Nicolas Huyghe, Elena Benidovskaya, Tariq Masoodi, Isabelle Sinapi, Astrid De Cuyper, Fazulur Vempalli, Simon Beyaert, Caroline Bouzin, Finoula Maestre Osorio, Luigi Ferraro, Nicolas van Baren, Raphaël Helaers, Pierre Goffette, Benoit Ghaye, Aline van Maanen, Marie-Laure Castella, Michele Ceccarelli, Davide Bedognetti, Jérôme Galon, Wouter R L Hendrickx, Javier Carrasco, Marc Van den Eynde
{"title":"Impact of the tumor immune contexture in microsatellite-stable metastatic colorectal cancer treated with avelumab, cetuximab, and irinotecan.","authors":"Nicolas Huyghe, Elena Benidovskaya, Tariq Masoodi, Isabelle Sinapi, Astrid De Cuyper, Fazulur Vempalli, Simon Beyaert, Caroline Bouzin, Finoula Maestre Osorio, Luigi Ferraro, Nicolas van Baren, Raphaël Helaers, Pierre Goffette, Benoit Ghaye, Aline van Maanen, Marie-Laure Castella, Michele Ceccarelli, Davide Bedognetti, Jérôme Galon, Wouter R L Hendrickx, Javier Carrasco, Marc Van den Eynde","doi":"10.1016/j.xcrm.2025.102201","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102201","url":null,"abstract":"<p><p>The treatment of patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) remains a significant clinical challenge. Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), induces immunogenic cell death, potentially synergizing with immune checkpoint inhibitors. The phase 2, proof-of-concept, single-arm AVETUXIRI trial (ClinicalTrials.gov: NCT03608046) evaluates the safety and efficacy of cetuximab, irinotecan (a topoisomerase I inhibitor), and avelumab (an anti-programmed cell death ligand 1 [PD-L1]) in 57 patients with RAS wild-type or mutated MSS mCRC refractory to chemotherapy and anti-EGFR mAbs. Exploratory objectives include investigating the tumor immune microenvironment within mCRC biopsies performed during the trial and correlating it with treatment activity. A manageable safety profile is observed. Although the overall efficacy endpoints are not met, biomarkers associated with clinical efficacy are identified. Patients exhibiting a high Immunoscore, strong cytotoxic and T cell proximity to tumor cells, and a high genetic immunoediting score within mCRC biopsies before treatment demonstrate significant therapeutic survival benefit, independent of RAS tumor mutation status.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102201"},"PeriodicalIF":11.7,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandria DeCarlo, Graham MacLeod, Carolina Fernandes da Silva, Li Qing Shen, Julija Povilaikaite, Madeline Deane, Lucas Aragao, Mariska Sie, Deborah Termini, Jonathan Magee, Brian Gudenas, Sneha Sukumaran, Frederic Charron, Richard Marcellus, Rima Al-Awar, Ahmed Aman, Denis Reynaud, Amarine Trolat, Leanne Wybenga-Groot, Uri Tabori, Carolina Nör, Shane M Harding, Michael F Moran, Paul A Northcott, Peter Dirks, Stephane Angers, Vijay Ramaswamy
{"title":"Targeting synthetic lethality between non-homologous end joining and radiation in very-high-risk medulloblastoma.","authors":"Alexandria DeCarlo, Graham MacLeod, Carolina Fernandes da Silva, Li Qing Shen, Julija Povilaikaite, Madeline Deane, Lucas Aragao, Mariska Sie, Deborah Termini, Jonathan Magee, Brian Gudenas, Sneha Sukumaran, Frederic Charron, Richard Marcellus, Rima Al-Awar, Ahmed Aman, Denis Reynaud, Amarine Trolat, Leanne Wybenga-Groot, Uri Tabori, Carolina Nör, Shane M Harding, Michael F Moran, Paul A Northcott, Peter Dirks, Stephane Angers, Vijay Ramaswamy","doi":"10.1016/j.xcrm.2025.102202","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102202","url":null,"abstract":"<p><p>Specific and biologically informed treatments for medulloblastoma, especially for the highly lethal TP53-mutant SHH subgroup, remain elusive, where radiotherapy is the primary treatment modality. Leveraging genome-wide CRISPR-Cas9 dropout screening in combination with lethal doses of radiotherapy, we identify loss of p53 as the main driver of radiation resistance in SHH medulloblastoma. A negative-selection CRISPR-Cas9 screen across multiple models of Trp53-deficient SHH medulloblastoma reveals a strong synthetic lethal interaction between components of the non-homologous end-joining pathway and radiation, particularly DNA-dependent protein kinase (DNA-PK) and its binding partners. Both genetic and pharmacological perturbation of DNA-PK enhance radiosensitivity in TP53-deficient SHH medulloblastoma, leading to cell death. In vivo treatment of both somatic and germline TP53-mutant SHH medulloblastoma models with peposertib, a small-molecule inhibitor of DNA-PK, significantly improves survival when combined with radiotherapy, strongly supporting further clinical investigation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102202"},"PeriodicalIF":11.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"AI-powered digital probing improves periodontal disease diagnosis.","authors":"Jiamin Wu, James Kit Hon Tsoi","doi":"10.1016/j.xcrm.2025.102185","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102185","url":null,"abstract":"<p><p>Current periodontal disease diagnosis often relies on manual probing. Here, Tan et al. present PerioAI, an AI system combining intra-oral scans and cone-beam CT for automated, precise, and non-invasive periodontal assessment, enhancing early detection and guiding treatment without manual probing.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 6","pages":"102185"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Safety and efficacy of perioperative dual PD-1 and HER2 blockade in HER2-positive gastric cancer.","authors":"Run-Cong Nie, Xiao-Jiang Chen, Cheng-Cai Liang, Bai-Wei Zhao, Wei Wang, Fei-Yang Zhang, Mu-Yan Cai, Hai-Bo Qiu, Zhi-Cheng Xue, Guo-Ming Chen, Zhi-Min Liu, Jun Chi, Jin-Ling Duan, Dong-Sheng Zhang, Ying-Bo Chen, Zhi-Wei Zhou, Yong-Ming Chen, Shu-Qiang Yuan, Yuan-Fang Li","doi":"10.1016/j.xcrm.2025.102190","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102190","url":null,"abstract":"<p><p>The use of trastuzumab and programmed death-1 (PD-1) inhibitor is effective in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer; however, their use has not been investigated in patients with localized disease. This phase 2 trial evaluates the safety and efficacy of dual PD-1 (sintilimab) and HER2 blockade with chemotherapy in patients with resectable HER2-positive gastric and gastro-esophageal junction adenocarcinoma. 22 patients are enrolled, and 20 patients undergo surgery. The primary endpoint is achieved; 12 (55%, 95% confidence interval [CI]: 32-76) of 22 patients have a major pathological response, and 11 (50%, 95% CI: 28-72) of 22 patients achieve pathological complete response. The most common grade 3 treatment-related adverse events are neutropenia and thrombocytopenia. No treatment-related deaths occur. Transcriptomic analysis, bioinformatics analysis, and immunofluorescence staining demonstrate that regulatory T cells are associated with possibility of drug resistance. This study was registered at the Chinese Clinical Trial Registry (identifier: ChiCTR2200058732).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"6 6","pages":"102190"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-05-20DOI: 10.1016/j.xcrm.2025.102138
Pan Sun, Zhengbo He, Erwei Chu, Xiang Fan, Yue Cai, Guoyu Lan, Lin Liu, Dai Shi, Li Liang, Jie Yang, Anqi Li, Yalin Zhu, Xin Zhou, Lili Fang, Yiying Wang, Laihong Zhang, Zhen Liu, Ting Ma, Guanxun Cheng, Linsen Xu, Tengfei Guo
{"title":"White matter fractional anisotropy decreases precede hyperintensities in Alzheimer's disease.","authors":"Pan Sun, Zhengbo He, Erwei Chu, Xiang Fan, Yue Cai, Guoyu Lan, Lin Liu, Dai Shi, Li Liang, Jie Yang, Anqi Li, Yalin Zhu, Xin Zhou, Lili Fang, Yiying Wang, Laihong Zhang, Zhen Liu, Ting Ma, Guanxun Cheng, Linsen Xu, Tengfei Guo","doi":"10.1016/j.xcrm.2025.102138","DOIUrl":"10.1016/j.xcrm.2025.102138","url":null,"abstract":"<p><p>The associations of β-amyloid (Aβ) and tau deposition with white matter (WM) degeneration in Alzheimer's disease (AD) remain inadequately elucidated. We investigate baseline and longitudinal changes of microstructural fractional anisotropy (FA) and macrostructural white matter hyperintensities (WMHs) and their relationships with Aβ and tau positron emission tomography (PET) and vascular risk factors in different Aβ/tau stages defined by PET imaging. Lower levels and faster decline rates of FA occur in the AD continuum, particularly in tau-positive individuals. Tau-related FA decreases are correlated with higher burden and faster increase rates of WMH but not vice versa. These results are substantially replicated in an independent cohort. This study suggests that tau is tightly linked with microstructural WM degeneration, appearing earlier than macrostructural WM alteration in AD. Our findings provide valuable insights for detecting and monitoring early WM degeneration in AD, highlighting the importance of targeting tau clearance to maintain healthy WM integrity.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102138"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","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.2025.102145
Liangyu Bie, Chen Wei, Suxia Luo, Shuailei Dong, Zhiwei Gu, Yijie Ma, Qingxin Xia, He Zhang, Jing Li, Wenying Deng, Ning Li
{"title":"Benmelstobart plus anlotinib and chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: A phase 2 study.","authors":"Liangyu Bie, Chen Wei, Suxia Luo, Shuailei Dong, Zhiwei Gu, Yijie Ma, Qingxin Xia, He Zhang, Jing Li, Wenying Deng, Ning Li","doi":"10.1016/j.xcrm.2025.102145","DOIUrl":"10.1016/j.xcrm.2025.102145","url":null,"abstract":"<p><p>This phase 2 study investigates first-line benmelstobart plus anlotinib and chemotherapy in human epidermal growth factor receptor 2 (HER2)-negative unresectable locally advanced/metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Twenty-five eligible patients receive benmelstobart plus anlotinib and chemotherapy for 6 cycles, followed by benmelstobart and anlotinib maintenance. Of 24 patients with post-treatment imaging, objective response rate (ORR) is 75.0% (95% confidence interval [CI], 53.3%-90.2%; partial response [PR], 18 [75.0%]), and disease control rate (DCR) is 100.0%. The median duration of response (DoR) is 10.9 months. By the date cutoff, the median follow-up is 15.8 months. Median progression-free survival (PFS) and overall survival (OS) among all 25 patients are 10.3 and 18.2 months, respectively. Survival outcomes are not associated with programmed death-ligand 1 (PD-L1) expression. Lymphocytes, T cells, and CD3<sup>+</sup>CD8<sup>+</sup> T cells are enriched in patients with long-term response (PFS > 12 months). Most common grade ≥3 treatment-related adverse event (TRAE) is neutrophil count decreased (12%). This study shows promising efficacy and safety, representing a potential first-line option in patients with HER2-negative advanced G/GEJ cancer, regardless of PD-L1 expressions. The study was registered at ClinicalTrials.gov (NCT04891900).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102145"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-06-05DOI: 10.1016/j.xcrm.2025.102154
Eric J Jaehnig, Aranzazu Fernandez-Martinez, Tanmayi D Vashist, Matthew V Holt, LaTerrica Williams, Jonathan T Lei, Chang In Moon, Beom-Jun Kim, Yongchao Dou, Haoquan Zhao, Viktoriya Korchina, Richard A Gibbs, Donna Marie Muzny, Harshavardhan Doddapaneni, Charles M Perou, Lisa A Carey, Ana I Robles, Terry Hyslop, Yujia Wen, Linda McCart, Azra Krek, Francesca Petralia, George Miles, Shyam M Kavuri, Michael A Gillette, D R Mani, Steven A Carr, Bing Zhang, Matthew J Ellis, Shankha Satpathy, Meenakshi Anurag
{"title":"Proteogenomic analysis of the CALGB 40601 (Alliance) HER2+ breast cancer neoadjuvant trial reveals resistance biomarkers.","authors":"Eric J Jaehnig, Aranzazu Fernandez-Martinez, Tanmayi D Vashist, Matthew V Holt, LaTerrica Williams, Jonathan T Lei, Chang In Moon, Beom-Jun Kim, Yongchao Dou, Haoquan Zhao, Viktoriya Korchina, Richard A Gibbs, Donna Marie Muzny, Harshavardhan Doddapaneni, Charles M Perou, Lisa A Carey, Ana I Robles, Terry Hyslop, Yujia Wen, Linda McCart, Azra Krek, Francesca Petralia, George Miles, Shyam M Kavuri, Michael A Gillette, D R Mani, Steven A Carr, Bing Zhang, Matthew J Ellis, Shankha Satpathy, Meenakshi Anurag","doi":"10.1016/j.xcrm.2025.102154","DOIUrl":"10.1016/j.xcrm.2025.102154","url":null,"abstract":"<p><p>Proteogenomic analysis is applied to samples from the CALGB 40601 (Alliance) randomized neoadjuvant trial of trastuzumab, lapatinib, or the combination to identify biomarkers associated with pathological response status. Absence of ERBB2 gene amplification and human epidermal growth factor receptor 2 (HER2) protein overexpression by proteogenomics is associated with non-pathological compete response (pCR) (p < 0.05), highlighting potential false positives from standard diagnostics. Pathway analysis in proteogenomics-confirmed HER2+ samples identifies elevated epithelial-mesenchymal transition (EMT) and WNT-β-catenin signaling in non-pCR cases before treatment. Twenty-four pCR-associated proteins reproduce in a second proteomic dataset, and four (GPRC5A, TPBG, SP140L, and NEU1) are significant in a third. A meta-analysis of ten diverse neoadjuvant anti-HER2 treatment regimens from four independent studies confirms that non-pCR cases express higher levels of mRNA for G protein-coupled receptor class C group 5 member A (GPRC5A, p = 0.0002) and trophoblast glycoprotein (TPBG, p = 0.00008). Thus, proteogenomic analysis identifies negative biomarkers for pCR and alternative plasma membrane targets for treatment-resistant HER2+ breast cancer. This trial is registered at clinicaltrials.gov (NCT00770809).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102154"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziwei Zhou, Si Chen, Jianli Zhao, Xin Du, Haibin Yin, Chao Zhou, Hai Hu, Yunfang Yu, Yinghua Zhu, Herui Yao
{"title":"EGFR TKIs suppress MUC1 glycosylation through the PI3K/AKT/SP1/C1GALT1 pathway to enhance TnMUC1 CAR-T efficacy in EGFR-mutant NSCLC.","authors":"Ziwei Zhou, Si Chen, Jianli Zhao, Xin Du, Haibin Yin, Chao Zhou, Hai Hu, Yunfang Yu, Yinghua Zhu, Herui Yao","doi":"10.1016/j.xcrm.2025.102199","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102199","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for EGFR-mutant cancer (non-small cell lung cancer [NSCLC]), achieving an objective response rate (ORR) of approximately 60%-70%. However, optimizing their therapeutic efficacy remains a challenge. NSCLC cells express the tumor-specific hypoglycosylated Thomsen-nouvelle (Tn) mucin 1 (MUC1) antigen, making them suitable targets for TnMUC1 chimeric antigen receptor (CAR)-T cell therapy. This study shows that EGFR TKIs enhance the efficacy of TnMUC1 CAR-T cell therapy in EGFR-mutant NSCLC, both in vitro and in vivo. EGFR TKIs upregulate TnMUC1 by reducing MUC1 glycosylation, thereby improving TnMUC1 CAR-T cell recognition and cytotoxicity. Specifically, EGFR TKIs modulate TnMUC1-related glycosyltransferases, with core1-beta1,3-galactosyltransferase 1 (C1GALT1) identified as a key enzyme downregulated by EGFR TKIs, suggesting C1GALT1 as a potential therapeutic target.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102199"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-05-23DOI: 10.1016/j.xcrm.2025.102143
Eugenia Li Ling Yeo, Boon Hao Hong, Shi Hui Tay, Jialing Neo, Enya Hui Wen Ong, Wen Min Chow, Kah Min Tan, Kar Perng Low, Adelene Yen Ling Sim, Tianzhu Lu, Xin Zhang, Luo Huang, Janice Ser Huey Tan, Joseph Tien Seng Wee, Yoke Lim Soong, Kam Weng Fong, Terence Wee Kiat Tan, Sze Yarn Sin, Xin Xiu Sam, Jacqueline Siok Gek Hwang, Tony Kiat Hon Lim, Jia-Ying Joey Lee, Lit-Hsin Loo, Khee Chee Soo, Narayanan Gopalakrishna Iyer, Kwok Seng Loh, Joshua K Tay, Jianjun Liu, Mei Kim Ang, Joe Poh Sheng Yeong, Jin Xin Bei, Sze Huey Tan, Darren Wan Teck Lim, Melvin Lee Kiang Chua
{"title":"Tumor immune microenvironment delineates progression trajectories of distinct nasopharyngeal carcinoma phenotypes.","authors":"Eugenia Li Ling Yeo, Boon Hao Hong, Shi Hui Tay, Jialing Neo, Enya Hui Wen Ong, Wen Min Chow, Kah Min Tan, Kar Perng Low, Adelene Yen Ling Sim, Tianzhu Lu, Xin Zhang, Luo Huang, Janice Ser Huey Tan, Joseph Tien Seng Wee, Yoke Lim Soong, Kam Weng Fong, Terence Wee Kiat Tan, Sze Yarn Sin, Xin Xiu Sam, Jacqueline Siok Gek Hwang, Tony Kiat Hon Lim, Jia-Ying Joey Lee, Lit-Hsin Loo, Khee Chee Soo, Narayanan Gopalakrishna Iyer, Kwok Seng Loh, Joshua K Tay, Jianjun Liu, Mei Kim Ang, Joe Poh Sheng Yeong, Jin Xin Bei, Sze Huey Tan, Darren Wan Teck Lim, Melvin Lee Kiang Chua","doi":"10.1016/j.xcrm.2025.102143","DOIUrl":"10.1016/j.xcrm.2025.102143","url":null,"abstract":"<p><p>We investigate the molecular landscape of locally advanced nasopharyngeal carcinoma (LA-NPC) subtypes: limited (L), ascending (A), descending (D), and ascending-descending (AD). Using a cohort of 994 patients, we perform germline and somatic whole-exome sequencing (WES), transcriptomic profiling, multiplex immunohistochemistry (mIHC), and spatial histopathological analyses of tumor whole-slide images (WSIs). Germline WES reveals the most variants in AD subtypes, but somatic WES shows no subtype-specific mutations. Transcriptomics reveals higher extracellular matrix (ECM) gene expression in A and AD subtypes and higher immune gene expression in D and AD subtypes, agreeing with deconvolution and mIHC. Tumor immune microenvironment (TIME) of node-negative (N0) and node-positive (N+) L subtypes, considered early nasopharyngeal carcinoma (NPC), resembles A and D subtypes, respectively, suggesting distinct evolutionary trajectories. Spatial WSI analyses identify the most immune-dense tumors among D subtypes and association of TIME with disease-free survival in AD subtypes. These findings highlight the TIME's role in LA-NPC progression and its potential impact on treatment strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102143"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2025-06-17Epub Date: 2025-05-28DOI: 10.1016/j.xcrm.2025.102151
Hao Zhu, Xiaoyu Tong, Nancy B Carlisle, Hua Xie, Corey J Keller, Desmond J Oathes, Feng Liu, Charles B Nemeroff, Gregory A Fonzo, Yu Zhang
{"title":"Contrastive functional connectivity defines neurophysiology-informed symptom dimensions in major depression.","authors":"Hao Zhu, Xiaoyu Tong, Nancy B Carlisle, Hua Xie, Corey J Keller, Desmond J Oathes, Feng Liu, Charles B Nemeroff, Gregory A Fonzo, Yu Zhang","doi":"10.1016/j.xcrm.2025.102151","DOIUrl":"10.1016/j.xcrm.2025.102151","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is highly heterogeneous, posing challenges for effective treatment due to complex interactions between clinical symptoms and neurobiological features. To address this, we apply contrastive principal-component analysis to fMRI-based resting-state functional connectivity, isolating disorder-specific variations by contrasting data from 233 MDD patients and 285 healthy controls. Subsequently, we use sparse canonical correlation analysis to identify two significant dimensions linking distinct brain circuits with clinical profiles. One dimension relates to an internalizing-externalizing symptom spectrum involving visual and limbic networks and is associated with cognitive task reaction times. The other dimension, linked to personality traits protective against depression (e.g., extraversion), is driven by dorsal attention network connections and correlates with cognitive control and psychomotor performance. This approach illuminates stable symptom dimensions and their neurophysiological underpinnings, aiding in precision phenotyping for MDD and supporting the development of targeted, individualized therapeutic strategies for mental health care.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102151"},"PeriodicalIF":11.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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