Cell Reports Medicine最新文献

{"title":"Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques.","authors":"Tiffany M Styles, Akil Akhtar, Chunyang Gu, Gabriele Neumann, Hiromi Muramatsu, Justine S McPartlan, Poulami Talukder, Derrik Gratz, Kasey Stokdyk, Hannah L Turner, James A Ferguson, Alesandra J Rodriguez, Madhumathi Loganathan, Benjamin Francis, Anass Abbad, Ghania Chikh, Ying K Tam, Zhaohui S Qin, Julianna Han, Juan Manuel Carreño, Andrew B Ward, Jasdave S Chahal, Christian W Mandl, Norbert Pardi, Yoshihiro Kawaoka, Florian Krammer, Rafi Ahmed, Rama R Amara","doi":"10.1016/j.xcrm.2025.102369","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102369","url":null,"abstract":"<p><p>A universal influenza vaccine that elicits a strong and lasting stalk-specific antibody response is advantageous. We utilize nucleoside-modified mRNA in lipid nanoparticles (mRNA-LNP) and unmodified self-amplifying mRNA in modified dendritic nanoparticles (sam-MDNP), expressing chimeric hemagglutinin (cHA) antigens to induce stalk-specific humoral immunity in non-human primates with pre-existing influenza virus immunity. mRNA-LNP immunization induces strong stalk-specific binding antibodies capable of protecting mice from lethal heterologous influenza virus challenges and bone marrow plasma cells (BMPCs) that persist for up to 8 months. sam-MDNP vaccine induces lower humoral immunity, despite showing strong innate activation. Transcriptomic and cytokine analyses reveal a more persistent induction of interferon responses, interleukin (IL)-1β signaling, and IL-6 production in the mRNA-LNP group, correlating with the induction of serum antibody responses and BMPCs. These results identify a transcriptional signature associated with induction of BMPCs following mRNA vaccination and highlight the utility of cHA-based mRNA-LNP vaccines in inducing persistent stalk-directed protective antibody responses.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102369"},"PeriodicalIF":10.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173701","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":"Phocaeicola vulgatus induces immunotherapy resistance in hepatocellular carcinoma via reducing indoleacetic acid production.","authors":"Cai-Ning Zhao, Shan-Shan Li, Thomas Yau, Wen-Qi Chen, Ren Ji, Xin-Yuan Guan, Feng-Ming Spring Kong","doi":"10.1016/j.xcrm.2025.102370","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102370","url":null,"abstract":"<p><p>Immunotherapy has made remarkable achievements in various cancers, but response rates in hepatocellular carcinoma (HCC) remain highly variable. Understanding mechanisms behind this heterogeneity and identifying responsive patients are urgent clinical challenges. In this study, the metagenomic analysis of 65 HCC patients reveals distinct gut microbiota profiles distinguishing responders (Rs) from non-responders (NRs). These findings are further validated through fecal microbiota transplantation (FMT) in mouse models. Notably, Phocaeicola vulgatus (P. vulgatus) is enriched in NRs and diminishes anti-PD-1 efficacy in both syngeneic and orthotopic tumor models. Mechanistically, P. vulgatus suppresses the production of indoleacetic acid (IAA), thereby weakening interferon (IFN)-γ⁺ and granzyme B (GzmB)⁺CD8⁺ T cells and impairing the antitumor immune response. Furthermore, supplementation with IAA restores CD8⁺ T cell cytotoxicity and counteracts the immune-suppressive effects of P. vulgatus. Our findings establish a causal relationship between P. vulgatus and anti-PD-1 resistance in HCC, highlighting IAA as a potential therapeutic target to enhance immunotherapy outcomes.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102370"},"PeriodicalIF":10.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173913","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":"Large language model as clinical decision support system augments medication safety in 16 clinical specialties.","authors":"Jasmine Chiat Ling Ong, Liyuan Jin, Kabilan Elangovan, Gilbert Yong San Lim, Daniel Yan Zheng Lim, Gerald Gui Ren Sng, Yu He Ke, Joshua Yi Min Tung, Ryan Jian Zhong, Christopher Ming Yao Koh, Keane Zhi Hao Lee, Xiang Chen, Jack Kian Ch'ng, Aung Than, Ken Junyang Goh, Chuan Poh Lim, Tat Ming Ng, Nan Liu, Daniel Shu Wei Ting","doi":"10.1016/j.xcrm.2025.102323","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102323","url":null,"abstract":"<p><p>Large language models (LLMs) have emerged as tools to support healthcare delivery, from automating tasks to aiding clinical decision-making. This study evaluated LLMs as alternative to rule-based alert systems, focusing on their ability to identify prescribing errors. This was designed as a prospective, cross-over, open-label study involving 91 error scenarios based on 40 clinical vignettes across 16 medical and surgical specialties. We developed and validated five LLM models using a retrieval-augmented generation framework. The best-performing model evaluated three different implementation strategies: LLM-based clinical decision support system (CDSS) alone, pharmacist plus LLM-based CDSS (co-pilot), and pharmacist alone. The co-pilot arm demonstrated the best performance with an accuracy of 61% (precision 0.57, recall 0.61, and F1 0.59). In detecting errors posing serious harm, the co-pilot mode increased accuracy by 1.5-fold over the pharmacist alone. Effective LLM integration for complex tasks like medication chart reviews can enhance healthcare professional performance, improving patient safety.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102323"},"PeriodicalIF":10.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147951","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":"The multiomics blueprint of the individual with the most extreme lifespan.","authors":"Eloy Santos-Pujol, Aleix Noguera-Castells, Marta Casado-Pelaez, Carlos A García-Prieto, Claudia Vasallo, Ignacio Campillo-Marcos, Carlos Quero-Dotor, Eva Crespo-García, Alberto Bueno-Costa, Fernando Setién, Gerardo Ferrer, Veronica Davalos, Elisabetta Mereu, Raquel Pluvinet, Carles Arribas, Carolina de la Torre, Francisco Villavicencio, Lauro Sumoy, Isabel Granada, Natalie S Coles, Pamela Acha, Francesc Solé, Mar Mallo, Caterina Mata, Sara Peregrina, Toni Gabaldón, Marc Llirós, Meritxell Pujolassos, Robert Carreras-Torres, Aleix Lluansí, Librado Jesús García-Gil, Xavier Aldeguer, Sara Samino, Pol Torné, Josep Ribalta, Montse Guardiola, Núria Amigó, Oscar Yanes, Paula Martínez, Raúl Sánchez-Vázquez, Maria A Blasco, Jose Oviedo, Bernardo Lemos, Julia Rius-Bonet, Marta Torrubiano, Marta Massip-Salcedo, Kamal A Khidir, Thong Huy Cao, Paulene A Quinn, Donald J L Jones, Salvador Macip, Eva Brigos-Barril, Mauricio Moldes, Fabio Barteri, Gerard Muntané, Hafid Laayouni, Arcadi Navarro, Manel Esteller","doi":"10.1016/j.xcrm.2025.102368","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102368","url":null,"abstract":"<p><p>Extreme human lifespan, exemplified by supercentenarians, presents a paradox in understanding aging: despite advanced age, they maintain relatively good health. To investigate this duality, we have performed a high-throughput multiomics study of the world's oldest living person, interrogating her genome, transcriptome, metabolome, proteome, microbiome, and epigenome, comparing the results with larger matched cohorts. The emerging picture highlights different pathways attributed to each process: the record-breaking advanced age is manifested by telomere attrition, abnormal B cell population, and clonal hematopoiesis, whereas absence of typical age-associated diseases is associated with rare European-population genetic variants, low inflammation levels, a rejuvenated bacteriome, and a younger epigenome. These findings provide a fresh look at human aging biology, suggesting biomarkers for healthy aging, and potential strategies to increase life expectancy. The extrapolation of our results to the general population will require larger cohorts and longitudinal prospective studies to design potential anti-aging interventions.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102368"},"PeriodicalIF":10.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148018","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":"Translating the science of care and cure for children with cancer.","authors":"Catherine G Lam, Aye Aye Khaing, Joyce Kambugu, Sanjeeva Gunasekera, Poonam Bagai, Carmen Salaverria, Mhamed Harif, Guillermo Chantada, Carlos Rodriguez-Galindo","doi":"10.1016/j.xcrm.2025.102366","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102366","url":null,"abstract":"<p><p>The past 50 years have seen great progress for children with cancer, and yet, this progress has been largely unreached for most children. We examine how global efforts aimed at spreading, scaling, and sustaining interventions to improve access, quality, and integration in systems and policies can transform the landscape.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102366"},"PeriodicalIF":10.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136835","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":"FLT3L-based drug conjugate effectively targets chemoresistant leukemia stem cells in acute myeloid leukemia.","authors":"Dengyang Zhang, Yao Guo, Zhiyong Peng, Yan Xiao, Zhiguang Chang, Liuting Yu, Yuming Zhao, Qi Zhang, Lingling Ma, Shuping Li, Chi-Kong Li, Kam Tong Leung, Zhizhuang Joe Zhao, Chun Chen, Yun Chen","doi":"10.1016/j.xcrm.2025.102365","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102365","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a heterogeneous malignancy with poor prognosis due to relapse and chemotherapy resistance. FLT3 mutations promote AML and predict adverse outcomes. As most AML cells express FLT3, it represents a promising therapeutic target. In this study, we develop FL-Fc-DM1, a FLT3-targeted conjugate linking FLT3 ligand-Fc to DM1. FL-Fc-DM1 demonstrates potent anti-leukemic activity in vitro, ex vivo, and in both cell line- and patient-derived xenograft models. Notably, it effectively targets cytarabine-resistant AML cells by promoting cell cycle entry and inducing apoptosis. FL-Fc-DM1 also significantly reduces functional leukemia stem cell frequency, as demonstrated by limiting dilution transplantation assays. The therapeutic efficacy can be further strengthened by BH3 mimetics. Importantly, toxicity assessments in a humanized mouse model show limited impact on normal human hematopoiesis at therapeutic doses. Our findings suggest that FL-Fc-DM1 is a promising candidate for AML treatment, even for cell cycle-arrested or slow-cycling chemo-resistant AML cells.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102365"},"PeriodicalIF":10.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102660","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":"Phenotypic heterogeneity of type 2 diabetes and risks of all-cause and cause-specific mortality.","authors":"Zixin Qiu, Frank Qian, Jun Liu, Rui Li, Hancheng Yu, Yue Wang, Xiao Zhang, Tingting Geng, Xuefeng Yu, Oscar H Franco, An Pan, Maigeng Zhou, Kai Huang, Gang Liu","doi":"10.1016/j.xcrm.2025.102367","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102367","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is a heterogeneous condition, but its phenotypic variation and links with mortality are unclear. We apply the discriminative dimensionality reduction with trees (DDRTree) algorithm to seven clinical variables in 10,091 adults with newly diagnosed T2D from a nationally representative Chinese cohort. Distinct mortality patterns are observed across phenotypes. Cardiovascular mortality is highest in the most hypertensive and obese individuals, while diabetic ketoacidosis/coma mortality is largely driven by the combination of hyperglycemia and dyslipidemia. Additionally, chronic obstructive pulmonary disease mortality is higher in those with elevated high-density lipoprotein (HDL) and total cholesterol levels. These patterns are similar in UK Biobank, though cardiovascular mortality is highest in those with dyslipidemia and obesity. Predictive models incorporating these variables show good performance and an online tool is provided for individual risk prediction. Overall, this study visualizes phenotypic variation in T2D and its impact on mortality, underscoring the need for personalized treatment strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102367"},"PeriodicalIF":10.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102693","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":"Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts.","authors":"Nao Nishida-Aoki, Songli Zhu, Marina Chan, Yuqi Kang, Maihi Fujita, Xiuyun Jiang, Maxwell McCabe, Joel M Vaz, Nancy E Davidson, Cyrus M Ghajar, Kirk Hansen, Alana L Welm, Venu G Pillarisetty, Taranjit S Gujral","doi":"10.1016/j.xcrm.2025.102357","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102357","url":null,"abstract":"<p><p>Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening results from conventional 2D cancer cell lines with 3D tumor tissues and find that, on average, three times more drugs are effective in 3D microtumors. We confirm the effectiveness of doramapimod, a compound that reduces microtumor viability and suppresses tumor growth in mouse models but has no effect on cancer cell growth in monolayers. Mechanistically, doramapimod targets DDR1/2 and MAPK12 kinases in cancer-associated fibroblasts (CAFs), decreasing extracellular matrix (ECM) production and enhancing interferon signaling. These kinases regulate ECM through GLI1 activity in CAFs, independently of canonical hedgehog signaling. Inhibiting the DDR1/2-MAPK12-GLI axis enhances the effectiveness of chemotherapy and immunotherapy in patient tumor slices and preclinical models. These findings highlight the importance of DDR1/2-MAPK12-GLI axis in CAF function and demonstrate the utility of 3D tissue models in identifying microenvironment-specific therapeutic targets.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102357"},"PeriodicalIF":10.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102713","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":"A phase 1 trial of APG-1387, an IAP antagonist, with nab-paclitaxel and gemcitabine in patients with refractory metastatic pancreatic cancer.","authors":"Si Shi, Jian Zhang, Rujiao Liu, Shuiping Gao, Jin Xu, Wei Wang, Miaoyan Wei, Jialin Li, Chen Liu, Xiaowu Xu, Wentao Pan, Xiaohong Tian, Lichuang Men, Hengbang Wang, Zhiyan Liang, Min Zhu, Dajun Yang, Yifan Zhai, XianJun Yu","doi":"10.1016/j.xcrm.2025.102364","DOIUrl":"https://doi.org/10.1016/j.xcrm.2025.102364","url":null,"abstract":"<p><p>Advanced pancreatic cancer presents dismal survival with limited effective, well-tolerated options beyond chemotherapy. This phase 1 trial evaluates the safety, tolerability, and efficacy of bivalent IAP antagonist APG-1387 with nab-paclitaxel and gemcitabine (AG) in patients failing or intolerant to standard care. In 28-day cycles, patients receive intravenous infusions of APG-1387 (20, 30, or 45 mg) on days 1, 8, 15, and 22, and nab-paclitaxel (125 mg/m²) and gemcitabine (1,000 mg/m²) on days 1, 8, and 15, with dose-limiting toxicity (DLT) as the primary endpoint per NCI CTCAE v5.0. Of 28 screened, 21 are enrolled; one grade 4 DLT recovers within 3 days, and 9 (42.9%) experience grade ≥3 treatment-related adverse events, mostly AG-related bone marrow toxicities. Among 15 efficacy-evaluable patients, 3 achieve partial responses, including 1 (33%) without prior AG. APG-1387 with AG demonstrates tolerability and encouraging posterior-line antitumor effects in AG-naive patients (NCT04643405).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102364"},"PeriodicalIF":10.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102684","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":"Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models.","authors":"Peyton C High, Zhengdong Liang, Cara Guernsey-Biddle, Shraddha Subramanian, Yueh-Ming Shyu, Adela M Aldana, Yukimatsu Toh, Kendra S Carmon","doi":"10.1016/j.xcrm.2025.102363","DOIUrl":"10.1016/j.xcrm.2025.102363","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains the second-leading cause of cancer-associated deaths, indicating an urgent need for improved therapeutic options. We previously generated antibody-drug conjugates (ADCs) targeting the cancer stem-like cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). However, tumor relapse due to LGR5 downregulation and suboptimal payload selection warrants strategies to improve ADC efficacy. Here, we report that cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody indicated for RAS^WT metastatic CRC, augments LGR5 expression independent of RAS/PIK3CA mutation status and promotes EGFR-LGR5 interactions. Furthermore, we describe the development of LGR5 ADCs incorporating a camptothecin-derived payload that is well tolerated and significantly inhibits tumor growth. Importantly, cetuximab in combination with LGR5 ADCs results in enhanced tumor inhibition or regression versus single-agent treatment and extends survival in RAS^MUT patient-derived xenografts. These findings support growing evidence that ADC combination therapies may be more effective than monotherapies and suggest a broader clinical use for cetuximab in treating RAS^MUT CRC.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102363"},"PeriodicalIF":10.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091214","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}