers. en-copyright= kn-copyright= en-aut-name=KanehiraNoriyuki en-aut-sei=Kanehira en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TeraishiFuminori en-aut-sei=Teraishi en-aut-mei=Fuminori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TajimaTomoyuki en-aut-sei=Tajima en-aut-mei=Tomoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OsoneTatsunori en-aut-sei=Osone en-aut-mei=Tatsunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 ORCID= en-aut-name=FujimotoTakuya en-aut-sei=Fujimoto en-aut-mei=Takuya 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=KondoNatsuko en-aut-sei=Kondo en-aut-mei=Natsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NagahisaNarikazu en-aut-sei=Nagahisa en-aut-mei=Narikazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KameiKaoru en-aut-sei=Kamei en-aut-mei=Kaoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=FujitaTaiga en-aut-sei=Fujita en-aut-mei=Taiga kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MoriharaAkira en-aut-sei=Morihara en-aut-mei=Akira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=TakaguchiYutaka en-aut-sei=Takaguchi en-aut-mei=Yutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 ORCID= en-aut-name=TakaradaTakeshi en-aut-sei=Takarada en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 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=17 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=18 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=19 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Medical Laboratory Science, Okayama University Graduate School of Health 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=Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=8 en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University 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=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=11 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= affil-num=12 en-affil=Graduate School of Environmental, Life Science, Okayama University kn-affil= affil-num=13 en-affil=Faculty of Sustainable Design, Department of Material Design and Engineering, University of Toyama kn-affil= affil-num=14 en-affil=Department of Applied Chemistry, Kindai University kn-affil= affil-num=15 en-affil=Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Institute for Integrated Radiation and Nuclear Science, Kyoto University kn-affil= affil-num=18 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=19 en-affil=Neutron Therapy Research Center, Okayama University kn-affil= en-keyword=Boron neutron capture therapy (BNCT) kn-keyword=Boron neutron capture therapy (BNCT) en-keyword=Precision BNCT kn-keyword=Precision BNCT en-keyword=Fucose-conjugated medicine kn-keyword=Fucose-conjugated medicine en-keyword=CA19-9 kn-keyword=CA19-9 en-keyword=Drug discovery kn-keyword=Drug discovery END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=10 article-no= start-page=1714 end-page=1722 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250829 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Osmotic pressure‐induced calcium response states en-subtitle= kn-subtitle= en-abstract= kn-abstract=Osmotic pressure is essential for maintaining cellular homeostasis; however, the mechanisms by which cells sense and respond to acute osmotic stress remain incompletely understood. Here, we applied rapid osmotic pressure stimulation to cultured HEK293T cells and observed dynamic intracellular calcium responses. Acute hypotonic stimulation evoked calcium response patterns, whereas hypertonic and isotonic stress did not elicit similar effects. Mechanistically, these calcium signals originated from the endoplasmic reticulum via ryanodine receptor 2 and propagated to neighboring cells through Connexin 43-mediated gap junctions. These findings reveal a previously unrecognized role for calcium signaling in the acute cellular response to osmotic stress, providing new insights into the mechanisms of intercellular communication during osmotic adaptation. en-copyright= kn-copyright= en-aut-name=GaoZidan en-aut-sei=Gao en-aut-mei=Zidan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NaruseKeiji en-aut-sei=Naruse en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MorimatsuMasatoshi en-aut-sei=Morimatsu en-aut-mei=Masatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Department of Cardiovascular Physiology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Okayama Japan kn-affil= affil-num=3 en-affil=Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Okayama Japan kn-affil= en-keyword=calcium wave kn-keyword=calcium wave en-keyword=Connexin 43 kn-keyword=Connexin 43 en-keyword=hypotonic pressure kn-keyword=hypotonic pressure en-keyword=osmotic pressure kn-keyword=osmotic pressure en-keyword=ryanodine receptor kn-keyword=ryanodine receptor END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=JCO-24-02835 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose For patients with advanced non–small cell lung cancer (NSCLC) harboring atypical epidermal growth factor receptor (EGFR) mutations (eg, S768I, L861Q, G719X), efficacy of current treatment options is limited.
Patients and Methods CHRYSALIS-2 Cohort C enrolled participants with NSCLC harboring atypical EGFR mutations (G719X, S768I, L861Q, etc) and ≤2 previous lines of therapy. Participants were treatment-naïve or previously received first- or second-generation EGFR tyrosine kinase inhibitors. Coexisting exon 20 insertions, exon 19 deletions, or exon 21 L858R mutations were exclusionary. Participants received 1,050 mg (1,400 mg if ≥80 kg) intravenous amivantamab once weekly for the first 4 weeks and then once every 2 weeks plus 240 mg oral lazertinib once daily. The primary end point was investigator-assessed objective response rate (ORR).
Results As of January 12, 2024, 105 participants received amivantamab-lazertinib. Most common atypical mutations were G719X (56%), L861X (26%), and S768I (23%), including single and compound mutations. In the overall population (median follow-up: 16.1 months), the ORR was 52% (95% CI, 42 to 62). The median duration of response (mDoR) was 14.1 months (95% CI, 9.5 to 26.2). The median progression-free survival (mPFS) was 11.1 months (95% CI, 7.8 to 17.8); median overall survival (mOS) was not estimable (NE; 95% CI, 22.8 to NE). Adverse events were consistent with previous studies and primarily grade 1 and 2. Among treatment-naïve participants, the ORR was 57% (95% CI, 42 to 71). The mPFS was 19.5 months (95% CI, 11.2 to NE), the mDoR was 20.7 months (95% CI, 9.9 to NE), and mOS was NE (95% CI, 26.3 to NE). Solitary or compound EGFR mutations had no major impact on ORR. The ORR in participants with P-loop and αC-helix compressing, classical-like, and T790M-like mutations was 45% (n = 38), 64% (n = 14), and 67% (n = 3), respectively.
Conclusion In participants with atypical EGFR-mutated advanced NSCLC, amivantamab-lazertinib demonstrated clinically meaningful antitumor activity with no new safety signals. en-copyright= kn-copyright= en-aut-name=TomasiniPascale en-aut-sei=Tomasini en-aut-mei=Pascale kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WangYongsheng en-aut-sei=Wang en-aut-mei=Yongsheng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=LiYongsheng en-aut-sei=Li en-aut-mei=Yongsheng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FelipEnriqueta en-aut-sei=Felip en-aut-mei=Enriqueta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WuLin en-aut-sei=Wu en-aut-mei=Lin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=CuiJiuwei en-aut-sei=Cui en-aut-mei=Jiuwei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=BesseBenjamin en-aut-sei=Besse en-aut-mei=Benjamin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SpiraAlexander I. en-aut-sei=Spira en-aut-mei=Alexander I. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NealJoel W. en-aut-sei=Neal en-aut-mei=Joel W. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=GotoKoichi en-aut-sei=Goto en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=BaikChristina S. en-aut-sei=Baik en-aut-mei=Christina S. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MarmarelisMelina E. en-aut-sei=Marmarelis en-aut-mei=Melina E. 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=ZhangYiping en-aut-sei=Zhang en-aut-mei=Yiping kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=LeeJong-Seok en-aut-sei=Lee en-aut-mei=Jong-Seok kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=LeeSe-Hoon en-aut-sei=Lee en-aut-mei=Se-Hoon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=YangJames Chih-Hsin en-aut-sei=Yang en-aut-mei=James Chih-Hsin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=MichelsSebastian en-aut-sei=Michels en-aut-mei=Sebastian kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=AnastasiouZacharias en-aut-sei=Anastasiou en-aut-mei=Zacharias kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=CurtinJoshua C. en-aut-sei=Curtin en-aut-mei=Joshua C. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=LyuXuesong en-aut-sei=Lyu en-aut-mei=Xuesong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=MahoneyJanine en-aut-sei=Mahoney en-aut-mei=Janine kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= en-aut-name=DemirdjianLevon en-aut-sei=Demirdjian en-aut-mei=Levon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=23 ORCID= en-aut-name=MeyerCraig S. en-aut-sei=Meyer en-aut-mei=Craig S. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=24 ORCID= en-aut-name=ZhangYouyi en-aut-sei=Zhang en-aut-mei=Youyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 ORCID= en-aut-name=LeconteIsabelle en-aut-sei=Leconte en-aut-mei=Isabelle kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=26 ORCID= en-aut-name=LorenziniPatricia en-aut-sei=Lorenzini en-aut-mei=Patricia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=KnoblauchRoland E. en-aut-sei=Knoblauch en-aut-mei=Roland E. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=TraniLeonardo en-aut-sei=Trani en-aut-mei=Leonardo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 ORCID= en-aut-name=BaigMahadi en-aut-sei=Baig en-aut-mei=Mahadi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=30 ORCID= en-aut-name=BaumlJoshua M. en-aut-sei=Bauml en-aut-mei=Joshua M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=ChoByoung Chul en-aut-sei=Cho en-aut-mei=Byoung Chul kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= affil-num=1 en-affil=Aix Marseille University - CNRS, INSERM, CRCM; CEPCM - AP-HM Hôpital de La Timone kn-affil= affil-num=2 en-affil=Division of Thoracic Tumor Multimodality Treatment, Cancer Center and Clinical Trial Center, West China Hospital, Sichuan University kn-affil= affil-num=3 en-affil=Chongqing University Cancer Hospital kn-affil= affil-num=4 en-affil=Medical Oncology Service, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona kn-affil= affil-num=5 en-affil=Department of Thoracic Medical Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University kn-affil= affil-num=6 en-affil=The First Hospital of Jilin University kn-affil= affil-num=7 en-affil=Paris-Saclay University, Institut Gustave Roussy kn-affil= affil-num=8 en-affil=Virginia Cancer Specialists kn-affil= affil-num=9 en-affil=Stanford Cancer Institute, Stanford University kn-affil= affil-num=10 en-affil=National Cancer Center Hospital East kn-affil= affil-num=11 en-affil=University of Washington Fred Hutchinson Cancer Research Center kn-affil= affil-num=12 en-affil=Perelman School of Medicine, University of Pennsylvania kn-affil= affil-num=13 en-affil=Center for Clinical Oncology, Okayama University Hospital kn-affil= affil-num=14 en-affil=Zhejiang Cancer Hospital kn-affil= affil-num=15 en-affil=Seoul National University College of Medicine and Seoul National University Hospital kn-affil= affil-num=16 en-affil=Samsung Medical Center, Sungkyunkwan University School of Medicine kn-affil= affil-num=17 en-affil=National Taiwan University Cancer Center kn-affil= affil-num=18 en-affil=Department I for Internal Medicine, Faculty of Medicine and University Hospital Cologne, Lung Cancer Group Cologne, Center for Integrated Oncology Aachen Köln Bonn Düsseldorf, University of Cologne kn-affil= affil-num=19 en-affil=Johnson & Johnson kn-affil= affil-num=20 en-affil=Johnson & Johnson kn-affil= affil-num=21 en-affil=Johnson & Johnson kn-affil= affil-num=22 en-affil=Johnson & Johnson kn-affil= affil-num=23 en-affil=Johnson & Johnson kn-affil= affil-num=24 en-affil=Johnson & Johnson kn-affil= affil-num=25 en-affil=Johnson & Johnson kn-affil= affil-num=26 en-affil=Johnson & Johnson kn-affil= affil-num=27 en-affil=Johnson & Johnson kn-affil= affil-num=28 en-affil=Johnson & Johnson kn-affil= affil-num=29 en-affil=Johnson & Johnson kn-affil= affil-num=30 en-affil=Johnson & Johnson kn-affil= affil-num=31 en-affil=Johnson & Johnson kn-affil= affil-num=32 en-affil=Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine kn-affil= END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=1 article-no= start-page=2586329 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251130 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Asiatic acid, a novel ciprofloxacin adjuvant inhibits Shigella flexneri infection en-subtitle= kn-subtitle= en-abstract= kn-abstract=Bacterial infection caused by intracellular pathogens such as Shigella flexneri is a rapidly increasing global health concern that requires urgent and necessary action. The dearth of licensed vaccines against shigellosis and the decline in susceptibility to conventional antibiotics has encouraged the development of new antibiotic principles and drugs. The treatment options are decreasing faster than the discovery rate of new antibacterial agents. Combinatorial approach of antibiotics with non-antibiotic adjuvants is a promising aspect to treat resistant bacterial infections. Asiatic acid, a membrane-disrupting triterpenoid with wide antimicrobial and immunomodulatory properties, can potentiate antibiotics, but the exact mechanisms remain broadly unexplored. Therefore, in this study, we screened the interaction of asiatic acid with several antibiotics. The results showed synergistic interactions of asiatic acid with antibiotics against susceptible and multidrug-resistant S. flexneri clinical isolates. Particularly important was the interaction of asiatic acid with the quinolone antibiotics ciprofloxacin and nalidixic acid. A detailed study showed that combined treatment of asiatic acid with ciprofloxacin inhibited S. flexneri biofilm formation and resistance development. An increase in membrane disruption and depolarization upon co-treatment was evident by surface electron and confocal microscopy. In addition, asiatic acid and ciprofloxacin synergism was identified to inhibit efflux activity and intracellular bacterial viability. However, asiatic acid showed no synergistic toxicity with ciprofloxacin towards mammalian cells. The antibacterial activity was further verified in a S. flexneri infected mice model. Therapeutic benefits were evident with reduced bacterial burden, recovery from intestinal tissue damage and increase in mice survivability. The results showed that this combination can target the bacterial membrane, efflux pump proteins and biofilm formation, thereby preventing resistance development. The combination treatment offers a proof of concept in targeting essential bacterial activities and might be developed into a novel and efficient treatment alternative against S. flexneri. en-copyright= kn-copyright= en-aut-name=MaitraPriyanka en-aut-sei=Maitra en-aut-mei=Priyanka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=BhuktaSamhati en-aut-sei=Bhukta en-aut-mei=Samhati kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GopeAnimesh en-aut-sei=Gope en-aut-mei=Animesh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KayetPratanu en-aut-sei=Kayet en-aut-mei=Pratanu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=BasakSurajit en-aut-sei=Basak en-aut-mei=Surajit kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=KitaharaKei en-aut-sei=Kitahara en-aut-mei=Kei 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=BhattacharyaSushmita en-aut-sei=Bhattacharya en-aut-mei=Sushmita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections kn-affil= affil-num=2 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections kn-affil= affil-num=3 en-affil=Division of Clinical Medicine, ICMR-National Institute for Research in Bacterial Infections kn-affil= affil-num=4 en-affil=Division of Bioinformatics, ICMR-National Institute for Research in Bacterial Infections kn-affil= affil-num=5 en-affil=Division of Bioinformatics, ICMR-National Institute for Research in Bacterial Infections kn-affil= affil-num=6 en-affil=Division of Pharmaceutical Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Collaborative Research Center of Okayama University for Infectious Diseases in India, ICMR-National Institute for Research in Bacterial Infections kn-affil= affil-num=8 en-affil=Department of Bacteriology, ICMR-National Institute for Research in Bacterial Infections kn-affil= affil-num=9 en-affil=Division of Biochemistry, ICMR-National Institute for Research in Bacterial Infections kn-affil= en-keyword=Shigella flexneri kn-keyword=Shigella flexneri en-keyword=asiatic acid kn-keyword=asiatic acid en-keyword=ciprofloxacin kn-keyword=ciprofloxacin en-keyword=adjuvant kn-keyword=adjuvant en-keyword=membrane damage kn-keyword=membrane damage en-keyword=depolarization kn-keyword=depolarization en-keyword=nuclear damage kn-keyword=nuclear damage en-keyword=efflux inhibitor kn-keyword=efflux inhibitor END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=e13537 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251203 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Atomic-Level Insights into Thermal Carbonization of Ethynyl-Containing Boron Compounds en-subtitle= kn-subtitle= en-abstract= kn-abstract=This study reports the design, synthesis, and characterization of boron-doped carbon (BDC) derived from a triethynylborane-pyridine complex. Triethynylborane is stabilized by coordination with pyridine, facilitating its synthesis and handling in ambient conditions. The complex is subjected to thermal treatment at various temperatures to form BDC. Powder XRD and single-crystal XRD analyses reveal that BDC prepared at 200 °C retains an ordered structure, while higher temperatures induce alkyne structural changes without significant weight or surface area alterations. Coin cells are assembled using BDC as the anode, demonstrating unique Li-ion and Na-ion storage properties distinct from graphite. These results suggest that the BDC reflects the precursor's crystal structure, enabling novel electrochemical behavior. These findings offer insight into the development of advanced BDC materials for energy storage applications. en-copyright= kn-copyright= en-aut-name=OhkuraKentaro en-aut-sei=Ohkura en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HayakawaSatoshi en-aut-sei=Hayakawa en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakahashiNaoki en-aut-sei=Takahashi en-aut-mei=Naoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamazakiKen en-aut-sei=Yamazaki en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KanoJun en-aut-sei=Kano en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NishinaYuta en-aut-sei=Nishina en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= affil-num=2 en-affil=Faculty of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environment Life Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environment Life Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Environment Life Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= en-keyword=boron-doped carbon kn-keyword=boron-doped carbon en-keyword=carbonization kn-keyword=carbonization en-keyword=ethynyl group kn-keyword=ethynyl group en-keyword=Li-ion kn-keyword=Li-ion en-keyword=Na-ion kn-keyword=Na-ion END start-ver=1.4 cd-journal=joma no-vol=5 cd-vols= no-issue=1 article-no= start-page=ycaf192 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202501 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Proliferation of a bloom-forming phytoplankton via uptake of polyphosphate-accumulating bacteria under phosphate-limiting conditions en-subtitle= kn-subtitle= en-abstract= kn-abstract=Harmful algal blooms negatively impact the ecosystem and fisheries in affected areas. Eutrophication is a major factor contributing to bloom occurrence, and phosphorus is particularly important in limiting the growth of bloom-forming algae. Although algae efficiently utilize orthophosphate (Pi) as a phosphorous source over other molecular forms, Pi is often limited in the marine environment. While uptake and utilization of soluble inorganic and organic phosphorous by bloom-forming algae has been extensively studied, the details of geochemical and biological phosphorous cycling remain to be elucidated. Here, we report for the first time that the bloom-forming alga Heterosigma akashiwo can phagocytose bacteria and grow under phosphate-depleted conditions. The addition of Vibrio comitans to Pi-depleted H. akashiwo enabled the alga propagate to high cell densities, whereas other bacterial strains had only a minor effect. Importantly, V. comitans accumulates polyphosphate—a linear polymer of Pi—at high levels. The extent of algal proliferation induced by the addition of Vibrio species and polyphosphate-accumulating Escherichia coli correlated strongly with their polyphosphate content, indicating that bacterial polyphosphate served as an alternative PO43− source for H. akashiwo. The direct uptake of polyphosphate-accumulating bacteria through algal phagocytosis may represent a novel biological phosphorous-cycling pathway in marine ecosystems. The role of polyphosphate-accumulating marine bacteria as a hidden phosphorous source required for bloom formation warrants further investigation. en-copyright= kn-copyright= en-aut-name=FukuyamaSeiya en-aut-sei=Fukuyama en-aut-mei=Seiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=UsamiFumiko en-aut-sei=Usami en-aut-mei=Fumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HirotaRyuichi en-aut-sei=Hirota en-aut-mei=Ryuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=OharaShizuka en-aut-sei=Ohara en-aut-mei=Shizuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KondoKen en-aut-sei=Kondo en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=GomibuchiYuki en-aut-sei=Gomibuchi en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YasunagaTakuo en-aut-sei=Yasunaga en-aut-mei=Takuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OndukaToshimitsu en-aut-sei=Onduka en-aut-mei=Toshimitsu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KurodaAkio en-aut-sei=Kuroda en-aut-mei=Akio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KoikeKazuhiko en-aut-sei=Koike en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=UekiShoko en-aut-sei=Ueki en-aut-mei=Shoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=Graduate School of Integrated Sciences for Life, Hiroshima 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 Integrated Sciences for Life, Hiroshima University kn-affil= affil-num=6 en-affil=Research Institute of Environment, Agriculture and Fisheries , Osaka Prefecture kn-affil= affil-num=7 en-affil=Department of Physics and Information Technology, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology kn-affil= affil-num=8 en-affil=Department of Physics and Information Technology, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology kn-affil= affil-num=9 en-affil=Hatsukaichi Branch, Fisheries Technology Institute , Fisheries Research and Education Agency kn-affil= affil-num=10 en-affil=Graduate School of Integrated Sciences for Life, Hiroshima University kn-affil= affil-num=11 en-affil=Graduate School of Integrated Sciences for Life, Hiroshima University kn-affil= affil-num=12 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=68 cd-vols= no-issue=1 article-no= start-page=100720 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=Dynamin 2 is involved in osteoblast migration by regulating the organization of F-actin en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objectives: Dynamin, a GTPase that regulates membrane dynamics, has recently been implicated in actin cytoskeletal remodeling. This study aimed to elucidate the role of dynamin in osteoblast migration by examining the effects of dynamin inhibition on the localization and organization of F-actin and dynamin 2 in MC3T3-E1 cells.
Methods: MC3T3-E1 cells were treated with dynamin inhibitors (Dyngo 4a and Dynole 34-2), and cell migration was assessed using a wound-healing assay. Fluorescent staining was performed to analyze the intracellular localization of F-actin and dynamin 2.
Results: Dynamin inhibition significantly reduced the migration of MC3T3-E1 cells. Fluorescence analysis revealed a marked decrease in the accumulation and colocalization of F-actin and dynamin 2 at the protrusion edge. Additionally, dynamin inhibition suppressed the formation of lamellipodia and stress fibers while promoting the appearance of abnormal F-actin clusters in the cytoplasm.
Conclusions: These findings suggest that dynamin plays an essential role in osteoblast migration by regulating actin cytoskeletal remodeling, particularly through the formation of lamellipodia and stress fibers. en-copyright= kn-copyright= en-aut-name=MoriyaTakumi en-aut-sei=Moriya en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SurongA. en-aut-sei=Surong en-aut-mei=A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TatsumiNanami en-aut-sei=Tatsumi en-aut-mei=Nanami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamadaHiroshi en-aut-sei=Yamada en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakemotoFumiko en-aut-sei=Takemoto en-aut-mei=Fumiko 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=OkamuraHirohiko en-aut-sei=Okamura en-aut-mei=Hirohiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=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 Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Neuroscience, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Orthodontics, Okayama University Hospital 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 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=Dynamin kn-keyword=Dynamin en-keyword=Cell migration kn-keyword=Cell migration en-keyword=Osteoblasts kn-keyword=Osteoblasts en-keyword=F-actin kn-keyword=F-actin END start-ver=1.4 cd-journal=joma no-vol=27 cd-vols= no-issue=1 article-no= start-page=219 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251121 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Does perioperative discontinuation of anti-rheumatic drugs increase postoperative complications in orthopedic surgery for rheumatoid arthritis? en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective This study aimed to investigate whether discontinuation of biological or targeted synthetic antirheumatic disease-modifying drugs (bDMARDs or tsDMARDs) influences the incidence of postoperative complications in patients with rheumatoid arthritis (RA) undergoing orthopedic surgery.
Methods A retrospective multicenter cohort study including patients receiving bDMARDs or tsDMARDs who underwent orthopedic surgery was conducted. Data collected encompassed the duration of drug discontinuation and postoperative adverse events, such as delayed wound healing, surgical site infection (SSI), disease flare-ups, and mortality. The association between drug discontinuation and these outcomes was analyzed. Multivariate analyses were conducted to identify potential risk factors for these events.
Results A total of 2,060 cases were initially enrolled. After applying inclusion and exclusion criteria, data from 1,953 patients were analyzed. No significant differences were observed between the groups regarding delayed wound healing, SSI, or mortality. However, the incidence of disease flare-ups was substantially higher in the drug discontinuation group and in the interleukin (IL)-6 inhibitor group. Multivariate analysis identified that tumor necrosis factor α and IL-6 inhibitor use was associated with a higher risk of delayed wound healing relative to T-cell function modifiers.
Conclusion In orthopedic surgery for patients with RA, maintaining the standard or the half of administration interval of bDMARD appears safe in the preoperative period. However, the drug discontinuation may increase the risk of postoperative flare-ups, particularly with IL-6 inhibitors. In addition, T-cell function modifiers may be associated with a lower risk of delayed wound healing, suggesting their safety profile in this context. en-copyright= kn-copyright= en-aut-name=ItoHiromu en-aut-sei=Ito en-aut-mei=Hiromu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IshikawaHajime en-aut-sei=Ishikawa en-aut-mei=Hajime kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TsujiShigeyoshi en-aut-sei=Tsuji en-aut-mei=Shigeyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 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=5 ORCID= en-aut-name=MochizukiTakeshi en-aut-sei=Mochizuki en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=EbinaKosuke en-aut-sei=Ebina en-aut-mei=Kosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KojimaToshihisa en-aut-sei=Kojima en-aut-mei=Toshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MatsumotoTakumi en-aut-sei=Matsumoto en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KubotaAyako en-aut-sei=Kubota en-aut-mei=Ayako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=NakajimaArata en-aut-sei=Nakajima en-aut-mei=Arata kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KanekoAtsushi en-aut-sei=Kaneko en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MatsushitaIsao en-aut-sei=Matsushita en-aut-mei=Isao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=HaraRyota en-aut-sei=Hara en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=SakurabaKoji en-aut-sei=Sakuraba en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=AkasakiYukio en-aut-sei=Akasaki en-aut-mei=Yukio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=MatsubaraTsukasa en-aut-sei=Matsubara en-aut-mei=Tsukasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=MochidaYuichi en-aut-sei=Mochida en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=KanbeKatsuaki en-aut-sei=Kanbe en-aut-mei=Katsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=NakagawaNatsuko en-aut-sei=Nakagawa en-aut-mei=Natsuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=MurataKoichi en-aut-sei=Murata en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= en-aut-name=MomoharaShigeki en-aut-sei=Momohara en-aut-mei=Shigeki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=22 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Kurashiki Central Hospital kn-affil= affil-num=2 en-affil=Department of Rheumatology, Niigata Rheumatic Center kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Osaka Minami Medical Center kn-affil= affil-num=4 en-affil=Department of Orthopaedic Surgery, International University of Health and Welfare kn-affil= affil-num=5 en-affil=Locomotive Pain Center, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery, Kamagaya General Hospital kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Osaka University Faculty of Medicine Graduate School of Medicine kn-affil= affil-num=8 en-affil=Department of Orthopaedic Surgery, Nagoya University Hospital kn-affil= affil-num=9 en-affil=Department of Orthopaedic Surgery, University of Tokyo kn-affil= affil-num=10 en-affil=Department of Orthopaedic Surgery, Toho University Omori Medical Center kn-affil= affil-num=11 en-affil=Department of Orthopaedic Surgery and Rehabilitation, Toho University Sakura Medical Center kn-affil= affil-num=12 en-affil=Department of Orthopaedic Surgery, Nagoya Medical Center kn-affil= affil-num=13 en-affil=Department of Rehabilitation Medicine, Kanazawa Medical University kn-affil= affil-num=14 en-affil=The Center for Rheumatic Diseases, Nara Medical University kn-affil= affil-num=15 en-affil=Department of Orthopaedic Surgery, Kyushu Medical Center kn-affil= affil-num=16 en-affil=Department of Orthopaedic Surgery, Kyushu University kn-affil= affil-num=17 en-affil=Department of Orthopaedic Surgery, Matsubara Mayflower Hospital kn-affil= affil-num=18 en-affil=Department of Orthopaedic Surgery, Yokohama City University Medical Center kn-affil= affil-num=19 en-affil=Department of Orthopaedic Surgery, Nippori Orthopaedics and Rheumatic Clinic kn-affil= affil-num=20 en-affil=Department of Orthopaedic Surgery, Kakogawa Medical Center kn-affil= affil-num=21 en-affil=Department of Orthopaedic Surgery, Kyoto University Graduate School of Medicine kn-affil= affil-num=22 en-affil=Endowed Course for Advanced Therapy for Musculoskeletal Disorders, Keio University School of Medicine kn-affil= en-keyword=Rheumatoid arthritis kn-keyword=Rheumatoid arthritis en-keyword=Orthopaedic surgery kn-keyword=Orthopaedic surgery en-keyword=DMARD kn-keyword=DMARD en-keyword=Perioperative complications kn-keyword=Perioperative complications END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=19 article-no= start-page=9630 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251002 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Critical Requirement of Senescence-Associated CCN3 Expression in CD44-Positive Stem Cells for Osteoarthritis Progression en-subtitle= kn-subtitle= en-abstract= kn-abstract=Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage breakdown, synovial inflammation, and subchondral bone remodeling. Previous studies have shown that cellular communication network factor 3 (CCN3) expression increases with age in cartilage, and its overexpression promotes OA-like changes by inducing senescence-associated secretory phenotypes. This study aimed to investigate the effect of Ccn3 knockout (KO) on OA development using a murine OA model. Destabilization of the medial meniscus (DMM) surgery was performed in wild-type (WT) and Ccn3-KO mice. Histological scoring and staining were used to assess cartilage degeneration and proteoglycan loss. Gene and protein expressions of catabolic enzyme (Mmp9), hypertrophic chondrocyte marker (Col10a1), senescence marker, and cyclin-dependent kinase inhibitor 1A (Cdkn1a) were evaluated. Single-cell RNA sequencing (scRNA-seq) data from WT and Sox9-deficient cartilage were reanalyzed to identify Ccn3+ progenitor populations. Immunofluorescence staining assessed CD44 and Ki67 expression in articular cartilage. The effects of Ccn3 knockdown on IL-1β-induced Mmp13 and Adamts5 expression in chondrocytes were examined in vitro. Ccn3 KO mice exhibited reduced cartilage degradation and catabolic gene expression compared with WT mice post-DMM. scRNA-seq revealed enriched Ccn3-Cd44 double-positive cells in osteoblast progenitor, synovial mesenchymal stem cell, and mesenchymal stem cell clusters. Immunofluorescence showed increased CCN3+/CD44+ cells in femoral and tibial cartilage and meniscus. Ki67+ cells were significantly increased in DMM-treated Ccn3 KO cartilage, mostly CD44+. In vitro Ccn3 knockdown attenuated IL-1β-induced Mmp13 and Adamts5 expressions in chondrocytes. Ccn3 contributes to OA pathogenesis by promoting matrix degradation, inducing hypertrophic changes, and restricting progenitor cell proliferation, highlighting Ccn3 as a potential therapeutic target for OA. en-copyright= kn-copyright= en-aut-name=HabumugishaJanvier en-aut-sei=Habumugisha en-aut-mei=Janvier kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OkudaRyuichiro en-aut-sei=Okuda en-aut-mei=Ryuichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HiroseKazuki en-aut-sei=Hirose en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KuwaharaMiho en-aut-sei=Kuwahara en-aut-mei=Miho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OnoMitsuaki en-aut-sei=Ono en-aut-mei=Mitsuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KamiokaHiroshi en-aut-sei=Kamioka en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 ORCID= en-aut-name=HattoriTakako en-aut-sei=Hattori en-aut-mei=Takako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Molecular Biology and Biochemistry, 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 Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=articular kn-keyword=articular en-keyword=cartilage kn-keyword=cartilage en-keyword=mesenchymal stem cells kn-keyword=mesenchymal stem cells en-keyword=nephroblastoma overexpressed protein kn-keyword=nephroblastoma overexpressed protein en-keyword=osteoarthritis kn-keyword=osteoarthritis END start-ver=1.4 cd-journal=joma no-vol=1873 cd-vols= no-issue=2 article-no= start-page=120091 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=SPRED2 controls the severity of cisplatin-induced acute kidney injury by inhibiting ERK activation and TNFα production in mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cisplatin is an effective chemotherapeutic agent used to treat solid tumors, but its clinical use is limited by acute kidney injury (AKI), in which ERK signaling plays a crucial role. Here, we investigated whether Sprouty-related EVH1 domain-containing protein 2 (SPRED2), an endogenous inhibitor of the Ras/Raf/ERK pathway, protects against cisplatin-induced AKI. Spred2−/− mice showed more severe renal injury and stronger ERK activation than wild-type (WT) mice, whereas pretreatment with the MEK inhibitor U0126 markedly attenuated the injury. In HK-2 cells (proximal tubular cells), SPRED2 knockdown enhanced cisplatin-induced apoptosis and caspase-3 activation, accompanied by decreased Bcl-2 expression. Spred2−/− kidneys displayed increased macrophage infiltration and elevated Tnfα, Il1b, and Ccl2 expression. Neutralization of TNFα with anti-TNFα antibody ameliorated renal injury and reduced the levels of Il1b and Ccl2 mRNA in Spred2−/− mice. In vitro, TNFα slightly decreased the viability of control and SPRED2 knockdown HK-2 cells without cisplatin treatment, but the decreased viability was augmented in SPRED2 knockdown cells by cisplatin. Immunohistochemistry revealed that macrophages were the predominant TNFα-positive cell population. Bone marrow–derived macrophages from Spred2−/− mice produced higher levels of TNFα in response to cisplatin compared with control cells, and this increase was markedly suppressed by U0126.
These findings indicate that endogenous SPRED2 protects kidneys from cisplatin-induced AKI by limiting ERK activation, tubular apoptosis, and TNFα-mediated inflammation. en-copyright= kn-copyright= en-aut-name=YangXu en-aut-sei=Yang en-aut-mei=Xu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HeJiali en-aut-sei=He en-aut-mei=Jiali kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 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=4 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=5 ORCID= en-aut-name=KunkelSteven L. en-aut-sei=Kunkel en-aut-mei=Steven L. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshimuraTeizo en-aut-sei=Yoshimura en-aut-mei=Teizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsukawaAkihiro en-aut-sei=Matsukawa en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of 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, University of Michigan Medical School 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=Cisplatin kn-keyword=Cisplatin en-keyword=ERK kn-keyword=ERK en-keyword=Macrophage kn-keyword=Macrophage en-keyword=SPRED2 kn-keyword=SPRED2 en-keyword=TNFα kn-keyword=TNFα END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251123 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A rare case of supratentorial ependymosarcoma harboring ZFTA::RELA fusion en-subtitle= kn-subtitle= en-abstract= kn-abstract=Ependymosarcoma is an exceedingly rare variant of ependymoma characterized by a mixture of ependymomatous and sarcomatous components. We report a case of supratentorial ependymosarcoma harboring a ZFTA::RELA fusion in a 10-year-old girl. Histologically, the tumor comprised an ependymomatous component resembling clear cell ependymoma and a sarcomatous component. ZFTA::RELA fusion was confirmed in both components. Genome-wide methylation profiling classified both components as supratentorial ependymoma, ZFTA fusion–positive by the German Cancer Research Center (DKFZ) CNS tumor classifier v12b8. However, their copy number alteration profiles were distinct. The ependymomatous component exhibited a gain of chromosome 1q and a loss of chromosomes 1p, 9, and 19q, while the sarcomatous component showed a loss of chromosome 14. These findings suggest that both components may have differentiated from a common precursor despite their distinct morphologies. The patient underwent gross total resection followed by adjuvant chemoradiotherapy and remains recurrence-free eight years post-treatment. Further investigation of additional cases is warranted to better understand the pathogenesis of this rare tumor. en-copyright= kn-copyright= en-aut-name=MatsumotoYuji en-aut-sei=Matsumoto en-aut-mei=Yuji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SurugaYasuki en-aut-sei=Suruga en-aut-mei=Yasuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SatomiKaishi en-aut-sei=Satomi en-aut-mei=Kaishi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=InoueYohei en-aut-sei=Inoue en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HattoriYasuhiko en-aut-sei=Hattori en-aut-mei=Yasuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=IshidaJoji en-aut-sei=Ishida en-aut-mei=Joji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KurozumiKazuhiko en-aut-sei=Kurozumi en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NobusawaSumihito en-aut-sei=Nobusawa en-aut-mei=Sumihito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HiratoJunko en-aut-sei=Hirato en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=10 ORCID= en-aut-name=YanaiHiroyuki en-aut-sei=Yanai en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=WashioKana en-aut-sei=Washio en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=IchimuraKoichi en-aut-sei=Ichimura en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=IchikawaTomotsugu en-aut-sei=Ichikawa en-aut-mei=Tomotsugu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=OtaniYoshihiro en-aut-sei=Otani en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TanakaShota en-aut-sei=Tanaka en-aut-mei=Shota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Pathology, Faculty of Medicine, Kyorin University kn-affil= affil-num=4 en-affil=Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=5 en-affil=Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of Neurosurgery, Hamamatsu University Hospital kn-affil= affil-num=8 en-affil=Department of Human Pathology, Gunma University School of Medicine kn-affil= affil-num=9 en-affil=Department of Pathology, Public Tomioka General Hospital kn-affil= affil-num=10 en-affil=Department of Pathology, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Pathology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Pediatrics, Okayama University Hospital kn-affil= affil-num=13 en-affil=Department of Pathology, Faculty of Medicine, Kyorin University kn-affil= affil-num=14 en-affil=Department of Neurosurgery, Kagawa Prefectural Central Hospital kn-affil= affil-num=15 en-affil=Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=16 en-affil=Department of Neurological Surgery, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= en-keyword=Ependymoma kn-keyword=Ependymoma en-keyword=Ependymosarcoma kn-keyword=Ependymosarcoma en-keyword=ZFTA kn-keyword=ZFTA en-keyword=RELA kn-keyword=RELA en-keyword=Methylation profiling kn-keyword=Methylation profiling END start-ver=1.4 cd-journal=joma no-vol=64 cd-vols= no-issue=6 article-no= start-page=104265 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202512 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Novel leukocytapheresis method using highly concentrated sodium citrate solution for the manufacturing of tisagenlecleucel en-subtitle= kn-subtitle= en-abstract= kn-abstract=For the manufacturing of tisagenlecleucel (tisa-cel) requires the non-mobilized mononuclear cell collection (MNC). CD3+ cell collection is performed using the same protocol as autologous peripheral blood stem cell harvest (auto-PBSCH), but this procedure necessitates the same target CD3+ cell yields regardless of age or body weight, which may take several days especially in pediatric and small female patients with low white blood cell counts. We previously demonstrated a novel method using highly concentration sodium citrate (HSC), which reduced the need for an anticoagulant (AC) solution and shortened the procedure time in auto-PBSCH. This novel method was expected to offer advantages for smaller patients, prompting us to investigate its application in leukocytapheresis for the manufacturing of tisa-cel. We retrospectively analyzed consecutive leukocytapheresis data obtained using Spectra Optia continuous MNC mode between November 2022 and June 2024 at our institution (n = 9). In six of nine patients, pre-leukocytapheresis CD3+ cell counts were less than 500 /μL, but all could obtain the target CD3+ cell yields in one day upon processing blood volume adjustment. When we compared patients who had received CD3+ cell collection using normal-concentration sodium citrate (NSC) as our previously reported using propensity score-matched pair analysis, the total AC solution volume was significantly lower (1168 vs. 316 mL, p < 0.001) and procedure time was significantly shorter (254 vs. 228 min, p = 0.04) in the HSC group compared to the NSC group. In conclusion, this procedure was also useful for non-mobilized MNC. Our findings warrant validation in a larger patient cohort. en-copyright= kn-copyright= en-aut-name=KitamuraWataru en-aut-sei=Kitamura en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=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=AbeMasaya en-aut-sei=Abe en-aut-mei=Masaya 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=WashioKana en-aut-sei=Washio en-aut-mei=Kana 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 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 Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Pediatrics, 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 and Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=Chimeric antigen receptor T cell therapy kn-keyword=Chimeric antigen receptor T cell therapy en-keyword=Anticoagulant kn-keyword=Anticoagulant en-keyword=Acid citrate dextrose solution A kn-keyword=Acid citrate dextrose solution A en-keyword=Highly concentrated sodium citrate kn-keyword=Highly concentrated sodium citrate END start-ver=1.4 cd-journal=joma no-vol=65 cd-vols= no-issue=9 article-no= start-page=1662 end-page=1672 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250725 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Novel method for autologous peripheral blood stem cell harvest using highly concentrated sodium citrate solution replacing acid citrate dextrose solution A en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: As the processed blood volume increases, a larger amount of anticoagulant (AC) is required, which leads to a serious issue of fluid dilution in large-volume leukocytapheresis (defined as ≥3-fold total blood volume). We previously reported a novel method for allogeneic peripheral blood stem cell harvest (PBSCH) using highly concentrated sodium citrate (HSC; 5.32%), which shortened the procedure time and reduced the need for an AC solution without heparin. In this study, we extended this novel method to autologous PBSCH (auto-PBSCH) and compared it with patients who received auto-PBSCH using normal concentrated sodium citrate (NSC; 2.2%).
Study Design and Methods: We retrospectively analyzed consecutive auto-PBSCH data obtained using the Spectra Optia continuous mononuclear cell collection mode between May 2017 and May 2025 at our institution.
Results: Leukocytapheresis was performed using NSC in 36 patients and HSC in 22. In the HSC group, patients tended to be younger, had significantly lower body weight, and had significantly fewer hematopoietic tumors as primary diseases compared to the NSC group. After propensity score-matched cohort adjusted for patient background, the total amount of AC solution was significantly lower (694 [range, 77–1648] vs. 298 mL [range, 64–797], p = .02), and procedure time was significantly shorter (224 [range, 117–395] vs. 181 min [range, 103–309], p = .048) in the HSC group. Furthermore, the loss rates of magnesium and potassium were lower in the HSC group.
Conclusion: This novel leukocytapheresis method demonstrated the efficacy and safety in auto-PBSCH, while minimizing the patient burden. en-copyright= kn-copyright= en-aut-name=KitamuraWataru en-aut-sei=Kitamura en-aut-mei=Wataru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=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=AbeMasaya en-aut-sei=Abe en-aut-mei=Masaya 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=WashioKana en-aut-sei=Washio en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OtsukaFumio en-aut-sei=Otsuka en-aut-mei=Fumio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MaedaYoshinobu en-aut-sei=Maeda en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Hematology 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 Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Pediatrics, Okayama University Hospital kn-affil= affil-num=7 en-affil=Division of Clinical Laboratory, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=acid citrate dextrose solution A kn-keyword=acid citrate dextrose solution A en-keyword=anticoagulant kn-keyword=anticoagulant en-keyword=autologous kn-keyword=autologous en-keyword=highly concentrated sodium citrate kn-keyword=highly concentrated sodium citrate en-keyword=peripheral blood stem cell kn-keyword=peripheral blood stem cell END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=10 article-no= start-page=e95808 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251031 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=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=Skeletal-related events (SREs) frequently occur in patients with bone metastases from non-small cell lung cancer (NSCLC). This study aimed to identify risk factors for SREs in patients with NSCLC. Based on these factors, we also aimed to stratify patients into subgroups to facilitate the assessment of SRE risk. This retrospective analysis used medical records of 139 patients with NSCLC bone metastases who received treatment at our institution between 2011 and 2014. The incidence of SREs was assessed, and SRE-free survival was analyzed using the Kaplan-Meier method. Clinical information collected at registration was assessed to identify factors associated with the onset of SREs within six months. Univariate analysis was performed using Fisher’s exact test, and multivariate analysis was performed using Cox regression. Of the 139 patients, 36 (26%) developed SREs after registration. The SRE-free survival rates were 80% and 64% at 6 and 12 months, respectively. The univariate and multivariate analyses revealed that the absence of epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangement (hazard ratio (HR): 4.51, 95% confidence interval (CI): 1.32-15.7, p = 0.017) and a lactate dehydrogenase (LDH) level ≥400 U/L (HR: 8.08, 95% CI: 1.78-36.6, p = 0.0067) were risk factors for SRE presentation within six months. Patients were classified into the following three subgroups: with EGFR mutation or ALK rearrangement and LDH level <400 U/L; without EGFR mutation or ALK rearrangement and LDH level <400 U/L; with/without EGFR mutation or ALK rearrangement and LDH level ≥400 U/L. The corresponding six-month SRE-free survival rates were 92%, 69%, and 34%, respectively, showing significant differences (p < 0.001). Close monitoring is recommended for patients with LDH levels ≥400 U/L in daily clinical practice, particularly with the help of the proficiency of orthopedic and radiological experts, to prevent complications such as pathological fractures and paraplegia. en-copyright= kn-copyright= en-aut-name=SakamotoYoshihiro en-aut-sei=Sakamoto en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=HamadaMasanori en-aut-sei=Hamada en-aut-mei=Masanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatayamaYoshimi en-aut-sei=Katayama en-aut-mei=Yoshimi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SugiharaShinsuke en-aut-sei=Sugihara en-aut-mei=Shinsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= affil-num=1 en-affil=Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Orthopedic Surgery, Shikoku Cancer Center kn-affil= affil-num=6 en-affil=Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=anaplastic lymphoma kinase kn-keyword=anaplastic lymphoma kinase en-keyword=bone metastases kn-keyword=bone metastases en-keyword=epidermal growth factor receptor-tyrosine kinase kn-keyword=epidermal growth factor receptor-tyrosine kinase en-keyword=lactate dehydrogenase kn-keyword=lactate dehydrogenase en-keyword=non-small cell lung cancer kn-keyword=non-small cell lung cancer en-keyword=skeletal related events kn-keyword=skeletal related events END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=急性鶏コクシジウム症感染早期におけるγδ T細胞の機能的役割に関する研究 kn-title=Studies on the functional roles of γδ T cells in the early phase of acute avian coccidiosis en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=LE VIET QUAN en-aut-sei=LE VIET QUAN en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil=岡山大学大学院環境生命科学研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=気孔開閉運動を制御するシロイヌナズナの孔辺細胞Ca2+チャネルCNGC2の機能解析 kn-title=Functional characterization of a guard cell Ca2+ channel CNGC2 involved in regulation of stomatal movement in Arabidopsis thaliana en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=ROJINA AKTER en-aut-sei=ROJINA AKTER en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil=岡山大学大学院環境生命科学研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=ベトナム中部エビ養殖池排水路における水質保全のための底質微生物燃料電池の改良 kn-title=Improving sediment microbial fuel cells for water quality control in shrimp pond drainages in Central Vietnam en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NGUYEN TU UYEN en-aut-sei=NGUYEN TU UYEN en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil=岡山大学大学院環境生命科学研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=歯小囊と歯根膜の細胞が高分化型口腔扁平上皮癌の骨浸潤におよぼす影響 kn-title=Impacts of Dental Follicle Cells and Periodontal Ligament Cells on the Bone Invasion of Well-Differentiated Oral Squamous Cell Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=CHANGANQI en-aut-sei=CHANG en-aut-mei=ANQI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=腫瘍周囲組織が口腔扁平上皮癌の生物学的性格に与える影響 kn-title=The Origin of Stroma Influences the Biological Characteristics of Oral Squamous Cell Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=OMORIHaruka en-aut-sei=OMORI en-aut-mei=Haruka kn-aut-name=大森悠加 kn-aut-sei=大森 kn-aut-mei=悠加 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Treg細胞の高い抗原性は、Treg細胞における高いPD-1発現を介してPD-1ブロック療法に対する抵抗性を与える kn-title=High Antigenicity for Treg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in Treg Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=MATSUURAHiroaki en-aut-sei=MATSUURA en-aut-mei=Hiroaki kn-aut-name=松浦宏昌 kn-aut-sei=松浦 kn-aut-mei=宏昌 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=原発性鼻腔副鼻腔びまん性大細胞型B細胞リンパ腫におけるMYD88およびCD79B遺伝子変異の解析：MCD様サブタイプの同定 kn-title=High Prevalence of MYD88 and CD79B Mutations in Primary Sinonasal Diffuse Large B-Cell Lymphoma: Identification of an MCD-like Subtype en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=PENGFANGLI en-aut-sei=PENG en-aut-mei=FANGLI kn-aut-name=彭芳丽 kn-aut-sei=彭 kn-aut-mei=芳丽 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Japanese title：食道扁平上皮癌の予後因子としての特異的形態を有する腫瘍微小血管 kn-title=Tumor microvessels with specific morphology as a prognostic factor in esophageal squamous cell carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=HNIN THIDA TUN en-aut-sei=HNIN THIDA TUN en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=分泌REICタンパク質によるPD-L1制御を介した抗腫瘍機序の解明 kn-title=Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=GOHARAYuma en-aut-sei=GOHARA en-aut-mei=Yuma kn-aut-name=合原勇馬 kn-aut-sei=合原 kn-aut-mei=勇馬 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=EGFRとMETを標的とする二重特異性抗体であるアミバンタマブのALK融合遺伝子陽性非小細胞肺癌細胞株に対する有効性 kn-title=Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NISHITatsuya en-aut-sei=NISHI en-aut-mei=Tatsuya kn-aut-name=西達也 kn-aut-sei=西 kn-aut-mei=達也 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=HIF-PH阻害剤はT細胞に擬似低酸素状態を誘導し、抗腫瘍免疫応答を増強することでマイクロサテライト安定型大腸癌の増殖を抑制する kn-title=HIF‐PH inhibitors induce pseudohypoxia in T cells and suppress the growth of microsatellite stable colorectal cancer by enhancing antitumor immune responses en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=CHENYUEHUA en-aut-sei=CHEN en-aut-mei=YUEHUA kn-aut-name=陈悦华 kn-aut-sei=陈 kn-aut-mei=悦华 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=中枢神経原発リンパ腫における形質芽細胞様リンパ腫細胞のシングルセル並びに空間解析 kn-title=Single-cell and spatial characterization of plasmablast-like lymphoma cells in primary central nervous system lymphoma en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=KOBAYASHIHiroki en-aut-sei=KOBAYASHI en-aut-mei=Hiroki kn-aut-name=小林宏紀 kn-aut-sei=小林 kn-aut-mei=宏紀 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=骨肉腫細胞由来CCL2による腫瘍関連マクロファージ集積を介した肺転移促進機序 kn-title=Osteosarcoma cell–derived CCL2 facilitates lung metastasis via accumulation of tumor-associated macrophages en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=KONDOHiroya en-aut-sei=KONDO en-aut-mei=Hiroya kn-aut-name=近藤宏也 kn-aut-sei=近藤 kn-aut-mei=宏也 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=虚血性脳卒中モデルラットにおけるヒト改変骨髄由来間質細胞（SB623）の脳内移植と随意運動および強制運動の治療効果 kn-title=Therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) with voluntary and forced exercise in a rat model of ischemic stroke en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=NAGASETakayuki en-aut-sei=NAGASE en-aut-mei=Takayuki kn-aut-name=永瀬喬之 kn-aut-sei=永瀬 kn-aut-mei=喬之 aut-affil-num=1 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil=岡山大学大学院医歯薬学総合研究科 END start-ver=1.4 cd-journal=joma no-vol=55 cd-vols= no-issue=4 article-no= start-page=313 end-page=326 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250203 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Current management of neurotrophic receptor tyrosine kinase fusion-positive sarcoma: an updated review en-subtitle= kn-subtitle= en-abstract= kn-abstract=In recent years, pembrolizumab has demonstrated significant efficacy in treating tumors characterized by a high tumor mutational burden and high microsatellite instability. Tropomyosin receptor kinase (TRK) inhibitors have shown considerable efficacy against tumors harboring neurotrophic receptor tyrosine kinase (NTRK) fusion genes, highlighting the growing importance of personalized medicine in cancer treatment. Advanced sequencing technologies enable the rapid analysis of numerous genetic abnormalities in tumors, facilitating the identification of patients with positive biomarkers. These advances have increased the likelihood of providing effective, tailored treatments. NTRK fusion genes are present in various cancer types, including sarcomas, and the TRK inhibitors larotrectinib and entrectinib have been effectively used for these malignancies. Consequently, the treatment outcomes for NTRK fusion-positive tumors have improved significantly, reflecting a shift toward more personalized therapeutic approaches. This review focuses on NTRK fusion-positive sarcomas and comprehensively evaluates their epidemiology, clinical features, and radiological and histological characteristics. We also investigated the treatment landscape, including the latest methodologies involving TRK inhibitors, and discussed the long-term efficacy of these inhibitors, and their optimal order of use. Notably, larotrectinib has demonstrated a high response rate in infantile fibrosarcoma, and its efficacy has been confirmed even in advanced cases. However, further research is warranted to optimize treatment duration and subsequent management strategies. The accumulation of clinical cases worldwide will play a pivotal role in refining the treatment approaches for tumors associated with NTRK fusion genes. en-copyright= kn-copyright= en-aut-name=KubotaYuta en-aut-sei=Kubota en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KawanoMasanori en-aut-sei=Kawano en-aut-mei=Masanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IwasakiTatsuya en-aut-sei=Iwasaki en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ItonagaIchiro en-aut-sei=Itonaga en-aut-mei=Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KakuNobuhiro en-aut-sei=Kaku en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 ORCID= affil-num=1 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Oita University kn-affil= affil-num=2 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Oita University kn-affil= affil-num=3 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Oita University kn-affil= affil-num=4 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Oita University kn-affil= affil-num=5 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Oita University kn-affil= affil-num=6 en-affil=Department of Orthopaedic Surgery , Science of Functional Recovery and Reconstruction, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Orthopaedic Surgery, Faculty of Medicine, Oita University kn-affil= en-keyword=NTRK fusion-positive sarcoma kn-keyword=NTRK fusion-positive sarcoma en-keyword=larotrectinib kn-keyword=larotrectinib en-keyword=entrectinib kn-keyword=entrectinib en-keyword=infantile fibrosarcoma kn-keyword=infantile fibrosarcoma en-keyword=NTRK-rearranged spindle cell neoplasms kn-keyword=NTRK-rearranged spindle cell neoplasms END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=42195 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251126 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Elucidation of puberulic acid–induced nephrotoxicity using stem cell-based kidney organoids en-subtitle= kn-subtitle= en-abstract= kn-abstract=Recent cases of acute kidney injury (AKI) in Japan have been linked to Beni-koji CholesteHelp supplements, with puberulic acid identified as a potential nephrotoxic contaminant. To address the need for a reliable in vitro nephrotoxicity testing platform, we developed a screening model using kidney organoids derived from adult rat kidney stem (KS) cells. The organoids were exposed to known nephrotoxicants, including cisplatin and gentamicin, to validate the system. Puberulic acid toxicity was evaluated in both KS cell-derived organoids and wild-type mice. The organoids recapitulated tubular injury induced by known nephrotoxins and showed significant Kim-1 mRNA upregulation. Puberulic acid-treated organoids and mice exhibited morphological features of acute tubular necrosis (ATN), mitochondrial damage, and reduced cytochrome c oxidase subunit IV (COX-IV) expression. Markers of oxidative stress and apoptosis, such as 8-hydroxy-2’-deoxyguanosine (8-OHdG) and cleaved caspase-3, were also elevated. These findings suggest that puberulic acid induces mitochondrial dysfunction and oxidative stress, leading to tubular cell death. Puberulic acid-induced nephrotoxicity was demonstrated using our kidney organoid model. KS cell-derived kidney organoids may provide a simple, reproducible, and rapid platform for nephrotoxicity assessment, which may complement conventional animal experiments. en-copyright= kn-copyright= en-aut-name=NakanohHiroyuki en-aut-sei=Nakanoh en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TsujiKenji en-aut-sei=Tsuji en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UchidaNaruhiko en-aut-sei=Uchida en-aut-mei=Naruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FukushimaKazuhiko en-aut-sei=Fukushima en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HaraguchiSoichiro en-aut-sei=Haraguchi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KitamuraShinji en-aut-sei=Kitamura en-aut-mei=Shinji 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, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Kidney organoid kn-keyword=Kidney organoid en-keyword=Kidney stem cell kn-keyword=Kidney stem cell en-keyword=Puberulic acid kn-keyword=Puberulic acid en-keyword=Nephrotoxicity kn-keyword=Nephrotoxicity en-keyword=Mitochondrial dysfunction kn-keyword=Mitochondrial dysfunction END start-ver=1.4 cd-journal=joma no-vol=30 cd-vols= no-issue=5 article-no= start-page=e70057 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=A Case of IgA Nephropathy With Membranoproliferative Glomerulonephritis-Like Features Miyu Kanazawa, en-subtitle= kn-subtitle= en-abstract= kn-abstract=A 73-year-old man was referred due to the onset of nephrotic-range proteinuria. He had been diagnosed with rheumatoid arthritis 18 years prior and had achieved remission with treatment, including methotrexate and janus kinase (JAK) inhibitor. Although routine follow-ups had not revealed any urinary abnormalities, subsequent tests detected proteinuria and hematuria in the absence of infection or other symptoms. As the urinary abnormalities persisted, with a serum albumin decrease and proteinuria measuring 5.7 g/day, indicating nephrotic syndrome, the patient was referred to our hospital for further evaluation, and a renal biopsy was performed. Light microscopy revealed mesangial cell proliferation, endocapillary proliferation and double-contoured basement membranes. Immunofluorescence microscopy showed IgA-dominant deposits in both mesangial areas and glomerular capillary walls. Transmission electron microscopy demonstrated electron-dense deposits in the mesangium and subendothelial regions, leading to the diagnosis of membranoproliferative glomerulonephritis (MPGN)-type IgA nephropathy. Immunostaining with the Gd-IgA1 (galactose-deficient IgA1)-specific antibody (KM55) was positive, consistent with the diagnosis. Following the initiation of steroid therapy, proteinuria rapidly decreased, achieving complete remission within 5 months. IgA nephropathy with MPGN-like features often presents as nephrotic syndrome, differing from the typical pathological and clinical presentation of IgA nephropathy, making differentiation from secondary MPGN and other diseases sometimes challenging. This case suggests that KM55 staining may offer additional information in differentiating atypical IgA nephropathy with non-classical pathological features. en-copyright= kn-copyright= en-aut-name=KanazawaMiyu en-aut-sei=Kanazawa en-aut-mei=Miyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TsujiKenji en-aut-sei=Tsuji en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AokiRyoya en-aut-sei=Aoki en-aut-mei=Ryoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SueMihiro en-aut-sei=Sue en-aut-mei=Mihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MiyakeHiromasa en-aut-sei=Miyake en-aut-mei=Hiromasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UchidaNaruhiko en-aut-sei=Uchida en-aut-mei=Naruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakanohHiroyuki en-aut-sei=Nakanoh en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FukushimaKazuhiko en-aut-sei=Fukushima en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 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=10 ORCID= affil-num=1 en-affil=Okayama University Medical School kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Okayama University Medical School kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Gd-IgA1 kn-keyword=Gd-IgA1 en-keyword=IgA nephropathy kn-keyword=IgA nephropathy en-keyword=membranoproliferative glomerulonephritis kn-keyword=membranoproliferative glomerulonephritis en-keyword=nephrotic syndrome kn-keyword=nephrotic syndrome en-keyword=rheumatoid arthritis kn-keyword=rheumatoid arthritis END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=5762 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250217 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Hypoglycemia and hyperinsulinemia induced by phenolic uremic toxins in CKD and DKD patients en-subtitle= kn-subtitle= en-abstract= kn-abstract=Patients with end-stage renal disease have lower fasting plasma glucose and HbA1c levels, with significantly higher insulin levels. For a long time, it has been believed that this higher insulin level in renal failure is due to decreased insulin clearance caused by reduced renal function. However, here we reported that accumulation of the gut microbiota-derived uremic toxin, phenyl sulfate (PS) in the renal failure, increased insulin secretion from the pancreas by enhanced glucose-stimulated insulin secretion. Other endogenous sulfides compounds which accumulated as in the renal failure also increased glucose-stimulated insulin secretion from β-cell. With RNA-seq analyses and gene knock down, we demonstrated that insulin secretion evoked by PS was mediated by Ddah2. In addition, we also found that PS increased insulin resistance through lncRNA expression and Erk phosphorylation in the adipocytes. To confirm the relationship between PS and glucose metabolism in human, we recruited 2 clinical cohort studies (DKD and CKD) including 462 patients, and found that there was a weak negative correlation between PS and HbA1c. Because these trials did not measure fasting insulin level, we alternatively used the urinary C-peptide/creatinine ratio (UCPCR) as an indicator of insulin resistance. We found that PS may induce insulin resistance in patients with eGFR < 60 mL/min/1.73 m2. These data suggest that the accumulation of uremic toxins modulates glucose metabolism and induced insulin resistance in CKD and DKD patients. Considering HbA1c as a reflection of chronic hyperglycemia and UCPCR as a reflection of chronic hyperinsulinemia, our findings indicate that PS is negatively associated with hyperglycemia independent of CKD, and positively associated with hyperinsulinemia in DKD patients. en-copyright= kn-copyright= en-aut-name=TonguYoshiyasu en-aut-sei=Tongu en-aut-mei=Yoshiyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KasaharaTomoko en-aut-sei=Kasahara en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AkiyamaYasutoshi en-aut-sei=Akiyama en-aut-mei=Yasutoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=HoHsin-Jung en-aut-sei=Ho en-aut-mei=Hsin-Jung kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MatsumotoYotaro en-aut-sei=Matsumoto en-aut-mei=Yotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KujiraiRyota en-aut-sei=Kujirai en-aut-mei=Ryota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KikuchiKoichi en-aut-sei=Kikuchi en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NataKoji en-aut-sei=Nata en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KanzakiMakoto en-aut-sei=Kanzaki en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=SuzukiKenshin en-aut-sei=Suzuki en-aut-mei=Kenshin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=WatanabeShun en-aut-sei=Watanabe en-aut-mei=Shun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KawabeChiharu en-aut-sei=Kawabe en-aut-mei=Chiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MiyataYui en-aut-sei=Miyata en-aut-mei=Yui kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=ItaiShun en-aut-sei=Itai en-aut-mei=Shun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=ToyoharaTakafumi en-aut-sei=Toyohara en-aut-mei=Takafumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=SuzukiChitose en-aut-sei=Suzuki en-aut-mei=Chitose kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=TanakaTetsuhiro en-aut-sei=Tanaka en-aut-mei=Tetsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 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=19 ORCID= en-aut-name=TomiokaYoshihisa en-aut-sei=Tomioka en-aut-mei=Yoshihisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= en-aut-name=AbeTakaaki en-aut-sei=Abe en-aut-mei=Takaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 ORCID= affil-num=1 en-affil=Tohoku University School of Medicine kn-affil= affil-num=2 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=5 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Medical Biochemistry, School of Pharmacy, Iwate Medical University kn-affil= affil-num=10 en-affil=Department of Biomedical Engineering, Tohoku University kn-affil= affil-num=11 en-affil=Tohoku University School of Medicine kn-affil= affil-num=12 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=13 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=14 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=15 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=16 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= affil-num=18 en-affil=Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine kn-affil= affil-num=19 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=20 en-affil=Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences kn-affil= affil-num=21 en-affil=Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine kn-affil= en-keyword=CKD, DKD, Phenyl sulfate, Uremic toxin, Insulin secretion, Insulin resistance, Gut microbiota kn-keyword=CKD, DKD, Phenyl sulfate, Uremic toxin, Insulin secretion, Insulin resistance, Gut microbiota END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue= article-no= start-page=1568338 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250807 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A pilot transcriptomic study of a novel multitargeted BRT regimen for anti–MDA5 antibody-positive dermatomyositis: improving survival over conventional therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis (MDA5-DM) is associated with severe outcomes, primarily due to rapidly progressive interstitial lung disease (RP-ILD), which is often refractory to standard therapies such as calcineurin inhibitors (e.g., tacrolimus) combined with cyclophosphamide (TC-Tx). This study evaluated the efficacy of a novel multitargeted regimen combining baricitinib, rituximab, and tacrolimus (BRT-Tx) in improving survival outcomes for MDA5-DM patients with poor prognostic factors.
Methods: Fourteen MDA5-DM patients with multiple adverse prognostic factors were studied. Seven received the BRT-Tx regimen, and the remaining seven, previously treated with TC-Tx, served as historical controls. Twelve-month survival was assessed. Transcriptome analysis was performed for six patients (BRT=3, TC=3), beginning with cluster analysis to evaluate whether changes in peripheral blood gene expression varied according to treatment or prognosis. Gene ontology analysis characterized expression profiles in survivors and distinguished treatment effects. Alterations in the type I, II, and III interferon signatures were also assessed.
Results: In the TC-Tx group, four of seven patients succumbed to RP-ILD, whereas all seven BRT-Tx patients survived the 12-month observation period. Only one BRT-Tx patient required combined rescue therapies, including plasma exchange, and one case of unexplained limbic encephalitis (LE) occurred. Cytomegalovirus reactivation was observed in both groups (BRT: 5/7; TC: 6/7). Transcriptomic analysis revealed no treatment-specific clustering of differentially expressed genes (DEGs) before and after therapy. However, survivors and nonsurvivors formed distinct clusters, with survivors showing significant posttreatment suppression of B-cell-related gene expression. Moreover, interferon signature scores were significantly lower after treatment in survivors than in nonsurvivors. BRT-Tx effectively suppressed B-cell-mediated immune responses and maintained a low interferon signature, while TC-Tx resulted in nonspecific gene suppression, and in nonsurvivors, an elevated interferon signature was observed.
Conclusion: BRT-Tx has the potential to improve survival in MDA5-DM patients by effectively targeting hyperactive immune pathways. The combination of rituximab and tacrolimus is expected to disrupt B-cell–T-cell interactions and reduce autoantibody production, whereas baricitinib may suppress both IFN and GM-CSF signaling, regulating excessive autoimmunity mediated by cells such as macrophages. Unlike TC-Tx, BRT-Tx avoids cyclophosphamide-associated risks such as infertility and secondary malignancies. Future randomized controlled trials are warranted to validate its efficacy and safety. en-copyright= kn-copyright= en-aut-name=TokunagaMoe en-aut-sei=Tokunaga en-aut-mei=Moe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NakaiYu en-aut-sei=Nakai en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SatoYoshiharu en-aut-sei=Sato en-aut-mei=Yoshiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HiratsukaMitori en-aut-sei=Hiratsuka en-aut-mei=Mitori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MatsumotoYoshinori en-aut-sei=Matsumoto en-aut-mei=Yoshinori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakatsueTakeshi en-aut-sei=Nakatsue en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SaekiTakako en-aut-sei=Saeki en-aut-mei=Takako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UmayaharaTakatsune en-aut-sei=Umayahara en-aut-mei=Takatsune kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 ORCID= en-aut-name=KoyamaYoshinobu en-aut-sei=Koyama en-aut-mei=Yoshinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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= affil-num=2 en-affil=Division of Rheumatology, Center for Autoimmune Diseases, Japanese Red Cross Okayama Hospital kn-affil= affil-num=3 en-affil=DNA Chip Research Inc., Medical Laboratory kn-affil= affil-num=4 en-affil=DNA Chip Research Inc., Medical Laboratory kn-affil= affil-num=5 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Division of Rheumatology and Nephrology, Department of Internal Medicine, Nagaoka Red Cross Hospital kn-affil= affil-num=7 en-affil=Division of Rheumatology and Nephrology, Department of Internal Medicine, Nagaoka Red Cross Hospital kn-affil= affil-num=8 en-affil=Division of Dermatology, Center for Autoimmune Diseases, Japanese Red Cross Okayama Hospital kn-affil= affil-num=9 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Division of Rheumatology, Center for Autoimmune Diseases, Japanese Red Cross Okayama Hospital kn-affil= en-keyword=anti-MDA5 antibody-positive dermatomyositis (MDA5-DM) kn-keyword=anti-MDA5 antibody-positive dermatomyositis (MDA5-DM) en-keyword=JAK inhibitor kn-keyword=JAK inhibitor en-keyword=baricitinib kn-keyword=baricitinib en-keyword=rituximab kn-keyword=rituximab en-keyword=multitargeted treatment kn-keyword=multitargeted treatment en-keyword=IFN signature kn-keyword=IFN signature en-keyword=transcriptome analysis kn-keyword=transcriptome analysis END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251128 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=p53-armed oncolytic adenovirus induces apoptosis in pancreatic cancer-associated stellate cells via macropinocytosis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pancreatic ductal adenocarcinoma (PDAC)-associated pancreatic stellate cells (PSCs) promote PDAC tumor progression. Notably, PDAC tumors display enhanced macropinocytosis, resulting in enhanced uptake of extracellular particles, including nutrients and viruses. We previously demonstrated the therapeutic potential of telomerase-specific oncolytic adenoviruses OBP-301 and p53-armed OBP-702 against human PDAC cells. However, it remains unclear whether macropinocytosis promotes the virus sensitivity of PDAC-associated PSCs. Here, we show that PSCs activated by human PDAC cells (Panc-1 and BxPC-3) exhibit enhanced sensitivity to wild-type and oncolytic adenoviruses via enhanced macropinocytosis. The virus sensitivity of PSCs was analyzed for the infectivity, replication, and cytopathic activity of wild-type and oncolytic adenoviruses. PDAC-associated PSCs were more sensitive to wild-type and oncolytic adenoviruses than were control PSCs; this sensitivity was mediated by activation of macropinocytosis. In three-dimensional (3D) culture models, p53-armed OBP-702 decreased the viability of PDAC-associated PSCs more strongly than did non-armed OBP-301, reflecting induction of p53-mediated apoptosis. Co-inoculation of PSCs enhanced the growth of PDAC tumors, an effect that was attenuated by OBP-702-mediated p53 activation in the tumor stroma. Our results suggest that p53-armed oncolytic adenovirus OBP-702 eliminates PDAC-associated PSCs via enhancement of macropinocytosis-mediated virus entry and induction of p53-mediated apoptosis. en-copyright= kn-copyright= en-aut-name=NishiyamaTakeyoshi en-aut-sei=Nishiyama en-aut-mei=Takeyoshi 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=NagaiYasuo en-aut-sei=Nagai en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ShojiRyohei en-aut-sei=Shoji en-aut-mei=Ryohei 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=HashimotoNaoyuki en-aut-sei=Hashimoto en-aut-mei=Naoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakahashiYosuke en-aut-sei=Takahashi en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 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=9 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=10 ORCID= en-aut-name=NomaKazuhiro en-aut-sei=Noma en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=YoshidaRyuichi en-aut-sei=Yoshida en-aut-mei=Ryuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=13 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=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= en-aut-name=MasamuneAtsushi en-aut-sei=Masamune en-aut-mei=Atsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 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=17 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=18 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Pharmaceutical Biomedicine, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=15 en-affil=Department of Pharmaceutical Biomedicine, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=16 en-affil=Division of Gastroenterology, Tohoku University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Oncolys BioPharma, Inc. kn-affil= affil-num=18 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=19 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=10 article-no= start-page=e94951 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251019 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Bladder Trigone as a Sensory Hub: A Narrative Review en-subtitle= kn-subtitle= en-abstract= kn-abstract=The bladder trigone is an anatomically and functionally distinct region within the lower urinary tract (LUT), characterized by a dense network of afferent sensory fibers, specialized urothelial interactions, and prominent mechanotransduction mechanisms. Its intricate neuroarchitecture enables precise detection of bladder filling and coordination of micturition, whereas dysregulation of these pathways contributes to lower urinary tract symptoms (LUTS), including urgency, frequency, and bladder pain. Despite its recognized clinical relevance, the structural and functional basis of trigonal sensory signaling - and its role - remain incompletely understood.
This review synthesizes current evidence on trigonal afferent organization, integrating data from anatomical mapping, receptor profiling, electrophysiological characterization, and translational research. Seminal anatomical observations are combined with recent advances in mechanotransduction and purinergic, peptidergic, and transient receptor potential (TRP) signaling to provide a comprehensive perspective. The trigone exhibits three principal afferent classes: (1) intraepithelial fibers penetrating umbrella cells, marked by P2X purinoceptor 3 (P2X3), transient receptor potential vanilloid 1 (TRPV1), calcitonin gene-related peptide (CGRP), and substance P (SP); (2) subepithelial plexuses surrounding microvasculature, enriched in vasoactive neuropeptides and exhibiting plastic hypertrophy in overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS); and (3) encapsulated corpuscular endings at the lamina propria-detrusor junction, expressing PIEZO1/2 and acid-sensing ion channels (ASICs) for rapid adaptation. In trigeminal dorsal root ganglion (DRG) neurons, high expression of PIEZO2, P2RX3, and voltage-gated sodium channel, type 1.8 (Nav1.8) was observed, revealing their role as the foundation for multisensory information processing. Functional assays highlight distinct mechanotransductive and chemosensory pathways, with aging, inflammation, and neurotrophic factors driving afferent plasticity underlying abnormal bladder sensation, such as urgency, frequency, and pain. Early clinical trials of P2X3 antagonists and intravesical TRPV1 inhibitors demonstrate promising symptomatic benefits. Collectively, evidence positions the bladder trigone as a critical sensory hub where neuronal, urothelial, and immune signals converge to regulate bladder sensation. Understanding its molecular and structural specialization may inform the development of region-specific neuromodulatory therapies targeting sensory urgency and afferent-driven bladder dysfunction. en-copyright= kn-copyright= en-aut-name=SadahiraTakuya en-aut-sei=Sadahira en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MaruyamaYuki en-aut-sei=Maruyama en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MitsuiYosuke en-aut-sei=Mitsui en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SekitoTakanori en-aut-sei=Sekito en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WatanabeTomofumi en-aut-sei=Watanabe en-aut-mei=Tomofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=WatanabeMasami en-aut-sei=Watanabe en-aut-mei=Masami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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= en-keyword=bladder trigone kn-keyword=bladder trigone en-keyword=botulinum toxin kn-keyword=botulinum toxin en-keyword=lower urinary tract symptoms kn-keyword=lower urinary tract symptoms en-keyword=sensory afferents kn-keyword=sensory afferents en-keyword=varicosities kn-keyword=varicosities END start-ver=1.4 cd-journal=joma no-vol=786 cd-vols= no-issue= article-no= start-page=152753 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=Hydrogen-rich gas enhances mitochondrial membrane potential and respiratory function recovery in Caco-2 cells post-ischemia-reperfusion injury en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Ischemia-reperfusion (I/R) injury induces oxidative stress, leading to damage in highly susceptible intestinal tissues. Molecular hydrogen (H2) has shown therapeutic potential in I/R injuries, with our prior research showing its efficacy in improving outcomes in rat intestinal transplantation models. However, its impact on mitochondrial function remain insufficiently understood. This study aims to elucidate how H2 modulates mitochondrial function impaired by I/R injury.
Methods: To assess the effects of H2 on I/R injury, cells were divided into three groups: a control group, a hypoxic group (99 % N2, 1 % O2, without H2 for 3, 6, or 24 h), and a hypoxic-H2 group (99 % H2, 1 % O2, for the same durations). After treatment, cells were reoxygenated under normoxic conditions (21 % O2) for 1, 2, 4, or 6 h. Mitochondrial membrane potential, oxygen consumption, and ATP production were measured. Reactive oxygen species production and apoptotic and metabolic regulators were also assessed.
Results: H2 markedly promoting mitochondrial recovery following I/R injury, by enhancing ATP production, restoring mitochondrial membrane potential, and improving oxygen consumption. It also reduced ROS levels and suppressed pro-apoptotic signaling. Notably, H2 suppressed the expression of HIF1α and PDK1, suggesting that H2 may act upstream of hypoxia-driven signaling pathways. These changes promoted oxidative phosphorylation and overall cellular function during reperfusion.
Conclusions: Our findings reveal that H2 therapy supports mitochondrial function, suppresses ROS, and modulates hypoxia-driven pathways in I/R injury. These insights advance the understanding of H2's potential in addressing I/R injury and provide a foundation for its application in other hypoxia-related conditions. en-copyright= kn-copyright= en-aut-name=SeyaMizuki en-aut-sei=Seya en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=MengYing en-aut-sei=Meng en-aut-mei=Ying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=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=NojimaTsuyoshi en-aut-sei=Nojima en-aut-mei=Tsuyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshinoriKosaki en-aut-sei=Yoshinori en-aut-mei=Kosaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 ORCID= en-aut-name=WatanabeAkihiro en-aut-sei=Watanabe en-aut-mei=Akihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YamadaTaihei en-aut-sei=Yamada en-aut-mei=Taihei 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=Biological Process of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology 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 Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Emergency, Critical Care and Disaster Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University kn-affil= affil-num=10 en-affil=Department of Emergency, Disaster and Critical Care Medicine, Hyogo Medical University 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= en-keyword=Intestinal ischemia-reperfusion injury kn-keyword=Intestinal ischemia-reperfusion injury en-keyword=Molecular hydrogen kn-keyword=Molecular hydrogen en-keyword=Hydrogen gas therapy kn-keyword=Hydrogen gas therapy en-keyword=Caco-2 cells kn-keyword=Caco-2 cells en-keyword=Mitochondrial function kn-keyword=Mitochondrial function en-keyword=Hypoxia-inducible factor-1α (HIF1α) kn-keyword=Hypoxia-inducible factor-1α (HIF1α) END start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=18 article-no= start-page=1481 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250922 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=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=The recruitment of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) of oral squamous carcinoma (OSCC) affects significant cancer invasion; however, in the normal host tissue that is located in the cancer’s surrounding area, this is poorly investigated. In this study, we examined the impact of gingival connective tissue cells (GCTCs) and periodontal ligament cells (PDLCs), which are involved in the invasive pathway of OSCC, on oral cancer invasion via TAMs recruitment. Transwell (migration) assays were used to examine the effects of GCTCs and PDLCs on the migration of macrophages, which indicated that the interaction between GCTCs and HSC-2/HSC-3 (human oral squamous cell carcinoma cell line) promoted the recruitment of macrophages, whereas the interaction between PDLCs was inhibited. An indirect co-culture was then used to examine the effects of GCTCs and PDLCs on the differentiation of macrophages, which indicated that the interaction between GCTCs enhanced their ability to transform into M2-type macrophages. Furthermore, the effects of GCTCs and PDLCs on the recruitment of CD45(+) monocytes, F4/80(+) M0 macrophages, iNOS(+) M1 macrophages, and CD163(+) M2 TAMs were assayed by immunohistochemistry. The results revealed that the interaction between GCTCs and HSC-2/HSC-3 promoted the infiltration of CD45(+) monocytes, F4/80(+) M0 macrophages, and CD163(+) M2 TAMs, whereas the PDLCs inhibited it, while their effect on iNOS(+) M1 macrophages was limited. Collectively, the GCTCs contributed to the infiltration of TAMs into the TME of OSCC cells, whereas the PDLCs exerted an inhibitory effect. These findings suggest a potential regulatory mechanism underlying the progression of OSCC. 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= en-aut-name=TakabatakeKiyofumi en-aut-sei=Takabatake en-aut-mei=Kiyofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ArashimaTakuma en-aut-sei=Arashima en-aut-mei=Takuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZhaoYulu en-aut-sei=Zhao en-aut-mei=Yulu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 ORCID= 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=6 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=7 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=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=NagatsukaHitoshi en-aut-sei=Nagatsuka en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 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=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Oral Pathology and Medicine, 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=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=oral squamous cell carcinoma (OSCC) kn-keyword=oral squamous cell carcinoma (OSCC) en-keyword=gingival connective tissue cells (GCTCs) kn-keyword=gingival connective tissue cells (GCTCs) en-keyword=periodontal ligament cells (PDLCs) kn-keyword=periodontal ligament cells (PDLCs) en-keyword=tumor-associated macrophages (TAMs) kn-keyword=tumor-associated macrophages (TAMs) en-keyword=macrophage polarity kn-keyword=macrophage polarity en-keyword=tumor microenvironment (TME) kn-keyword=tumor microenvironment (TME) END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=17 article-no= start-page=2770 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250825 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Refining the Role of Tumor-Associated Macrophages in Oral Squamous Cell Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=In the tumor microenvironment, various immune and stromal cells, such as fibroblasts and vascular endothelial cells, contribute to tumor growth and progression by interacting with cancer cells. Tumor-associated macrophages (TAMs) have attracted attention as major players in the tumor microenvironment. The origin of TAMs is believed to be the infiltration of monocytes derived from bone marrow progenitor cells into tumor tissues and their differentiation into macrophages, whereas tissue-resident macrophages derived from yolk sacs have recently been reported. TAMs infiltrating tumor tissues act in a tumor-promoting manner through immunosuppression, angiogenesis, and the promotion of cancer cell invasion. Reflecting the nature of TAMs, increased TAM invasion and TAM-specific gene expression in tumor tissues may be the new biomarkers for cancer. Moreover, new therapeutic strategies targeting TAMs, such as transformation into immunostimulatory macrophages, suppression of TAM infiltration, and promotion of phagocytosis, are being investigated, and many clinical trials are underway. As the origin and function of TAMs are further elucidated, TAM-targeted therapy is expected to become a new option for the immunotherapy of various cancers, including oral cancers. en-copyright= kn-copyright= en-aut-name=TakabatakeKiyofumi en-aut-sei=Takabatake en-aut-mei=Kiyofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TianyanPiao en-aut-sei=Tianyan en-aut-mei=Piao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ArashimaTakuma en-aut-sei=Arashima en-aut-mei=Takuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ChangAnqi en-aut-sei=Chang en-aut-mei=Anqi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 ORCID= 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=6 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=7 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=8 ORCID= en-aut-name=FujiiMasae en-aut-sei=Fujii en-aut-mei=Masae kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=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 Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 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=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Oral Pathology and Medicine, 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=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=11 en-affil=Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=tumor-associated macrophage (TAM) kn-keyword=tumor-associated macrophage (TAM) en-keyword=oral squamous cell carcinoma (OSCC) kn-keyword=oral squamous cell carcinoma (OSCC) en-keyword=macrophage polarity kn-keyword=macrophage polarity en-keyword=invasion kn-keyword=invasion en-keyword=carcinogenesis kn-keyword=carcinogenesis END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=14 article-no= start-page=4055 end-page=4070 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250922 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=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=The C-X-C chemokine receptor type 4 (CXCR4) is a G protein-coupled transmembrane receptor that contributes to tumor growth and angiogenesis. While prior studies have primarily focused on CXCR4 expression in cancer cells and its role in metastasis, a few have examined its involvement in tumor-associated vasculature. In this study, we reported for the first time that CXCR4 expression within the tumor vasculature is significantly associated with higher pathological grades of human oral squamous cell carcinoma (OSCC) (p<0.03). A previous study reported that inhibiting CXCR4 with AMD3100 induces tumor cell death and enhances the efficacy of the chemotherapeutic agent cisplatin. These findings suggest that CXCR4 is an important target for cancer treatment. However, the tumor vascular system is known to be heterogeneous within the tumor microenvironment (TME), which may influence the treatment outcomes. Therefore, this study aimed to explore the effect of CXCR4 antagonism on various blood vessels present within the oral squamous cell carcinoma (OSCC) tumor stroma. Although the efficiency of AMD3100 was not significant in MOC cancer cells, necrosis was induced in the TME when applied to a poorly differentiated OSCC model, highlighting the role of the TME. Notably, CXCR4 is found to be highly overlapped with CD105+ angiogenic tumor vessels among various vascular markers. Treatment with AMD3100 leads to a marked reduction in the CD105+ vessels and impairs the maturation of tumor micro-vessels, explaining the cause of observed necrosis. Thus, CXCR4 serves as a promising biomarker in OSCC, and its inhibition with AMD3100 offers the therapeutic potential, particularly in cases with advanced pathological grades. 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= 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=EainHtoo Shwe en-aut-sei=Eain en-aut-mei=Htoo Shwe kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=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=MinZin Zin en-aut-sei=Min en-aut-mei=Zin Zin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=8 ORCID= en-aut-name=NagatsukaHitoshi en-aut-sei=Nagatsuka en-aut-mei=Hitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= 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 Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University kn-affil= affil-num=4 en-affil=Preliminary Examination Room, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Pathophysiology and Drug Discovery, 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= en-keyword=CXCR4 kn-keyword=CXCR4 en-keyword=tumor angiogenesis kn-keyword=tumor angiogenesis en-keyword=chemokine receptors kn-keyword=chemokine receptors en-keyword=tumor microenvironment kn-keyword=tumor microenvironment en-keyword=oral squamous cell carcinoma (OSCC) kn-keyword=oral squamous cell carcinoma (OSCC) en-keyword=AMD3100 kn-keyword=AMD3100 END start-ver=1.4 cd-journal=joma no-vol=122 cd-vols= no-issue=5 article-no= start-page=689 end-page=699 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250617 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cytomegalovirus reactivation in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes of relapsed and/or refractory large B-cell lymphoma (r/r LBCL). However, its off-tumor effects result in severe prolonged humoral immune deficiency. Cytomegalovirus (CMV) is a latent virus that can be life-threatening in immunosuppressed patients. In the setting of CAR T-cell therapy, Asian race is a risk factor for clinically significant CMV infection. However, the effect of CAR T-cell therapy on CMV reactivation in Japanese patients remains unclear. Previous reports used polymerase chain reaction (PCR), but we used the pp65 antigenemia assay to retrospectively investigate long-term effects in patients with r/r LBCL. The study included 46 patients. Nine (19.6%) developed CMV reactivation, with a median onset of 13 days. Six of these patients received preemptive therapy, and none developed CMV end-organ disease. Primary refractory disease, grade 2–4 cytokine release syndrome, and high-dose corticosteroids were risk factors for CMV reactivation. Long-term follow-up showed that CMV reactivation rarely occurred later than 28 days post-infusion. Our study using the pp65 antigenemia assay showed a similar incidence of CMV reactivation, onset, and risk factors to those in the previous reports using PCR. en-copyright= kn-copyright= en-aut-name=HayashinoKenta en-aut-sei=Hayashino en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=MasunariTaro en-aut-sei=Masunari en-aut-mei=Taro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HashidaRisa en-aut-sei=Hashida en-aut-mei=Risa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OkaSatoshi en-aut-sei=Oka en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujiwaraYuki en-aut-sei=Fujiwara en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=8 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=9 ORCID= en-aut-name=KamoiChihiro en-aut-sei=Kamoi en-aut-mei=Chihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 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=12 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=13 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=14 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=15 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=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= affil-num=1 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=3 en-affil=Department of Hematology, Chugoku Central Hospital kn-affil= affil-num=4 en-affil=Division of Hematology, Ehime Prefectural Central Hospital kn-affil= affil-num=5 en-affil=Department of Hematology and Blood Transfusion, Kochi Health Science Center kn-affil= affil-num=6 en-affil=Department of Hematology and Oncology, Japanese Red Cross Society Himeji Hospital kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=8 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=10 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=12 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=13 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=14 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=16 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= affil-num=17 en-affil=Department of Hematology and Oncology, Okayama University kn-affil= en-keyword=Cytomegalovirus reactivation kn-keyword=Cytomegalovirus reactivation en-keyword=Large B-cell lymphoma kn-keyword=Large B-cell lymphoma en-keyword=CAR T-cell therapy kn-keyword=CAR T-cell therapy en-keyword=Hypogammaglobulinemia kn-keyword=Hypogammaglobulinemia END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251019 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Impact of methotrexate-dosing regimens for GVHD prophylaxis on clinical outcomes of HLA-matched allogeneic HSCT en-subtitle= kn-subtitle= en-abstract= kn-abstract=Severe graft-versus-host disease (GVHD) remains a major complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT), necessitating optimal immunosuppressive strategies. This retrospective study used data from the Japanese Transplant Registry Unified Management Program to compare three methotrexate (MTX)-dosing regimens for GVHD prophylaxis in patients undergoing human leucocyte antigen (HLA)-matched allo-HSCT: a low-dose 3-day regimen (Ld3:10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6), a low-dose 4-day regimen (Ld4: Ld3 with an additional 7 mg/m2 on day 11) and an original-dose 3-day regimen (Od3: 15 mg/m2 on day 1, 10 mg/m2 on days 3 and 6). Among 2537 analysed patients, Ld3 was the most commonly used regimen. Multivariate analyses showed no significant differences in the cumulative incidence of grade II–IV acute GVHD among regimens. However, Od3 was associated with an increased risk of grade III–IV acute GVHD, and Ld4 was linked to delayed neutrophil engraftment. This study is the first large-scale retrospective analysis of the impact of different MTX-dosing regimens on the outcomes of HLA-matched allo-HSCT, providing valuable insights into optimal MTX-dosing strategies in clinical practice. en-copyright= kn-copyright= en-aut-name=SuzukiTomotaka en-aut-sei=Suzuki en-aut-mei=Tomotaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=JoTomoyasu en-aut-sei=Jo en-aut-mei=Tomoyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshifujiKota en-aut-sei=Yoshifuji en-aut-mei=Kota 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=DokiNoriko en-aut-sei=Doki en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 ORCID= en-aut-name=OnishiYasushi en-aut-sei=Onishi en-aut-mei=Yasushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=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=SawaMasashi en-aut-sei=Sawa en-aut-mei=Masashi 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=SerizawaKentaro en-aut-sei=Serizawa en-aut-mei=Kentaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=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=YoshimitsuMakoto en-aut-sei=Yoshimitsu en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 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=17 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=18 ORCID= affil-num=1 en-affil=Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences kn-affil= affil-num=2 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=3 en-affil=Department of Hematology, Institute of Science Tokyo kn-affil= affil-num=4 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=5 en-affil=Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Centre, Komagome Hospital kn-affil= affil-num=6 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Centre kn-affil= affil-num=7 en-affil=Department of Hematology, Japanese Red Cross Aichi Medical Centre Nagoya Daiichi Hospital kn-affil= affil-num=8 en-affil=Department of Hematology, Tohoku University Hospital kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Haematopoietic Stem Cell Transplantation, National Cancer Centre Hospital kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Anjo Kosei Hospital kn-affil= affil-num=12 en-affil=Department of Hematology, Hokkaido University Hospital kn-affil= affil-num=13 en-affil=Department of Hematology and Rheumatology, Kindai University Faculty of Medicine kn-affil= affil-num=14 en-affil=Department of Hematology, Sapporo Hokuyu Hospital kn-affil= affil-num=15 en-affil=Department of Hematology, Kanagawa Cancer Centre kn-affil= affil-num=16 en-affil=Department of Hematology and Rheumatology, Graduate School of Medical and Dental Sciences, Kagoshima University kn-affil= affil-num=17 en-affil=Japanese Data Centre for Haematopoietic Cell Transplantation kn-affil= affil-num=18 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= en-keyword=allo-HSCT kn-keyword=allo-HSCT en-keyword=dosing regimens kn-keyword=dosing regimens en-keyword=graft-versus-host disease kn-keyword=graft-versus-host disease en-keyword=GVHD prophylaxis kn-keyword=GVHD prophylaxis en-keyword=methotrexate kn-keyword=methotrexate END start-ver=1.4 cd-journal=joma no-vol=6 cd-vols= no-issue=5 article-no= start-page=e70138 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250902 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Late‐Onset Invasive Aspergillosis With Pituitary Involvement and Dysfunction Following CD19 Chimeric Antigen Receptor T‐Cell Therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction: Invasive fungal infection (IFI) after chimeric antigen receptor (CAR) T-cell therapy is less common than bacterial and viral infections, but can be fatal once it develops. As most cases occur within 30 days after CAR T-cell infusion, late-onset IFI—particularly mould infection—appears to be under-recognised.
Discussion: We report an illustrative case of pituitary aspergillosis developing as late as one year after CD19 CAR T-cell therapy, highlighting a persistent risk in certain patients with delayed immune reconstitution.
Conclusion: This case underscores the need for continued vigilance and individualised antifungal strategies to prevent IFI beyond the early post-infusion period.
Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission. en-copyright= kn-copyright= en-aut-name=IkedaDaisuke en-aut-sei=Ikeda en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NawadaTomohiro en-aut-sei=Nawada en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=ShinoharaTakayuki en-aut-sei=Shinohara en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 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=6 ORCID= en-aut-name=HiyamaRyuichiro en-aut-sei=Hiyama en-aut-mei=Ryuichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=UenoMasaya en-aut-sei=Ueno en-aut-mei=Masaya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 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=10 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=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=EnnishiDaisuke en-aut-sei=Ennishi en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 ORCID= en-aut-name=FujiiNobuharu en-aut-sei=Fujii en-aut-mei=Nobuharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=MakitaMasanori en-aut-sei=Makita en-aut-mei=Masanori 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= 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=The Center for Graduate Medical Education, 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 Fungal Infection, National Institute of Infectious Diseases kn-affil= affil-num=5 en-affil=Department of Hematology and Oncology, 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 and Oncology, Okayama University Hospital kn-affil= affil-num=8 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=12 en-affil=Department of Hematology and Oncology, Okayama University Hospital 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, Chugoku Central Hospital kn-affil= affil-num=17 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= en-keyword=aspergillosis kn-keyword=aspergillosis en-keyword=CD19 CAR T kn-keyword=CD19 CAR T en-keyword=invasive fungal infection kn-keyword=invasive fungal infection en-keyword=pituitary kn-keyword=pituitary END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=18 article-no= start-page=4640 end-page=4653 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250912 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Refinement of day 28 treatment response criteria for acute GVHD: a collaboration study of the JSTCT and MAGIC en-subtitle= kn-subtitle= en-abstract= kn-abstract=Overall response (OR) that combines complete (CR) and partial responses (PR) is the conventional end point for acute graft-versus-host disease (GVHD) trials. Because PR includes heterogeneous clinical presentations, reclassifying PR could produce a better end point. Patients in the primary treatment cohort from the Japanese Society for Transplantation and Cellular Therapy (JSTCT) were randomly divided into training and validation sets. In the training set, a classification and regression tree algorithm generated day 28 refined response (RR) criteria based on symptoms at treatment and day 28. We then evaluated RR for primary and second-line treatments, using the area under the receiver operating characteristic curve (AUC) and negative predictive value (NPV) for 6-month nonrelapse mortality as performance measures. RR considered patients with grade 0/1 at day 28 without additional treatment as responders. RR for primary treatment produced higher AUCs than OR with small improvement of NPVs in both validation sets: JSTCT (AUC, 0.73 vs 0.69 [P < .001]; NPV, 92.0% vs 89.6% [P < .001]) and the Mount Sinai Acute GVHD International Consortium (MAGIC; AUC, 0.71 vs 0.68 [P = .032]; NPV, 90.9% vs 89.8% [P = .009]). RR for second-line treatment produced similar AUCs but much higher NPVs than OR in both validation sets of JSTCT (AUC, 0.64 vs 0.63 [P = .775]; NPV, 74.5% vs 66.0% [P < .001]) and MAGIC (AUC, 0.67 vs 0.64 [P = .105]; NPV, 86.8% vs 76.1% [P = .004]). Classifying persistent but mild skin symptoms as responses and residual lower gastrointestinal GVHD as nonresponses were major drivers in improving the prognostic performance of RR. Our externally validated day 28 RR would serve as a better end point than conventional criteria in future first- and second-line treatment trials. en-copyright= kn-copyright= en-aut-name=AkahoshiYu en-aut-sei=Akahoshi en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=InamotoYoshihiro en-aut-sei=Inamoto en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SpyrouNikolaos en-aut-sei=Spyrou en-aut-mei=Nikolaos kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=DinizMarcio A. en-aut-sei=Diniz en-aut-mei=Marcio A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=AyukFrancis en-aut-sei=Ayuk en-aut-mei=Francis kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ChoeHannah K. en-aut-sei=Choe en-aut-mei=Hannah K. 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=EtoTetsuya en-aut-sei=Eto en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=EtraAaron M. en-aut-sei=Etra en-aut-mei=Aaron M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HexnerElizabeth O. en-aut-sei=Hexner en-aut-mei=Elizabeth O. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=13 ORCID= en-aut-name=HoganWilliam J. en-aut-sei=Hogan en-aut-mei=William J. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=HollerErnst en-aut-sei=Holler en-aut-mei=Ernst kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 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=16 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=17 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=18 ORCID= en-aut-name=TanakaTakashi en-aut-sei=Tanaka en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 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=20 ORCID= en-aut-name=VasovaIngrid en-aut-sei=Vasova en-aut-mei=Ingrid kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=21 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=22 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=23 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=24 ORCID= en-aut-name=ChenYi-Bin en-aut-sei=Chen en-aut-mei=Yi-Bin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=25 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=26 ORCID= en-aut-name=NakamuraRyotaro en-aut-sei=Nakamura en-aut-mei=Ryotaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=27 ORCID= en-aut-name=AtsutaYoshiko en-aut-sei=Atsuta en-aut-mei=Yoshiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=28 ORCID= en-aut-name=FerraraJames L. M. en-aut-sei=Ferrara en-aut-mei=James L. M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=29 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=30 ORCID= en-aut-name=LevineJohn E. en-aut-sei=Levine en-aut-mei=John E. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=31 ORCID= en-aut-name=TeshimaTakanori en-aut-sei=Teshima en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=32 ORCID= affil-num=1 en-affil=Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai kn-affil= affil-num=2 en-affil=Department of Blood and Marrow Transplantation and Cellular Therapy, Fujita Health University School of Medicine kn-affil= affil-num=3 en-affil=Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai kn-affil= affil-num=4 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= affil-num=5 en-affil=Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai kn-affil= affil-num=6 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf kn-affil= affil-num=8 en-affil=Division of Hematology, Blood and Marrow Transplantation Program, The Ohio State University Comprehensive Cancer Center 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, Hamanomachi Hospital kn-affil= affil-num=11 en-affil=Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai kn-affil= affil-num=12 en-affil=Department of Medicine and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania kn-affil= affil-num=13 en-affil=Department of Hematology, Kobe City Medical Center General Hospital kn-affil= affil-num=14 en-affil=Division of Hematology, Mayo Clinic kn-affil= affil-num=15 en-affil=Department of Hematology and Oncology, Internal Medicine III, University of Regensburg kn-affil= affil-num=16 en-affil=Division of Molecular Oncology, National Cancer Center Research Institute kn-affil= affil-num=17 en-affil=Department of Hematology, National Hospital Organization Kumamoto Medical Center kn-affil= affil-num=18 en-affil=Department of Hematology, Kanagawa Cancer Center kn-affil= affil-num=19 en-affil=Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital kn-affil= affil-num=20 en-affil=Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital kn-affil= affil-num=21 en-affil=Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen kn-affil= affil-num=22 en-affil=Department of Hematology, Hyogo Medical University Hospital kn-affil= affil-num=23 en-affil=Technical Department, Japanese Red Cross Blood Service Headquarters kn-affil= affil-num=24 en-affil=Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital kn-affil= affil-num=25 en-affil=Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital kn-affil= affil-num=26 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=27 en-affil=Department of Hematology and Hematopoietic Cell Transplantation, City of Hope kn-affil= affil-num=28 en-affil=Japanese Data Center for Hematopoietic Cell Transplantation kn-affil= affil-num=29 en-affil=Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai kn-affil= affil-num=30 en-affil=Division of Hematology, Jichi Medical University Saitama Medical Center kn-affil= affil-num=31 en-affil=Division of Hematology/Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai kn-affil= affil-num=32 en-affil=Department of Hematology, Hokkaido University Faculty of Medicine and Graduate School of Medicine kn-affil= END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250908 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Efficacy of ciclosporin monotherapy in non-severe aplastic anaemia not requiring transfusions: Results from a multicentre phase II study en-subtitle= kn-subtitle= en-abstract= kn-abstract=The efficacy of ciclosporin (CsA) to treat transfusion-independent non-severe aplastic anaemia (TI-NSAA) has not yet been systematically evaluated. We conducted a prospective trial in patients with TI-NSAA treated with CsA monotherapy. CsA (3.5 mg/kg/day) was administered to patients with TI-NSAA aged ≥16. The CsA dose was adjusted to maintain a blood CsA level of ≥600 ng/mL at 2 h post-administration. Blood cell counts were assessed after 8, 16 and 52 weeks of therapy. Thirty-two evaluable patients from 21 institutions were enrolled. The median age was 63.5 (range: 16–83) years. At 8 weeks, haematological improvement, with increases in haemoglobin (Hb) ≥1.5 g/dL (haematological improvement in erythrocytes [HI-E]) and platelet count ≥30 × 109/L (haematological improvement in platelets [HI-P]), was observed in 0/25 (0%) and 6/32 (19%) evaluable cases respectively. HI-E and HI-P occurred in 1/25 (4%) and 10/32 (31%) patients at 16 weeks, respectively, and at 52 weeks in 5/25 (20%) and 16/32 (50%) patients respectively. Nine grade 3 adverse events (AEs) occurred in six patients, but there were no grade ≥4 AEs. Ten of the 32 patients experienced grade 2 renal toxicity. Low-dose CsA is effective in TI-NSAA patients and demonstrates minimal renal toxicity. However, at least 16 weeks are necessary to adequately evaluate its efficacy. en-copyright= kn-copyright= en-aut-name=IshiyamaKen en-aut-sei=Ishiyama en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YamazakiMasahide en-aut-sei=Yamazaki en-aut-mei=Masahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MaruyamaHiroyuki en-aut-sei=Maruyama en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HosonoNaoko en-aut-sei=Hosono en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YamaguchiHiroki en-aut-sei=Yamaguchi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=TanimotoKazuki en-aut-sei=Tanimoto en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SugiuraHiroyuki en-aut-sei=Sugiura en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=UsukiKensuke en-aut-sei=Usuki en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YoshimuraKenichi en-aut-sei=Yoshimura en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OgawaSeishi en-aut-sei=Ogawa en-aut-mei=Seishi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=KanakuraYuzuru en-aut-sei=Kanakura en-aut-mei=Yuzuru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MatsumuraItaru en-aut-sei=Matsumura en-aut-mei=Itaru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=AkashiKoichi en-aut-sei=Akashi en-aut-mei=Koichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NakaoShinji en-aut-sei=Nakao en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Hematology, Kanazawa University Hospital kn-affil= affil-num=2 en-affil=Department of Internal Medicine, Keiju Medical Center kn-affil= affil-num=3 en-affil=Department of Hematology, Kanazawa University Hospital kn-affil= affil-num=4 en-affil=Department of Hematology and Oncology, University of Fukui Hospital kn-affil= affil-num=5 en-affil=Department of Hematology, Nippon Medical School kn-affil= affil-num=6 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=7 en-affil=Department of Hematology and Oncology, Japanese Red Cross Fukuoka Hospital kn-affil= affil-num=8 en-affil=Department of Hematology, Chugoku Central Hospital of Japan Mutual Aid Association of Public School Teachers kn-affil= affil-num=9 en-affil=Department of Hematology, NTT Medical Center Tokyo kn-affil= affil-num=10 en-affil=Department of Biostatistics and Health Data Science, Graduate School of Medical Science, Nagoya City University kn-affil= affil-num=11 en-affil=Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University kn-affil= affil-num=12 en-affil=Sumitomo Hospital kn-affil= affil-num=13 en-affil=Department of Hematology and Rheumatology, Kindai University Faculty of Medicine kn-affil= affil-num=14 en-affil=Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences kn-affil= affil-num=15 en-affil=Department of Hematology, Kanazawa University Hospital kn-affil= en-keyword=ciclosporin kn-keyword=ciclosporin en-keyword=prospective study kn-keyword=prospective study en-keyword=renal toxicity kn-keyword=renal toxicity en-keyword=transfusion-independent non-severe aplastic anaemia kn-keyword=transfusion-independent non-severe aplastic anaemia END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=6 article-no= start-page=e098532 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202506 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Protocol for a multicentre, open-label, dose-escalation phase I/II study evaluating the tolerability, safety, efficacy and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with aggressive natural killer cell leukaemia en-subtitle= kn-subtitle= en-abstract= kn-abstract=Introduction Aggressive natural killer cell leukaemia (ANKL) is a rare form of NK cell lymphoma with a very low incidence and poor prognosis. While multi-agent chemotherapy including L-asparaginase has been used to treat ANKL patients, they often cannot receive adequate chemotherapy at diagnosis due to liver dysfunction. PPMX-T003, a fully human monoclonal antibody targeting the transferrin receptor 1, shows promise in treating ANKL by helping patients recover from fulminant clinical conditions, potentially enabling a transition to chemotherapy. This study aimed to evaluate the tolerability, safety, efficacy, and pharmacokinetics of repeated continuous intravenous PPMX-T003 in patients with ANKL.
Methods and analysis This multicentre, open-label, dose-escalation phase I/II study will be conducted at nine hospitals in Japan. Patients diagnosed with ANKL (whether as a primary or recurrent disease) and exhibiting abnormal liver function or hepatomegaly due to the primary disease will be included. The primary endpoint is the tolerability and safety of repeated continuous intravenous administration of PPMX-T003 in the first course, based on adverse events and dose-limiting toxicities. PPMX-T003 will be administered as a continuous intravenous infusion every 24 hours for five consecutive days, followed by a 2-day break. Pretreatment will be provided to minimise the risk of infusion-related reactions. Initial doses of PPMX-T003 will be 0.5, 1.0 or 2.0 mg/kg, with subsequent dose increases determined by the Data and Safety Monitoring Committee. The sample size is set at seven participants, with enrolment increased to up to 12 participants if dose-limiting toxicities occur, based on feasibility due to the rarity of ANKL. Descriptive statistics will summarise data according to initial dose, and pharmacokinetic analysis will be conducted based on administered dose.
Ethics and dissemination This study was approved by the institutional review boards at participating hospitals. The results will be disseminated in peer-reviewed journals.
Trial registration number jRCT2061230008 (jRCT); NCT05863234 (ClinicalTrials.gov). en-copyright= kn-copyright= en-aut-name=FukuharaNoriko en-aut-sei=Fukuhara en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=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=AsadaNoboru en-aut-sei=Asada en-aut-mei=Noboru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 ORCID= en-aut-name=AndoKiyoshi en-aut-sei=Ando en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Hematology, Tohoku University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Hematology and Oncology, Tokai University School of Medicine Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Hematology, Graduate School of Medicine, Kyoto University kn-affil= affil-num=4 en-affil=Department of Hematology and Oncology, Okayama University Hospital kn-affil= affil-num=5 en-affil=Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University kn-affil= affil-num=6 en-affil=Department of Hematology, Hiroshima University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=98 cd-vols= no-issue= article-no= start-page=103224 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=The vicious cycle between nutrient deficiencies and antibiotic-induced nutrient depletion at the host cell-pathogen interface: Coenzyme Q10 and omega-6 as key molecular players en-subtitle= kn-subtitle= en-abstract= kn-abstract=The increasing prevalence of antibiotic resistance and pathological inflammation underscores the importance of understanding the underlying biochemical and immune processes that govern the host-pathogen interface. Nutrient deficiency, compounded by antibiotic-induced nutrient depletion, forms a vicious cycle of overt inflammation, contributing to bacterial toxin translocation in human inter-organ and intra-organs milieus. Coenzyme Q10 (CoQ10) and omega-6 linoleic acid (LA 18:2ω6) are integral to cellular membrane integrity and immune defense. However, the complex enzymatic steps at the host cell-pathogen interface remain poorly understood. This study is particularly timely, as it explores these knowledge gaps, which can inform the development of nutritional and therapeutic strategies that modulate or target these mechanisms. Using an infectious-inflamed cell co-culture model of the gut-liver axis, we exposed triple cell co-cultures of human intestinal epithelial cells (T84), macrophage-like THP-1 cells, and hepatic cells (Huh7) to linoleic acid-producing Lactobacillus casei (L. casei) and Pseudomonas aeruginosa strain PAO1 (PAO1). The cultures were incubated for 6 h in medium with or without ceftazidime antibiotic. PAO1 and L. casei exerted opposing effects on the secretion of Th1 cytokines IL-1β, IL-6, and the Th 2-type cytokine IL-10. Inoculation with PAO1 decreased CoQ10 and linoleic acid levels compared to uninfected controls. L. casei restored cellular health and biofunctionality impaired by PAO1, indicating its benefit to the host's well-being. The antibiotic ceftazidime exerted dual effects, alleviating PAO1 toxicity while marginally disrupting the beneficial effects of L. casei. Our results show how the vicious cycle of nutrient deficiency and antibiotic-induced nutrient loss reinforces pathological inflammation at the host cell-pathogen interface and highlights the need for more appropriate targeted antibiotic use that preserves essential nutrients like CoQ10 and omega-6 fatty acids. Inflammatory responses driven by opportunistic pathogens and LA-producing bacteria represent opposing immunometabolic pathways that may provide insights into novel approaches for treating infection and reducing antibiotic resistance. en-copyright= kn-copyright= en-aut-name=GhadimiDarab en-aut-sei=Ghadimi en-aut-mei=Darab kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=BlömerSophia en-aut-sei=Blömer en-aut-mei=Sophia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=Şahi̇n KayaAysel en-aut-sei=Şahi̇n Kaya en-aut-mei=Aysel kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KrügerSandra en-aut-sei=Krüger en-aut-mei=Sandra kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=RöckenChristoph en-aut-sei=Röcken en-aut-mei=Christoph kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SchäferHeiner en-aut-sei=Schäfer en-aut-mei=Heiner kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UchiyamaJumpei en-aut-sei=Uchiyama en-aut-mei=Jumpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MatsuzakiShigenobu en-aut-sei=Matsuzaki en-aut-mei=Shigenobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=BockelmannWilhelm en-aut-sei=Bockelmann en-aut-mei=Wilhelm kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= affil-num=2 en-affil=Faculty of Medicine, Christian-Albrechts-University of Kiel kn-affil= affil-num=3 en-affil=Department of Nutrition and Dietetics, Faculty of Health Sciences, Antalya Bilim University kn-affil= affil-num=4 en-affil=Institute of Pathology, Kiel University, University Hospital, Schleswig-Holstein kn-affil= affil-num=5 en-affil=Institute of Pathology, Kiel University, University Hospital, Schleswig-Holstein kn-affil= affil-num=6 en-affil=Laboratory of Molecular Gastroenterology & Hepatology, Christian-Albrechts-University & UKSH Campus Kiel kn-affil= affil-num=7 en-affil=Department of Bacteriology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Laboratory Science, Faculty of Health Sciences, Kochi Gakuen University kn-affil= affil-num=9 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= en-keyword=Antibiotics kn-keyword=Antibiotics en-keyword=Coenzyme Q10 kn-keyword=Coenzyme Q10 en-keyword=Infection kn-keyword=Infection en-keyword=Inflammation kn-keyword=Inflammation en-keyword=Micronutrients kn-keyword=Micronutrients en-keyword=Oxidative stress kn-keyword=Oxidative stress END start-ver=1.4 cd-journal=joma no-vol=81 cd-vols= no-issue= article-no= start-page=152587 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=The diagnostic utility and frequency of CD56 expression in plasma cell myeloma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Plasma cell myeloma (PCM) is a hematological malignancy characterized by systemic proliferation of neoplastic plasma cells within the bone marrow. Diagnosis requires clinical findings and immunohistochemical staining, including CD138, CD79a, cyclin D1, immunoglobulin κ (Igκ), and λ (Igλ). However, CD79a and cyclin D1 have limited sensitivity and specificity, and Igκ/Igλ assessment is often difficult due to overstaining. Therefore, more reliable antibodies are needed to accurately diagnose PCM. In this study, we examined the diagnostic utility of CD56 expression in PCM. We retrospectively performed immunostaining for CD138, CD56, CD79a, cyclin D1, Igκ, and Igλ in bone marrow samples from 116 patients with PCM.
CD56 expression was observed in 85/116 cases (73.3 %), CD79a was downregulated in 46/116 cases (39.7 %), and cyclin D1 expression was observed in 42/116 cases (36.2 %). The expression of CD56 was significantly higher than that of CD79a and cyclin D1 (both p < 0.001). The combination of two antibodies resulted in the highest detection rate when combining CD56 and CD79a (105/116, 90.5 %), which was significantly higher than the detection rates of CD56 and cyclin D1 (93/116, 80.2 %) and CD79a and cyclin D1 (75/116, 64.7 %) (both p < 0.001). In contrast, lymphoplasmacytic lymphoma and marginal zone lymphoma lacked CD56 and cyclin D1 expression. Furthermore, in cases where light chain restriction was undetectable (11/116, 9.5 %), all could be diagnosed as PCM based on CD56, CD79a, and cyclin D1. Among these, CD56 showed the highest detection rate (8/11, 72.7 %).
These findings highlight CD56 as a helpful marker for PCM diagnosis and support further clinical research.
en-copyright= kn-copyright= en-aut-name=ImaiMidori en-aut-sei=Imai en-aut-mei=Midori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 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=4 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=5 ORCID= en-aut-name=KatoSyoma en-aut-sei=Kato en-aut-mei=Syoma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TabeMizuha en-aut-sei=Tabe en-aut-mei=Mizuha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=YanaiHiroyuki en-aut-sei=Yanai en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=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= 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 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=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=7 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= affil-num=8 en-affil=Department of Diagnostic Pathology, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Pathology and Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences kn-affil= en-keyword=Plasma cell myeloma kn-keyword=Plasma cell myeloma en-keyword=Immunohistochemical staining kn-keyword=Immunohistochemical staining en-keyword=CD56 kn-keyword=CD56 END start-ver=1.4 cd-journal=joma no-vol=152 cd-vols= no-issue=22 article-no= start-page=dev204763 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251115 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=ROS produced by Dual oxidase regulate cell proliferation and haemocyte migration during leg regeneration in the cricket en-subtitle= kn-subtitle= en-abstract= kn-abstract=Many animals regenerate lost body parts through several signalling pathways; however, the triggers that initiate regeneration remain unclear. In the present study, we focused on the role of reactive oxygen species (ROS) produced by the NADPH oxidase Dual oxidase (Duox) during cricket leg regeneration. The results showed that ROS levels were upregulated during leg regeneration and decreased by DuoxRNAi. In DuoxRNAi nymphs, wound closure and scab formation were incomplete 2 days after amputation, and hypertrophy occurred in the distal region of the regenerating legs at 5 days after amputation. In addition, the hypertrophic phenotype was induced by DuoxARNAi and NADPH oxidase inhibitor treatment. During hypertrophy, haemocytes, including plasmatocytes, oenocytoids and granulocytes, accumulated. Proliferation of haemocytes in regenerating legs was not increased by DuoxRNAi; however, haemocyte accumulation was regulated by the Spatzle (Spz) family molecules, which are Toll receptor ligands. As the exoskeleton of DuoxRNAi nymphs was thinner than that of the control, excessive haemocyte accumulation can cause hypertrophy in DuoxRNAi nymphs. Thus, Duox-derived ROS are involved in wound healing and haemocyte accumulation through the Spz/Toll signalling pathway during leg regeneration in crickets. en-copyright= kn-copyright= en-aut-name=Okumura-HironoMisa en-aut-sei=Okumura-Hirono en-aut-mei=Misa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=BandoTetsuya en-aut-sei=Bando en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HamadaYoshimasa en-aut-sei=Hamada en-aut-mei=Yoshimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=OhuchiHideyo en-aut-sei=Ohuchi en-aut-mei=Hideyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Cytology and Histology, 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 Cytology and Histology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Regeneration kn-keyword=Regeneration en-keyword=Reactive oxygen species (ROS) kn-keyword=Reactive oxygen species (ROS) en-keyword=NADPH oxidase (Nox) kn-keyword=NADPH oxidase (Nox) en-keyword=Dual oxidase (Duox) kn-keyword=Dual oxidase (Duox) en-keyword=Inflammation kn-keyword=Inflammation en-keyword=Gryllus bimaculatus kn-keyword=Gryllus bimaculatus END start-ver=1.4 cd-journal=joma no-vol=386 cd-vols= no-issue= article-no= start-page=115145 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=Therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) with voluntary and forced exercise in a rat model of ischemic stroke en-subtitle= kn-subtitle= en-abstract= kn-abstract=Ischemic stroke results in significant long-term disability and mortality worldwide. Although existing therapies, such as recombinant tissue plasminogen activator and mechanical thrombectomy, have shown promise, their application is limited by stringent conditions. Mesenchymal stem cell (MSC) transplantation, especially using SB623 cells (modified human bone marrow-derived MSCs), has emerged as a promising alternative, promoting neurogenesis and recovery. This study evaluated the effects of voluntary and forced exercise, alone and in combination with SB623 cell transplantation, on neurological and psychological outcomes in a rat model of ischemic stroke. Male Wistar rats that had undergone middle cerebral artery occlusion (MCAO) were divided into six groups: control, voluntary exercise (V-Ex), forced exercise (F-Ex), SB623 transplantation, SB623 + V-Ex, and SB623 + F-Ex. Voluntary exercise was facilitated using running wheels, while forced exercise was conducted on treadmills. Neurological recovery was assessed using the modified neurological severity score (mNSS). Psychological symptoms were evaluated through the open field test (OFT) and forced swim test (FST), and neurogenesis was assessed via BrdU labeling. Both exercise groups exhibited significant changes in body weight post-MCAO. Both exercises enhanced the treatment effect of SB623 transplantation. The forced exercise showed a stronger treatment effect on ischemic stroke than voluntary exercise alone, and the sole voluntary exercise improved depression-like behavior. The SB623 + F-Ex group demonstrated the greatest improvements in motor function, infarct area reduction, and neurogenesis. The SB623 + V-Ex group was most effective in alleviating depression-like behavior. Future research should optimize these exercise protocols and elucidate the underlying mechanisms to develop tailored rehabilitation strategies for stroke patients. en-copyright= kn-copyright= en-aut-name=NagaseTakayuki en-aut-sei=Nagase en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YasuharaTakao en-aut-sei=Yasuhara en-aut-mei=Takao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KinKyohei en-aut-sei=Kin en-aut-mei=Kyohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SasadaSusumu en-aut-sei=Sasada en-aut-mei=Susumu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawauchiSatoshi en-aut-sei=Kawauchi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YabunoSatoru en-aut-sei=Yabuno en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SugaharaChiaki en-aut-sei=Sugahara en-aut-mei=Chiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HirataYuichi en-aut-sei=Hirata en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MiyakeHayato en-aut-sei=Miyake en-aut-mei=Hayato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SasakiTatsuya en-aut-sei=Sasaki en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KawaiKoji en-aut-sei=Kawai en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=TanimotoShun en-aut-sei=Tanimoto en-aut-mei=Shun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SaijoTomoya en-aut-sei=Saijo en-aut-mei=Tomoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=TanakaShota en-aut-sei=Tanaka en-aut-mei=Shota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Ischemic stroke kn-keyword=Ischemic stroke en-keyword=Post-stroke depression kn-keyword=Post-stroke depression en-keyword=Regenerative medicine kn-keyword=Regenerative medicine en-keyword=Rehabilitation kn-keyword=Rehabilitation en-keyword=SB623 kn-keyword=SB623 END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue= article-no= start-page=e2025-0034 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251031 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Optimal Virtual-target Definition for Detecting Feeding Arteries of Renal Cell Carcinoma Using Automated Feeder-detection Software en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose: To determine the optimal virtual-target definition for detecting renal cell carcinoma feeders using transarterial computed tomography angiography with automated feeder-detection software.
Material and Methods: This retrospective study included 17 patients with 17 renal cell carcinomas who underwent transarterial ethiodized-oil marking before cryoablation. Tumor feeders were automatically detected on transarterial renal computed tomography angiography images using the automated feeder-detection software with three virtual-target definitions: small (ellipsoidal area maximized within the tumor contour), medium (ellipsoidal area covering the entire tumor with a minimal peripheral margin), and large (ellipsoidal area including the tumor and a 5-mm peripheral margin). The detected feeders were classified as true or false positives according to the findings of selective renal arteriography, by consensus of two interventional radiologists. Feeder-detection sensitivity and the mean number of false-positive feeders per tumor were calculated for each virtual-target definition.
Results: For 17 tumors, 25 feeding arteries were identified on the arteriography. The feeder-detection sensitivity of the software was 80.0% (20/25), 88.0% (22/25), and 48.0% (12/25) for small, medium, and large virtual targets, respectively. The mean ± standard deviation number of false-positive feeders per tumor was 0.82 ± 1.3, 1.41 ± 1.1, and 2.82 ± 1.6 when using small, medium, and large virtual-target definitions, respectively.
Conclusions: The detection rate of renal cell carcinoma feeders with the automated feeder-detection software varies according to the virtual-target definition. Using a medium virtual target, covering the entire tumor with a minimal peripheral margin, may provide the highest sensitivity and an acceptable number of false-positive feeders. en-copyright= kn-copyright= en-aut-name=OkamotoSoichiro en-aut-sei=Okamoto en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsuiYusuke en-aut-sei=Matsui en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KawabataTakahiro en-aut-sei=Kawabata en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TomitaKoji en-aut-sei=Tomita en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MunetomoKazuaki en-aut-sei=Munetomo en-aut-mei=Kazuaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UmakoshiNoriyuki en-aut-sei=Umakoshi en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HigakiFumiyo en-aut-sei=Higaki en-aut-mei=Fumiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IguchiToshihiro en-aut-sei=Iguchi en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HirakiTakao en-aut-sei=Hiraki en-aut-mei=Takao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= affil-num=1 en-affil=Department of Radiology, Medical Development Field, Okayama University kn-affil= affil-num=2 en-affil=Department of Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Radiology, Tsuyama Chuo Hospital kn-affil= affil-num=4 en-affil=Department of Radiology, Medical Development Field, Okayama University kn-affil= affil-num=5 en-affil=Department of Radiology, Medical Development Field, Okayama University kn-affil= affil-num=6 en-affil=Department of Radiology, Medical Development Field, Okayama University kn-affil= affil-num=7 en-affil=Department of Radiology, Medical Development Field, Okayama University kn-affil= affil-num=8 en-affil=Department of Radiological Technology, Faculty of Health Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Radiology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=computed tomography angiography kn-keyword=computed tomography angiography en-keyword=kidney kn-keyword=kidney en-keyword=software kn-keyword=software en-keyword=therapeutic embolization kn-keyword=therapeutic embolization END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250924 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=DSOK-0011 Potentially Regulates Circadian Misalignment and Affects Gut Microbiota Composition in Activity-Based Anorexia Model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objective: Anorexia nervosa (AN) is a metabolic-psychiatric disorder characterized by severe weight loss, hypercortisolemia, and hypothalamic–pituitary–adrenal (HPA) axis activation. In this study, we investigated the effect of inhibiting cortisol regeneration via the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) on the pathophysiology of AN.
Method: Female C57BL/6J mice underwent a 7-day activity-based anorexia (ABA) paradigm, involving 3 h daily feeding and free access to wheels, until 25% body weight loss or experiment completion. Mice were orally treated once daily with a potent 11β-HSD1 inhibitor, DSOK-0011, or vehicle. Body weight, food intake, and activity transitions were recorded; plasma corticosterone and cholesterol levels were measured using a fluorometric assay; gut microbiota were analyzed using 16S rRNA sequencing; and hippocampal glial cells were analyzed using immunohistochemistry.
Results: DSOK-0011-treated mice exhibited a modest but significant increase in postprandial wheel-running activity compared to baseline (4–5 p.m., p = 0.018; 5–6 p.m., p = 0.043), whereas vehicle-treated mice showed higher preprandial activity (9–10 a.m., p = 0.0229). Gut microbiota analysis revealed increased alpha diversity in ABA mice, with a specific enrichment of the Lachnospiraceae family in the DSOK-0011 group. However, DSOK-0011 did not significantly affect body weight, food intake, corticosterone, and lipid levels, or hippocampal glial cell populations.
Conclusion: Inhibition of 11β-HSD1 by DSOK-0011 was associated with microbiota alterations and subtle shifts in activity timing under energy-deficient conditions. These findings suggest that peripheral glucocorticoid metabolism may influence microbial and behavioral responses in the ABA model, although its metabolic impact appears limited in the acute phase. en-copyright= kn-copyright= en-aut-name=KawaiHiroki en-aut-sei=Kawai en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WadaNanami en-aut-sei=Wada en-aut-mei=Nanami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SakamotoShinji en-aut-sei=Sakamoto en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MiyazakiKenji en-aut-sei=Miyazaki en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KatoTaro en-aut-sei=Kato en-aut-mei=Taro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HoriuchiYoshihiro en-aut-sei=Horiuchi en-aut-mei=Yoshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KiriiHiroshi en-aut-sei=Kirii en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NguyenHoang Duy en-aut-sei=Nguyen en-aut-mei=Hoang Duy kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HinotsuKenji en-aut-sei=Hinotsu en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OhyaYoshio en-aut-sei=Ohya en-aut-mei=Yoshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AsadaTakahiro en-aut-sei=Asada en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=YokodeAkiyoshi en-aut-sei=Yokode en-aut-mei=Akiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=OkahisaYuko en-aut-sei=Okahisa en-aut-mei=Yuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MiyazakiHaruko en-aut-sei=Miyazaki en-aut-mei=Haruko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=OohashiToshitaka en-aut-sei=Oohashi en-aut-mei=Toshitaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TakakiManabu en-aut-sei=Takaki en-aut-mei=Manabu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Sumitomo Pharma Co. Ltd kn-affil= affil-num=5 en-affil=Sumitomo Pharma Co. Ltd kn-affil= affil-num=6 en-affil=Sumitomo Pharma Co. Ltd kn-affil= affil-num=7 en-affil=Department of Animal Applied Microbiology, Okayama University Graduate School of Environmental, Life, Natural Science and Technology kn-affil= affil-num=8 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=9 en-affil=Department of Neuropsychiatry, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Molecular Biology and Biochemistry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Neuropsychiatry, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=11β-HSD1 kn-keyword=11β-HSD1 en-keyword=activity-based anorexia kn-keyword=activity-based anorexia en-keyword=anorexia nervosa kn-keyword=anorexia nervosa en-keyword=corticosterone kn-keyword=corticosterone en-keyword=eating disorders kn-keyword=eating disorders en-keyword=microbiota kn-keyword=microbiota END start-ver=1.4 cd-journal=joma no-vol=33 cd-vols= no-issue=1 article-no= start-page=22 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251031 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Protective impact of landiolol against acute lung injury following hemorrhagic shock and resuscitation in rats en-subtitle= kn-subtitle= en-abstract= kn-abstract=Hemorrhagic shock and resuscitation (HSR) induces pulmonary inflammation, leading to acute lung injury (ALI). Notably, blocking β1 receptors can lead to organ protection through anti‑inflammatory and anti‑apoptotic effects. Additionally, although the β1 receptor pathway is blocked by the β1 blocker, the β2 receptor pathway may be preserved and activate the 5' adenosine monophosphate‑activated protein kinase (AMPK) pathway. The present study aimed to examine whether administration of the β1 blocker landiolol could achieve lung protection in a model of HSR‑ALI, alongside improvements in inflammation and apoptosis. Male Sprague‑Dawley rats underwent hemorrhage keeping their mean arterial pressure at 30 mmHg for 1 h. Resuscitation by reinfusion was initiated to restore blood pressure to pre‑hemorrhage levels for >15 min, followed by a 45‑min stabilization period to create the HSR‑ALI model. Landiolol (100 mg/kg/min) or saline was continuously administered after resuscitation. The lung tissues, which were collected for assessing inflammation and apoptosis‑related damage, underwent analyses, including histological examination, neutrophil count, assessment of lung wet/dry weight ratio, detection of the mRNA levels of tumor necrosis factor‑α (TNF‑α) and inducible nitric oxide synthase (iNOS), identification of terminal deoxynucleotidyl transferase dUTP nick‑end labeling (TUNEL)‑positive cells, and evaluation of caspase‑3 expression. In addition, phosphorylated AMPKα (pAMPKα) expression was tested via western blotting. Compared with the HSR/saline group, the HSR/landiolol group demonstrated a reduction in lung tissue damage score, and significant reductions in neutrophil count, lung wet/dry weight ratio, lung TNF‑α and iNOS mRNA levels, TUNEL‑positive cells and cleaved caspase‑3 expression. Furthermore, landiolol administration following HSR treatment increased pAMPKα expression. No significant hypotension occurred between the HSR/landiolol and HSR/saline groups; and blood loss did not differ significantly between the groups. In conclusion, landiolol administration after HSR reduced lung inflammation and apoptosis, suggesting a potential improvement in tissue damage. Furthermore, pAMPKα activation in the HSR/landiolol group may be the mechanism underlying the pulmonary protective effects of landiolol. en-copyright= kn-copyright= en-aut-name=SakamotoRisa en-aut-sei=Sakamoto en-aut-mei=Risa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShimizuHiroko en-aut-sei=Shimizu en-aut-mei=Hiroko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakamuraRyu en-aut-sei=Nakamura en-aut-mei=Ryu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=LuYifu en-aut-sei=Lu en-aut-mei=Yifu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LiYaqiang en-aut-sei=Li en-aut-mei=Yaqiang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OmoriEmiko en-aut-sei=Omori en-aut-mei=Emiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakahashiToru en-aut-sei=Takahashi en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MorimatsuHiroshi en-aut-sei=Morimatsu 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 Anesthesiology and Resuscitology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Anesthesiology and Resuscitology, Okayama University Medical School kn-affil= affil-num=3 en-affil=Department of Anesthesiology and Resuscitology, Okayama University Medical School kn-affil= affil-num=4 en-affil=Department of Human Anatomy, Shantou University Medical College kn-affil= affil-num=5 en-affil=Department of Anesthesiology and Resuscitology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Anesthesiology and Resuscitology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Anesthesiology, Okayama Saidaiji Hospital kn-affil= affil-num=8 en-affil=Department of Anesthesiology and Resuscitology, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=HSR kn-keyword=HSR en-keyword=lung injury kn-keyword=lung injury en-keyword=landiolol kn-keyword=landiolol en-keyword=β1 blocker kn-keyword=β1 blocker en-keyword=inflammation kn-keyword=inflammation en-keyword=apoptosis kn-keyword=apoptosis END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue=1 article-no= start-page=234 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251114 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Rotenone targets midbrain astrocytes to produce glial dysfunction-mediated dopaminergic neurodegeneration en-subtitle= kn-subtitle= en-abstract= kn-abstract=Exposure to pesticides, such as rotenone or paraquat, is an environmental factor that plays an important role in the pathogenesis of Parkinson's disease (PD). Rotenone induces PD-like pathology and is therefore used to develop parkinsonian animal models. Dopaminergic neurotoxicity caused by rotenone has been attributed to the inhibition of mitochondrial complex I, oxidative stress and neuroinflammation; however, the mechanisms underlying selective dopaminergic neurodegeneration by rotenone remain unclear. To resolve this, we focused on glial diversity and examined whether the brain region-specific glial response to rotenone could determine the vulnerability of dopaminergic neurons using primary cultured neurons, astrocytes and microglia from the midbrain and striatum of rat embryos and rotenone-injected PD model mice. Direct neuronal treatment with low-dose rotenone failed to damage dopaminergic neurons. Conversely, rotenone exposure in the presence of midbrain astrocyte and microglia or conditioned media from rotenone-treated midbrain glial cultures containing astrocytes and microglia produced dopaminergic neurotoxicity, but striatal glia did not. Surprisingly, conditioned media from rotenone-treated midbrain astrocytes or microglia monocultures did not affect neuronal survival. We also demonstrated that rotenone targeted midbrain astrocytes prior to microglia to induce dopaminergic neurotoxicity. Rotenone-treated astrocytes produced secreted protein acidic and rich in cysteine (SPARC) extracellularly, which induced microglial proliferation, increase in IL-1β and TNF-α, and NF-κB (p65) nuclear translocation in microglia, resulting in dopaminergic neurodegeneration. In addition, rotenone exposure caused the secretion of NFAT-related inflammatory cytokines and a reduction in the level of an antioxidant metallothionein (MT)-1 from midbrain glia. Furthermore, we observed microglial proliferation and a decrease in the number of MT-positive astrocytes in the substantia nigra, but not the striatum, of low-dose rotenone-injected PD model mice. Our data highlight that rotenone targets midbrain astrocytes, leading to SPARC secretion, which promotes the neurotoxic conversion of microglia and leads to glial dysfunction-mediated dopaminergic neurodegeneration. en-copyright= kn-copyright= en-aut-name=MiyazakiIkuko en-aut-sei=Miyazaki en-aut-mei=Ikuko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=IsookaNami en-aut-sei=Isooka en-aut-mei=Nami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KikuokaRyo en-aut-sei=Kikuoka en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ImafukuFuminori en-aut-sei=Imafuku en-aut-mei=Fuminori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MasaiKaori en-aut-sei=Masai en-aut-mei=Kaori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TomimotoKana en-aut-sei=Tomimoto en-aut-mei=Kana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 ORCID= en-aut-name=SogawaChiharu en-aut-sei=Sogawa en-aut-mei=Chiharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SogawaNorio en-aut-sei=Sogawa en-aut-mei=Norio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=10 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=11 ORCID= affil-num=1 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=8 en-affil=Department of Food and Health Sciences, Faculty of Environmental Studies, Hiroshima Institute of Technology kn-affil= affil-num=9 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=10 en-affil=Department of Pharmacotherapy, School of Pharmacy, Shujitsu University kn-affil= affil-num=11 en-affil=Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Rotenone kn-keyword=Rotenone en-keyword=Astrocyte kn-keyword=Astrocyte en-keyword=Microglia kn-keyword=Microglia en-keyword=SPARC kn-keyword=SPARC en-keyword=Parkinson's disease kn-keyword=Parkinson's disease END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=38590 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251104 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Serum extracellular vesicles containing adenoviral E1A-DNA as a predictive biomarker for liquid biopsy in oncolytic adenovirus therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Oncolytic adenoviruses replicate selectively in tumor cells and induce immunogenic cell death, but predictive biomarkers for early therapeutic response are lacking. This study evaluated extracellular vesicle-encapsulated adenoviral E1A-DNA (EV-E1A-DNA) as a minimally invasive biomarker for monitoring responses to telomerase-specific oncolytic adenoviruses OBP-301 and OBP-502. EVs were isolated from human and murine cancer cell lines and from the serum of treated mice using ultracentrifugation. EV-associated E1A-DNA levels were measured by quantitative polymerase chain reaction and found to correlate with cytotoxicity in vitro and tumor regression in vivo. In xenograft models, serum EV-E1A-DNA levels at 2 days post-treatment showed strong correlations with final tumor volume and survival, supporting their utility as an early predictive biomarker. In immunocompetent mice pre-immunized with wild-type adenovirus, free viral DNA was undetectable in serum due to neutralizing antibodies, whereas EV-E1A-DNA remained detectable. This “stealth effect” indicates that EVs protect viral components from immune clearance. These results demonstrate that EV-E1A-DNA is a sensitive and virus-specific biomarker that enables early assessment of therapeutic efficacy, even in the presence of antiviral immunity. This strategy offers a promising liquid biopsy approach for personalized monitoring of oncolytic virotherapy and may be applicable to other virus-based therapies. en-copyright= kn-copyright= en-aut-name=YagiChiaki en-aut-sei=Yagi en-aut-mei=Chiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KurodaShinji en-aut-sei=Kuroda en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KakiuchiYoshihiko en-aut-sei=Kakiuchi en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HanzawaShunya en-aut-sei=Hanzawa en-aut-mei=Shunya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KadowakiDaisuke en-aut-sei=Kadowaki en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YoshidaYusuke en-aut-sei=Yoshida en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SakamotoMasaki en-aut-sei=Sakamoto en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=HamadaYuki en-aut-sei=Hamada en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SugimotoRyoma en-aut-sei=Sugimoto en-aut-mei=Ryoma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OhtaniTomoko en-aut-sei=Ohtani en-aut-mei=Tomoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=KumonKento en-aut-sei=Kumon en-aut-mei=Kento kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=HashimotoMasashi en-aut-sei=Hashimoto en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=13 ORCID= en-aut-name=KikuchiSatoru en-aut-sei=Kikuchi en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=KagawaShunsuke en-aut-sei=Kagawa en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=TazawaHiroshi en-aut-sei=Tazawa en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=UrataYasuo en-aut-sei=Urata en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 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=18 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=2 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=3 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=4 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=5 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=8 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= affil-num=17 en-affil=Oncolys BioPharma, Inc. kn-affil= affil-num=18 en-affil=Department of Gastroenterological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine kn-affil= en-keyword=Oncolytic adenovirus kn-keyword=Oncolytic adenovirus en-keyword=Extracellular vesicle kn-keyword=Extracellular vesicle en-keyword=Liquid biopsy kn-keyword=Liquid biopsy en-keyword=Predictive biomarker kn-keyword=Predictive biomarker en-keyword=Stealth effect kn-keyword=Stealth effect END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Gemcitabine-induced neutrophil extracellular traps via interleukin-8-CXCR1/2 pathway promote chemoresistance in pancreatic cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, and chemoresistance poses a significant challenge in its treatment. Neutrophil extracellular traps (NETs) have emerged as key players in the tumour microenvironment, but their role in chemoresistance remains unclear.
Methods: We investigated the involvement of NETs in PDAC chemoresistance using patient tumour samples, in vitro assays with gemcitabine (GEM)-treated PDAC cells, and in vivo mouse models. We evaluated cytokine production, NET formation and tumour response to GEM, with or without the CXCR1/2 inhibitor navarixin.
Results: NETs are significantly accumulated in the tumours of PDAC patients exhibiting poor response to chemotherapy. GEM-treated PDAC cells secrete pro-inflammatory cytokines such as interleukin-8 (IL-8). IL-8 promote the formation of chemotherapy-induced NETs (chemoNETosis) through activation of CXCR 1/2 on neutrophils. Importantly, treatment with navarixin significantly suppressed chemoNETosis, restored sensitivity to GEM, and significantly reduced tumour growth in vivo.
Conclusions: Our findings reveal that NETs contribute to chemoresistance in PDAC and that IL-8–mediated chemoNETosis plays a pivotal role in this process. Inhibition of CXCR1/2-mediated NET formation enhances the efficacy of GEM. This approach may represent a promising therapeutic strategy for overcoming chemoresistance in PDAC. These results support further clinical investigation of anti-NETs therapies. en-copyright= kn-copyright= en-aut-name=NogiShohei en-aut-sei=Nogi en-aut-mei=Shohei 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=TaniguchiAtsuki en-aut-sei=Taniguchi en-aut-mei=Atsuki 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=KakiuchiYoshihiko en-aut-sei=Kakiuchi en-aut-mei=Yoshihiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YasuiKazuya en-aut-sei=Yasui en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=FujiTomokazu en-aut-sei=Fuji en-aut-mei=Tomokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KonoYoshiyasu en-aut-sei=Kono en-aut-mei=Yoshiyasu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=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=TakagiKosei en-aut-sei=Takagi en-aut-mei=Kosei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 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=12 ORCID= en-aut-name=TeraishiFuminori en-aut-sei=Teraishi en-aut-mei=Fuminori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=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 Gastroenterology and Hepatology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= END start-ver=1.4 cd-journal=joma no-vol=32 cd-vols= no-issue=11 article-no= start-page=1677 end-page=1685 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250819 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Role of Cytoreductive Nephrectomy in the Immune Checkpoint Inhibitor Era: A Multicenter Collaborative Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Objectives: We aimed to evaluate overall survival (OS) and determine the optimal timing of cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma (mRCC) receiving immune checkpoint inhibitor (ICI)-based therapy.
Methods: This retrospective study reviewed medical records of 447 patients with mRCC treated with ICI at multiple Japanese institutions between January 2018 and August 2023. From this cohort, 178 patients with lymph node or distant metastases received either cytoreductive nephrectomy (CN group; n = 72) or ICI therapy without cytoreductive nephrectomy (non-CN group; n = 106) as first-line treatment.
Results: Median progression-free survival was 15.7 months, and median overall survival was 58.1 months. CN significantly improved OS, with the CN group's median OS not reached, compared to 29.6 months in the non-CN group (p = 0.01). Deferred CN also showed improved survival outcomes. Poor prognostic factors for immediate CN included International Metastatic Renal Cell Carcinoma Database Consortium poor risk, sarcomatoid differentiation, and a high neutrophil-to-lymphocyte ratio.
Conclusions: We developed a prognostic model to guide patient selection for CN, emphasizing the need for personalized treatment strategies. en-copyright= kn-copyright= en-aut-name=NukayaTakuhisa en-aut-sei=Nukaya en-aut-mei=Takuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 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=4 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=5 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=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=BekkuKensuke en-aut-sei=Bekku en-aut-mei=Kensuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 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=10 ORCID= en-aut-name=HirasawaYosuke en-aut-sei=Hirasawa en-aut-mei=Yosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 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=12 ORCID= en-aut-name=HashimotoTakeshi en-aut-sei=Hashimoto en-aut-mei=Takeshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 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=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=OhnoYoshio en-aut-sei=Ohno en-aut-mei=Yoshio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=ShirokiRyoichi en-aut-sei=Shiroki en-aut-mei=Ryoichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= affil-num=2 en-affil=Department of Urology, Fujita-Health University School 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, Kindai University Faculty 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, The Jikei University School of Medicine kn-affil= affil-num=7 en-affil=Department of Urology, Okayama University Graduate School of Medicine kn-affil= affil-num=8 en-affil=Department of Urology, Okayama University Graduate School of Medicine kn-affil= affil-num=9 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University 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, Tokyo Medical University 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, Tokyo Medical University kn-affil= affil-num=14 en-affil=Department of Urology, Osaka Medical and Pharmaceutical University kn-affil= affil-num=15 en-affil=Department of Urology, Okayama University Graduate School of Medicine kn-affil= affil-num=16 en-affil=Department of Urology, Kindai University Faculty of Medicine kn-affil= affil-num=17 en-affil=Department of Urology, Tokyo Medical University kn-affil= affil-num=18 en-affil=Department of Urology, Fujita-Health University School of Medicine kn-affil= en-keyword=cytoreductive nephrectomy kn-keyword=cytoreductive nephrectomy en-keyword=IMDC classification kn-keyword=IMDC classification en-keyword=immune checkpoint inhibitor kn-keyword=immune checkpoint inhibitor en-keyword=neutrophil-to- lymphocyte ratio kn-keyword=neutrophil-to- lymphocyte ratio en-keyword=sarcomatoid differentiation kn-keyword=sarcomatoid differentiation END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251104 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Optogenetic Cancer Therapy Using the Light-Driven Outward Proton Pump Rhodopsin Archaerhodopsin-3 (AR3) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Medicines used for cancer treatment often cause serious side effects by damaging normal cells due to nonspecific diffusion. To address this issue, we previously developed an optical method to induce apoptotic cell death via intracellular pH alkalinization using the outward proton pump rhodopsin, Archaerhodopsin-3 (AR3) in various noncancer model cells in vitro and in vivo. In this study, we applied this method to cancer cells and tumors to evaluate its potential as an anticancer therapeutic strategy. First, we confirmed that AR3-expressing murine cancer cell lines (MC38, B16F10) showed apoptotic cell death upon green light irradiation, as indicated by increased levels of cell death and apoptosis-related markers. Next, we established stable AR3-expressing MC38 and B16F10 cells by using viral vectors. When these AR3-expressing cells were subcutaneously transplanted into C57BL/6 mice, the resulting tumors initially grew at a rate comparable to that of control tumors lacking AR3 expression or light stimulation. However, upon green light irradiation, AR3-expressing tumors exhibited either a marked reduction in size or significantly suppressed growth, accompanied by the induction of apoptosis signals and decreased proliferation signals. These results demonstrate that AR3-mediated cell death has potent antitumor effects both in vitro and in vivo. This optical method thus holds promise as a novel cancer therapy with potentially reduced side effects. en-copyright= kn-copyright= en-aut-name=NakaoShin en-aut-sei=Nakao en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KojimaKeiichi en-aut-sei=Kojima en-aut-mei=Keiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SatoKeita en-aut-sei=Sato en-aut-mei=Keita kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KemmotsuNaoya en-aut-sei=Kemmotsu en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OhuchiHideyo en-aut-sei=Ohuchi en-aut-mei=Hideyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 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= affil-num=7 en-affil=Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=281 cd-vols= no-issue= article-no= start-page=111174 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=N-terminal domains and site-specific glycosylation regulate the secretion of avian melanocortin inverse agonists, agouti signaling protein (ASIP) and agouti-related protein (AGRP) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Agouti signaling protein (ASIP) and agouti-related protein (AGRP) are paralogous inverse agonists of melanocortin receptors with distinct physiological roles, but their structural and biochemical properties in birds remain poorly understood. Here, we characterized chicken ASIP and AGRP proteins. Analysis of available sequences revealed that a motif resembling the mammalian proprotein convertase 1/3 (PC1/3, also known as PCSK1) cleavage site is conserved across a broad range of avian orders, but Western blot analysis of transfected Chinese hamster ovary (CHO-K1) cells and chicken hypothalamus detected no cleavage, suggesting that avian AGRP may not be post-translationally processed at this site. Chicken ASIP mRNA contains an in-frame upstream ATG (uATG) and a putative N-linked glycosylation site at Asn-42, both conserved across multiple avian orders. Overexpression in CHO-K1 cells showed that ASIP translated from either ATG produces a mature protein of the same size that is N-glycosylated at Asn-42 and exhibits markedly lower secretion efficiency than AGRP. Domain-swapping experiments revealed that the N-terminal domain reduces secretion, whereas a naturally occurring ASIP-b variant with an additional N-glycan at Asn-47 shows enhanced secretion. Proteasome inhibition increased intracellular ASIP, and endoglycosidase H (Endo H) sensitivity indicated endoplasmic reticulum (ER) retention, suggesting that the N-terminal domain limits secretion via ER-associated proteasomal degradation. These findings reveal species-specific post-translational regulation of avian melanocortin inverse agonists, in which N-terminal features and site-specific N-glycosylation determine secretion efficiency, likely contributing to their distinct roles in pigmentation and hypothalamic energy balance. en-copyright= kn-copyright= en-aut-name=FukuchiHibiki en-aut-sei=Fukuchi en-aut-mei=Hibiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=WatanabeRyoya en-aut-sei=Watanabe en-aut-mei=Ryoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IidaYuna en-aut-sei=Iida en-aut-mei=Yuna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakanoSaya en-aut-sei=Nakano en-aut-mei=Saya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MizutaniAya en-aut-sei=Mizutani en-aut-mei=Aya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AboTatsuhiko en-aut-sei=Abo en-aut-mei=Tatsuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=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=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= 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= en-keyword=Agouti signaling protein kn-keyword=Agouti signaling protein en-keyword=Agouti-related protein kn-keyword=Agouti-related protein en-keyword=Avian melanocortin inverse agonists kn-keyword=Avian melanocortin inverse agonists en-keyword=Post-translational modification kn-keyword=Post-translational modification en-keyword=N-linked glycosylation kn-keyword=N-linked glycosylation en-keyword=Protein secretion kn-keyword=Protein secretion END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=11 article-no= start-page=1680 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251029 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Kidney Organoids: Current Advances and Applications en-subtitle= kn-subtitle= en-abstract= kn-abstract=Kidney organoids, derived from stem cells, including pluripotent stem cells and adult progenitor cells, have been reported as three-dimensional in vitro models that reflect key aspects of kidney development, structure, and function. Advances in differentiation protocols and tissue engineering have enabled the generation of organoids that exhibit nephron-like structures, including glomerular and tubular structures. Kidney organoids have been widely applied in several directions, including disease modeling and therapeutic screening, drug nephrotoxicity evaluation, and regenerative medicine. In particular, kidney organoids offer a promising platform for studying genetic kidney diseases, such as polycystic kidney disease and congenital anomalies of the kidney and urinary tract (CAKUT), by allowing patient-specific modeling for the analysis of pathophysiology and therapeutic screening. Despite several current limitations, such as incomplete maturation, lack of full nephron segmentation, and variability between protocols and cell conditions, further technological innovations such as microfluidics and bioengineering may refine kidney organoid systems. This review highlights recent advances in kidney organoid research, outlines major applications, and discusses future directions to enhance their physiological relevance, functional maturity, and translational integration into preclinical and clinical nephrology. en-copyright= kn-copyright= en-aut-name=NakanohHiroyuki en-aut-sei=Nakanoh en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TsujiKenji en-aut-sei=Tsuji en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=FukushimaKazuhiko en-aut-sei=Fukushima en-aut-mei=Kazuhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UchidaNaruhiko en-aut-sei=Uchida en-aut-mei=Naruhiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HaraguchiSoichiro en-aut-sei=Haraguchi en-aut-mei=Soichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KitamuraShinji en-aut-sei=Kitamura en-aut-mei=Shinji 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, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, 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 Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=kidney organoid kn-keyword=kidney organoid en-keyword=stem cell kn-keyword=stem cell en-keyword=disease modeling kn-keyword=disease modeling en-keyword=drug toxicity kn-keyword=drug toxicity en-keyword=drug screening kn-keyword=drug screening en-keyword=regenerative medicine kn-keyword=regenerative medicine END start-ver=1.4 cd-journal=joma no-vol=23 cd-vols= no-issue=27 article-no= start-page=6557 end-page=6563 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=Fluorescence detection of DNA with a single-base mismatch by a Tm-independent peptide nucleic acid (PNA) twin probe en-subtitle= kn-subtitle= en-abstract= kn-abstract=There is a need to develop efficient methods for detecting target nucleic acids to enable the rapid diagnosis and early treatment of diseases. We previously demonstrated that a peptide nucleic acid (PNA) twin probe, consisting of two PNAs each containing a fluorescent dye, with pyrene at one end, detects target DNA sequence-specifically through pyrene excimer emission. In this study, to advance the development of this probe system, we further investigated the fluorescence properties of the PNA twin probe P1 and P2, and found that the excimer fluorescence was significantly reduced when a mismatched base in the DNA sequence was present at the site of P1 closest to the pyrene. In other words, this probe was found to detect single-base mismatches without taking into account the thermal stability of the PNA/DNA hybrid. The detection limit of this PNA twin probe for the single-base-mismatched DNA was 2.7 nM. In the future, this probe should lead to a method to detect point mutations in endogenous nucleic acids within cells. en-copyright= kn-copyright= en-aut-name=IshiiKoki en-aut-sei=Ishii en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShigetoHajime en-aut-sei=Shigeto en-aut-mei=Hajime kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamamuraShohei en-aut-sei=Yamamura en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ImaiYoshitane en-aut-sei=Imai en-aut-mei=Yoshitane 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=KitamatsuMizuki en-aut-sei=Kitamatsu en-aut-mei=Mizuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Applied Chemistry, Kindai University kn-affil= affil-num=2 en-affil=Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=3 en-affil=Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST) kn-affil= affil-num=4 en-affil=Department of Applied Chemistry, Kindai University kn-affil= affil-num=5 en-affil=Department of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Applied Chemistry, Kindai University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=20 article-no= start-page=3351 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251017 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tertiary Lymphoid Structures Are Associated with Favorable Clinical Outcomes and Negatively Correlated with Cancer-Associated Fibroblasts in Esophageal Cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Esophageal cancer remains a highly aggressive malignant tumor with poor prognosis, despite advances in combination therapies and novel immunotherapies. Tertiary lymphoid structures (TLSs), characterized by densely packed CD20+ B cells in a germinal-center-like structure, have recently been recognized as immune-stimulating components within the tumor microenvironment. In contrast, cancer-associated fibroblasts (CAFs) are stromal cells expressing fibroblast-activating protein (FAP) involved in immunosuppression. Methods: In this retrospective study, 124 clinical samples from patients who underwent radical surgery for esophageal cancer at our institute were analyzed. We investigated whether TLSs could serve as a prognostic factor and examined their association with tumor microenvironment factors. Results: The presence of TLSs was an independent prognostic factor for overall and progression-free survival in multivariate analyses. A high level of TLS formation correlated with better nutritional status, fewer M2 macrophages, and greater plasma cell infiltration. Additionally, little TLS formation was observed in areas with abundant CAFs, and quantitative analyses revealed a significant negative correlation between TLSs and CAFs. Conclusions: TLSs enhance antitumor immunity via macrophages and plasma cells and can be a valuable prognostic indicator in patients undergoing surgery for esophageal cancer. Targeting CAFs may prove to be a promising therapeutic strategy to enhance tumor-immunity-related TLSs. en-copyright= kn-copyright= en-aut-name=KunitomoTomoyoshi en-aut-sei=Kunitomo en-aut-mei=Tomoyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NomaKazuhiro en-aut-sei=Noma en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NishiwakiNoriyuki en-aut-sei=Nishiwaki en-aut-mei=Noriyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishimuraSeitaro en-aut-sei=Nishimura en-aut-mei=Seitaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakedaYasushige en-aut-sei=Takeda en-aut-mei=Yasushige kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MatsumotoHijiri en-aut-sei=Matsumoto en-aut-mei=Hijiri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakahashiTatsuya en-aut-sei=Takahashi en-aut-mei=Tatsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KawasakiKento en-aut-sei=Kawasaki en-aut-mei=Kento kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AkaiMasaaki en-aut-sei=Akai en-aut-mei=Masaaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MaedaNaoaki en-aut-sei=Maeda en-aut-mei=Naoaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 ORCID= en-aut-name=TanabeShunsuke en-aut-sei=Tanabe en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 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=13 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=14 ORCID= en-aut-name=ShirakawaYasuhiro en-aut-sei=Shirakawa en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=FujiwaraToshiyoshi en-aut-sei=Fujiwara en-aut-mei=Toshiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= affil-num=1 en-affil=Department of Gastroenterological Surgery, 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= affil-num=11 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=16 en-affil=Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=tertiary lymphoid structures (TLSs) kn-keyword=tertiary lymphoid structures (TLSs) en-keyword=cancer-associated fibroblasts (CAFs) kn-keyword=cancer-associated fibroblasts (CAFs) en-keyword=esophageal cancer kn-keyword=esophageal cancer en-keyword=tumor microenvironment kn-keyword=tumor microenvironment en-keyword=prognosis kn-keyword=prognosis END start-ver=1.4 cd-journal=joma no-vol=7 cd-vols= no-issue=6 article-no= start-page=738 end-page=748 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=Risk of Heart Failure Hospitalization in Patients Treated With Osimertinib en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Osimertinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, is used to treat patients with epidermal growth factor receptor–mutant non–small-cell lung cancer. Although osimertinib has been linked to heart failure (HF), detailed risk estimates remain unclear.
Objectives The aim of this study was to examine the association between osimertinib use and HF hospitalization.
Methods In this retrospective cohort study using a large-scale Japanese claims database, patients diagnosed with lung cancer between April 2008 and December 2021 who received cancer therapy were identified. Patients were categorized into osimertinib and control groups according to treatment received. The incidence of HF hospitalization during the treatment period was compared between the groups. Multivariable analyses were performed before and after propensity score matching.
Results The osimertinib and control groups included 11,391 and 108,144 patients, respectively. Among the entire cohort, the median age was 70 years (Q1-Q3: 64-76 years), and the median follow-up duration was 173 days (Q1-Q3: 73-448 days). The incidence of HF hospitalization was 9.9 and 4.1 cases per 1,000 person-years in the osimertinib and control groups, respectively. In multivariable analysis, osimertinib was associated with a higher risk for HF hospitalization than control therapy (subdistribution HR: 2.56; 95% CI: 2.07-3.18; P < 0.001). This association remained significant after propensity score matching (subdistribution HR: 2.29; 95% CI: 1.62-3.24; P < 0.001).
Conclusions Osimertinib use was associated with an increased risk for HF hospitalization. Cardiac function should be closely monitored in patients receiving osimertinib. en-copyright= kn-copyright= en-aut-name=TatebeYasuhisa en-aut-sei=Tatebe en-aut-mei=Yasuhisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanakaYuta en-aut-sei=Tanaka en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ManabeYohei en-aut-sei=Manabe en-aut-mei=Yohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OkanoShinobu en-aut-sei=Okano en-aut-mei=Shinobu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 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=6 ORCID= en-aut-name=MurakawaKiminaka en-aut-sei=Murakawa en-aut-mei=Kiminaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 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 Pharmacy, Okayama University Hospital kn-affil= en-keyword=adverse events kn-keyword=adverse events en-keyword=cardiotoxicity kn-keyword=cardiotoxicity en-keyword=epidermal growth factor receptor tyrosine kinase inhibitor kn-keyword=epidermal growth factor receptor tyrosine kinase inhibitor en-keyword=heart failure kn-keyword=heart failure en-keyword=lung cancer kn-keyword=lung cancer en-keyword=pharmacotherapy kn-keyword=pharmacotherapy en-keyword=propensity score matching kn-keyword=propensity score matching END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251020 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Coupling effects of biochar and sediment microbial fuel cells on CH4 and CO2 emissions from straw-amended paddy soil en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose The independent incorporation of biochar and sediment microbial fuel cells (SMFCs) into paddy soil has been shown to reduce methane (CH4) emissions. However, the application of rice straw into paddy soil enhances the availability of labile carbon that stimulates methanogen growth, counteracting the mitigation effects of both methods. This study, therefore, aimed to investigate the effect of coupling biochar and SMFC on CH4 and CO2 emissions from straw-amended paddy soil.
Materials and methods Single chamber SMFC setups constructed using acrylic columns (height, 25 cm; inner diameter, 9 cm) with six treatments were established using soil amended with 0% (0BC), 1% (1BC), and 2% (2BC) biochar: with and without SMFC conditions. Stainless steel mesh (15 × 3 cm) and graphite felt (6 × 5 cm) were used as anode and cathode materials, respectively.
Results Cumulative emission of CH4 in the 0BC treatment with SMFC was 39% less than in that without SMFC. Biochar addition and SMFC operation together further reduced CH4 emission by 57% and 60% in 1BC and 2BC treatments, respectively, compared to that in the 0BC treatment without SMFC operation. The relative abundance of microbial communities indicated methane-oxidizing bacteria were enriched in the presence of biochar and hydrogenotrophic Methanoregula were suppressed by SMFC operation. This suggested that SMFC mainly inhibited CH4 production by outcompeting hydrogenotrophic archaea.
Conclusion The use of biochar made from leftover rice straw has an interactive effect on SMFC operation and both methods can be used to reduce CH4 emission from straw-amended paddy soil. en-copyright= kn-copyright= en-aut-name=BekeleAdhena Tesfau en-aut-sei=Bekele en-aut-mei=Adhena Tesfau kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MaedaMorihiro en-aut-sei=Maeda en-aut-mei=Morihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakaharaNozomi en-aut-sei=Nakahara en-aut-mei=Nozomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HashiguchiAyumi en-aut-sei=Hashiguchi en-aut-mei=Ayumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SomuraHiroaki en-aut-sei=Somura en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AkaoSatoshi en-aut-sei=Akao en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakanoChiyu en-aut-sei=Nakano en-aut-mei=Chiyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NishinaYuta en-aut-sei=Nishina en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=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=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=Faculty of Science and Engineering, Doshisha University kn-affil= affil-num=7 en-affil=Department of Comprehensive Technical Solutions, Okayama University kn-affil= affil-num=8 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= en-keyword=Electrogenesis kn-keyword=Electrogenesis en-keyword=Methane oxidation kn-keyword=Methane oxidation en-keyword=Pyrolysis kn-keyword=Pyrolysis en-keyword=Paddy field kn-keyword=Paddy field en-keyword=Methanogens kn-keyword=Methanogens END start-ver=1.4 cd-journal=joma no-vol=22 cd-vols= no-issue=6 article-no= start-page=836 end-page=849 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251028 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=C1orf50 Accelerates Epithelial-Mesenchymal Transition and the Cell Cycle of Hepatocellular Carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: Hepatocellular carcinoma (HCC) is a heterogeneous liver cancer with limited treatment options and a poor prognosis in advanced stages. To identify novel biomarkers and therapeutic targets, we investigated the role of chromosome 1 open reading frame 50 (C1orf50), a gene with a previously uncharacterized function in HCC.
Materials and Methods: We performed a comprehensive transcriptome data analysis of the human hepatocellular carcinoma project from The Cancer Genome Atlas (TCGA) and subsequently validated the oncogenic roles of C1orf50 using HCC cell lines.
Results: Using transcriptomic and clinical data from TCGA, we stratified 355 primary HCC samples based on C1orf50 expression levels. Patients with high C1orf50 expression exhibited significantly shorter overall survival, suggesting its association with aggressive tumor behavior. Differential expression and enrichment analyses revealed that C1orf50-high tumors were enriched in oncogenic pathways, including epithelial-mesenchymal transition (EMT), cell cycle activation, and stemness-related properties. Transcriptional regulatory network analysis detected 456 significantly dysregulated regulons, including ZEB1/2 and E2F2, key drivers of EMT and cell cycle, in the C1orf50-high group. In addition, we observed increased YAP1/TAZ signaling, further linking C1orf50 to stemness and therapeutic resistance. Functional data from CRISPR-based dependency screening suggested that several transcription factors up-regulated in the C1orf50-high state, such as ZBTB11 and CTCE, are essential for the survival of HCC cells. These findings indicate potential therapeutic vulnerabilities and support the rationale for targeting C1orf50-associated pathways.
Conclusion: C1orf50 is a novel biomarker of poor prognosis in HCC and a key regulator of oncogenic features such as EMT, cell cycle progression, and stemness. This study highlights the therapeutic potential of targeting C1orf50-related networks in aggressive subtypes of liver cancer. en-copyright= kn-copyright= en-aut-name=TANAKAATSUSHI en-aut-sei=TANAKA en-aut-mei=ATSUSHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OTANIYUSUKE en-aut-sei=OTANI en-aut-mei=YUSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MAEKAWAMASAKI en-aut-sei=MAEKAWA en-aut-mei=MASAKI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ROGACHEVSKAYAANNA en-aut-sei=ROGACHEVSKAYA en-aut-mei=ANNA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=PEÑATIRSO en-aut-sei=PEÑA en-aut-mei=TIRSO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=CHINVANESSA D. en-aut-sei=CHIN en-aut-mei=VANESSA D. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TOYOOKASHINICHI en-aut-sei=TOYOOKA en-aut-mei=SHINICHI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ROEHRLMICHAEL H. en-aut-sei=ROEHRL en-aut-mei=MICHAEL H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 ORCID= affil-num=1 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=2 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=3 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=4 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=5 en-affil=Department of Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=6 en-affil=UMass Chan Medical School, UMass Memorial Medical Center 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 Pathology, Beth Israel Deaconess Medical Center kn-affil= affil-num=9 en-affil=Department of Cellular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=C1orf50 kn-keyword=C1orf50 en-keyword=hepatocellular carcinoma kn-keyword=hepatocellular carcinoma en-keyword=stemness kn-keyword=stemness en-keyword=cell cycle kn-keyword=cell cycle en-keyword=epithelial‑mesenchymal transition kn-keyword=epithelial‑mesenchymal transition END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=10 article-no= start-page=e95411 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Primary Lacrimal Sac Diffuse Large B-cell Lymphoma Treated With Local Radiotherapy Alone: A Case With No Relapse After 21 Years of Follow-Up en-subtitle= kn-subtitle= en-abstract= kn-abstract=Primary lacrimal sac lymphoma is rare and diagnosed as diffuse large B-cell lymphoma in a predominant histopathological type. Systemic chemotherapy would be the standard of care, but local radiotherapy may be a treatment option toward a localized lesion. The present patient is a 54-year-old otherwise healthy woman with a right lacrimal sac mass, which was proven by excisional biopsy to be diffuse large B-cell lymphoma. Since she did not have any other systemic lesions on gallium scintigraphy and neck-to-abdominal computed tomography scans, which were the standard procedure at that time, she underwent local radiotherapy at 40 Gy. Two years later, at the age of 56 years, she developed radiation retinopathy with macular edema in the right eye and had spotty laser photocoagulation in the nasal half of the fundus. At the age of 57 years, she developed radiation cataract and underwent cataract surgery with intraocular lens implantation in the right eye. At the age of 58 years, the macular edema in the right eye became worse and remained active, resulting in poor visual acuity of 0.1. She thus underwent 25-gauge vitrectomy in the right eye to peel off the adhering posterior vitreous surface, together with the internal limiting membrane, as the standard procedure at that time. The visual acuity in the right eye was elevated to 0.6. She maintained the visual acuity afterward and had no relapse of lymphoma in 21 years from the diagnosis of primary right lacrimal sac diffuse large B-cell lymphoma. Local radiotherapy would still be a treatment option for localized lymphoma lesions such as primary lacrimal sac lymphoma. 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= 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=TakemotoMitsuhiro en-aut-sei=Takemoto en-aut-mei=Mitsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= affil-num=1 en-affil=Healthcare Science, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Pathology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Radiotherapy, Himeji Red Cross Hospital kn-affil= en-keyword=diffuse large b-cell lymphoma kn-keyword=diffuse large b-cell lymphoma en-keyword=excisional biopsy kn-keyword=excisional biopsy en-keyword=lacrimal sac kn-keyword=lacrimal sac en-keyword=laser photocoagulation kn-keyword=laser photocoagulation en-keyword=macular edema kn-keyword=macular edema en-keyword=pathology kn-keyword=pathology en-keyword=radiation cataract kn-keyword=radiation cataract en-keyword=radiation retinopathy kn-keyword=radiation retinopathy en-keyword=radiotherapy kn-keyword=radiotherapy en-keyword=vitrectomy kn-keyword=vitrectomy END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251014 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Comparative analysis of interactions between five strains of Pseudomonas syringae pv. tabaci and Nicotiana benthamiana en-subtitle= kn-subtitle= en-abstract= kn-abstract=Pseudomonas syringae pv. tabaci 6605 (Pta 6605), the agent of wildfire disease in tobacco, has been used as a model strain for elucidating the virulence mechanisms of Pta. However, the host genes involved in resistance or susceptibility to Pta remain largely unknown. Nicotiana benthamiana is a model plant species in the Solanaceae family and is useful in functional analyses of genes. We herein compared five Pta strains (6605, 6823, 7372, 7375, and 7380) in terms of their phenotypes on medium and interactions with N. benthamiana. Pta 6605 and Pta 6823 showed more active proliferation than the other strains in a high cell density culture. Moreover, Pta 6605 exhibited markedly higher swarming motility than the other strains. In inoculated leaves of N. benthamiana, Pta 6605 and Pta 6823 caused more severe disease symptoms and proliferated to a higher cell density than the other strains. However, Pta 6823 as well as Pta 7372 and Pta 7380 induced the high accumulation of salicylic acid (SA). Moreover, the inoculations of Pta 6823 and Pta 7372 resulted in the upregulation of ethylene biosynthesis genes. On the other hand, Pta 6605 induced neither SA accumulation nor the expression of ethylene biosynthesis genes, and suppressed the expression of jasmonate biosynthesis genes. Moreover, chlorosis was clearly induced in the upper uninoculated leaves of Pta 6605-infected plants. These results suggest that Pta 6605 escapes from or suppresses plant immune systems and, thus, is the most virulent on N. benthamiana among the five strains tested. en-copyright= kn-copyright= en-aut-name=NakaoYuna en-aut-sei=Nakao en-aut-mei=Yuna kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AsaiShuta en-aut-sei=Asai en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 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=4 ORCID= en-aut-name=KatouShinpei en-aut-sei=Katou en-aut-mei=Shinpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Graduate School of Medicine, Science and Technology, Shinshu University kn-affil= affil-num=2 en-affil=Graduate School of Environmental, Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Environmental, Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Environmental, Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Medicine, Science and Technology, Shinshu University kn-affil= en-keyword=Chlorosis kn-keyword=Chlorosis en-keyword=Nicotiana benthamiana kn-keyword=Nicotiana benthamiana en-keyword=Phytohormones kn-keyword=Phytohormones en-keyword=Pseudomonas syringae pv. tabaci kn-keyword=Pseudomonas syringae pv. tabaci END start-ver=1.4 cd-journal=joma no-vol=150 cd-vols= no-issue= article-no= start-page=110530 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202506 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Surrogate-assisted motion planning and layout design of robotic cellular manufacturing systems en-subtitle= kn-subtitle= en-abstract= kn-abstract=A surrogate-assisted multi-objective evolutionary algorithm is proposed for simultaneous optimization of robot motion planning and layout design in robotic cellular manufacturing systems. A sequence-pair is used to represent the layout of components in a robotic cell to avoid overlapping in the evolutionary computation. The robot motion planning with Rapidly exploring Random Trees Star (RRT*) is applied to compute the total operation time of a robot arm for each layout. Non-dominated Sorting Genetic Algorithm II (NSGA-II) is used to minimize the total required layout area and the operation time for a robot arm. The proposed surrogate model can estimate the robot’s operation time with 98% of accuracy without explicit computations of the motion planning algorithm. The experimental results with a physical 6 Degree of Freedom (DOF) manipulator show that the total computation time is approximately 1/400, significantly shorter than the conventional methods. en-copyright= kn-copyright= en-aut-name=KawabeTomoya en-aut-sei=Kawabe en-aut-mei=Tomoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NishiTatsushi en-aut-sei=Nishi en-aut-mei=Tatsushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=LiuZiang en-aut-sei=Liu en-aut-mei=Ziang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FujiwaraTomofumi en-aut-sei=Fujiwara en-aut-mei=Tomofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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 Environmental, Life and Natural Science and Technology, Okayama University kn-affil= en-keyword=Robotics kn-keyword=Robotics en-keyword=Cellular manufacturing kn-keyword=Cellular manufacturing en-keyword=Layout design kn-keyword=Layout design en-keyword=Sequence-pair kn-keyword=Sequence-pair en-keyword=Motion planning kn-keyword=Motion planning en-keyword=Surrogate optimization kn-keyword=Surrogate optimization en-keyword=Machine learning kn-keyword=Machine learning en-keyword=Artificial intelligence kn-keyword=Artificial intelligence END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=20 article-no= start-page=10072 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251016 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Neurofibromin Encoded by the Neurofibromatosis Type 1 (NF1) Gene Promotes the Membrane Translocation of SPRED2, Thereby Inhibiting the ERK Pathway in Breast Cancer Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Neurofibromin (NF) inhibits the RAS/RAF/ERK pathway through its interaction with SPRED1 (Sprouty-related EVH1 domain-containing protein 1). Here, we investigated the functional relationship between NF and SPRED2 in breast cancer (BC). Human BC cell lines were transfected to downregulate or overexpress NF and SPRED2 and subsequently subjected to functional assays. Protein and mRNA levels were analyzed by Western blotting and RT-qPCR, respectively. Protein–protein interactions were examined by immunoprecipitation. Database analyses and immunohistochemistry (IHC) of BC tissues were performed to validate the in vitro findings. Downregulating NF or SPRED2 expression in BC cells enhanced cell proliferation, migration and invasion accompanied by RAF/ERK activation, whereas overexpression produced opposite effects. NF formed a protein complex with SPRED2 and facilitated its translocation to the plasma membrane. By IHC, SPRED2 membrane localization was absent in NF-negative luminal A and triple-negative BC (TNBC) but present in a subset of luminal A BC. By database analyses, both NF1 and SPRED2 mRNA levels were reduced in BC tissues, and luminal A BC patients with high expression of both NF1 and SPRED2 mRNA exhibited improved relapse-free survival. These results suggest a critical role for the NF–SPRED2 axis in BC progression and highlight it as a potential therapeutic target. en-copyright= kn-copyright= en-aut-name=Su PwintNang Thee en-aut-sei=Su Pwint en-aut-mei=Nang Thee kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 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=3 ORCID= en-aut-name=WangYuze en-aut-sei=Wang en-aut-mei=Yuze kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=FujisawaMasayoshi en-aut-sei=Fujisawa en-aut-mei=Masayoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SakaguchiMasakiyo en-aut-sei=Sakaguchi en-aut-mei=Masakiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=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 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 Cell Biology, 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=SPRED2 kn-keyword=SPRED2 en-keyword=neurofibromatosis type 1 kn-keyword=neurofibromatosis type 1 en-keyword=neurofibromin kn-keyword=neurofibromin en-keyword=RAS/RAF/ERK kn-keyword=RAS/RAF/ERK END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251017 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=ATPase copper transporting beta contributes to cisplatin resistance as a regulatory factor of extracellular vesicles in head and neck squamous cell carcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cisplatin (CDDP) resistance remains a major clinical challenge in the treatment of head and neck squamous cell carcinoma (HNSC). Our group identified ATPase copper transporting beta (ATP7B) as a mediator of CDDP resistance through its role in drug efflux and small extracellular vesicle (sEV) secretion. Herein, we uncovered a novel mechanism by which ATP7B regulates sEV dynamics and the intercellular transmission of CDDP resistance. Using transcriptomic analyses of HNSC datasets, we demonstrate that ATP7B expression correlates with endocytosis- and epithelial-mesenchymal transition (EMT)-related gene sets and with elevated levels of EV-associated proteins. CDDP-resistant HNSC cells exhibited upregulated ATP7B, Rab5/Rab7, and preferentially secreted HSP90- and EpCAM-rich sEVs. These sEVs were leading to increased ATP7B expression and reduced CDDP sensitivity in recipient cells. A pharmacological inhibition of sEV biogenesis with GW4869 suppressed ATP7B and Atox1 expressions, inhibited late endosome maturation, and significantly enhanced CDDP-induced apoptosis in HNSC cells. In vivo, GW4869 reduced the sEV protein content and ATP7B expression in xenograft tumors. These findings establish that ATP7B is a critical modulator of sEV cargo and resistance propagation. Our results highlight a previously unrecognized ATP7B–sEV axis driving chemoresistance and identify sEV inhibition as a promising strategy to overcome therapeutic failure in HNSC. en-copyright= kn-copyright= en-aut-name=OgawaTatsuo en-aut-sei=Ogawa en-aut-mei=Tatsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OnoKisho en-aut-sei=Ono en-aut-mei=Kisho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=RyumonShoji en-aut-sei=Ryumon en-aut-mei=Shoji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=SatoKohei en-aut-sei=Sato en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UmemoriKoki en-aut-sei=Umemori en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YoshidaKunihiro en-aut-sei=Yoshida en-aut-mei=Kunihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 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=9 ORCID= en-aut-name=OkuiTatsuo en-aut-sei=Okui en-aut-mei=Tatsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OkamotoKuniaki en-aut-sei=Okamoto en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=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=Momen-HeraviFatemeh en-aut-sei=Momen-Heravi en-aut-mei=Fatemeh kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 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=Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University 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 Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Maxillofacial Diagnostic and Surgical Science, Field of Oral and Maxillofacial Rehabilitation, Graduate School of Medical and Dental Sciences, Kagoshima University kn-affil= affil-num=11 en-affil=Department of Dental Pharmacology, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=12 en-affil=Department of Oral Pathology and Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=13 en-affil=Department of Orofacial Sciences, School of Dentistry, University of California San Francisco kn-affil= affil-num=14 en-affil=Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=23 cd-vols= no-issue=5 article-no= start-page=234 end-page=249 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=Biochar-amended Sediment Microbial Fuel Cells for Water Quality Improvement in Intensive and Extensive Pond Drainages in Central Vietnam en-subtitle= kn-subtitle= en-abstract= kn-abstract=The use of nutrient-rich feed in shrimp farming in Central Vietnam has led to high nitrogen (N) and phosphorus (P) contents in the pond sediment. The objectives of the study were to assess the effectiveness of biochar-sediment microbial fuel cells (BC-SMFCs) in suppressing P and N release from two types of sediment in intensive (Int) and extensive (Ext) pond drainages in Central Vietnam. Single chamber SMFCs were set up and operated under open or closed-circuit (no SMFC or SMFC) conditions. Coconut shell biochar (BC) was amended to sediments at 1%. For Int-sediment, total phosphorus (TP) release was reduced by no BC-SMFCs through co-precipitation with Fe. On the other hand, BC-SMFCs did not suppress TP release because P was released from BC and organic matter decomposition was enhanced in the sediment. Application of BC enhanced organic N mineralization in the sediment. Nitrification and denitrification occurred in the overlying water, reducing mineral N concentrations. For Ext-sediment, BC addition and SMFC conditions did not affect TP and total nitrogen (TN) release because of low initial organic matter content, and less reductive condition. Our study suggested that the effect of SMFCs was masked by BC which released more P from Int-sediment to the water. en-copyright= kn-copyright= en-aut-name=NguyenUyen Tu en-aut-sei=Nguyen en-aut-mei=Uyen Tu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MaedaMorihiro en-aut-sei=Maeda en-aut-mei=Morihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SomuraHiroaki en-aut-sei=Somura en-aut-mei=Hiroaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakaharaNozomi en-aut-sei=Nakahara en-aut-mei=Nozomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=PereraGamamada Liyanage Erandi Priyangika en-aut-sei=Perera en-aut-mei=Gamamada Liyanage Erandi Priyangika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakanoChiyu en-aut-sei=Nakano en-aut-mei=Chiyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=LeHuu Tien en-aut-sei=Le en-aut-mei=Huu Tien kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NishinaYuta en-aut-sei=Nishina en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Graduate School of Environmental and Life Science, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Environmental, 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=Department of Comprehensive Technical Solutions, 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=Department of Education, Science and Technology Quang Tri Branch, Hue University kn-affil= affil-num=8 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= en-keyword=biochar kn-keyword=biochar en-keyword=Central Vietnam kn-keyword=Central Vietnam en-keyword=electricity generation kn-keyword=electricity generation en-keyword=redox potential kn-keyword=redox potential en-keyword=shrimp farming kn-keyword=shrimp farming END start-ver=1.4 cd-journal=joma no-vol=42 cd-vols= no-issue=3 article-no= start-page=215 end-page=227 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250925 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Root-exuded sugars as drivers of rhizosphere microbiome assembly en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sugars in root exudates play a pivotal role in shaping plant-microbe interactions in the rhizosphere, serving as carbon sources and signaling molecules that orchestrate microbial behavior, community structure, and plant resilience. Recent research has shed light on the dynamics of sugar levels in root exudates, the factors that influence their secretion, and the mechanisms by which these sugars drive microbial colonization and community assembly in the rhizosphere. Microbial communities, in turn, contribute to plant physiological changes that enhance growth and stress tolerance. While well-studied sugars such as glucose, sucrose, and fructose are known to promote chemotaxis, motility, and biofilm formation, emerging evidence suggests that less-studied sugars like arabinose and trehalose may also play significant roles in microbial interactions and stress resilience. Key challenges remain, including the accurate measurement of labile sugars that are rapidly metabolized by microbes, and the elucidation of genetic mechanisms underlying rhizosphere metabolic interactions in both host plants and microbes. Addressing these challenges will advance our understanding of sugar-mediated interactions and inform the development of sustainable agricultural innovations. en-copyright= kn-copyright= en-aut-name=HemeldaNiarsi Merry en-aut-sei=Hemelda en-aut-mei=Niarsi Merry kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= affil-num=1 en-affil=Department of Biology, Faculty of Mathematics and Natural Sciences, University of Indonesia kn-affil= affil-num=2 en-affil=Graduate School of Environmental, Life, Natural Science and Technology, Okayama University kn-affil= en-keyword=carbon sources kn-keyword=carbon sources en-keyword=plant-derived sugars kn-keyword=plant-derived sugars en-keyword=plant-microbe interactions kn-keyword=plant-microbe interactions en-keyword=rhizosphere kn-keyword=rhizosphere en-keyword=root exudate kn-keyword=root exudate END start-ver=1.4 cd-journal=joma no-vol=34 cd-vols= no-issue=1 article-no= start-page=46 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20251009 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Highly efficient transgenesis mediated by Tip100 transposon system in medaka en-subtitle= kn-subtitle= en-abstract= kn-abstract=Transgenesis mediated by transposon is an effective approach for introducing exogenous DNA into the nuclear genome and establishing stable transgenic strains that efficiently express genetic tools. Although the DNA transposon Tol2 is widely used for transgenesis in zebrafish, its endogenous transpositional activity can lead to unintended transgene mobilization, making it unsuitable for transgenesis in medaka (Oryzias latipes). Here, we demonstrated that the DNA transposon Tip100, originally identified in the common morning glory (Ipomoea purpurea), an ornamental plant, can serve as a useful tool for transgenesis in Japanese medaka. The GFP transgene cassette, when co-injected with Tip100 transposase mRNA, was expressed in significantly higher number of somatic cells in the injected fish. Furthermore, a transgene flanked by truncated recognition sequences (100 bp each) exhibited expression levels comparable to those of the original vector containing the full 2.2 kb recognition sequence. Injection of a transgene driven by a germline-specific promoter revealed that fish injected with Tip100 mRNA exhibited a significantly higher germline transmission rate (42/68; 62.7%) compared to those injected without the mRNA (13/62; 21.0%). We successfully established transgenic strains by outcrossing injected founders with GFP-positive germ cells (7/7; 100%) and demonstrated that the transgenes were randomly integrated into the medaka genome, generating 8-bp duplications at the insertional sites–an insertional signature of the hAT superfamily of transposons. Our findings indicate that the Tip100 system is a promising tool for generating stable transgenic strains that express various genetic tools in medaka and potentially other fish species. en-copyright= kn-copyright= en-aut-name=TanakaYoshitaka en-aut-sei=Tanaka en-aut-mei=Yoshitaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SekiTakahide en-aut-sei=Seki en-aut-mei=Takahide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HoshinoAtsushi en-aut-sei=Hoshino en-aut-mei=Atsushi 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= affil-num=1 en-affil=Ushimado Marine Institute (UMI), Okayama University kn-affil= affil-num=2 en-affil=Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University kn-affil= affil-num=3 en-affil=National Institute for Basic Biology kn-affil= affil-num=4 en-affil=Ushimado Marine Institute (UMI), Okayama University kn-affil= en-keyword=Fish kn-keyword=Fish en-keyword=Medaka kn-keyword=Medaka en-keyword=Morning glory kn-keyword=Morning glory en-keyword=Transgenic kn-keyword=Transgenic en-keyword=Transposon kn-keyword=Transposon END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=5 article-no= start-page=399 end-page=404 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=Epstein-Barr Virus-Associated Early Gastric Carcinoma with Lymphoid Stroma Mimicking a Submucosal Tumor: A Typical Case Diagnosed by Endoscopic Resection and Treated by Local Resection with Sentinel Node Navigation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Gastric cancer with lymphoid stroma (GCLS) accounts for 1%-7% of gastric cancers; ~80% are Epstein-Barr virus (EBV)-positive. The rate of lymph node metastasis is relatively low, even when an early GCLS has invaded the submucosa. We report an early GCLS with massive submucosal invasion mimicking a submucosal tumor (SMT), diagnosed by endoscopic submucosal resection (ESD) and treated with local resection and sentinel node navigation surgery (SNNS). The patient was a 40-year-old Japanese man. A protruding lesion on the greater curvature of the middle part of his stomach was detected by X-ray, and an endoscopic examination revealed a 2.5-cm protruding tumor covered with a normal mucosa and small ulcers at the apex. ESD was performed for a diagnosis. The pathological diagnosis was lymphoepithelioma-like gastric cancer (GCLS), pT1b(SM2), Ly0, V0, pHM1, pVM1. EBV infection in the cancer cells was confirmed pathologically by EBV-encoded RNA. The local resection was performed using SNNS. The patient has had no recurrence or post-gastrectomy syndrome 4 years postsurgery. EBV-associated early GCLS resembling an SMT is relatively rare, and clinicians need to be aware of this disease. Local resection using SNNS may be a surgical option for GCLS cases with a low rate of lymphatic metastasis. en-copyright= kn-copyright= en-aut-name=IsozakiHiroshi en-aut-sei=Isozaki en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MatsumotoSasau en-aut-sei=Matsumoto en-aut-mei=Sasau kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TakamaTakehiro en-aut-sei=Takama en-aut-mei=Takehiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IsozakiYuka en-aut-sei=Isozaki en-aut-mei=Yuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MurakamiShigeki en-aut-sei=Murakami en-aut-mei=Shigeki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Surgery, Oomoto Hospital kn-affil= affil-num=2 en-affil=Department of Surgery, Oomoto Hospital kn-affil= affil-num=3 en-affil=Department of Surgery, Oomoto Hospital kn-affil= affil-num=4 en-affil=Department of Surgery, Oomoto Hospital kn-affil= affil-num=5 en-affil=Department of Surgery, Oomoto Hospital kn-affil= en-keyword=gastric cancer kn-keyword=gastric cancer en-keyword=gastric cancer with lymphoid stroma kn-keyword=gastric cancer with lymphoid stroma en-keyword=lymphoepithelioma-like carcinoma kn-keyword=lymphoepithelioma-like carcinoma en-keyword=Epstein Barr virus kn-keyword=Epstein Barr virus en-keyword=sentinel node navigation surgery kn-keyword=sentinel node navigation surgery END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=5 article-no= start-page=369 end-page=379 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=Blood Pressure and Heart Rate Patterns Identified by Unsupervised Machine Learning and Their Associations with Subclinical Cerebral and Renal Damage in a Japanese Community: The Masuda Study en-subtitle= kn-subtitle= en-abstract= kn-abstract=We applied unsupervised machine learning to analyze blood pressure (BP) and resting heart rate (HR) patterns measured during a 1-year period to assess their cross-sectional relationships with subclinical cerebral and renal target damage. Dimension reduction via uniform manifold approximation and projection, followed by K-means++ clustering, was used to categorize 362 community-dwelling participants (mean age, 56.2 years; 54.9% women) into three groups: Low BP and Low HR (Lo-BP/Lo-HR), High BP and High HR (Hi-BP/Hi-HR), and Low BP and High HR (Lo-BP/Hi-HR). Cerebral vessel lesions were defined as the presence of at least one of the following magnetic resonance imaging findings: lacunar infarcts, white matter hyperintensities, cerebral microbleeds, or intracranial artery stenosis. A high urinary albumin-to-creatinine ratio (UACR) was defined as the top 10% (≥ 12 mg/g) of the mean value from ≥2 measurements. Poisson regression with robust error variance, adjusted for demographics, lifestyle, and medical history, showed that the Hi-BP/Hi-HR group had relative risks of 3.62 (95% confidence interval, 1.75-7.46) for cerebral vessel lesions and 3.58 (1.33-9.67) for high UACR, and the Lo-BP/Hi-HR group had a relative risk of 3.09 (1.12-8.57) for high UACR, compared with the Lo-BP/Lo-HR group. These findings demonstrate the utility of an unsupervised, data-driven approach for identifying physiological patterns associated with subclinical target organ damage. en-copyright= kn-copyright= en-aut-name=HisamatsuTakashi en-aut-sei=Hisamatsu en-aut-mei=Takashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KinutaMinako en-aut-sei=Kinuta en-aut-mei=Minako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MunetomoSosuke en-aut-sei=Munetomo en-aut-mei=Sosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FukudaMari en-aut-sei=Fukuda en-aut-mei=Mari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KojimaKatsuhide en-aut-sei=Kojima en-aut-mei=Katsuhide kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TaniguchiKaori en-aut-sei=Taniguchi en-aut-mei=Kaori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NakahataNoriko en-aut-sei=Nakahata en-aut-mei=Noriko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KandaHideyuki en-aut-sei=Kanda 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 Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Radiology, Okayama University Hospital kn-affil= affil-num=6 en-affil=Department of Environmental Medicine and Public Health, Izumo, Shimane University Faculty of Medicine kn-affil= affil-num=7 en-affil=Department of Health and Nutrition, The University of Shimane Faculty of Nursing and Nutrition kn-affil= affil-num=8 en-affil=Department of Public Health, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=blood pressure kn-keyword=blood pressure en-keyword=heart rate kn-keyword=heart rate en-keyword=subclinical disease kn-keyword=subclinical disease en-keyword=uniform manifold approximation and projection kn-keyword=uniform manifold approximation and projection en-keyword=unsupervised machine learning kn-keyword=unsupervised machine learning END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=5 article-no= start-page=353 end-page=358 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=Comparison of Extraocular Muscles in Patients with Exotropia and Healthy Participants Using Anterior Segment Optical Coherence Tomography en-subtitle= kn-subtitle= en-abstract= kn-abstract=To analyze and characterize the medial and lateral rectus muscles in patients with exotropia using anterior segment optical coherence tomography (AS-OCT). This study included 24 patients with exotropia (48 eyes) and 25 healthy individuals (50 eyes). Anterior segment optical coherence tomography was used to construct the en face images. The anterior chamber angle to the extraocular muscle insertion distance, muscle width, and muscle fiber angle from the muscle insertion sites were compared between the exotropia and the control groups. The correlation between these parameters and age or angle of deviation was evaluated. The mean ages were 13.2±4.1 years for the exotropia group and 17.6±7.2 years for the control group. The lateral rectus angle was significantly more inwardly rotated in the exotropia group than in the control group (1.6±6.3°, −1.4±4.0°, p=0.014). With increasing angle of deviation, the width of the lateral rectus increased (p=0.002). Our results indicate that the lateral rectus angle is significantly more inwardly rotated in patients with exotropia. These findings should contribute to a deeper understanding of the extraocular muscles in patients with this condition. en-copyright= kn-copyright= en-aut-name=ChiharaYuki en-aut-sei=Chihara en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HamasakiIchiro en-aut-sei=Hamasaki en-aut-mei=Ichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShibataKiyo en-aut-sei=Shibata en-aut-mei=Kiyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MorisawaShin en-aut-sei=Morisawa en-aut-mei=Shin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KonoReika en-aut-sei=Kono en-aut-mei=Reika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KanenagaKeisuke en-aut-sei=Kanenaga en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MorizaneYuki en-aut-sei=Morizane en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=6 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=7 en-affil=Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=exotropia kn-keyword=exotropia en-keyword=AS-OCT kn-keyword=AS-OCT en-keyword=anterior chamber angle to extraocular muscle insertion distance kn-keyword=anterior chamber angle to extraocular muscle insertion distance en-keyword=muscle width kn-keyword=muscle width en-keyword=muscle fiber angle kn-keyword=muscle fiber angle END start-ver=1.4 cd-journal=joma no-vol=79 cd-vols= no-issue=5 article-no= start-page=345 end-page=352 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 Air-Exposure Stress–Induced Autolysis in Clostridium perfringens by Zn2+ en-subtitle= kn-subtitle= en-abstract= kn-abstract=Clostridium perfringens is a pathogenic anaerobe that causes gas gangrene and food poisoning. Although autolysin-mediated reorganization of the bacterial cell wall is crucial for cell division, excessive autolysin activity induced by stressors can lead to cell lysis. In C. perfringens, air exposure is a significant stressor that causes cell lysis, and Acp (N-acetylglucosaminidase) is known to be a major autolysin. To further facilitate C. perfringens research, a technology to prevent air-induced cell lysis must be developed. This study investigated the role of Acp in air-induced autolysis and explored potential inhibitors that would prevent cell lysis during experimental procedures. Morphological analyses confirmed that Acp functions as an autolysin in C. perfringens, as acpdeficient strains exhibited filamentous growth. The mutants exhibited negligible autolysis under air-exposure stress, confirming the involvement of Acp in the autolytic process. We also evaluated the effects of various divalent cations on Acp activity in vitro and identified Zn2+ as a potent inhibitor. Brief treatment with a Zn2+- containing buffer induced dose-dependent cell elongation and autolysis inhibition in C. perfringens. These findings demonstrate that simple Zn2+ treatment before experiments stabilizes C. perfringens cells, reducing autolysis under aerobic conditions and facilitating various biological studies, except morphological analyses. en-copyright= kn-copyright= en-aut-name=MatsunagaNozomu en-aut-sei=Matsunaga en-aut-mei=Nozomu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=EgusaSeira en-aut-sei=Egusa en-aut-mei=Seira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AonoRiyo en-aut-sei=Aono en-aut-mei=Riyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TamaiEiji en-aut-sei=Tamai en-aut-mei=Eiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HitusmotoYasuo en-aut-sei=Hitusmoto en-aut-mei=Yasuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KatayamaSeiichi en-aut-sei=Katayama en-aut-mei=Seiichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Life Science, Faculty of Science, Okayama University of Science kn-affil= affil-num=2 en-affil=Department of Life Science, Faculty of Science, Okayama University of Science kn-affil= affil-num=3 en-affil=Department of Medical Technology, Kagawa Prefectural University of Health Sciences kn-affil= affil-num=4 en-affil=Department of Infectious Disease, College of Pharmaceutical Science, Matsuyama University kn-affil= affil-num=5 en-affil=Department of Life Science, Faculty of Science, Okayama University of Science kn-affil= affil-num=6 en-affil=Department of Life Science, Faculty of Science, Okayama University of Science kn-affil= en-keyword=Clostridium perfringens kn-keyword=Clostridium perfringens en-keyword=autolysin kn-keyword=autolysin en-keyword=zinc kn-keyword=zinc en-keyword=air-exposure autolysis kn-keyword=air-exposure autolysis END start-ver=1.4 cd-journal=joma no-vol=39 cd-vols= no-issue=5 article-no= start-page=2787 end-page=2793 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=Accuracy of Contrast-enhanced CT in Diagnosing Small-sized cT3a Renal Cell Carcinoma and Analysis of Factors Predicting Downstaging to pT1 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background/Aim: This study assessed the accuracy of preoperative contrast-enhanced computed tomography (CECT) scans in staging small-sized, locally advanced (cT3a) renal cell carcinoma (RCC) and identified predictors of pathological downstaging following surgery.
Patients and Methods: Seventy-six patients who underwent radical nephrectomy for cT3aN0M0 RCC with tumors ≤7 cm were analyzed. Preoperative CECT evaluated features such as venous, peritumoral, or renal sinus fat, and urinary tract invasion, predictive values, and concordance index between radiological and pathological findings were calculated for these categories. The study also examined the impact of clinicopathologic factors on downstaging.
Results: Of 76 patients with cT3 RCC, 37% were down-staged to pT1. Down-staged cases had a higher proportion of male patients and non-clear cell carcinoma (86% vs. 58%, 32% vs. 6%; p=0.02, p=0.007, respectively). Multiple cT3a factors were less common in down-staged cases (4% vs. 23%, p=0.04). Non-clear cell carcinoma was significantly associated with downstaging compared to clear cell carcinoma (75% vs. 30%, p=0.006). Multivariate analysis confirmed non-clear cell carcinoma as an independent predictor (odds ratio=8.2, p=0.01). For venous invasion, CECT sensitivity and positive predictive value were high (73.5% and 83.3%, respectively) and the degree of agreement was substantial (κ=0.62).
Conclusion: The accuracy of preoperative CECT was acceptable for detecting venous invasion. The downstaging to pT1 occurred in 37% of cT3a RCC cases in the final pathology, with non-clear cell carcinoma being a significant predictor.
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=YOSHINAGAKASUMI en-aut-sei=YOSHINAGA en-aut-mei=KASUMI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=INOUESHOTA en-aut-sei=INOUE en-aut-mei=SHOTA kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MITSUIYOSUKE en-aut-sei=MITSUI en-aut-mei=YOSUKE kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 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=6 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=7 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=8 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=9 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=10 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=11 ORCID= en-aut-name=EDAMURAKOHEI en-aut-sei=EDAMURA en-aut-mei=KOHEI kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KOBAYASHITOMOKO en-aut-sei=KOBAYASHI en-aut-mei=TOMOKO kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 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= 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, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Urology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Contrast‑enhanced CT kn-keyword=Contrast‑enhanced CT en-keyword=renal cell carcinoma kn-keyword=renal cell carcinoma en-keyword=staging kn-keyword=staging en-keyword=T3a kn-keyword=T3a en-keyword=downstaging kn-keyword=downstaging END start-ver=1.4 cd-journal=joma no-vol=105 cd-vols= no-issue=4 article-no= start-page=1157 end-page=1167 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250505 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Effect of environmental conditions on seed germination and seedling growth in Cuscuta campestris en-subtitle= kn-subtitle= en-abstract= kn-abstract=Dodder (Cuscuta) is an obligate parasitic plant that cannot survive without a host and causes significant damage to crop yields. To understand its growth characteristics before parasitism, we examined the effects of environmental conditions on seed germination and seedling growth in Cuscuta campestris Yunck. Among various factors, we focused on the effects of light, pH, temperature, sugars, salts, hormones, amino acids and polyamines on seeds sown on agar plates. Regarding the effect of light on germination, far-red light was preferable rather than red light and the reversible response of seeds to red and far-red light was confirmed, implicating a phytochrome-mediated signaling pathway opposite to that in many seed plants. Among the amino acids, aspartic acid and alanine had a promotive effect, while histidine had an inhibitory effect on germination. We further found that, in addition to gibberellic acid, methyl jasmonate stimulated both germination and shoot elongation. While 2,4-D extended the viability of trichomes around the root cap, kinetin induced the formation of scale leaves on the shoot and undifferentiated cell clusters at the base of the shoot and root tip. Real-time reverse transcriptase PCR (RT-PCR) experiments confirmed that the expression of a putative RbcS gene for photosynthesis showed no response to light, whereas that of a Phytochrome A homolog increased in the dark. Our results indicate that some of the molecular mechanisms involved in responding to light and hormone signals are uniquely modified in dodder seedlings, providing clues for understanding the survival strategy of parasitic plants. en-copyright= kn-copyright= en-aut-name=NagaoKoki en-aut-sei=Nagao en-aut-mei=Koki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=YokoyamaRyusuke en-aut-sei=Yokoyama en-aut-mei=Ryusuke 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 Life Sciences, Tohoku University kn-affil= en-keyword=Cuscuta kn-keyword=Cuscuta en-keyword=Environmental conditions kn-keyword=Environmental conditions en-keyword=Germination kn-keyword=Germination en-keyword=Hormone responses kn-keyword=Hormone responses en-keyword=Seedling growth kn-keyword=Seedling growth END start-ver=1.4 cd-journal=joma no-vol=28 cd-vols= no-issue=4 article-no= start-page=51 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250930 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cancer-associated fibroblast-derived SOD3 enhances lymphangiogenesis to drive metastasis in lung adenocarcinoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Despite advancements in diagnostic and therapeutic strategies, lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality due to its aggressive metastatic potential. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme that regulates oxidative stress and is regarded as a tumor suppressor. However, studies have demonstrated that SOD3 can either promote or inhibit cell proliferation and survival in various cancers, and its molecular mechanisms within the tumor microenvironment are poorly understood. In this study, we report a breakthrough in uncovering the role of SOD3 derived from cancer-associated fibroblasts (CAFs) in LUAD. Using LUAD xenograft models co-implanted with SOD3-overexpressing CAFs (CAFSOD3), we observe an aggressive tumor phenotype characterized by increased lymphangiogenesis and lymphatic vessel invasion (LVI) of the tumor. Additionally, LUAD patients with elevated SOD3 levels exhibit a higher incidence of LVI and metastasis. Notably, RNA sequencing of CAFSOD3 reveals that SOD3-mediated VEGF-dependent tumor progression and lymphangiogenesis are up-regulated. Furthermore, single-cell transcriptomic analysis of LUAD clinical samples confirms a strong correlation between SOD3 expression in fibroblasts and characteristics of tumor exacerbation, such as lymphangiogenesis and metastasis. These findings underscore new insights into the role of CAF-derived SOD3 in LUAD progression and highlight its potential as a biomarker and therapeutic target. en-copyright= kn-copyright= 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=1 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=2 ORCID= en-aut-name=MashimaTomoha en-aut-sei=Mashima en-aut-mei=Tomoha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TorigataKosuke en-aut-sei=Torigata en-aut-mei=Kosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ThuYin Min en-aut-sei=Thu en-aut-mei=Yin Min kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HabuTomohiro en-aut-sei=Habu en-aut-mei=Tomohiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=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=TomidaShuta en-aut-sei=Tomida en-aut-mei=Shuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=ItoSachio en-aut-sei=Ito en-aut-mei=Sachio kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=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=ToyookaShinichi en-aut-sei=Toyooka en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 ORCID= affil-num=1 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=School of Medicine, Kobe University kn-affil= affil-num=5 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=6 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=7 en-affil=Department of Oral Pathology and 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=Center for Comprehensive Genomic Medicine, Okayama University Hospital kn-affil= affil-num=10 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 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 Thoracic Surgery, National Hospital Organization, Shikoku Cancer Center kn-affil= affil-num=13 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=14 en-affil=Department of Pathophysiology and Drug Discovery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Cancer-associated fibroblast kn-keyword=Cancer-associated fibroblast en-keyword=Superoxide dismutase 3 kn-keyword=Superoxide dismutase 3 en-keyword=Lymphangiogenesis kn-keyword=Lymphangiogenesis en-keyword=Angiogenesis kn-keyword=Angiogenesis en-keyword=Metastasis kn-keyword=Metastasis en-keyword=Lung adenocarcinoma kn-keyword=Lung adenocarcinoma END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=1 article-no= start-page=519 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250926 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Specific induction of right ventricular-like cardiomyocytes from human pluripotent stem cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background Applications employing human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) require well-characterized, chamber-specific hPSC-CMs. Distinct first heart field (FHF) and second heart field (SHF) cardiac progenitor populations give rise to the left ventricular (LV) and right ventricular (RV) cardiomyocytes, respectively. This developmental difference in cardiomyocyte origin suggests that chamber-specific cardiomyocytes have unique characteristics. Therefore, efficient strategies to differentiate human pluripotent stem cells (hPSCs) specifically to LV-like or RV-like cardiomyocytes are needed and it is still unknown whether there is a phenotypic difference between LV-like cardiomyocytes and RV-like cardiomyocytes derived from hPSCs.
Methods An established hPSC cardiac differentiation protocol employing sequential GSK3β inhibition followed by Wnt inhibition (GiWi) was modified by addition of insulin or BMP antagonists during mesoderm formation. Cardiac progenitor populations were evaluated for FHF and SHF markers, and differentiated hPSC-CMs were characterized for chamber-specific markers.
Results The GiWi protocol produced mainly FHF-like progenitor cells that gave rise to LV-like cardiomyocytes. Inhibition of endogenous BMP signaling during mesoderm induction using insulin or BMP antagonists reduced expression of FHF markers and increased expression of SHF markers in cardiac progenitor cells. hPSC-CMs arising from the SHF-like progenitor cells showed an RV-like gene expression pattern and exhibited phenotypic differences in spontaneous contraction rate, Ca2+ transients, and cell size compared to control LV-like cardiomyocytes.
Conclusion This study establishes methodology to generate RV-like hPSC-CMs to support the development of disease modeling research using chamber-specific hPSC-CMs. en-copyright= kn-copyright= en-aut-name=SaitoYukihiro en-aut-sei=Saito en-aut-mei=Yukihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=KatanosakaYuki en-aut-sei=Katanosaka en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=IidaToshihiro en-aut-sei=Iida en-aut-mei=Toshihiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 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=5 ORCID= en-aut-name=SatoRyushi en-aut-sei=Sato en-aut-mei=Ryushi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AdachiRiki en-aut-sei=Adachi en-aut-mei=Riki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShimizuSatoshi en-aut-sei=Shimizu en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KurokawaJunko en-aut-sei=Kurokawa en-aut-mei=Junko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=AkagiSatoshi en-aut-sei=Akagi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=YoshidaMasashi en-aut-sei=Yoshida en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MiyoshiToru en-aut-sei=Miyoshi en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=MoritaHiroshi en-aut-sei=Morita en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=NaruseKeiji en-aut-sei=Naruse en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NishidaMikako en-aut-sei=Nishida en-aut-mei=Mikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=UdonoHeiichiro en-aut-sei=Udono en-aut-mei=Heiichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=ZhangJianhua en-aut-sei=Zhang en-aut-mei=Jianhua kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 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=18 ORCID= en-aut-name=KampTimothy J. en-aut-sei=Kamp en-aut-mei=Timothy J. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= en-aut-name=ItoHiroshi en-aut-sei=Ito en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 ORCID= affil-num=1 en-affil=Department of Cardiovascular Medicine, Okayama University Hospital kn-affil= affil-num=2 en-affil=Department of Cardiovascular Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Department of Cardiovascular Physiology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Biomedical Informatics and Molecular Biology, The Sakaguchi Laboratory, Keio University School of Medicine kn-affil= affil-num=6 en-affil=Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka kn-affil= affil-num=7 en-affil=Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka kn-affil= affil-num=8 en-affil=Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka kn-affil= affil-num=9 en-affil=Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka kn-affil= affil-num=10 en-affil=Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Cardiovascular Therapeutics, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Cardiovascular Physiology, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Metabolic Immune Regulation, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Department of Medicine, University of Wisconsin School of Medicine and Public Health kn-affil= affil-num=18 en-affil=Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=19 en-affil=Department of Medicine, University of Wisconsin School of Medicine and Public Health kn-affil= affil-num=20 en-affil=Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= en-keyword=Human pluripotent stem cell-derived cardiomyocytes kn-keyword=Human pluripotent stem cell-derived cardiomyocytes en-keyword=Anterior second heart field kn-keyword=Anterior second heart field en-keyword=Right ventricle kn-keyword=Right ventricle en-keyword=Bone morphogenetic protein kn-keyword=Bone morphogenetic protein END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250929 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Establishment of a regenerative endodontic procedures model of mature mouse teeth and evaluation of the wound healing process en-subtitle= kn-subtitle= en-abstract= kn-abstract=As the pulp regeneration for non-vital teeth is one of the ultimate clinical achievements, regenerative endodontic procedures (REPs) have become the most explored treatment modality. In this technique, periodontal tissue is guided from the apical region into the root canal and pulp chamber to promote attachment. It is well established that immature teeth are effective targets for treatment. However, the indications for this treatment have not yet expanded sufficiently to encompass mature teeth with closed apical apex. In the present study, a mouse model of REPs in mature teeth was established, employing the maxillary first molar mesial root. μCT analyses disclosed that the distance from the occlusal surface to the physiological apex of the maxillary first molar mesial root in mice is 2.14 mm ± 0.08 mm, and the distance from the occlusal surface to the periapical alveolar bone is 2.46 mm ± 0.10 mm. Mesial root canal was treated with several sizes of k-files, and 15# k-file was identified as the most suitable k-file for use (P = 0.0007). During the regenerative process, spindle-shaped fibroblast-like cells, fibrous tissue formation, and mineralized tissue formation were identified on days 14 and 28. This study demonstrated that it is feasible to use the maxillary first molar mesial root as a REPs model for mature teeth and provided a detailed protocol and analysis of the healing process. en-copyright= kn-copyright= en-aut-name=WangXiuting en-aut-sei=Wang en-aut-mei=Xiuting kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SuzukiShigeki en-aut-sei=Suzuki en-aut-mei=Shigeki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=TsaiShin-Ho en-aut-sei=Tsai en-aut-mei=Shin-Ho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NagasakiKarin en-aut-sei=Nagasaki en-aut-mei=Karin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=FahrezaRahmad Rifqi en-aut-sei=Fahreza en-aut-mei=Rahmad Rifqi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OmoriMasato en-aut-sei=Omori en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YamadaSatoru en-aut-sei=Yamada en-aut-mei=Satoru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=2 en-affil=Department of Operative Dentistry, Okayama University Graduate School, Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Operative Dentistry, Okayama University Graduate School, Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=5 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=6 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= affil-num=7 en-affil=Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry kn-affil= en-keyword=Regenerative endodontic procedures kn-keyword=Regenerative endodontic procedures en-keyword=Establishment of protocols kn-keyword=Establishment of protocols en-keyword=Mouse experimental model kn-keyword=Mouse experimental model en-keyword=Mature teeth kn-keyword=Mature teeth END start-ver=1.4 cd-journal=joma no-vol=17 cd-vols= no-issue=18 article-no= start-page=2927 end-page= 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=Lacticaseibacillus rhamnosus Probio-M9 Alters the Gut Microbiota and Mitigates Pulmonary Hypertension in a Rat Model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Intestinal microbiota plays an important role in the progression of pulmonary hypertension (PH). Colostrum-derived Lacticaseibacillus rhamnosus Probio-M9 (Probio-M9) has shown protective effects against inflammation and remodeling. We investigated whether Probio-M9 supplementation could improve the pathology of PH. Methods: The monocrotaline (MCT)-induced PH model rats are created followed by Probio-M9 treatment. Microbiota and pathological analyses were performed to investigate the therapeutic effects of Probio-M9. Results: Probio-M9 significantly suppressed cardiovascular remodeling and reduced mortality in rats. Analysis of the fecal microbiota revealed that Probio-M9 significantly altered the gut microbiota of MCT model rats. Specifically, Alistipes sp009774895 and Duncaniella muris populations increased, whereas Limosilactobacillus reuteri_D, Ligilactobacillus apodeme and Monoglobus sp900542675 decreased compared to those in the MCT group. Focusing on the expression of GPNMB in macrophages and the localization of CD44, we found that the number of these cells increased in the MCT group but significantly decreased with Probio-M9 treatment. In lung tissue from PH patients, more GPNMB-positive macrophages were found than non-PH lungs, and an increase in CD44-positive cells was confirmed in the vicinity of GPNMB. Conclusions: Probio-M9 had a significant impact on the intestinal microbiota and GPNMB/CD44 positive cells in the lungs of PH rats. en-copyright= kn-copyright= en-aut-name=ZhaoZhixin en-aut-sei=Zhao en-aut-mei=Zhixin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=LiGaopeng en-aut-sei=Li en-aut-mei=Gaopeng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OhmichiKiyomi en-aut-sei=Ohmichi en-aut-mei=Kiyomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=LiXiaodong en-aut-sei=Li en-aut-mei=Xiaodong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZhaoFeiyan en-aut-sei=Zhao en-aut-mei=Feiyan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=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=YokotaNaoya en-aut-sei=Yokota en-aut-mei=Naoya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=10 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=11 ORCID= affil-num=1 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=2 en-affil=Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University kn-affil= affil-num=3 en-affil=Department of Diagnostic Pathology, Kagawa University Hospital kn-affil= affil-num=4 en-affil=Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University kn-affil= affil-num=5 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=6 en-affil=Department of General Medicine, Kagawa University Hospital 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=Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University kn-affil= affil-num=10 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=11 en-affil=Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University kn-affil= en-keyword=pulmonary artery remodeling kn-keyword=pulmonary artery remodeling en-keyword=probiotics kn-keyword=probiotics en-keyword=gut microbiota kn-keyword=gut microbiota en-keyword=macrophages kn-keyword=macrophages en-keyword=GPNMB kn-keyword=GPNMB en-keyword=CD44 kn-keyword=CD44 END start-ver=1.4 cd-journal=joma no-vol=66 cd-vols= no-issue=7 article-no= start-page=1044 end-page=1060 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=Oxygen supply is a prerequisite for response to aluminum in cultured cells of tobacco (Nicotiana tabacum) en-subtitle= kn-subtitle= en-abstract= kn-abstract=Responses to aluminum (Al) were investigated in tobacco cells (cell line SL) in a calcium-sucrose solution for up to 24 h under shaking (aerobic) condition. Microarray analysis of upregulated and downregulated genes under Al exposure and following Gene Ontology (GO) enrichment analysis of biological process category revealed only one GO term to be enriched for the upregulated genes, “response to chitin,” annotated with genes encoding transcription factors (NtERF1 and NtMYB3) and MAP kinase (WIPK), and nine GO terms for the downregulated genes, including “cell wall loosening” and “lipid transport,” annotated with genes encoding expansin (NtEXPA4) and lipid transfer protein (LTP)/LTP-like (NtLTP3 and NtEIG-C29), respectively. Al triggered the production of nitric oxide (NO) then reactive oxygen species (ROS). Addition of NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide decreased the levels of NO and a part of the transcriptional changes described above, but increased the levels of ROS and a loss of growth capacity, suggesting a role of the NO to induce the transcriptional changes partly and to repress these toxic responses under Al exposure. Under non-shaking (anaerobic) condition, the cells exhibited upregulation of several hypoxia-responsive genes. The cells exposed to Al exhibited the same level of Al accumulation but much lower levels of the Al responses including NO production, ROS production, a loss of growth capacity, citrate secretion, and a part of the transcriptional changes described above, compared with the cells under shaking condition. These results suggest that coexistence of oxygen with Al is necessary to trigger the Al responses related to toxicity and tolerance. en-copyright= kn-copyright= en-aut-name=TsuchiyaYoshiyuki en-aut-sei=Tsuchiya en-aut-mei=Yoshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=SasakiTakayuki en-aut-sei=Sasaki en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YamamotoYoko en-aut-sei=Yamamoto en-aut-mei=Yoko 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=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= en-keyword=aluminum toxicity kn-keyword=aluminum toxicity en-keyword=aluminum-responsive genes kn-keyword=aluminum-responsive genes en-keyword=cell wall loosening kn-keyword=cell wall loosening en-keyword=chitin-responsive genes kn-keyword=chitin-responsive genes en-keyword=dioxygen kn-keyword=dioxygen en-keyword=hypoxia kn-keyword=hypoxia END start-ver=1.4 cd-journal=joma no-vol=25 cd-vols= no-issue=21 article-no= start-page=11479 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20241025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Dennd2c Negatively Controls Multinucleation and Differentiation in Osteoclasts by Regulating Actin Polymerization and Protrusion Formation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Osteoclasts are bone-resorbing multinucleated giant cells formed by the fusion of monocyte/macrophage lineages. Various small GTPases are involved in the multinucleation and differentiation of osteoclasts. However, the roles of small GTPases regulatory molecules in osteoclast differentiation remain unclear. In the present study, we examined the role of Dennd2c, a putative guanine nucleotide exchange factor for Rab GTPases, in osteoclast differentiation. Knockdown of Dennd2c promoted osteoclast differentiation, resorption, and expression of osteoclast markers. Morphologically, Dennd2c knockdown induced the formation of larger osteoclasts with several protrusions. In contrast, overexpression of Dennd2c inhibited the multinucleation and differentiation of osteoclasts, bone resorption, and the expression of osteoclast markers. Dennd2c-overexpressing macrophages exhibited spindle-shaped mononuclear cells and long thin protrusions. Treatment of Dennd2c-overexpressing cells with the Cdc42 inhibitor ML-141 or the Rac1 inhibitor 6-thio-GTP prevented protrusion formation. Moreover, treatment of Dennd2c-overexpressing cells with the actin polymerization inhibitor latrunculin B restored multinucleated and TRAP-positive osteoclast formation. These results indicate that Dennd2c negatively regulates osteoclast differentiation and multinucleation by modulating protrusion formation in macrophages. en-copyright= kn-copyright= en-aut-name=KoyanagiYu en-aut-sei=Koyanagi en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakaiEiko en-aut-sei=Sakai en-aut-mei=Eiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamaguchiYu en-aut-sei=Yamaguchi en-aut-mei=Yu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FarhanaFatima en-aut-sei=Farhana en-aut-mei=Fatima kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TairaYohsuke en-aut-sei=Taira en-aut-mei=Yohsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OkamotoKuniaki en-aut-sei=Okamoto en-aut-mei=Kuniaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MurataHiroshi en-aut-sei=Murata en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TsukubaTakayuki en-aut-sei=Tsukuba en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University kn-affil= affil-num=2 en-affil=Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University kn-affil= affil-num=3 en-affil=Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University kn-affil= affil-num=4 en-affil=Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University kn-affil= affil-num=5 en-affil=Division of Cariology and Restorative Dentistry, Department of Prosthetic Dentistry, Graduate School of Biomedical Sciences, Nagasaki 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=Division of Cariology and Restorative Dentistry, Department of Prosthetic Dentistry, Graduate School of Biomedical Sciences, Nagasaki University kn-affil= affil-num=8 en-affil=Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University kn-affil= en-keyword=osteoclast kn-keyword=osteoclast en-keyword=actin polymerization kn-keyword=actin polymerization en-keyword=protrusion formation kn-keyword=protrusion formation en-keyword=Dennd2c kn-keyword=Dennd2c END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=20056 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250612 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pharmacokinetics and the effectiveness of pyrogen-free bioabsorbable wet adhesives en-subtitle= kn-subtitle= en-abstract= kn-abstract=Bioabsorbable materials are essential for advanced therapies, including surgical sealing, cell therapy, and drug delivery. Natural bioabsorbable materials, including collagen and hyaluronic acid, have better biocompatibility than synthetic bioabsorbable polymers; however, they are mainly derived from animals, presenting infection risks. Non-animal origin polymers have a lower molecular weight than those of animal origins. Their viscosity increases with increase in molecular weight, making endotoxin removal difficult. Here, using the phosphoryl chloride disposal method, we present a strategy for synthesizing pyrogen-free bioabsorbable adhesives with controlled molecular weight. Phosphopullulan, a polysaccharide derivative, had less than detectable endotoxin levels and controllable average molecular weight of approximately 300,000 to over 1,400,000. Furthermore, it is important to ensure the safety as well as efficacy of bio-implantable materials. We have evaluated the biosafety of polysaccharide derivatives we are developing, and have examined their cell phagocytosis and pharmacokinetics in vitro and in vivo, and have confirmed that they are safe. We have also evaluated their adhesion to wet tissue adhesions and confirmed that they leak less than existing materials. en-copyright= kn-copyright= en-aut-name=OshimaRisa en-aut-sei=Oshima en-aut-mei=Risa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YoshiharaKumiko en-aut-sei=Yoshihara en-aut-mei=Kumiko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NakanishiKo en-aut-sei=Nakanishi en-aut-mei=Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AkasakaTsukasa en-aut-sei=Akasaka en-aut-mei=Tsukasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ShimojiShinji en-aut-sei=Shimoji en-aut-mei=Shinji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakamuraTeppei en-aut-sei=Nakamura en-aut-mei=Teppei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=OkiharaTakumi en-aut-sei=Okihara en-aut-mei=Takumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakamuraMariko en-aut-sei=Nakamura en-aut-mei=Mariko 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= en-aut-name=TamadaIkkei en-aut-sei=Tamada en-aut-mei=Ikkei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=Van MeerbeekBart en-aut-sei=Van Meerbeek en-aut-mei=Bart kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SugayaTsutomu en-aut-sei=Sugaya en-aut-mei=Tsutomu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=YoshidaYasuhiro en-aut-sei=Yoshida en-aut-mei=Yasuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Periodontology, Faculty of Dental Medicine, Hokkaido 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 Biomaterials and Bioengineering, Faculty of Dental Medicine, Hokkaido University kn-affil= affil-num=4 en-affil=Department of Biomaterials and Bioengineering, Faculty of Dental Medicine, Hokkaido University kn-affil= affil-num=5 en-affil=Department of Periodontology, Faculty of Dental Medicine, Hokkaido University kn-affil= affil-num=6 en-affil=Department of Applied Veterinary Science, Faculty of Veterinary Medicine, Hokkaido University kn-affil= affil-num=7 en-affil=Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Department of Clinical Psychology, School of Clinical Psychology, Kyushu University of Medical and Science 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= affil-num=10 en-affil=Department of Plastic and Reconstructive Surgery, Tokyo Metropolitan Children’s Medical Center kn-affil= affil-num=11 en-affil=BIOMAT, Department of Oral Health Sciences, & UZ Leuven, Dentistry, KU Leuven kn-affil= affil-num=12 en-affil=Department of Periodontology, Faculty of Dental Medicine, Hokkaido University kn-affil= affil-num=13 en-affil=Department of Biomaterials and Bioengineering, Faculty of Dental Medicine, Hokkaido University kn-affil= en-keyword=Phosphopullulan kn-keyword=Phosphopullulan en-keyword=Polysaccharide kn-keyword=Polysaccharide en-keyword=ADME kn-keyword=ADME en-keyword=Animal study kn-keyword=Animal study en-keyword=Endodontic sealer kn-keyword=Endodontic sealer END start-ver=1.4 cd-journal=joma no-vol=142 cd-vols= no-issue= article-no= start-page=104967 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202506 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cross-feeding between beneficial and pathogenic bacteria to utilize eukaryotic host cell-derived sialic acids and bacteriophages shape the pathogen-host interface milieu en-subtitle= kn-subtitle= en-abstract= kn-abstract=Under an inflamed-intestinal milieu, increased free sialic acids are associated with the overgrowth of some pathogenic bacterial strains. Recently, the protective immunomodulatory activity of gut bacteriophages (phages) has also been highlighted. However, the role of phages in triple reciprocal interactions between pathogenic bacteria, beneficial bacteria, and their host cell sialic acids has not been studied so far. We established a sialidase-explicit model in which beneficial and pathogenic bacteria interact through cross-feeding and competition for free sialic acid using a human triple co-culture cell model incorporating colonocytes (T84 cells), monocytes (THP-1 cells), and hepatocytes (Huh7 cells). Triple co-cultured cells were challenged with Gram-positive Bifidobacterium bifidum (B. bifidum) and Gram-negative Pseudomonas aeruginosa PAO1 (P. a PAO1) in the absence or presence of its KPP22 phage in two different cell culture mediums: 1) standard Dulbecco's Modified Eagle Medium (DMEM) and 2) DMEM with 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA). Changes in physiological, functional, and structural health markers of stimulated cocultured cells were evaluated. The concentrations of sialic acid and pro-inflammatory cytokines in the cell culture supernatants were quantified. P. a PAO1 triggered the release of interleukin 6 and 8 (IL-6 and IL-8), accompanied by increased levels of free sialic acid, reduced viability of co-cultured cells, and disrupted the integrity of the cellular monolayer. These disruptive effects were markedly attenuated by KPP22 phage and B. bifidum. In addition to well-documented differences in the structure and composition of the bacterial cell walls of Gram-negative pathogenic bacteria and bifidobacteria, two distinct factors seem to be pivotal in modulating the pathogen-host interface milieu: (i) the presence of phages and (ii) the utilization of free sialic acids secreted from host cells by bifidobacteria. 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=Fölster-HolstRegina en-aut-sei=Fölster-Holst en-aut-mei=Regina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=BlömerSophia en-aut-sei=Blömer en-aut-mei=Sophia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=EbsenMichael en-aut-sei=Ebsen en-aut-mei=Michael kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=RöckenChristoph en-aut-sei=Röcken en-aut-mei=Christoph kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=UchiyamaJumpei en-aut-sei=Uchiyama en-aut-mei=Jumpei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=7 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=8 ORCID= affil-num=1 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= affil-num=2 en-affil=Clinic of Dermatology, Venerology und Allergology, University Hospital Schleswig-Holstein kn-affil= affil-num=3 en-affil=Clinic of Dermatology, Venerology und Allergology, University Hospital Schleswig-Holstein kn-affil= affil-num=4 en-affil=Städtisches MVZ Kiel GmbH (Kiel City Hospital), Department of Pathology kn-affil= affil-num=5 en-affil=Institute of Pathology, Kiel University, University Hospital, Schleswig-Holstein kn-affil= affil-num=6 en-affil=Department of Bacteriology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Medical Laboratory Science, Faculty of Health Sciences, Kochi Gakuen University kn-affil= affil-num=8 en-affil=Department of Microbiology and Biotechnology, Max Rubner-Institut kn-affil= en-keyword=Bacterial sialidase kn-keyword=Bacterial sialidase en-keyword=Inflammation kn-keyword=Inflammation en-keyword=Cytokines kn-keyword=Cytokines en-keyword=Infection kn-keyword=Infection en-keyword=Bifidobacteria kn-keyword=Bifidobacteria en-keyword=Phages kn-keyword=Phages END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue=12 article-no= start-page=25 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20241216 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Disruption of the Enterococcus faecalis–Induced Biofilm on the Intraocular Lens Using Bacteriophages en-subtitle= kn-subtitle= en-abstract= kn-abstract=Purpose: To compare the effects of bacteriophages (phages) and vancomycin on Enterococcus faecalis–induced biofilms on the intraocular lens.
Methods: E. faecalis strains EF24, GU02, GU03, and phiEF14H1 were used. The expression of the enterococcus surface protein (esp) gene was analyzed using polymerase chain reaction. Phages or vancomycin was added to the biofilms formed on culture plates or acrylic intraocular lenses. The biofilms were quantified after staining with crystal violet. The structure of the biofilms was analyzed using scanning electron microscopy.
Results: E. faecalis strains EF24, GU02, and GU03 formed biofilms on cell culture plates; however, the esp-negative GU03 strain had a significantly lower biofilm-forming ability than the esp-positive strains EF24 and GU02. The addition of phiEF14H1 resulted in a significant reduction in biofilm mass produced by both EF24 and GU02 compared with the untreated control. However, the addition of vancomycin did not degrade the biofilms. Phages significantly degraded biofilms and reduced the viable EF24 and GU02 bacteria on the intraocular lens.
Conclusions: Phages can degrade biofilms formed on the intraocular lens and destroy the bacteria within it. Thus, phage therapy may be a new treatment option for refractory and recurrent endophthalmitis caused by biofilm-forming bacteria.
Translational Relevance: Phage therapy, a novel treatment option for refractory and recurrent endophthalmitis caused by biofilm-forming bacteria, effectively lyses E. faecalis–induced biofilms. en-copyright= kn-copyright= en-aut-name=KishimotoTatsuma en-aut-sei=Kishimoto en-aut-mei=Tatsuma kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=FukudaKen en-aut-sei=Fukuda en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IshidaWaka en-aut-sei=Ishida en-aut-mei=Waka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KuwanaAozora en-aut-sei=Kuwana en-aut-mei=Aozora kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TodokoroDaisuke en-aut-sei=Todokoro en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 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=7 ORCID= en-aut-name=YamashiroKenji en-aut-sei=Yamashiro en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University kn-affil= affil-num=2 en-affil=Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University kn-affil= affil-num=3 en-affil=Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University kn-affil= affil-num=4 en-affil=Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University kn-affil= affil-num=5 en-affil=Department of Ophthalmology, Gunma University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Bacteriology, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=Department of Medical Laboratory Science, Faculty of Health Sciences, Kochi Gakuen University kn-affil= affil-num=8 en-affil=Department of Ophthalmology and Visual Science, Kochi Medical School, Kochi University kn-affil= en-keyword=biofilm kn-keyword=biofilm en-keyword=bacteriophage kn-keyword=bacteriophage en-keyword=intraocular lens kn-keyword=intraocular lens en-keyword=endophthalmitis kn-keyword=endophthalmitis en-keyword=cataract kn-keyword=cataract en-keyword=enterococcus faecalis kn-keyword=enterococcus faecalis END start-ver=1.4 cd-journal=joma no-vol=23 cd-vols= no-issue=5 article-no= start-page=209 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250514 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Novel Anti-MRSA Peptide from Mangrove-Derived Virgibacillus chiguensis FN33 Supported by Genomics and Molecular Dynamics en-subtitle= kn-subtitle= en-abstract= kn-abstract=Antimicrobial resistance (AMR) is a global health threat, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the major resistant pathogens. This study reports the isolation of a novel mangrove-derived bacterium, Virgibacillus chiguensis FN33, as identified through genome analysis and the discovery of a new anionic antimicrobial peptide (AMP) exhibiting anti-MRSA activity. The AMP was composed of 23 amino acids, which were elucidated as NH3-Glu-Gly-Gly-Cys-Gly-Val-Asp-Thr-Trp-Gly-Cys-Leu-Thr-Pro-Cys-His-Cys-Asp-Leu-Phe-Cys-Thr-Thr-COOH. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for MRSA were 8 µg/mL and 16 µg/mL, respectively. FN33 AMP induced cell membrane permeabilization, suggesting a membrane-disrupting mechanism. The AMP remained stable at 30–40 °C but lost activity at higher temperatures and following exposure to proteases, surfactants, and extreme pH. All-atom molecular dynamics simulations showed that the AMP adopts a β-sheet structure upon membrane interaction. These findings suggest that Virgibacillus chiguensis FN33 is a promising source of novel antibacterial agents against MRSA, supporting alternative strategies for drug-resistant infections. en-copyright= kn-copyright= en-aut-name=SermkaewNamfa en-aut-sei=Sermkaew en-aut-mei=Namfa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AtipairinApichart en-aut-sei=Atipairin en-aut-mei=Apichart kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=BoonruamkaewPhetcharat en-aut-sei=Boonruamkaew en-aut-mei=Phetcharat kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KrobthongSucheewin en-aut-sei=Krobthong en-aut-mei=Sucheewin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AonbangkhenChanat en-aut-sei=Aonbangkhen en-aut-mei=Chanat kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=YingchutrakulYodying en-aut-sei=Yingchutrakul en-aut-mei=Yodying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SongnakaNuttapon en-aut-sei=Songnaka en-aut-mei=Nuttapon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=School of Pharmacy, Walailak University kn-affil= affil-num=2 en-affil=School of Pharmacy, Walailak University kn-affil= affil-num=3 en-affil=School of Pharmacy, Walailak University kn-affil= affil-num=4 en-affil=Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University kn-affil= affil-num=5 en-affil=Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University kn-affil= affil-num=6 en-affil=Department of Bacteriology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency kn-affil= affil-num=8 en-affil=School of Pharmacy, Walailak University kn-affil= en-keyword=anionic AMP kn-keyword=anionic AMP en-keyword=AMP kn-keyword=AMP en-keyword=antimicrobial peptide kn-keyword=antimicrobial peptide en-keyword=antimicrobial resistance kn-keyword=antimicrobial resistance en-keyword=FN33 kn-keyword=FN33 en-keyword=genome kn-keyword=genome en-keyword=molecular dynamics simulations kn-keyword=molecular dynamics simulations en-keyword=MRSA kn-keyword=MRSA en-keyword=Virgibacillus chiguensis kn-keyword=Virgibacillus chiguensis END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250811 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=RNA Delivery Using a Graphene Oxide-Polyethylenimine Hybrid Inhibiting Myotube Differentiation en-subtitle= kn-subtitle= en-abstract= kn-abstract=Graphene oxide (GO) conjugated with short polyethylenimine (PEI) chains (GO-PEI) has been designed as a candidate nanocarrier for small interfering RNA (siRNA) delivery to mammalian cells based on the efficient interaction between the positively charged GO-based platform and the negatively charged siRNA. The function and efficiency of siRNA delivery using GO-PEI were compared to those using the positive control Lipofectamine RNAiMax by analyzing the differentiation to myotubes, and myogenin gene and protein expression in C2C12 cells. RNAiMax transfection induced cellularization and reduction of both myogenin gene and protein expression, suggesting that the differentiation of C2C12 cells was triggered by gene silencing. While GO-PEI also promoted cellularization, the myogenin gene expression remained comparable to scrambled controls, whereas the protein levels were higher than those observed with RNAiMax. Mechanistically, we attributed the reduced gene silencing efficiency of GO-PEI to a poor endosomal escape, despite strong siRNA complexation. This limitation was likely due to a low buffering capacity of GO-PEI, as a significant fraction of nitrogen atoms were already protonated, reducing the availability of free amines necessary for endosomal disruption. An appropriate chemical modification to enhance siRNA release from the endosomes is therefore essential for advancing the development of GO-based platforms as versatile and efficient nanocarriers in gene therapy applications. en-copyright= kn-copyright= en-aut-name=MatsuuraKoji en-aut-sei=Matsuura en-aut-mei=Koji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ReinaGiacomo en-aut-sei=Reina en-aut-mei=Giacomo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GaoZhengfeng en-aut-sei=Gao en-aut-mei=Zhengfeng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NishinaYuta en-aut-sei=Nishina en-aut-mei=Yuta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=BiancoAlberto en-aut-sei=Bianco en-aut-mei=Alberto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISIS kn-affil= affil-num=2 en-affil=CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISIS kn-affil= affil-num=3 en-affil=CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISIS kn-affil= affil-num=4 en-affil=Research Institute for Interdisciplinary Science, Okayama University kn-affil= affil-num=5 en-affil=CNRS, Immunology, Immunopathology and Therapeutic Chemistry, UPR3572, University of Strasbourg, ISIS kn-affil= en-keyword=graphene oxide kn-keyword=graphene oxide en-keyword=polyethylenimine kn-keyword=polyethylenimine en-keyword=myotubes kn-keyword=myotubes en-keyword=myogenin kn-keyword=myogenin en-keyword=small interfering RNA kn-keyword=small interfering RNA en-keyword=transfection kn-keyword=transfection END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue=6 article-no= start-page=065001 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240613 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Inert structural transition in 4H and 6H SiC at high pressure and temperature: a Raman spectroscopy study en-subtitle= kn-subtitle= en-abstract= kn-abstract=We conducted Raman spectroscopy measurements of 4H-SiC and 6H-SiC up to 69 GPa and 1023 K to assess the stability and bonding of SiC at high pressure and temperature. Both optic and acoustic modes were observed at wide pressure and temperature ranges. The temperature shifts of the Raman frequencies were fitted by the equation with the Bose–Einstein distribution function, and we found that the shifts were almost insensitive to the pressure. The mode Grüneisen coefficients weakly depend on the pressure and temperature, suggesting the sluggish transition of the crystal structure, unlike the previous experiments showing the transition or decomposition of SiC at high pressure and temperature conditions. Inert transitions are confirmed by Raman measurements and annealing experiments using multiple high-pressure apparatuses. The crystallinity may be a hidden critical parameter in the experiments to determine the stable polytypes of SiC under high pressure and temperature. en-copyright= kn-copyright= en-aut-name=MaitaniShuhou en-aut-sei=Maitani en-aut-mei=Shuhou kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SinmyoRyosuke en-aut-sei=Sinmyo en-aut-mei=Ryosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 ORCID= en-aut-name=YozaKenji en-aut-sei=Yoza en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= affil-num=1 en-affil=Department of Physics, School of Science and Technology, Meiji University kn-affil= affil-num=2 en-affil=Department of Physics, School of Science and Technology, Meiji University kn-affil= affil-num=3 en-affil=Institute for Planetary Materials, Okayama University kn-affil= affil-num=4 en-affil=Bruker Japan kn-affil= en-keyword=SiC kn-keyword=SiC en-keyword=Raman kn-keyword=Raman en-keyword=phase transitions kn-keyword=phase transitions en-keyword=high pressure kn-keyword=high pressure en-keyword=high temperature kn-keyword=high temperature en-keyword=diamond anvil cell kn-keyword=diamond anvil cell en-keyword=crystal structure kn-keyword=crystal structure END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue=9 article-no= start-page=846 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240905 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Unveiling a New Antimicrobial Peptide with Efficacy against P. aeruginosa and K. pneumoniae from Mangrove-Derived Paenibacillus thiaminolyticus NNS5-6 and Genomic Analysis en-subtitle= kn-subtitle= en-abstract= kn-abstract=This study focused on the discovery of the antimicrobial peptide (AMP) derived from mangrove bacteria. The most promising isolate, NNS5-6, showed the closest taxonomic relation to Paenibacillus thiaminolyticus, with the highest similarity of 74.9%. The AMP produced by Paenibacillus thiaminolyticus NNS5-6 exhibited antibacterial activity against various Gram-negative pathogens, especially Pseudomonas aeruginosa and Klebsiella pneumoniae. The peptide sequence consisted of 13 amino acids and was elucidated as Val-Lys-Gly-Asp-Gly-Gly-Pro-Gly-Thr-Val-Tyr-Thr-Met. The AMP mainly exhibited random coil and antiparallel beta-sheet structures. The stability study indicated that this AMP was tolerant of various conditions, including proteolytic enzymes, pH (1.2–14), surfactants, and temperatures up to 40 °C for 12 h. The AMP demonstrated 4 µg/mL of MIC and 4–8 µg/mL of MBC against both pathogens. Time-kill kinetics showed that the AMP acted in a time- and concentration-dependent manner. A cell permeability assay and scanning electron microscopy revealed that the AMP exerted the mode of action by disrupting bacterial membranes. Additionally, nineteen biosynthetic gene clusters of secondary metabolites were identified in the genome. NNS5-6 was susceptible to various commonly used antibiotics supporting the primary safety requirement. The findings of this research could pave the way for new therapeutic approaches in combating antibiotic-resistant pathogens. en-copyright= kn-copyright= en-aut-name=SermkaewNamfa en-aut-sei=Sermkaew en-aut-mei=Namfa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AtipairinApichart en-aut-sei=Atipairin en-aut-mei=Apichart kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KrobthongSucheewin en-aut-sei=Krobthong en-aut-mei=Sucheewin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=AonbangkhenChanat en-aut-sei=Aonbangkhen en-aut-mei=Chanat kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YingchutrakulYodying en-aut-sei=Yingchutrakul en-aut-mei=Yodying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=6 ORCID= en-aut-name=SongnakaNuttapon en-aut-sei=Songnaka en-aut-mei=Nuttapon kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=School of Pharmacy, Walailak University kn-affil= affil-num=2 en-affil=School of Pharmacy, Walailak University kn-affil= affil-num=3 en-affil=Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University kn-affil= affil-num=4 en-affil=Center of Excellence in Natural Products Chemistry (CENP), Department of Chemistry, Faculty of Science, Chulalongkorn University kn-affil= affil-num=5 en-affil=National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency kn-affil= affil-num=6 en-affil=Department of Bacteriology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=7 en-affil=School of Pharmacy, Walailak University kn-affil= en-keyword=antimicrobial peptide kn-keyword=antimicrobial peptide en-keyword=antimicrobial resistance kn-keyword=antimicrobial resistance en-keyword=bacterial genome kn-keyword=bacterial genome en-keyword=biosynthetic gene cluster kn-keyword=biosynthetic gene cluster en-keyword=Klebsiella pneumoniae kn-keyword=Klebsiella pneumoniae en-keyword=Mangrove kn-keyword=Mangrove en-keyword=mass spectrometry kn-keyword=mass spectrometry en-keyword=NNS5-6 kn-keyword=NNS5-6 en-keyword=Paenibacillus thiaminolyticus kn-keyword=Paenibacillus thiaminolyticus en-keyword=Pseudomonas aeruginosa kn-keyword=Pseudomonas aeruginosa END start-ver=1.4 cd-journal=joma no-vol=4 cd-vols= no-issue=9 article-no= start-page=1135 end-page=1151 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250910 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Heart failure-specific cardiac fibroblasts contribute to cardiac dysfunction via the MYC–CXCL1–CXCR2 axis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Single-cell RNA sequencing of mouse hearts under pressure overload identified six CF subclusters, with one specific to the HF stage. This HF-specific CF population highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-specific CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes, and blocking the CXCL1–CXCR2 axis mitigates HF. CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls. These findings reveal that HF-specific CFs contribute to HF via the MYC–CXCL1–CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes. en-copyright= kn-copyright= en-aut-name=KomuroJin en-aut-sei=Komuro en-aut-mei=Jin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=KatsukiToshiomi en-aut-sei=Katsuki en-aut-mei=Toshiomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 ORCID= en-aut-name=KatohManami en-aut-sei=Katoh en-aut-mei=Manami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=KoToshiyuki en-aut-sei=Ko en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ItoMasamichi en-aut-sei=Ito en-aut-mei=Masamichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KatagiriMikako en-aut-sei=Katagiri en-aut-mei=Mikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KubotaMasayuki en-aut-sei=Kubota en-aut-mei=Masayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=YamadaShintaro en-aut-sei=Yamada en-aut-mei=Shintaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 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=12 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=13 ORCID= en-aut-name=KomuroKaoruko en-aut-sei=Komuro en-aut-mei=Kaoruko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 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=15 ORCID= en-aut-name=ItoShogo en-aut-sei=Ito en-aut-mei=Shogo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=NomuraSeitaro en-aut-sei=Nomura en-aut-mei=Seitaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=KomuroIssei en-aut-sei=Komuro en-aut-mei=Issei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 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=19 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=20 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=21 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 Frontier Cardiovascular Science, Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Frontier Cardiovascular Science, Graduate School of Medicine kn-affil= affil-num=7 en-affil=Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=8 en-affil=Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=9 en-affil=Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=10 en-affil=Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=11 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=12 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=13 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=14 en-affil=Department of Cardiology, 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 Cardiology, Keio University School of Medicine kn-affil= affil-num=17 en-affil=Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo kn-affil= affil-num=18 en-affil=Department of Frontier Cardiovascular Science, Graduate School of Medicine kn-affil= affil-num=19 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= affil-num=20 en-affil=Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=21 en-affil=Department of Cardiology, Keio University School of Medicine kn-affil= END start-ver=1.4 cd-journal=joma no-vol=5 cd-vols= no-issue=3 article-no= start-page=394 end-page=403 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240802 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Synthesis and Crystal Structure of Ilmenite-Type Silicate with Pyrope Composition en-subtitle= kn-subtitle= en-abstract= kn-abstract=Akimotoite, ilmenite-type MgSiO3 high-pressure polymorph can be stable in the lower-mantle transition zone along average mantle and subducting slab geotherms. Significant amounts of Al2O3 can be incorporated into the structure, having the pyrope (Mg3Al2Si3O12) composition. Previous studies have investigated the effect of Al2O3 on its crystal structure at nearly endmember compositions. In this study, we synthesized high-quality ilmenite-type Mg3Al2Si3O12 phase at 27 GPa and 1073 K by means of a Kawai-type multi-anvil press and refined the crystal structure at ambient conditions using a synchrotron X-ray diffraction data via the Rietveld method to examine the effect of Al2O3. The unit-cell lattice parameters were determined to be a = 4.7553(7) Å, c = 13.310(2) Å, and V = 260.66(6) Å3, with Z = 6 (hexagonal, R3̲ ). The volume of the present phase was placed on the akimotoite-corundum endmember join. However, the refined structure showed a strong nonlinear behavior of the a- and c-axes, which can be explained by Al incorporation into the MgO6 and SiO6 octahedral sites, which are distinctly different each other. Ilmenite-type Mg3Al2Si3O12 phase may be found in shocked meteorites and can be a good indicator for shock conditions at relatively low temperatures of 1027–1127 K. en-copyright= kn-copyright= en-aut-name=IshiiTakayuki en-aut-sei=Ishii en-aut-mei=Takayuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SinmyoRyosuke en-aut-sei=Sinmyo en-aut-mei=Ryosuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KatsuraTomoo en-aut-sei=Katsura en-aut-mei=Tomoo 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=Department of Physics, School of Science and Technology, Meiji University kn-affil= affil-num=3 en-affil=Bavarian Research Institute of Experimental Geochemistry and Geophysics, University of Bayreuth kn-affil= en-keyword=ilmenite kn-keyword=ilmenite en-keyword=akimotoite kn-keyword=akimotoite en-keyword=pyrope kn-keyword=pyrope en-keyword=high pressure kn-keyword=high pressure en-keyword=X-ray diffraction kn-keyword=X-ray diffraction en-keyword=crystal structure kn-keyword=crystal structure en-keyword=Rietveld analysis kn-keyword=Rietveld analysis en-keyword=mantle kn-keyword=mantle en-keyword=subducting slab kn-keyword=subducting slab en-keyword=corundum kn-keyword=corundum END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page=pcaf098 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250822 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Thylakostasis: key factors in thylakoid membrane organization with emphasis on biogenesis and remodeling proteins in vascular plants en-subtitle= kn-subtitle= en-abstract= kn-abstract=The thylakoid membrane (TM), a defining feature for almost all oxygen-evolving photosynthetic organisms, serves as the structural foundation for light-driven energy conversion. In vascular plants, the TM evolved into a complex architecture composed of single-layered stroma thylakoids and stacked grana thylakoids, enabling the spatial organization of two photosystems (PSII and PSI) to optimize light capture and energy transfer. In addition, two membrane regions, one connecting these two compartments (grana margin) and the other corresponding to the curvature domain in grana, function in dissipating excess energy, balancing electron transfer, and maintaining functional PSII. Recent advances in electron microscopy imaging and proteome analysis of membrane subcompartments have provided new insights into the structure and dynamic adaptations of the TM in response to diverse environmental conditions. To describe the mechanisms that govern TM architecture, dynamics, and integrity, I am introducing the concept of “thylakostasis” (thylakoid homeostasis). Here, I provide an overview of the molecular components and processes central to thylakostasis, including the biosynthesis of lipids, chlorophyll, and proteins. I focus particularly on the membrane remodeling proteins whose functions have been elucidated recently, such as VIPP1, a member of the evolutionarily conserved PspA/ESCRT-III superfamily; FZL, a dynamin-like GTPase; and CURT1, a curvature-inducing protein unique to photosynthetic organisms. Together, these factors orchestrate TM biogenesis, remodeling, and adaptive flexibility that is essential for photosynthetic efficiency. en-copyright= kn-copyright= en-aut-name=SakamotoWataru en-aut-sei=Sakamoto en-aut-mei=Wataru 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=chloroplast kn-keyword=chloroplast en-keyword=ESCRT-III (endosomal sorting complex required for transport complex III) kn-keyword=ESCRT-III (endosomal sorting complex required for transport complex III) en-keyword=grana kn-keyword=grana en-keyword=membrane trafficking kn-keyword=membrane trafficking en-keyword=photosynthesis kn-keyword=photosynthesis en-keyword=stroma thylakoid kn-keyword=stroma thylakoid END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=10 article-no= start-page=4724 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250515 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Stem Cell Factors BAM1 and WOX1 Suppressing Longitudinal Cell Division of Margin Cells Evoked by Low-Concentration Auxin in Young Cotyledon of Arabidopsis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Highly differentiated tissues and organs play essential biological functions in multicellular organisms. Coordination of organ developmental process with tissue differentiation is necessary to achieve proper development of mature organs, but mechanisms for such coordination are not well understood. We used cotyledon margin cells from Arabidopsis plant as a new model system to investigate cell elongation and cell division during organ growth and found that margin cells endured a developmental phase transition from the “elongation” phase to the “elongation and division” phase at the early stage in germinating seedlings. We also discovered that the stem cell factors BARELY ANY MERISTEM 1 (BAM1) and WUSCHEL-related homeobox1 (WOX1) are involved in the regulation of margin cell developmental phase transition. Furthermore, exogenous auxin treatment (1 nanomolar,nM) promotes cell division, especially longitudinal cell division. This promotion of cell division did not occur in bam1 and wox1 mutants. Based on these findings, we hypothesized a new “moderate auxin concentration” model which emphasizes that a moderate auxin concentration is the key to triggering the developmental transition of meristematic cells. en-copyright= kn-copyright= en-aut-name=JiangYuli en-aut-sei=Jiang en-aut-mei=Yuli kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=LiangJian en-aut-sei=Liang en-aut-mei=Jian kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WangChunyan en-aut-sei=Wang en-aut-mei=Chunyan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TanLi en-aut-sei=Tan en-aut-mei=Li kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KawanoYoji en-aut-sei=Kawano en-aut-mei=Yoji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NagawaShingo en-aut-sei=Nagawa en-aut-mei=Shingo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Institute for Translational Brain Reaearch, Fudan University kn-affil= affil-num=2 en-affil=Center for Excellence in Molecular Plant Science, Chinese Academy of Sciences kn-affil= affil-num=3 en-affil=Center for Excellence in Molecular Plant Science, Chinese Academy of Sciences kn-affil= affil-num=4 en-affil=Center for Excellence in Molecular Plant Science, Chinese Academy of Sciences kn-affil= affil-num=5 en-affil=Institute of Plant Science and Resources, Okayama University kn-affil= affil-num=6 en-affil=Center for Excellence in Molecular Plant Science, Chinese Academy of Sciences kn-affil= en-keyword=BAM1 kn-keyword=BAM1 en-keyword=WOX1 kn-keyword=WOX1 en-keyword=margin cells kn-keyword=margin cells en-keyword=auxin kn-keyword=auxin END start-ver=1.4 cd-journal=joma no-vol=25 cd-vols= no-issue=1 article-no= start-page=305 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250818 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= 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=Background Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among all cancers; hence, multidisciplinary treatment is essential for patients with PDAC. Although the resectability status, tumour marker, KRAS circulating tumour DNA (mutKRAS-ctDNA) mutations, and GATA binding 6 (GATA6) expression status are promising prognostic biomarkers, their effective integration before and after surgery remains unclear.
Methods In this retrospective cohort study, patients with PDAC who had undergone radical resection were enrolled, and pre- and postoperative independent factors associated with poor prognosis were identified using Cox hazard modelling. Risk stratification systems were developed using the identified prognostic factors and investigated for the ability to predict prognosis.
Results A total of 91 patients with PDAC were included (median follow-up duration, 28 months). Borderline resectable or locally advanced cancer at diagnosis, elevated carbohydrate antigen 19–9 (CA19-9) level, and mutKRAS-ctDNA-positive status were identified as independent preoperative factors associated with poor prognosis. The postoperative factors significantly associated with shorter overall survival were low GATA6 expression, elevated CA19-9 level, and mutKRAS-ctDNA-positive status. Finally, the preoperative and postoperative risk scoring systems developed using Cox modelling hazard ratio values could significantly stratify prognosis after curative resection for PDAC.
Conclusion A risk stratification system based on liquid biopsy, specialised for each phase (pre- and post-surgery), has been proven to be a useful, simple, and practical prognostic prediction clinical tool to determine the optimal multidisciplinary treatment protocol for PDAC. en-copyright= kn-copyright= en-aut-name=MiyamotoKokichi en-aut-sei=Miyamoto en-aut-mei=Kokichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=YasuiKazuya en-aut-sei=Yasui en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ShigeyasuKunitoshi en-aut-sei=Shigeyasu en-aut-mei=Kunitoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=YoshidaKazuhiro en-aut-sei=Yoshida en-aut-mei=Kazuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FujiTomokazu en-aut-sei=Fuji en-aut-mei=Tomokazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TakagiKosei en-aut-sei=Takagi en-aut-mei=Kosei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 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=8 ORCID= en-aut-name=MatsumotoKazuyuki en-aut-sei=Matsumoto en-aut-mei=Kazuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FujiiYuki en-aut-sei=Fujii en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 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=11 ORCID= en-aut-name=MoriwakeKazuya en-aut-sei=Moriwake en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KayanoMasashi en-aut-sei=Kayano en-aut-mei=Masashi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 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=14 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=15 ORCID= en-aut-name=YamamotoHideki en-aut-sei=Yamamoto en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=KatoHironari en-aut-sei=Kato en-aut-mei=Hironari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 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=18 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=19 ORCID= en-aut-name=OtsukaMotoyuki en-aut-sei=Otsuka en-aut-mei=Motoyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=20 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=21 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 Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=10 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=11 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=12 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=13 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=14 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=15 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=16 en-affil=Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=17 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=18 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=19 en-affil=Department of Biomedical Informatics, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=20 en-affil=Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science kn-affil= affil-num=21 en-affil=Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Pancreatic ductal adenocarcinoma kn-keyword=Pancreatic ductal adenocarcinoma en-keyword=Risk stratification kn-keyword=Risk stratification en-keyword=Prognosis kn-keyword=Prognosis en-keyword=Tumour marker kn-keyword=Tumour marker en-keyword=KRAS kn-keyword=KRAS END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250909 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=S100A8/A9-MCAM signaling promotes gastric cancer cell progression via ERK-c-Jun activation en-subtitle= kn-subtitle= en-abstract= kn-abstract=S100 protein family members S100A8 and S100A9 function primarily as a heterodimer complex (S100A8/A9) in vivo. This complex has been implicated in various cancers, including gastric cancer (GC). Recent studies suggest that these proteins play significant roles in tumor progression, inflammation, and metastasis. However, the exact mechanisms by which S100A8/A9 contributes to GC pathogenesis remain unclear. This study investigates the role of S100A8/A9 and its receptor in GC. Immunohistochemical analysis was performed on GC tissue samples to assess the expression of the S100A8/A9 receptor melanoma cell adhesion molecule (MCAM). In vitro transwell migration and invasion assays were used to evaluate the motility and invasiveness of GC cells. Cell proliferation was assessed using a growth assay, and Western blotting (WB) was employed to examine downstream signaling pathways, including ERK and the transcription factor c-Jun, in response to S100A8/A9–MCAM interaction. S100A8/A9 stimulation enhanced both proliferation and migration through MCAM binding in GC cell lines. These cellular events were accompanied by ERK activation and c-Jun induction. Downregulation of MCAM suppressed both ERK phosphorylation and c-Jun expression, highlighting the importance of the S100A8/A9‒MCAM‒ERK‒c-Jun axis in promoting GC progression. These findings indicate that S100A8/A9 contributes to GC progression via MCAM, which activates the ERK‒c-Jun pathway. The S100A8/A9‒signaling axis may represent a novel therapeutic target in GC. en-copyright= kn-copyright= en-aut-name=ChenYouyi en-aut-sei=Chen en-aut-mei=Youyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YangXu en-aut-sei=Yang en-aut-mei=Xu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=3 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=4 ORCID= en-aut-name=PanBo en-aut-sei=Pan en-aut-mei=Bo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=WuFangping en-aut-sei=Wu en-aut-mei=Fangping kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=ZhangXu en-aut-sei=Zhang en-aut-mei=Xu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SagayamaKazumi en-aut-sei=Sagayama en-aut-mei=Kazumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SunBei en-aut-sei=Sun en-aut-mei=Bei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=10 ORCID= affil-num=1 en-affil=Department of Breast Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine kn-affil= affil-num=2 en-affil=Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine 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=The First Affiliated Hospital, Zhejiang University School of Medicine kn-affil= affil-num=6 en-affil=School of Pharmaceutical Sciences, Zhejiang Chinese Medical University kn-affil= affil-num=7 en-affil=Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine kn-affil= affil-num=8 en-affil=Faculties of Educational and Research Management Field, Okayama University kn-affil= affil-num=9 en-affil=Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University kn-affil= affil-num=10 en-affil=Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=Gastric cancer kn-keyword=Gastric cancer en-keyword=S100 protein kn-keyword=S100 protein en-keyword=MCAM kn-keyword=MCAM en-keyword=Inflammation kn-keyword=Inflammation en-keyword=Metastasis kn-keyword=Metastasis END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=3 article-no= start-page=412 end-page=437 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250908 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Biophysical regulation of extracellular matrix in systemic lupus erythematosus en-subtitle= kn-subtitle= en-abstract= kn-abstract=Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by immune dysregulation and multi-organ damage. Recent advances have underscored the critical involvement of extracellular matrix (ECM) biophysical properties in shaping immune cell behavior and metabolic states that contribute to disease progression. This review systematically delineates the pathological remodeling of ECM biophysics in SLE, with a focus on their roles in mechanotransduction, immune-metabolic interplay, and organ-specific tissue injury. By integrating current evidence, we highlight how ECM-derived mechanical cues orchestrate aberrant immune responses and propose new perspectives for targeting ECM-immune crosstalk in the development of organ-specific, mechanism-based therapies for SLE. en-copyright= kn-copyright= en-aut-name=LiQiwei en-aut-sei=Li en-aut-mei=Qiwei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=LiQiang en-aut-sei=Li en-aut-mei=Qiang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=XiaoZhaoyang en-aut-sei=Xiao en-aut-mei=Zhaoyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NARUSEKeiji en-aut-sei=NARUSE en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakahashiKen en-aut-sei=Takahashi en-aut-mei=Ken kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University kn-affil= affil-num=4 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=systemic lupus erythematosus (SLE) kn-keyword=systemic lupus erythematosus (SLE) en-keyword=extracellular matrix (ECM) kn-keyword=extracellular matrix (ECM) en-keyword=mechanotransduction kn-keyword=mechanotransduction en-keyword=mechanism kn-keyword=mechanism en-keyword=immune regulation kn-keyword=immune regulation en-keyword=fibrosis kn-keyword=fibrosis en-keyword=organ-specific damage kn-keyword=organ-specific damage END start-ver=1.4 cd-journal=joma no-vol=34 cd-vols= no-issue=2 article-no= start-page=67 end-page=73 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240701 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Depletion of Lysyl Oxidase-Like 4 (LOXL4) Attenuates Colony Formation in vitro and Collagen Deposition in vivo Breast Cancer Model en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Lysyl oxidase (LOX) family proteins have recently become a topic in cancer progression. Our recent study found a high expression of LOX-like 4 (LOXL4) in MDA-MB-231 cells. Objective: To reveal the impact of depleted LOXL4 in both in vitro and in vivo breast cancer models from a histological perspective. Material and Method: Endogenous LOXL4 was depleted using the CRISPR/Cas9 on MDA-MB-231 parental cells. Based on the LOXL4 protein expression, the clone was determined for the next experiment, thus generating MDA-MB-231 LOXL4 KO. Cell assay was conducted using colony formation assay (n=3) followed by crystal violet staining. The indicated cells were inoculated orthotopically to female BALB/c nude mice (n=5). At the end of the experiment, tumors were isolated, fixed, and prepared for Masson Trichrome staining. Result: CRISPR/Cas9 completely depleted LOXL4 expression on clone number #2-22. Depletion of LOXL4 reduced the colony size formed by MDA-MB-231 cells. MDA-MB-231 LOXL4 KO #2-22 derived tumors showed depressed tumor volume compared to the parental group. Reduced collagen was also observed from the Masson Trichrome staining (p<0.001). Conclusion: Depletion of LOXL4 downregulates the growth of MDA-MB-231 cells in vitro and collagen deposition in vivo. en-copyright= kn-copyright= en-aut-name=Ni Luh Gede Yoni Komalasari en-aut-sei=Ni Luh Gede Yoni Komalasari en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=I Gde Haryo Ganesha en-aut-sei=I Gde Haryo Ganesha en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=I Gusti Nyoman Sri Wiryawan en-aut-sei=I Gusti Nyoman Sri Wiryawan en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=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, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=2 en-affil=Department of Histology, Faculty of Medicine, Udayana University kn-affil= affil-num=3 en-affil=Department of Histology, Faculty of Medicine, Udayana University kn-affil= affil-num=4 en-affil=Department of Cell Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= affil-num=5 en-affil=Department of Cell Biology, Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Okayama University kn-affil= en-keyword=Good health kn-keyword=Good health en-keyword=Lysyl oxidase kn-keyword=Lysyl oxidase en-keyword=Extracellular matrix kn-keyword=Extracellular matrix END start-ver=1.4 cd-journal=joma no-vol= cd-vols= no-issue= article-no= start-page= end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250830 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer en-subtitle= kn-subtitle= en-abstract= kn-abstract=Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super–polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation in vitro, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment. en-copyright= kn-copyright= en-aut-name=HamadaYusuke en-aut-sei=Hamada en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 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=2 ORCID= en-aut-name=ChenYuehua en-aut-sei=Chen en-aut-mei=Yuehua kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TeradaManato en-aut-sei=Terada en-aut-mei=Manato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=WangYuze en-aut-sei=Wang en-aut-mei=Yuze kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 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=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=YoshimuraTeizo en-aut-sei=Yoshimura en-aut-mei=Teizo 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 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 Oral Pathology and Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences 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=Lung cancer kn-keyword=Lung cancer en-keyword=iron kn-keyword=iron en-keyword=hypoxia-inducible factor kn-keyword=hypoxia-inducible factor en-keyword=immune checkpoint inhibitors kn-keyword=immune checkpoint inhibitors END start-ver=1.4 cd-journal=joma no-vol=26 cd-vols= no-issue=17 article-no= start-page=8145 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250822 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Augmentation of the Benzyl Isothiocyanate-Induced Antiproliferation by NBDHEX in the HCT-116 Human Colorectal Cancer Cell Line en-subtitle= kn-subtitle= en-abstract= kn-abstract=Increased drug metabolism and elimination are prominent mechanisms mediating multidrug resistance (MDR) to not only chemotherapy drugs but also anti-cancer natural products, such as benzyl isothiocyanate (BITC). To evaluate the possibility of combined utilization of a certain compound to overcome this resistance, we focused on glutathione S-transferase (GST)-dependent metabolism of BITC. The pharmacological treatment of a pi-class GST-selective inhibitor, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), significantly increased BITC-induced toxicity in human colorectal cancer HCT-116 cells. However, NBDHEX unexpectedly increased the level of the BITC–glutathione (GSH) conjugate as well as BITC-modified proteins, suggesting that NBDHEX might increase BITC-modified protein accumulation by inhibiting BITC–GSH excretion instead of inhibiting GST. Furthermore, NBDHEX significantly potentiated BITC-induced apoptosis with the enhanced activation of apoptosis-related pathways, such as c-Jun N-terminal kinase and caspase-3 pathways. These results suggested that combination treatment with NBDHEX may be an effective way to overcome MDR with drug efflux and thus induce the biological activity of BITC at lower doses. en-copyright= kn-copyright= en-aut-name=SunRuitong en-aut-sei=Sun en-aut-mei=Ruitong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YanoAina en-aut-sei=Yano en-aut-mei=Aina kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 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=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=NakamuraToshiyuki en-aut-sei=Nakamura en-aut-mei=Toshiyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 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=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 Interdisciplinary Science and Engineering in Health Systems, 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=benzyl isothiocyanate kn-keyword=benzyl isothiocyanate en-keyword=multidrug resistance kn-keyword=multidrug resistance en-keyword=glutathione S-transferase kn-keyword=glutathione S-transferase en-keyword=NBDHEX kn-keyword=NBDHEX en-keyword=apoptosis kn-keyword=apoptosis en-keyword=c-Jun N-terminal kinase kn-keyword=c-Jun N-terminal kinase END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=27047 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250725 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Prevalence of Streptococcus mutans harboring the cnm gene encoding cell surface protein Cnm in Japanese children en-subtitle= kn-subtitle= en-abstract= kn-abstract=Dental caries is a highly prevalent infectious disease primarily caused by the pathogenic bacterium Streptococcus mutans, which has also been associated with systemic disease. A 120-kDa collagen-binding protein (Cnm) produced by S. mutans contributes to cardiovascular disease pathogenicity. Few studies have addressed the current prevalence of S. mutans and the cnm gene in Japanese children or examined caries pathology in relation to cnm presence. Here, we investigated the prevalence of S. mutans and the distribution of cnm-positive S. mutans among 490 children who visited two university hospitals in Japan. The caries experience index (dmft/DMFT) was calculated, and the collagen-binding ability of cnm-positive S. mutans strains was assessed. S. mutans was isolated from the oral cavities of 158 patients (36.8%); 10.1% (16/158) harbored cnm-positive S. mutans. When caries experience indices were compared across dentitions, patients harboring cnm-positive strains had significantly higher dmft/DMFT scores than those with cnm-negative strains (P < 0.05). Additionally, a positive correlation was observed between the collagen-binding capacity of cnm-positive S. mutans and the dmft/DMFT score (r = 0.601, P < 0.05). These findings suggest that cnm contributes to caries progression through collagen-mediated adherence to tooth surfaces. The presence of cnm-positive S. mutans may represent a risk factor for increased caries susceptibility in children. en-copyright= kn-copyright= en-aut-name=SuehiroYuto en-aut-sei=Suehiro en-aut-mei=Yuto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OkudaMakoto en-aut-sei=Okuda en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=OtsuguMasatoshi en-aut-sei=Otsugu en-aut-mei=Masatoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OchiaiMarin en-aut-sei=Ochiai en-aut-mei=Marin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakagiMisato en-aut-sei=Takagi en-aut-mei=Misato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=TojoFumikazu en-aut-sei=Tojo en-aut-mei=Fumikazu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MikasaYusuke en-aut-sei=Mikasa en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=NakaShuhei en-aut-sei=Naka en-aut-mei=Shuhei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 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=9 ORCID= en-aut-name=LapirattanakulJinthana en-aut-sei=Lapirattanakul en-aut-mei=Jinthana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OkawaRena en-aut-sei=Okawa en-aut-mei=Rena kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 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=12 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=13 ORCID= affil-num=1 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=2 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=3 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=4 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka 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, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=7 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=8 en-affil=Department of Pediatric Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Department of Pediatric Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=10 en-affil=Department of Oral Microbiology, Faculty of Dentistry, Mahidol University kn-affil= affil-num=11 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= affil-num=12 en-affil=Department of Pediatric Dentistry, Graduate School of Biomedical and Health Sciences, Hiroshima University kn-affil= affil-num=13 en-affil=Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka kn-affil= en-keyword=Streptococcus mutans kn-keyword=Streptococcus mutans en-keyword=Collagen-binding protein kn-keyword=Collagen-binding protein en-keyword=Cnm kn-keyword=Cnm en-keyword=Prevalence kn-keyword=Prevalence en-keyword=Dental caries kn-keyword=Dental caries en-keyword=Japanese population kn-keyword=Japanese population END start-ver=1.4 cd-journal=joma no-vol=18 cd-vols= no-issue=8 article-no= start-page=e70325 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202508 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cardiotoxicity Assessment of EGFR Tyrosine Kinase Inhibitors Using Human iPS Cell‐Derived Cardiomyocytes and FDA Adverse Events Reporting System en-subtitle= kn-subtitle= en-abstract= kn-abstract=Recent advances in the development of anti-cancer drugs have contributed to prolonged survival of cancer patients. In contrast, drug-induced cardiotoxicity, particularly cardiac contractile dysfunction, is of growing concern in cancer treatment. Therefore, it is important to understand the risks of anti-cancer drug-induced cardiac contractile dysfunction in drug development. We have previously developed image-based motion analysis using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to assess the effect of drugs on contractility. However, the utility and predictive potential of image-based motion analysis using hiPSC-CMs for anti-cancer drug-induced cardiac contractile dysfunction have not been well understood. Here we focused on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and investigated the correlation between the hiPSC-CMs data and clinical signals of adverse events related to cardiac contractile dysfunction. We examined the effects of the four EGFR-TKIs, osimertinib, gefitinib, afatinib, and erlotinib, on the contractility of hiPSC-CMs using image-based motion analysis. We found that osimertinib decreased contraction velocity and deformation distance in a dose- and time-dependent manner, whereas gefitinib, afatinib, and erlotinib had little effect on these parameters. Next, we examined the real-world data of the EGFR-TKIs using FDA Adverse Event Reporting System (FAERS; JAPIC AERS). Only osimertinib showed significant clinical signals of adverse events related to cardiac contractile dysfunction. These data suggest that hiPSC-CM data correlate with clinical signals in FAERS analysis for four EGFR-TKIs. Thus, image-based motion analysis using hiPSC-CMs can be a useful platform for predicting the risk of anti-cancer drug-induced cardiac contractile dysfunction in patients. en-copyright= kn-copyright= en-aut-name=YanagidaShota en-aut-sei=Yanagida en-aut-mei=Shota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KawagishiHiroyuki en-aut-sei=Kawagishi en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SaitoMitsuo en-aut-sei=Saito en-aut-mei=Mitsuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 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=4 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=5 ORCID= en-aut-name=KandaYasunari en-aut-sei=Kanda en-aut-mei=Yasunari kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Division of Pharmacology, National Institute of Health Sciences (NIHS) kn-affil= affil-num=2 en-affil=Division of Pharmacology, National Institute of Health Sciences (NIHS) kn-affil= affil-num=3 en-affil=Japan Pharmaceutical Information Center (JAPIC) 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=Division of Pharmacology, National Institute of Health Sciences (NIHS) kn-affil= en-keyword=cardiomyocytes kn-keyword=cardiomyocytes en-keyword=cardiotoxicity kn-keyword=cardiotoxicity en-keyword=contractility kn-keyword=contractility en-keyword=EGFR-tyrosine kinase inhibitor kn-keyword=EGFR-tyrosine kinase inhibitor en-keyword=FAERS kn-keyword=FAERS en-keyword=human iPS cell kn-keyword=human iPS cell END start-ver=1.4 cd-journal=joma no-vol=188 cd-vols= no-issue= article-no= start-page=118137 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202507 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Unravelling the cardioprotective effects of calcitriol in Sunitinib-induced toxicity: A comprehensive in silico and in vitro study en-subtitle= kn-subtitle= en-abstract= kn-abstract=Sunitinib (SUN), a drug used to treat advanced renal cell carcinoma and other cancers, causes cardiotoxicity. This study aimed to identify a potential drug candidate to counteract SUN-induced cardiotoxicity. We analysed real-world data from adverse event report databases of existing clinically approved drugs to identify potential candidates. Through in silico analyses and in vitro experiments, the mechanisms of action were determined. The study identified calcitriol (CTL), an active form of vitamin D, as a promising candidate against SUN-induced cardiotoxicity. In H9c2 cells, SUN decreased cell viability significantly, whereas CTL mitigated this effect significantly. The SUN-treated group exhibited increased autophagy in H9c2 cells, which was reduced significantly in the CTL group. Bioinformatics analysis using Ingenuity Pathway Analysis revealed the mechanistic target of rapamycin (mTOR) as a common factor between autophagy and CTL. Notably, rapamycin, an mTOR inhibitor, nullified the effects of CTL on cell viability and autophagy. Furthermore, SUN treatment led to significant reductions in cardiomyocyte diameters and increases in their widths, changes that were inhibited by CTL. SUN also induced morphological changes in surviving H9c2 cells, causing them to adopt a rounded shape, whereas CTL improved their morphology to resemble the elongated shape of the control group. In conclusion, the findings of the present study suggest that CTL has the potential to prevent SUN-induced cardiomyocyte damage through autophagy, particularly via mTOR-mediated pathways. The findings indicate that CTL could serve as an effective prophylactic agent against SUN-induced cardiotoxicity, offering a promising avenue for further research and potential clinical applications. en-copyright= kn-copyright= en-aut-name=SakamotoYoshika en-aut-sei=Sakamoto en-aut-mei=Yoshika kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=NiimuraTakahiro en-aut-sei=Niimura en-aut-mei=Takahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=GodaMitsuhiro en-aut-sei=Goda en-aut-mei=Mitsuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TomochikaNanami en-aut-sei=Tomochika en-aut-mei=Nanami kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MurakawaWakana en-aut-sei=Murakawa en-aut-mei=Wakana kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AizawaFuka en-aut-sei=Aizawa en-aut-mei=Fuka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YagiKenta en-aut-sei=Yagi en-aut-mei=Kenta kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=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=Izawa-IshizawaYuki en-aut-sei=Izawa-Ishizawa en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 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=10 ORCID= en-aut-name=IshizawaKeisuke en-aut-sei=Ishizawa en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=2 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=3 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=4 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=5 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=6 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=7 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=8 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=9 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= affil-num=10 en-affil=Department of Pharmacy, Okayama University Hospital kn-affil= affil-num=11 en-affil=Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences kn-affil= en-keyword=Sunitinib kn-keyword=Sunitinib en-keyword=Advanced renal cell carcinoma kn-keyword=Advanced renal cell carcinoma en-keyword=Cardiotoxicity kn-keyword=Cardiotoxicity en-keyword=Calcitriol kn-keyword=Calcitriol en-keyword=Autophagy kn-keyword=Autophagy en-keyword=MTOR kn-keyword=MTOR END