Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-07-31DOI: 10.1016/j.xcrm.2025.102255
Matthew V Holt, Yongchao Dou, Meggie N Young, Alexander B Saltzman, Meenakshi Anurag, Jonathan T Lei, Antrix Jain, Mei Leng, Beom-Jun Kim, Lacey E Dobrolecki, Stefanie F Faucher, Sara Savage, Chenwei Wang, Zhiao Shi, Hugo Villanueva, Karoline Kremers, Kyle D Drinnon, Patricia D Castro, Michael M Ittmann, Mehak Mehboob Khatani, Sung Han Kim, Matthew J Ellis, Bing Zhang, Anna Malovannaya, Seth P Lerner
{"title":"Proteogenomic characterization unveils biomarkers associated with chemoresistance in muscle-invasive bladder cancer.","authors":"Matthew V Holt, Yongchao Dou, Meggie N Young, Alexander B Saltzman, Meenakshi Anurag, Jonathan T Lei, Antrix Jain, Mei Leng, Beom-Jun Kim, Lacey E Dobrolecki, Stefanie F Faucher, Sara Savage, Chenwei Wang, Zhiao Shi, Hugo Villanueva, Karoline Kremers, Kyle D Drinnon, Patricia D Castro, Michael M Ittmann, Mehak Mehboob Khatani, Sung Han Kim, Matthew J Ellis, Bing Zhang, Anna Malovannaya, Seth P Lerner","doi":"10.1016/j.xcrm.2025.102255","DOIUrl":"10.1016/j.xcrm.2025.102255","url":null,"abstract":"<p><p>To explore potential chemoresistance mechanisms and identify therapeutic opportunities in muscle-invasive bladder cancer (MIBC), we conduct comprehensive proteogenomic characterization of 46 pre- and 14 post-treatment MIBC tumors incorporating genomics, transcriptomics, proteomics, and phosphoproteomics. Multi-omics clustering not only recapitulated established molecular subtypes but also revealed subtypes associated with chemotherapy sensitivity. Protein isoform level analysis identifies protein abundance of a short isoform of ATAD1 and RAF family proteins as biomarkers of chemosensitivity. Integration of proteomic and phosphoproteomic data reveals Wnt signaling via GSK3B-S9 phosphorylation and the JAK/STAT pathway as potential targets to overcome chemoresistance. Correlations between PD-L1 and TROP-2/NECTIN-4 indicate an additive benefit of combination therapy targeting these proteins. Overall, this study serves as a valuable resource for researchers and clinicians aiming to better understand and treat chemoresistant MIBC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102255"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-08-07DOI: 10.1016/j.xcrm.2025.102278
Weicheng Ren, Mingyu Yang, Xianhuo Wang, Man Nie, Yuhua Huang, Hui Wan, Dongbing Liu, Xiaobo Li, Xiaofei Ye, Bin Meng, Wenqi Jiang, Huiqiang Huang, Zhiming Li, Huilai Zhang, Kui Wu, Qiang Pan-Hammarström
{"title":"Whole-genome sequencing reveals three follicular lymphoma subtypes with distinct cell of origin and patient outcomes.","authors":"Weicheng Ren, Mingyu Yang, Xianhuo Wang, Man Nie, Yuhua Huang, Hui Wan, Dongbing Liu, Xiaobo Li, Xiaofei Ye, Bin Meng, Wenqi Jiang, Huiqiang Huang, Zhiming Li, Huilai Zhang, Kui Wu, Qiang Pan-Hammarström","doi":"10.1016/j.xcrm.2025.102278","DOIUrl":"10.1016/j.xcrm.2025.102278","url":null,"abstract":"<p><p>Follicular lymphoma (FL) is characterized by clinical, phenotypic, and genetic heterogeneity. Here, we conduct whole-genome sequencing on 131 Chinese FL samples and identify three clinically relevant genetic subtypes. These include C1, associated with favorable prognoses and enriched for BCL6-related translocations and mutations in the NOTCH/nuclear factor κB (NF-κB)/immune evasion pathways; C2, characterized by BCL2-IGH translocations and mutations in chromatin modifiers; and C3, associated with poorer prognosis, lacking BCL2-IGH/BCL6-related translocations but exhibiting more copy number variations. We validate these subtypes in an independent Western cohort (n = 227) using the same classification strategy. Transcriptionally, C1 and C3 tumors display signatures of activated B cell-like diffuse large B cell lymphoma (DLBCL), whereas C2 tumors resemble germinal center B cell-like DLBCL. Furthermore, C1 tumors are distinguished from C3 by exhibiting gene signatures of age-associated B cells and an inflamed tumor microenvironment. Our findings illustrate the molecular heterogeneity of FL and define subtypes with distinct cell of origin and clinical outcomes, offering opportunities for personalized therapeutic strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102278"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-08-11DOI: 10.1016/j.xcrm.2025.102283
Yasser Morsy, Barbara Hubeli, Patrick Turko, Marjam Barysch, Julia M Martínez-Gómez, Nicola Zamboni, Gerhard Rogler, Reinhard Dummer, Mitchell P Levesque, Michael Scharl
{"title":"The serum metabolome serves as a diagnostic biomarker and discriminates patients with melanoma from healthy individuals.","authors":"Yasser Morsy, Barbara Hubeli, Patrick Turko, Marjam Barysch, Julia M Martínez-Gómez, Nicola Zamboni, Gerhard Rogler, Reinhard Dummer, Mitchell P Levesque, Michael Scharl","doi":"10.1016/j.xcrm.2025.102283","DOIUrl":"10.1016/j.xcrm.2025.102283","url":null,"abstract":"<p><p>Melanoma is a deadly cancer with increasing incidence and mortality rates, and biomarkers for diagnosis are urgently needed. The impact of the microbiome, genetic factors, and immunologic markers on disease outcomes is described, but a comprehensive serum metabolome profiling is missing. The serum metabolome of patients with melanoma might be valuable to identify potential biomarkers. We present an untargeted metabolomics analysis in an exploratory cohort (87 patients with melanoma), an independent validation cohort (37 additional patients with melanoma featuring late-stage tumors), and 18 healthy control individuals, revealing striking differences. We identify and validate six serum metabolites that can predict the diagnosis of melanoma with an area under the curve (AUC) >0.9544 in advanced-stage melanoma. The AUC of our lead biomarker, muramic acid, is 0.964, 0.908, and 0.9936 in patients with stage I (n = 22), stage II (n = 67), and advanced melanoma (n = 86), respectively. In summary, we identify potentially very powerful diagnostic biomarkers for clinical practice.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102283"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Enhanced regenerative and developmental potential of embryonal and stem cell-derived platelets compared to adult platelets.","authors":"Baiming Huang, Le Li, Shun Yao, Yue Feng, Runqing Zhang, Wei Liang, Yuting Wu, Pei Su, Fei Wang, Wen Zhou, Hongtao Wang, Cuicui Liu, Jiaxi Zhou","doi":"10.1016/j.xcrm.2025.102297","DOIUrl":"10.1016/j.xcrm.2025.102297","url":null,"abstract":"<p><p>The molecular features and multifaceted roles of platelets have been well characterized in adult mammals, but little is known about platelets at earlier developmental stages. In this study, we conduct transcriptomic and proteomic profiling of mouse embryonic platelets and find that, compared to adult platelets, they exhibit reduced classic immune-regulatory and procoagulant features but enhanced development-supporting traits. Notably, embryonic platelets interact more robustly with various cell types, including fibroblasts, and significantly accelerate refractory wound healing. Mechanistically, embryonic platelets promote fibroblast proliferation by releasing higher levels of IGF2. We also identify a CD59(a)<sup>+</sup> platelet subpopulation in adult mice and humans that mimics the function of embryonic platelets. Additionally, human induced pluripotent stem cell (iPSC)-derived platelets share similar molecular and functional properties with embryonic platelets. Our findings highlight the unique multi-omics signatures and superior regenerative potential of embryonic and human induced pluripotent stem cell (hiPSC)-derived platelets, offering promising directions for tailoring platelet-based therapies to specific clinical needs.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102297"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Phosphoglycerate kinase 1 contributes to diabetic kidney disease through enzyme-dependent and independent manners.","authors":"Hai-Jian Sun, Qing-Bo Lu, Shi-Jia Liu, Xiao Fu, Cheng-Li Yu, Jia-Bao Su, Xin-Yu Meng, Xi Guo, Xin Shao, Jun-Hui Li, Qing-Yi Sun, Xue-Xue Zhu, Jin-Jun Shan, Wei Zhou","doi":"10.1016/j.xcrm.2025.102241","DOIUrl":"10.1016/j.xcrm.2025.102241","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is characterized by abnormal metabolic profiles. Metabolomics reveals increased serum levels of 3-phosphoglycerate (3-PG) in DKD patients. The protein expression of phosphoglycerate kinase 1 (PGK1), a key rate-limiting enzyme for 3-PG synthesis, is concomitantly upregulated in DKD patients and mice. The development of DKD is significantly mitigated by renal tubular epithelial cell-specific knockout of PGK1 and robustly worsened by PGK1 overexpression. Mechanistically, PGK1-dependent enzymatic production of 3-PG facilitates DKD through inhibiting GPX1 to activate the NLRP3 inflammasome. PGK1 promotes UNC5CL-mediated inflammation by binding to aldehyde dehydrogenase-1 L1 (Aldh1l1) through its non-enzymatic activity. The transcription factor paired box protein 5 (PAX5) mediates the upregulation of PGK1 in DKD. High-throughput screening reveals that C-16 from ChemDiv, the natural product lirinidine, and the Food and Drug Administration (FDA)-approved oxantel pamoate are potent PGK1 antagonists and efficaciously prevent DKD. Overall, blocking PGK1 may be a promising avenue for DKD management.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102241"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-07-23DOI: 10.1016/j.xcrm.2025.102247
Daniel McCluskey, Muhammad R A Shipa, Kashfia Chowdhury, Judith A James, Laura A Cooney, Michael R Ehrenstein
{"title":"IgA2<sup>+</sup> B cells and IgA2 anti-dsDNA antibodies are selectively targeted by belimumab after rituximab therapy in systemic lupus erythematosus.","authors":"Daniel McCluskey, Muhammad R A Shipa, Kashfia Chowdhury, Judith A James, Laura A Cooney, Michael R Ehrenstein","doi":"10.1016/j.xcrm.2025.102247","DOIUrl":"10.1016/j.xcrm.2025.102247","url":null,"abstract":"<p><p>No theragnostic biomarkers exist for systemic lupus erythematosus (SLE) to enable a precision medicine approach. Baseline serum IgA2 anti-double-stranded DNA (dsDNA) antibody levels are associated with response to combination belimumab after rituximab therapy in SLE (BEAT-lupus trial, ISRCTN 47873003). Analysis of the CALIBRATE trial (NCT02260934) confirms that baseline IgA2 anti-dsDNA antibody levels are specifically associated with response to belimumab after rituximab (odds ratio [OR] = 16.9, confidence interval [CI]: 2.8-101, compared to rituximab alone-CALIBRATE and BEAT-lupus combined data). IgA2 anti-dsDNA antibody levels decrease alongside IgA2 expression in plasmablasts only after this combination treatment. Increased serum B cell-activating factor (BAFF) levels are associated with rising IgA2 anti-dsDNA antibody levels after rituximab. IgA2 plasmablasts have increased BAFF receptor and interleukin (IL)-10 expression compared to IgA1 plasmablasts and have a distinct integrin profile implicating a gut mucosal origin. These findings validate IgA2 anti-dsDNA antibodies as a theragnostic biomarker of response and provide mechanistic insight into the selective targeting of IgA2<sup>+</sup> B cells by combination belimumab after rituximab in SLE.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102247"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-07-31DOI: 10.1016/j.xcrm.2025.102260
Xiaoshan Huang, Xiaopeng Tang, Qiuyue He, Dawit Adisu Tadese, Kaixun Cao, Jinai Gao, Qiuyue Xu, Ruomei Cheng, Qiumin Lu, Yifan Chen, Min Yang, Yan Du, James Mwangi, Heyu Ni, Ren Lai
{"title":"High-fat diet increases circulating palmitic acid produced by gut Bacteroides thetaiotaomicron to promote thrombosis.","authors":"Xiaoshan Huang, Xiaopeng Tang, Qiuyue He, Dawit Adisu Tadese, Kaixun Cao, Jinai Gao, Qiuyue Xu, Ruomei Cheng, Qiumin Lu, Yifan Chen, Min Yang, Yan Du, James Mwangi, Heyu Ni, Ren Lai","doi":"10.1016/j.xcrm.2025.102260","DOIUrl":"10.1016/j.xcrm.2025.102260","url":null,"abstract":"<p><p>Circulating palmitic acid (PA) is generally considered to be provided from diets and endogenous synthesis and is adversely correlated with cardiovascular disease (CVD). It is unknown, however, if gut microbiota modulates circulating PA and potentiates CVD risk. Here we demonstrate that, in CVD patients, elevated circulating PA is accompanied with hypercoagulability and high gut Bacteroides thetaiotaomicron (BT) abundance. PA promotes coagulation by inhibiting a major endogenous anticoagulant activated protein C (APC) and enhancing platelet activation. Importantly, BT is capable of synthesizing PA, and high-fat diet amplifies gut BT colonization. Our findings show that BT transplantation elevates plasma PA and triggers hypercoagulation without alternating host lipogenesis. Hesperidin, a dietary flavonoid, inhibits PA-APC interaction to prevent hypercoagulation induced by PA or BT transplantation. Collectively, we reveal the promotion of high-fat diet on gut BT colonization that elevates circulating PA and CVD risk, suggesting an approach controlling CVD by targeting PA and BT.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102260"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-08-15DOI: 10.1016/j.xcrm.2025.102302
Michael E Barish, Maryam Aftabizadeh, Jonathan Hibbard, M Suzette Blanchard, Julie R Ostberg, Jamie R Wagner, Mishika Manchanda, Jinny Paul, Tracy Stiller, Brenda Aguilar, Renate Starr, Leonidas Arvanitis, Julie A Ressler, Julie Kilpatrick, Yuthana Kong, Dongrui Wang, Stephen J Forman, Massimo D'Apuzzo, Christine E Brown, Behnam Badie
{"title":"Chlorotoxin-directed CAR T cell therapy for recurrent glioblastoma: Interim clinical experience demonstrating feasibility and safety.","authors":"Michael E Barish, Maryam Aftabizadeh, Jonathan Hibbard, M Suzette Blanchard, Julie R Ostberg, Jamie R Wagner, Mishika Manchanda, Jinny Paul, Tracy Stiller, Brenda Aguilar, Renate Starr, Leonidas Arvanitis, Julie A Ressler, Julie Kilpatrick, Yuthana Kong, Dongrui Wang, Stephen J Forman, Massimo D'Apuzzo, Christine E Brown, Behnam Badie","doi":"10.1016/j.xcrm.2025.102302","DOIUrl":"10.1016/j.xcrm.2025.102302","url":null,"abstract":"<p><p>A challenge in treating glioblastoma (GBM) is its phenotypic heterogeneity between patients and within tumors. Chlorotoxin (CLTX), a peptide from scorpion venom, broadly binds glioma cells through a mechanism involving surface matrix metalloproteinase-2 (MMP-2). We previously developed chimeric antigen receptor (CAR) T cells incorporating CLTX as the GBM recognition domain. Here, we report interim clinical experience of a phase 1 trial evaluating intracavity/intratumoral (ICT) delivery of CLTX-CAR T cells in four patients with MMP-2-expressing recurrent GBM (NCT04214392), with the primary objectives of feasibility and safety. The therapy is well tolerated with no dose-limiting toxicities. Three of the four participants (75%) exhibit a best response of stable disease. CLTX-CAR T cells are detected in the tumor cavity fluid and at lower levels in the blood. Human anti-CAR antibody assays do not detect humoral immunogenicity against the CLTX-CAR. These observations support further clinical evaluation of CLTX-CAR therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102302"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-07-24DOI: 10.1016/j.xcrm.2025.102248
Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano
{"title":"Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.","authors":"Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano","doi":"10.1016/j.xcrm.2025.102248","DOIUrl":"10.1016/j.xcrm.2025.102248","url":null,"abstract":"<p><p>Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102248"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-08-19Epub Date: 2025-07-30DOI: 10.1016/j.xcrm.2025.102257
Julie J Ahn, Steven Dudics, David P Langan, Jeffrey D Smith, Alice H Hsu, Jacob C McCright, Sawyer R Smith, Alicia L Castleberry, Benjamin I George, Javier A Goitía Vázquez, Phillip N Kuri, Sri Sai Vivek Alla, Jennifer Garcia, Young Min Haider, Fatima W Hamdan, Jhonnatan Esquivel Juárez, Robert Reddy, Aranganathan Shanmuganathan, Yuanyuan Wang, Arielle Welch, David Boclair, Pavel A Khrimian, Christopher H Yaen, John B Mumm
{"title":"Coupling IL-2 with IL-10 to mitigate toxicity and enhance antitumor immunity.","authors":"Julie J Ahn, Steven Dudics, David P Langan, Jeffrey D Smith, Alice H Hsu, Jacob C McCright, Sawyer R Smith, Alicia L Castleberry, Benjamin I George, Javier A Goitía Vázquez, Phillip N Kuri, Sri Sai Vivek Alla, Jennifer Garcia, Young Min Haider, Fatima W Hamdan, Jhonnatan Esquivel Juárez, Robert Reddy, Aranganathan Shanmuganathan, Yuanyuan Wang, Arielle Welch, David Boclair, Pavel A Khrimian, Christopher H Yaen, John B Mumm","doi":"10.1016/j.xcrm.2025.102257","DOIUrl":"10.1016/j.xcrm.2025.102257","url":null,"abstract":"<p><p>Wild-type interleukin (IL)-2 induces anti-tumor immunity and toxicity, predominated by vascular leak syndrome (VLS) leading to edema, hypotension, organ toxicity, and regulatory T cell (Treg) expansion. Efforts to uncouple IL-2 toxicity from its potency have failed in the clinic. We hypothesize that IL-2 toxicity is driven by cytokine release syndrome (CRS) followed by VLS and that coupling IL-2 with IL-10 will ameliorate toxicity. Our data, generated using human primary cells, mouse models, and non-human primates, suggest that coupling of these cytokines prevents toxicity while retaining cytotoxic T cell activation and limiting Treg expansion. In syngeneic murine tumor models, DK2<sup>10</sup> epidermal growth factor receptor (EGFR), an IL-2/IL-10 fusion molecule targeted to EGFR via an anti-EGFR single-chain variable fragment (scFV), potently activates T cells and natural killer (NK) cells and elicits interferon (IFN)γ-dependent anti-tumor function without peripheral inflammatory toxicity or Treg accumulation. Therefore, combining IL-2 with IL-10 uncouples toxicity from immune activation, leading to a balanced and pleiotropic anti-tumor immune response.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102257"},"PeriodicalIF":10.6,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12432382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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