Cell Reports MedicinePub Date : 2025-05-20Epub Date: 2025-04-28DOI: 10.1016/j.xcrm.2025.102094
Michael M Halassa, Michael J Frank, Philippa Garety, Dost Ongur, Raag D Airan, Gerard Sanacora, Kafui Dzirasa, Sahil Suresh, Susan M Fitzpatrick, Douglas L Rothman
{"title":"Developing algorithmic psychiatry via multi-level spanning computational models.","authors":"Michael M Halassa, Michael J Frank, Philippa Garety, Dost Ongur, Raag D Airan, Gerard Sanacora, Kafui Dzirasa, Sahil Suresh, Susan M Fitzpatrick, Douglas L Rothman","doi":"10.1016/j.xcrm.2025.102094","DOIUrl":"10.1016/j.xcrm.2025.102094","url":null,"abstract":"<p><p>Modern psychiatry faces challenges in translating neurobiological insights into treatments for severe illnesses. The mid-20th century witnessed the rise of molecular mechanisms as pathophysiological and treatment models, with recent holistic proposals keeping this focus unaltered. In this perspective, we explore how psychiatry can utilize systems neuroscience to develop a vertically integrated understanding of brain function to inform treatment. Using schizophrenia as a case study, we discuss scale-related challenges faced by researchers studying molecules, circuits, networks, and cognition and clinicians operating within existing frameworks. We emphasize computation as a bridging language, with algorithmic models like hierarchical predictive processing offering explanatory potential for targeted interventions. Developing such models will not only facilitate new interventions but also optimize combining existing treatments by predicting their multi-level effects. We conclude with the prognosis that the future is bright, but that continued investment in research closely driven by clinical realities will be critical.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102094"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983812","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 : 2025-05-20Epub Date: 2025-04-24DOI: 10.1016/j.xcrm.2025.102091
Judith Wellens, Eva Vissers, Anaïs Dumoulin, Sien Hoekx, Julie Vanderstappen, Joke Verbeke, Roman Vangoitsenhoven, Muriel Derrien, Bram Verstockt, Marc Ferrante, Christophe Matthys, Jeroen Raes, Kristin Verbeke, Séverine Vermeire, João Sabino
{"title":"Cooking methods affect advanced glycation end products and lipid profiles: A randomized cross-over study in healthy subjects.","authors":"Judith Wellens, Eva Vissers, Anaïs Dumoulin, Sien Hoekx, Julie Vanderstappen, Joke Verbeke, Roman Vangoitsenhoven, Muriel Derrien, Bram Verstockt, Marc Ferrante, Christophe Matthys, Jeroen Raes, Kristin Verbeke, Séverine Vermeire, João Sabino","doi":"10.1016/j.xcrm.2025.102091","DOIUrl":"10.1016/j.xcrm.2025.102091","url":null,"abstract":"<p><p>Thermal treatments used in ultra-processed foods (UPFs) lead to advanced glycation end products (AGEs). UPFs and serum AGEs are associated with cardiometabolic disease. We explore differential cooking methods as a mechanistic link between UPFs and detrimental health outcomes through a randomized cross-over cooking method trial in healthy subjects using identical ingredients and a deep profiling analysis. We show that low-AGE-generating cooking methods such as boiling and steaming decrease serum AGEs, improve lipid profiles, and increase serum protein 4E-BP1. In contrast, high-AGE-generating cooking methods such as grilling and baking increase fecal butyrate. In sum, this suggests that low-AGE-generating cooking methods should be considered in cardiovascular risk prevention. Since current dietary guidelines focus on ingredients, but not cooking methods, our results suggest that culinary techniques should be considered as an important factor in cardiometabolic preventive strategies and future dietary trial design. This study was registered at ClinicalTrials.gov (NCT06547190).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102091"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955174","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 : 2025-05-20Epub Date: 2025-05-09DOI: 10.1016/j.xcrm.2025.102128
Pan Zhuang, Yuqi Wu, Jianxin Yao, Xiaohui Liu, Haoyin Liu, Xuzhi Wan, Wei Jia, Tao Wang, Yu Zhang, Jingjing Jiao
{"title":"Marine n-3 polyunsaturated fatty acids slow sleep impairment progression by regulating central circadian rhythms in type 2 diabetes.","authors":"Pan Zhuang, Yuqi Wu, Jianxin Yao, Xiaohui Liu, Haoyin Liu, Xuzhi Wan, Wei Jia, Tao Wang, Yu Zhang, Jingjing Jiao","doi":"10.1016/j.xcrm.2025.102128","DOIUrl":"10.1016/j.xcrm.2025.102128","url":null,"abstract":"<p><p>The role of marine n-3 polyunsaturated fatty acids (PUFAs) in promoting sleep has been proposed, yet their benefits for patients with type 2 diabetes (T2D) and the underlying molecular mechanisms remain poorly understood. In this study, we identify a significant association between habitual fish oil use and improved sleep quality in a cohort of 27,549 patients with T2D. A subsequent randomized controlled trial demonstrates that fish oil supplementation enhances sleep parameters in patients with T2D, accompanied by the upregulation of core circadian clock genes, including Clock, Bmal1, and Per2. In vitro, DHA and EPA restore the rhythmic oscillations of key clock genes in hypothalamic neurons disrupted by palmitic acid. Notably, n-3 PUFAs target RORα to regulate circadian clock oscillations and facilitate BMAL1 nuclear translocation. Collectively, our findings highlight the potential of marine n-3 PUFAs as a dietary intervention to improve sleep health in patients with T2D. This study was registered at ClinicalTrials.gov (NCT03708887).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102128"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978391","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 : 2025-05-20Epub Date: 2025-04-18DOI: 10.1016/j.xcrm.2025.102087
Alexander Hof, Max Landerer, Philipp Peitsmeyer, Ronja Herzog, Jens Alber, Maysam Ahdab, Felix Sebastian Nettersheim, Dennis Mehrkens, Simon Geißen, Simon Braumann, Henning Guthoff, Philipp von Stein, Harshal Nemade, Felix Simon Ruben Picard, Ramona Braun, Friedrich Felix Hoyer, Jens Claus Brüning, Alexander Pfeifer, Staffan Hildebrand, Holger Winkels, Stephan Baldus, Matti Adam, Jasper Schäkel, Martin Mollenhauer
{"title":"Myeloperoxidase impacts vascular function by altering perivascular adipocytes' secretome and phenotype in obesity.","authors":"Alexander Hof, Max Landerer, Philipp Peitsmeyer, Ronja Herzog, Jens Alber, Maysam Ahdab, Felix Sebastian Nettersheim, Dennis Mehrkens, Simon Geißen, Simon Braumann, Henning Guthoff, Philipp von Stein, Harshal Nemade, Felix Simon Ruben Picard, Ramona Braun, Friedrich Felix Hoyer, Jens Claus Brüning, Alexander Pfeifer, Staffan Hildebrand, Holger Winkels, Stephan Baldus, Matti Adam, Jasper Schäkel, Martin Mollenhauer","doi":"10.1016/j.xcrm.2025.102087","DOIUrl":"10.1016/j.xcrm.2025.102087","url":null,"abstract":"<p><p>Obesity, a main driver of cardiovascular morbidity, contributes to endothelial dysfunction and inflammation in adipose tissues. Perivascular adipose tissue (PVAT) surrounds arteries and influences vascular function. In obesity, immune cells, including myeloperoxidase (MPO)-releasing myeloid cells, accumulate in PVAT. In this study, we show MPO levels to correlate with body weight and endothelial function in obese patients (n = 33) and mice. In addition, MPO deficiency reduces immune cell frequency, enhances PVAT beiging via soluble guanylyl cyclase β1 (sGC-β1), and increases oxygen consumption in vivo. Further, nitrotyrosine formation and inflammatory cytokine release are attenuated in obese Mpo<sup>-/-</sup> mice. Mechanistically, adiponectin (APN) secretion improves endothelial function and reduces arterial stiffness. In vitro, MPO-treated human white adipocytes show lower APN and brown adipocyte marker expression but increased inflammation. Thus, MPO impairs vascular function via PVAT inflammation and suppression of vasoprotective mediators, making it a potential therapeutic target in obesity-related cardiovascular disease.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102087"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983289","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 : 2025-05-20Epub Date: 2025-05-01DOI: 10.1016/j.xcrm.2025.102101
Asbjørn Kjær, Nanna Kristjánsdóttir, Randi Istrup Juul, Iver Nordentoft, Karin Birkenkamp-Demtröder, Johanne Ahrenfeldt, Trine Strandgaard, Deema Radif, Darren Hodgson, Christopher Abbosh, Hugo J W L Aerts, Mads Agerbæk, Jørgen Bjerggaard Jensen, Nicolai J Birkbak, Lars Dyrskjøt
{"title":"Low T cell diversity associates with poor outcome in bladder cancer: A comprehensive longitudinal analysis of the T cell receptor repertoire.","authors":"Asbjørn Kjær, Nanna Kristjánsdóttir, Randi Istrup Juul, Iver Nordentoft, Karin Birkenkamp-Demtröder, Johanne Ahrenfeldt, Trine Strandgaard, Deema Radif, Darren Hodgson, Christopher Abbosh, Hugo J W L Aerts, Mads Agerbæk, Jørgen Bjerggaard Jensen, Nicolai J Birkbak, Lars Dyrskjøt","doi":"10.1016/j.xcrm.2025.102101","DOIUrl":"10.1016/j.xcrm.2025.102101","url":null,"abstract":"<p><p>T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. Here, we investigate the clinical relevance of the T cell receptor (TCR) repertoire in patients with bladder cancer. In advanced-stage disease, low pre-treatment peripheral TCR diversity is associated with worse overall survival (p = 0.024), particularly when coupled with low circulating T cell fractions (p = 0.00049). These low-diversity repertoires are dominated by hyper-expanded clones that persist throughout treatment. Further longitudinal analysis reveals reductions in TCR diversity after treatment, indicating adverse effects on the immune system. In early-stage disease, immunotherapy increases TCR diversity in patients with good outcomes. Furthermore, single-cell sequencing identifies most hyper-expanded clones as cytotoxic T cells, while non-expanded clones are predominantly naive T cells. Overall, this highlights TCR diversity as a promising biomarker, offering opportunities for tailored oncological treatments to enhance clinical outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102101"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983989","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":"MPXV infection activates cGAS-STING signaling and IFN-I treatment reduces pathogenicity of mpox in CAST/EiJ mice and rhesus macaques.","authors":"Lin Zhu, Qi Liu, Yongzhi Hou, Baoying Huang, Dong Zhang, Zhe Cong, Jianrong Ma, Na Li, Jiahan Lu, Jingjing Zhang, Lingyan Zhang, Ting Chen, Qiang Wei, Jiangning Liu, Wenjie Tan, Jing Xue","doi":"10.1016/j.xcrm.2025.102135","DOIUrl":"10.1016/j.xcrm.2025.102135","url":null,"abstract":"<p><p>The recent mpox outbreak underscores the urgent need for more accessible vaccines and treatments. However, the mpox virus (MPXV) clade IIb exhibits milder virulence and fails to develop typical pathological characteristics in mouse models. Herein, we found that CAST/EiJ mice infected intraperitoneally with MPXV clade IIb exhibited more efficient viral replication and experienced splenomegaly. Additionally, MPXV infection triggers the phosphorylation of stimulator of interferon genes (STING), TANK-binding kinase 1 (TBK1), and interferon regulatory factor 3 (IRF3) in ex vivo bone marrow-derived macrophages from mice and promotes the transcription of interferon (IFN)-β via the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-STING pathway. Notably, IFN-β treatment significantly reduced viral replication and alleviated splenomegaly in MPXV-infected CAST/EiJ mice. In rhesus macaques, the clinically approved pegylated IFN alpha-2b treatment markedly reduced the severity of MPXV infection by alleviating skin lesions and lowering plasma viremia. These findings demonstrate that MPXV clade IIb activates the cGAS-STING pathway and highlight the potential of type I interferon (IFN-I) treatment in CAST/EiJ mice and rhesus macaques for mpox.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 5","pages":"102135"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118987","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 : 2025-05-20Epub Date: 2025-05-01DOI: 10.1016/j.xcrm.2025.102095
Jenna J LaBelle, Rebecca D Haase, Alexander Beck, Jacob Haase, Li Jiang, Carlos Alberto Oliveira de Biagi, Sina Neyazi, Bernhard Englinger, Ilon Liu, Maria Trissal, Daeun Jeong, Olivia A Hack, Andrezza Nascimento, McKenzie L Shaw, Cuong M Nguyen, Sophia Castellani, Nathan D Mathewson, Orr Ashenberg, Gustavo Alencastro Veiga Cruzeiro, Tom Rosenberg, Jayne R Vogelzang, Jason Pyrdol, Sascha Marx, Adrienne M Luomo, Anze Godicelj, Alicia Baumgartner, Jacob S Rozowsky, Sibylle Madlener, Lisa Mayr, Andreas Peyrl, Rene Geyeregger, Daniela Loetsch, Christian Dorfer, Christine Haberler, Natalia Stepien, Irene Slavc, Tom Belle Davidson, Robert M Prins, Kee Kiat Yeo, Tabitha Cooney, Keith Ligon, Hart Lidov, Sanda Alexandrescu, Lissa C Baird, Johannes Gojo, Kai W Wucherpfennig, Mariella G Filbin
{"title":"Dissecting the immune landscape in pediatric high-grade glioma reveals cell state changes under therapeutic pressure.","authors":"Jenna J LaBelle, Rebecca D Haase, Alexander Beck, Jacob Haase, Li Jiang, Carlos Alberto Oliveira de Biagi, Sina Neyazi, Bernhard Englinger, Ilon Liu, Maria Trissal, Daeun Jeong, Olivia A Hack, Andrezza Nascimento, McKenzie L Shaw, Cuong M Nguyen, Sophia Castellani, Nathan D Mathewson, Orr Ashenberg, Gustavo Alencastro Veiga Cruzeiro, Tom Rosenberg, Jayne R Vogelzang, Jason Pyrdol, Sascha Marx, Adrienne M Luomo, Anze Godicelj, Alicia Baumgartner, Jacob S Rozowsky, Sibylle Madlener, Lisa Mayr, Andreas Peyrl, Rene Geyeregger, Daniela Loetsch, Christian Dorfer, Christine Haberler, Natalia Stepien, Irene Slavc, Tom Belle Davidson, Robert M Prins, Kee Kiat Yeo, Tabitha Cooney, Keith Ligon, Hart Lidov, Sanda Alexandrescu, Lissa C Baird, Johannes Gojo, Kai W Wucherpfennig, Mariella G Filbin","doi":"10.1016/j.xcrm.2025.102095","DOIUrl":"10.1016/j.xcrm.2025.102095","url":null,"abstract":"<p><p>Pediatric high-grade gliomas (pHGGs) are among the most lethal childhood tumors. While therapeutic approaches were largely adapted from adult treatment regime, significant biological differences between pediatric and adult gliomas exist, which influence the immune microenvironment and may contribute to the limited response to current pHGG treatment strategies. We provide a comprehensive transcriptomic analysis of the pHGG immune landscape using single-cell RNA sequencing and spatial transcriptomics. We analyze matched malignant, myeloid, and T cells from patients with pediatric diffuse high-grade glioma (HGG) or high-grade ependymoma, examining immune microenvironment distinctions after chemo-/radiotherapy, immune checkpoint inhibition treatment, and by age. Our analysis reveals differences in the proportions of pediatric myeloid subpopulations compared to adult counterparts. Additionally, we observe significant shifts toward immune-suppressive environments following cancer therapy. Our findings offer valuable insights into potential immunotherapy targets and serve as a robust resource for understanding immune microenvironmental variations across HGG age groups and treatment regimens.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102095"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978780","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 : 2025-05-20Epub Date: 2025-05-09DOI: 10.1016/j.xcrm.2025.102133
Patricia D B Tiburcio, Kenian Chen, Lin Xu, Kenneth S Chen
{"title":"Suppressing proteasome activity enhances sensitivity to actinomycin D in diffuse anaplastic Wilms tumor.","authors":"Patricia D B Tiburcio, Kenian Chen, Lin Xu, Kenneth S Chen","doi":"10.1016/j.xcrm.2025.102133","DOIUrl":"10.1016/j.xcrm.2025.102133","url":null,"abstract":"<p><p>Wilms tumor is the most common pediatric kidney cancer, and diffuse anaplastic Wilms tumor is the most chemoresistant subtype. Here, we explore how Wilms tumor cells evade the chemotherapy actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell-cycle progression. When ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components. Next, we find that the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment in vitro and prolongs survival in xenograft models. Lastly, increased levels of proteasome components are associated with anaplastic histology and worse prognosis in Wilms tumor patients. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102133"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960469","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 : 2025-05-20Epub Date: 2025-04-30DOI: 10.1016/j.xcrm.2025.102100
Juhyun Oh, Jan Hoelzl, Jonathan C T Carlson, Ruben Bill, Hannah M Peterson, William C Faquin, Mikael J Pittet, Sara I Pai, Ralph Weissleder
{"title":"Spatial analysis identifies DC niches as predictors of pembrolizumab therapy in head and neck squamous cell cancer.","authors":"Juhyun Oh, Jan Hoelzl, Jonathan C T Carlson, Ruben Bill, Hannah M Peterson, William C Faquin, Mikael J Pittet, Sara I Pai, Ralph Weissleder","doi":"10.1016/j.xcrm.2025.102100","DOIUrl":"10.1016/j.xcrm.2025.102100","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) shows variable response to anti-programmed cell death protein 1 (PD-1) therapy, which can be partially explained by a combined positive score (CPS) of tumor and immune cell expression of programmed death-ligand 1 (PD-L1) within the local tumor microenvironment (TME). To better define TME immune determinants associated with treatment efficacy, we conduct a study of n = 48 HNSCC tumors from patients prior to pembrolizumab therapy. Our investigation combines a rapid bioorthogonal multiplex staining method with computational analysis of whole-slide imaging to capture the single-cell spatial heterogeneity and complexity of the TME. Analyzing 6,316 fields of view (FOVs), we provide comprehensive PD-L1 phenotyping and cell proximity assays across the entirety of tissue sections. While none of the PD-L1 metrics adequately predict response, we find that the spatial organization of CCR7<sup>+</sup> dendritic cells (DCs) in niches better predicts overall patient survival than CPS alone. This study highlights the importance of understanding the spatial context of immune networks for immunotherapy.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102100"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967491","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 : 2025-05-20Epub Date: 2025-05-05DOI: 10.1016/j.xcrm.2025.102116
Zhenqi Zhou, Timothy M Moore, Alexander R Strumwasser, Vicent Ribas, Hirotaka Iwasaki, Noelle Morrow, Alice Ma, Peter H Tran, Jonathan Wanagat, Thomas Q de Aguiar Vallim, Bethan Clifford, Zhengyi Zhang, Tamer Sallam, Brian W Parks, Karen Reue, Orian Shirihai, Rebeca Acin-Perez, Marco Morselli, Matteo Pellegrini, Sushil K Mahata, Frode Norheim, Mingqi Zhou, Marcus M Seldin, Aldons J Lusis, Cathy C Lee, Mark O Goodarzi, Jerome I Rotter, Joshua R Hansen, Ben Drucker, Tyler J Sagendorf, Joshua N Adkins, James A Sanford, Francesco J DeMayo, Sylvia C Hewitt, Kenneth S Korach, Andrea L Hevener
{"title":"Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.","authors":"Zhenqi Zhou, Timothy M Moore, Alexander R Strumwasser, Vicent Ribas, Hirotaka Iwasaki, Noelle Morrow, Alice Ma, Peter H Tran, Jonathan Wanagat, Thomas Q de Aguiar Vallim, Bethan Clifford, Zhengyi Zhang, Tamer Sallam, Brian W Parks, Karen Reue, Orian Shirihai, Rebeca Acin-Perez, Marco Morselli, Matteo Pellegrini, Sushil K Mahata, Frode Norheim, Mingqi Zhou, Marcus M Seldin, Aldons J Lusis, Cathy C Lee, Mark O Goodarzi, Jerome I Rotter, Joshua R Hansen, Ben Drucker, Tyler J Sagendorf, Joshua N Adkins, James A Sanford, Francesco J DeMayo, Sylvia C Hewitt, Kenneth S Korach, Andrea L Hevener","doi":"10.1016/j.xcrm.2025.102116","DOIUrl":"10.1016/j.xcrm.2025.102116","url":null,"abstract":"<p><p>Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102116"},"PeriodicalIF":11.7,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062476","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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