Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-06-06DOI: 10.1016/j.xcrm.2025.102163
Jeppe Kjærgaard, Cecilie B Lindqvist, Júlia Prats Quesada, Søren Jessen, Farina Schlabs, Amy M Ehrlich, Caio Y Yonamine, Mario García-Ureña, Johann H Schmalbruch, Lewin Small, Martin Thomassen, Anders Krogh Lemminger, Kasper Eibye, Alba Gonzalez-Franquesa, Jacob V Stidsen, Kurt Højlund, Juleen R Zierath, Tuomas O Kilpeläinen, Jens Bangsbo, Jonas T Treebak, Morten Hostrup, Atul S Deshmukh
{"title":"Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.","authors":"Jeppe Kjærgaard, Cecilie B Lindqvist, Júlia Prats Quesada, Søren Jessen, Farina Schlabs, Amy M Ehrlich, Caio Y Yonamine, Mario García-Ureña, Johann H Schmalbruch, Lewin Small, Martin Thomassen, Anders Krogh Lemminger, Kasper Eibye, Alba Gonzalez-Franquesa, Jacob V Stidsen, Kurt Højlund, Juleen R Zierath, Tuomas O Kilpeläinen, Jens Bangsbo, Jonas T Treebak, Morten Hostrup, Atul S Deshmukh","doi":"10.1016/j.xcrm.2025.102163","DOIUrl":"10.1016/j.xcrm.2025.102163","url":null,"abstract":"<p><p>Skeletal muscle glucose uptake, essential for metabolic health, is regulated by both insulin and exercise. Using phosphoproteomics, we analyze skeletal muscle from healthy individuals following acute exercise or insulin stimulation, generating a valuable dataset. We identify 71 phosphosites on 55 proteins regulated by both stimuli in the same direction, suggesting a convergence of exercise and insulin signaling pathways. Among these, the vesicle-associated protein, REPS1, is highly phosphorylated at Ser709 in response to both stimuli. We identify p90 ribosomal S6 kinase (RSK) to be a key upstream kinase of REPS1 S709 phosphorylation and that the RSK-REPS1 signaling axis is involved in insulin-stimulated glucose uptake. Insulin-induced REPS1 Ser709 phosphorylation is closely linked to muscle and whole-body insulin sensitivity and is impaired in insulin-resistant mice and humans. These findings highlight REPS1 as a convergence point for insulin and exercise signaling, presenting a potential therapeutic target for treating individuals with insulin resistance.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102163"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246605","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":"Ultra-wide-field fundus photography and AI-based screening and referral for multiple ocular fundus diseases.","authors":"Xinyu Zhao, Xingwang Gu, Da Teng, Xiaolei Sun, Qijie Wei, Bo Wang, Jinrui Wang, Jianchun Zhao, Dayong Ding, Bilei Zhang, Yuelin Wang, Wenfei Zhang, Shiyu Cheng, Xinyu Liu, Lihui Meng, Bing Li, Xiao Zhang, Zhengming Shi, Anyi Liang, Guofang Jiao, Huiqin Lu, Changzheng Chen, Rishet Ahmat, Hao Zhang, Yakun Li, Dan Zhu, Han Zhang, Hongbin Lv, Donglei Zhang, Mengda Li, Ziwu Zhang, Ling Yuan, Chang Su, Dawei Sun, Qiuming Li, Dawa Xiao, Youxin Chen","doi":"10.1016/j.xcrm.2025.102187","DOIUrl":"10.1016/j.xcrm.2025.102187","url":null,"abstract":"<p><p>To address the difficulty in comprehensive screening of fundus diseases, we develop three deep learning algorithms (DLAs) based on different algorithms (Swin Transformer and cross-domain collaborative learning [CdCL]) and imaging modalities (ultra-wide-field [UWF] images and the cropped posterior-pole-region [PPR] images) to identify 25 fundus conditions and provide referral suggestions: WARM (CdCL + UWF images), BASE (Swin Transformer + UWF images), and WARM-PPR (CdCL + PPR images). 59,475 UWF images are included to establish internal and external datasets. WARM shows the best performance on the internal test (area under the receiver operating characteristic curve [AUC] for screening = 0.915; AUC for referral = 0.911) and the external multi-center test (AUC for screening = 0.912; AUC for referral = 0.902). UWF images and the CdCL approach significantly enhance the DLA's ability to detect abnormalities in the peripheral retina. The WARM model shows promise as a reliable and accurate tool for comprehensive fundus screening on a large scale.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102187"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274285","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":"PerioAI: A digital system for periodontal disease diagnosis from an intra-oral scan and cone-beam CT image.","authors":"Minhui Tan, Zhiming Cui, Yuan Li, Yu Fang, Lanzhuju Mei, Yue Zhao, Xinyu Wu, Hongchang Lai, Maurizio S Tonetti, Dinggang Shen","doi":"10.1016/j.xcrm.2025.102186","DOIUrl":"10.1016/j.xcrm.2025.102186","url":null,"abstract":"<p><p>Periodontal disease diagnosis and treatment planning are critical for preventing bone and tooth loss. Clinically, dentists manually measure periodontal pocket depth with probes while integrating bone structure from imaging to assess periodontal status, a process that is subjective, invasive, and cognitively burdensome. Here, we propose PerioAI, an accurate, automatic, and non-invasive system that directly measures the gingiva-bone distance (GBD) and provides soft and hard tissue information digitally. PerioAI is a full-stack process comprising four key components: intra-oral scan (IOS) segmentation, cone-beam computed tomography (CBCT) image segmentation, multimodal data fusion, and digital probing measurement. We evaluated PerioAI on multicenter cohorts comprising 2,507 patients. Outstanding IOS and CBCT segmentation performances ensure accuracy throughout the full-stack process. Moreover, digital probing achieves remarkable precision with only 0.040mm error. This approach has the potential to substantially improve clinical workflows in periodontal disease management, offering a more precise, patient-friendly method for diagnosis and treatment decision-making.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 6","pages":"102186"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324517","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 : 2025-06-17Epub Date: 2025-05-22DOI: 10.1016/j.xcrm.2025.102144
Zhi Yang, Yizheng Yao, Xi Chen, Victoria Madigan, Shanrui Pu, Xianqun Fan, Jun Pu, Fengfeng Bei
{"title":"Cross-species tropism of AAV.CPP.16 in the respiratory tract and its gene therapies against pulmonary fibrosis and viral infection.","authors":"Zhi Yang, Yizheng Yao, Xi Chen, Victoria Madigan, Shanrui Pu, Xianqun Fan, Jun Pu, Fengfeng Bei","doi":"10.1016/j.xcrm.2025.102144","DOIUrl":"10.1016/j.xcrm.2025.102144","url":null,"abstract":"<p><p>Efficient gene delivery vectors are crucial for respiratory and lung disease therapies. We report that AAV.CPP.16, an engineered adeno-associated virus (AAV) variant derived from AAV9, efficiently transduces airway and lung cells in mice and non-human primates via intranasal administration. AAV.CPP.16 outperforms AAV6 and AAV9, two wild-type AAVs with demonstrated tropism for respiratory tissues, and efficiently targets key respiratory cell types. It supports gene supplementation and editing therapies in two clinically relevant mouse models of respiratory and lung diseases. A single intranasal dose of AAV.CPP.16 expressing a dual-target, vascular endothelial growth factor (VEGF)/transforming growth factor (TGF)-β1-neutralizing protein protected lungs from idiopathic pulmonary fibrosis, while a similar application of AAV.CPP.16 carrying an \"all-in-one\" CRISPR-Cas13d system inhibited transcription of the SARS-CoV-2-derived RNA-dependent RNA polymerase (Rdrp) gene. Our findings highlight AAV.CPP.16 as a promising vector for respiratory and lung gene therapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102144"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131841","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 : 2025-06-17Epub Date: 2025-06-03DOI: 10.1016/j.xcrm.2025.102157
Anastasia Conti, Kety Giannetti, Federico Midena, Stefano Beretta, Nicolò Gualandi, Rosaria De Marco, Edoardo Carsana, Angelica Varesi, Teresa Tavella, Laura Alessandrini, Parinaz Zarghamian, Alessandra Weber, Samuele Ferrari, Chiara Brombin, Diego Gilioli, Lucrezia Della Volpe, Stephanie Z Xie, Ivan Merelli, Toni Cathomen, Luigi Naldini, Raffaella Di Micco
{"title":"Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.","authors":"Anastasia Conti, Kety Giannetti, Federico Midena, Stefano Beretta, Nicolò Gualandi, Rosaria De Marco, Edoardo Carsana, Angelica Varesi, Teresa Tavella, Laura Alessandrini, Parinaz Zarghamian, Alessandra Weber, Samuele Ferrari, Chiara Brombin, Diego Gilioli, Lucrezia Della Volpe, Stephanie Z Xie, Ivan Merelli, Toni Cathomen, Luigi Naldini, Raffaella Di Micco","doi":"10.1016/j.xcrm.2025.102157","DOIUrl":"10.1016/j.xcrm.2025.102157","url":null,"abstract":"<p><p>Gene editing (GE) using homology-directed repair (HDR) in hematopoietic stem and progenitor cells (HSPCs) offers promise for long-range gene correction of inherited genetic disorders. However, cellular responses induced by CRISPR-Cas9/AAV6 engineering impair the long-term repopulating potential of HDR-edited HSPCs, adversely impacting the safety and efficacy of clinical translation. Our study uncovers a durable senescence-like response in genetically engineered HSPCs triggered by p53 and interleukin (IL)-1/nuclear factor κB (NF-κB) activation, which restricts graft size and clonal diversity in long-term transplantation assays. We show that transient p53 inhibition or blocking inflammatory pathways mitigates senescence-associated responses, improving the repopulating capacity of edited HSPCs. Importantly, we identify treatment with Anakinra, an IL-1 signaling antagonist, as a promising strategy to enhance polyclonal output in HDR-edited cells while minimizing genotoxicity risks associated with the editing procedure. Overall, our findings present strategies to overcome key hurdles in HDR-based HSPC gene therapies, providing a framework for enhancing their efficacy and safety in clinical applications.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102157"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224434","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 : 2025-06-17Epub Date: 2025-05-29DOI: 10.1016/j.xcrm.2025.102150
Benjamin Bone, Nicola Cotugno, Chiara Pighi, Arianna Rotili, Seohyun Hong, Leah Carrere, Elena Morrocchi, Giuseppe Rubens Pascucci, Ce Gao, Nicole Colantoni, Weiwei Sun, Giovanna Leone, David R Collins, Mpho J Olatotse, Giovanna Del Principe, Toong Seng Tan, Melanie Lancien, Alessia Neri, Libera Sessa, Giulio Olivieri, Kailey Shapiro, Isabelle Roseto, Catherine Koofhethile, Elena Emili, Stefania Bernardi, Ann Chahroudi, Paolo Rossi, Bruce D Walker, Xu G Yu, Mathias Lichterfeld, Paolo Palma
{"title":"Distinct viral reservoirs and immune signatures in individuals on long-term antiretroviral therapy with perinatally acquired HIV-1.","authors":"Benjamin Bone, Nicola Cotugno, Chiara Pighi, Arianna Rotili, Seohyun Hong, Leah Carrere, Elena Morrocchi, Giuseppe Rubens Pascucci, Ce Gao, Nicole Colantoni, Weiwei Sun, Giovanna Leone, David R Collins, Mpho J Olatotse, Giovanna Del Principe, Toong Seng Tan, Melanie Lancien, Alessia Neri, Libera Sessa, Giulio Olivieri, Kailey Shapiro, Isabelle Roseto, Catherine Koofhethile, Elena Emili, Stefania Bernardi, Ann Chahroudi, Paolo Rossi, Bruce D Walker, Xu G Yu, Mathias Lichterfeld, Paolo Palma","doi":"10.1016/j.xcrm.2025.102150","DOIUrl":"10.1016/j.xcrm.2025.102150","url":null,"abstract":"<p><p>Early initiation of antiretroviral therapy (ART) following HIV-1 infection restricts the size of the latent reservoir, following both horizontal and vertical infections. Here, we comprehensively profile the reservoirs and immunological milieus of nine young adults who acquired HIV-1 perinatally and remained on suppressive long-term ART (median: 20 years) since infancy (LeukoHIV cohort). Genome-intact reservoirs are markedly smaller compared to a cohort of adults on suppressive ART started in adulthood, with some LeukoHIV individuals characterized by an absence or near absence of intact proviruses in up to a billion peripheral blood mononuclear cells (PBMCs). Higher frequencies of functional CD56<sup>bright</sup> natural killer (NK) cells with increased cytotoxic activity are detectable in the LeukoHIV cohort compared to an adult reference cohort, while one LeukoHIV participant displayed a potent HIV-1-specific CD8<sup>+</sup> T cell response. Collectively, our data suggest that long-term ART initiated in early life following perinatal transmission may facilitate an immune environment better equipped to restrict the HIV-1 reservoir.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102150"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186613","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":"Combined therapy with DR5-targeting antibody-drug conjugate and CDK inhibitors as a strategy for advanced colorectal cancer.","authors":"Dongdong Zhou, Er'jiang Tang, Wenjun Wang, Youban Xiao, Jianming Huang, Jie Liu, Chao Zheng, Kai Zhang, Ruxia Hu, Feiqi Wang, Peng Xiong, Xin Chu, Weisong Li, Dongqin Liu, Xiangfu Zeng, Dexian Zheng, Liefeng Wang, Yong Zheng, Shuyong Zhang","doi":"10.1016/j.xcrm.2025.102158","DOIUrl":"10.1016/j.xcrm.2025.102158","url":null,"abstract":"<p><p>Targeted therapies for advanced microsatellite stable (MSS) subtype colorectal cancer (MSS-CRC) remain a clinical challenge. Here, we show that death receptor 5 (DR5) is elevated in both MSS and microsatellite instability-high (MSI-H) colorectal cancer (CRC) cohorts, highlighting its potential as a clinical target. Oba01, a clinical-stage DR5-targeting antibody-drug conjugate (ADC) delivering the microtubule-disrupting agent monomethyl auristatin E (MMAE), shows superior efficacy in CRC cell lines, patient-derived xenografts and their corresponding organoids, irrespective of MSS or MSI-H status. Importantly, our functional multi-omics analysis reveals that the cell cycle pathway and cyclin-dependent kinases (CDKs) are key synergistic targets of Oba01's tumor-killing activity. We further show that Oba01 synergizes with the Food and Drug Administration (FDA)-approved CDK inhibitor abemaciclib in clinically relevant in vivo models. This synergy is also observed with other CDK inhibitors, underscoring the potential of combining Oba01 with CDK inhibition as a therapeutic strategy for advanced CRC, particularly the refractory MSS subtype.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102158"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191582","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":"Toward general text-guided multimodal brain MRI synthesis for diagnosis and medical image analysis.","authors":"Yulin Wang, Honglin Xiong, Kaicong Sun, Shuwei Bai, Ling Dai, Zhongxiang Ding, Jiameng Liu, Qian Wang, Qian Liu, Dinggang Shen","doi":"10.1016/j.xcrm.2025.102182","DOIUrl":"10.1016/j.xcrm.2025.102182","url":null,"abstract":"<p><p>Multimodal brain magnetic resonance imaging (MRI) offers complementary insights into brain structure and function, thereby improving the diagnostic accuracy of neurological disorders and advancing brain-related research. However, the widespread applicability of MRI is substantially limited by restricted scanner accessibility and prolonged acquisition times. Here, we present TUMSyn, a text-guided universal MRI synthesis model capable of generating brain MRI specified by textual imaging metadata from routinely acquired scans. We ensure the reliability of TUMSyn by constructing a brain MRI database comprising 31,407 3D images across 7 MRI modalities from 13 worldwide centers and pre-training an MRI-specific text encoder to process text prompts effectively. Experiments on diverse datasets and physician assessments indicate that TUMSyn-generated images can be utilized along with acquired MRI scan(s) to facilitate large-scale MRI-based screening and diagnosis of multiple brain diseases, substantially reducing the time and cost of MRI in the healthcare system.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102182"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265440","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 : 2025-06-17Epub Date: 2025-05-07DOI: 10.1016/j.xcrm.2025.102125
Sobuj Mia, Georgios Siokatas, Rafailia Sidiropoulou, Matthew Hoffman, Konstantinos Fragkiadakis, Eftychia Markopoulou, Mahmoud I Elesawy, Rajika Roy, Scott Blair, Yasuhide Kuwabara, Erjola Rapushi, Dipayan Chaudhuri, Catherine A Makarewich, Erhe Gao, Walter J Koch, Joel D Schilling, Jeffery D Molkentin, Maria Marketou, Konstantinos Drosatos
{"title":"Hepato-cardiac interorgan communication controls cardiac hypertrophy via combined endocrine-autocrine FGF21 signaling.","authors":"Sobuj Mia, Georgios Siokatas, Rafailia Sidiropoulou, Matthew Hoffman, Konstantinos Fragkiadakis, Eftychia Markopoulou, Mahmoud I Elesawy, Rajika Roy, Scott Blair, Yasuhide Kuwabara, Erjola Rapushi, Dipayan Chaudhuri, Catherine A Makarewich, Erhe Gao, Walter J Koch, Joel D Schilling, Jeffery D Molkentin, Maria Marketou, Konstantinos Drosatos","doi":"10.1016/j.xcrm.2025.102125","DOIUrl":"10.1016/j.xcrm.2025.102125","url":null,"abstract":"<p><p>Fibroblast growth factor (FGF) 21 is a hormone produced mainly by the liver but also other organs, including the heart. Although FGF21 analogs are used for treating obesity and metabolic syndrome in humans, preclinical and clinical studies have elicited mixed results about whether prolonged FGF21 signaling is protective or detrimental for cardiac function. Based on our findings, showing elevated serum and cardiac FGF21 levels in humans with increased left ventricular afterload, we explore the involvement of FGF21 in cardiac hypertrophy. Our mouse studies reveal interorgan liver-heart crosstalk, which is controlled by an initial hepatic FGF21 release followed by the induction of cardiomyocyte (CM) FGF21 expression. Tissue-specific genetic ablation or anti-sense oligonucleotide-based inhibition of FGF21 shows that, in response to pressure overload, CM FGF21 upregulation is a critical event that is stimulated by liver-derived FGF21 and drives cardiac hypertrophy likely by interfering with cardioprotective oxytocin signaling. Conclusively, the hepato-cardiac FGF21-based signaling axis governs cardiac hypertrophy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102125"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955632","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 : 2025-06-17Epub Date: 2025-06-03DOI: 10.1016/j.xcrm.2025.102141
Lucas Blanchard, Estefania Vina, Jerko Ljubetic, Cécile Meneur, Dorian Tarroux, Maria Baez, Alessandra Marino, Nathalie Ortega, David A Knorr, Jeffrey V Ravetch, Jean-Philippe Girard
{"title":"Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade.","authors":"Lucas Blanchard, Estefania Vina, Jerko Ljubetic, Cécile Meneur, Dorian Tarroux, Maria Baez, Alessandra Marino, Nathalie Ortega, David A Knorr, Jeffrey V Ravetch, Jean-Philippe Girard","doi":"10.1016/j.xcrm.2025.102141","DOIUrl":"10.1016/j.xcrm.2025.102141","url":null,"abstract":"<p><p>The lack of T cells in tumors is a major hurdle to successful immune checkpoint therapy (ICT). Therefore, therapeutic strategies promoting T cell recruitment into tumors are warranted to improve the treatment efficacy. Here, we report that Fc-optimized anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies are potent remodelers of tumor vasculature that increase tumor-associated high endothelial venules (TA-HEVs), specialized blood vessels supporting lymphocyte entry into tumors. Mechanistically, this effect is dependent on the Fc domain of anti-CTLA-4 antibodies and CD4<sup>+</sup> T cells and involves interferon gamma (IFNγ). Unexpectedly, we find that the human anti-CTLA-4 antibody ipilimumab fails to increase TA-HEVs in a humanized mouse model. However, increasing its Fc effector function rescues the modulation of TA-HEVs, promotes CD4<sup>+</sup> and CD8<sup>+</sup> T cell infiltration into tumors, and sensitizes recalcitrant tumors to programmed cell death protein 1 (PD-1) blockade. Our findings suggest that Fc-optimized anti-CTLA-4 antibodies could be used to reprogram tumor vasculature in poorly immunogenic cold tumors and improve the efficacy of ICT.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102141"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215048","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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