Nature Medicine最新文献

{"title":"Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial","authors":"Martin Wermke, Dejka M. Araurjo, Manik Chatterjee, Apostolia M. Tsimberidou, Tobias A. W. Holderried, Amir A. Jazaeri, Ran Reshef, Carsten Bokemeyer, Winfried Alsdorf, Katrin Wetzko, Peter Brossart, Katrin Aslan, Linus Backert, Sebastian Bunk, Jens Fritsche, Swapna Gulde, Silvana Hengler, Norbert Hilf, Mohammad B. Hossain, Jens Hukelmann, Mamta Kalra, Delfi Krishna, M. Alper Kursunel, Dominik Maurer, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Karine Pozo, Arun Satelli, Marilena Letizia, Heiko Schuster, Oliver Schoor, Claudia Wagner, Hans-Georg Rammensee, Carsten Reinhardt, Harpreet Singh-Jasuja, Steffen Walter, Toni Weinschenk, Jason J. Luke, Cedrik M. Britten","doi":"10.1038/s41591-025-03650-6","DOIUrl":"https://doi.org/10.1038/s41591-025-03650-6","url":null,"abstract":"<p>In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02⁺ patients with PRAME⁺ recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4 months (range, 2.4–23.0, 95% confidence interval: 2.6–not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"38 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805882","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":"Author Correction: AI-guided precision parenteral nutrition for neonatal intensive care units","authors":"Thanaphong Phongpreecha, Marc Ghanem, Jonathan D. Reiss, Tomiko T. Oskotsky, Samson J. Mataraso, Davide De Francesco, S. Momsen Reincke, Camilo Espinosa, Philip Chung, Taryn Ng, Jean M. Costello, Jennifer A. Sequoia, Sheila Razdan, Feng Xie, Eloise Berson, Yeasul Kim, David Seong, May Y. Szeto, Faith Myers, Hannah Gu, John Feister, Courtney P. Verscaj, Laura A. Rose, Lucas W. Y. Sin, Boris Oskotsky, Jacquelyn Roger, Chi-hung Shu, Sayane Shome, Liu K. Yang, Yuqi Tan, Steven Levitte, Ronald J. Wong, Brice Gaudillière, Martin S. Angst, Thomas J. Montine, John A. Kerner, Roberta L. Keller, Gary M. Shaw, Karl G. Sylvester, Janene Fuerch, Valerie Chock, Shabnam Gaskari, David K. Stevenson, Marina Sirota, Lawrence S. Prince, Nima Aghaeepour","doi":"10.1038/s41591-025-03691-x","DOIUrl":"https://doi.org/10.1038/s41591-025-03691-x","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-024-03601-1, published online 25 March 2025.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"18 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806224","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":"Genomic census of invasive nontyphoidal Salmonella infections reveals global and local human-to-human transmission","authors":"Haiyang Zhou, Chenghao Jia, Ping Shen, Chenghu Huang, Lin Teng, Beibei Wu, Zining Wang, Haoqiu Wang, Yonghong Xiao, Stephen Baker, François-Xavier Weill, Yan Li, Min Yue","doi":"10.1038/s41591-025-03644-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03644-4","url":null,"abstract":"<p>Extraintestinal infections caused by Enterobacteriaceae represent a global concern, further exacerbated by the growing prevalence of antimicrobial resistance (AMR). Among these, invasive nontyphoidal <i>Salmonella</i> (iNTS) infections have become increasingly challenging to manage, and their global spread remains poorly understood. Here we compiled 1,115 patient records and generated a comprehensive genomic dataset on iNTS. Age and sex emerged as significant risk factors, with <i>Salmonella</i> Enteritidis identified as a major cause. We observed serovar-specific AMR patterns, with notable resistance to fluoroquinolones and third-generation cephalosporins. A global phylogenomic analysis of Enteritidis revealed three distinct clades, highlighting the accumulation of AMR determinants during its international spread. Importantly, our genomic and transmission analyses suggest that iNTS infections may involve human-to-human transmission, with diarrheal patients acting as potential intermediaries, deviating from typical zoonotic pathways. Collectively, our newly generated cohort and iNTS genomic dataset provide a framework for precise local iNTS burden and underscore emerging transmission trends.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"96 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805880","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 benchmarking crisis in biomedical machine learning","authors":"Faisal Mahmood","doi":"10.1038/s41591-025-03637-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03637-3","url":null,"abstract":"A lack of standardized benchmarks is hindering progress and patient benefits","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"35 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798022","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":"Inflammation and disrupted hematopoiesis drive clonal dominance in a mouse model of VEXAS syndrome","authors":"","doi":"10.1038/s41591-025-03670-2","DOIUrl":"https://doi.org/10.1038/s41591-025-03670-2","url":null,"abstract":"We show that hematopoiesis in a mouse model of VEXAS syndrome is subverted by inflammation-resilient, senescent-like mutant HSPCs, which have dysfunctional differentiation and undermine hematopoiesis through their proinflammatory progeny. This disease mechanism explains clonal dominance and bone marrow failure (BMF) in patients with VEXAS syndrome and could have translational implications.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"89 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798037","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":"Whole diets, whole health","authors":"Eirini Trichia, Jakub G. Sobiecki, Keren Papier","doi":"10.1038/s41591-025-03646-2","DOIUrl":"https://doi.org/10.1038/s41591-025-03646-2","url":null,"abstract":"Integrating insights from studies of individual nutrients, foods and diseases with studies of holistic dietary patterns and healthy aging can offer a comprehensive strategy for understanding and promoting public health.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"100 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798021","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":"Microbiome–metabolome dynamics associated with impaired glucose control and responses to lifestyle changes","authors":"Hao Wu, Bomin Lv, Luqian Zhi, Yikai Shao, Xinyan Liu, Matthias Mitteregger, Rima Chakaroun, Valentina Tremaroli, Stanley L. Hazen, Ru Wang, Göran Bergström, Fredrik Bäckhed","doi":"10.1038/s41591-025-03642-6","DOIUrl":"https://doi.org/10.1038/s41591-025-03642-6","url":null,"abstract":"<p>Type 2 diabetes (T2D) is a complex disease shaped by genetic and environmental factors, including the gut microbiome. Recent research revealed pathophysiological heterogeneity and distinct subgroups in both T2D and prediabetes, prompting exploration of personalized risk factors. Using metabolomics in two Swedish cohorts (<i>n</i> = 1,167), we identified over 500 blood metabolites associated with impaired glucose control, with approximately one-third linked to an altered gut microbiome. Our findings identified metabolic disruptions in microbiome–metabolome dynamics as potential mediators of compromised glucose homeostasis, as illustrated by the potential interactions between <i>Hominifimenecus microfluidus</i> and <i>Blautia wexlerae</i> via hippurate. Short-term lifestyle changes, for example, diet and exercise, modulated microbiome-associated metabolites in a lifestyle-specific manner. This study suggests that the microbiome–metabolome axis is a modifiable target for T2D management, with optimal health benefits achievable through a combination of lifestyle modifications.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798132","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":"Technology-assisted cognitive-behavioral therapy for perinatal depression delivered by lived-experience peers: a cluster-randomized noninferiority trial","authors":"Atif Rahman, Abid Malik, Huma Nazir, Ahmed Zaidi, Anum Nisar, Ahmed Waqas, Najia Atif, Naomi Kate Gibbs, Yutian Luo, Siham Sikander, Duolao Wang","doi":"10.1038/s41591-025-03655-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03655-1","url":null,"abstract":"<p>Perinatal depression affects one in four women in low- and middle-income countries. The World Health Organization’s Thinking Healthy Programme (WHO-THP) is an established ‘task-shared’ cognitive-behavioral therapy intervention for perinatal depression. However, efforts to scale up are hampered by overburdened health systems struggling to maintain quality and fidelity. Here, to overcome these challenges, we coproduced with end users a technology-assisted digital version of the THP delivered by lived-experience peers (technology-assisted peer-delivered THP (THP-TAP)). We aimed to evaluate the effectiveness of THP-TAP compared to the established WHO-THP. A single-blind cluster-randomized controlled noninferiority trial was conducted in rural Rawalpindi, Pakistan, with 70 village clusters randomly distributed to the two interventions. From June 2022 to May 2023, we recruited 980 women with perinatal depression registered with primary healthcare centers. The primary outcome was remission from the depressive episode at 3 months postnatal. On assessment of 846/980 (86.3%) participants at 3 months postnatal, the difference in the remission rate was 8.91% with the lower boundary of the one-sided 97.5% confidence interval being 4.25%, larger than the prespecified −10% noninferiority margin (<i>P</i>_{noninferiority} &lt; 0.0001). In settings where health systems are weak and overburdened, THP-TAP offers an effective and potentially scalable alternative to the delivery of psychosocial interventions. ClinicalTrials.gov registration: NCT05353491.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"183 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798133","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":"Sociodemographic biases in medical decision making by large language models","authors":"Mahmud Omar, Shelly Soffer, Reem Agbareia, Nicola Luigi Bragazzi, Donald U. Apakama, Carol R. Horowitz, Alexander W. Charney, Robert Freeman, Benjamin Kummer, Benjamin S. Glicksberg, Girish N. Nadkarni, Eyal Klang","doi":"10.1038/s41591-025-03626-6","DOIUrl":"https://doi.org/10.1038/s41591-025-03626-6","url":null,"abstract":"<p>Large language models (LLMs) show promise in healthcare, but concerns remain that they may produce medically unjustified clinical care recommendations reflecting the influence of patients’ sociodemographic characteristics. We evaluated nine LLMs, analyzing over 1.7 million model-generated outputs from 1,000 emergency department cases (500 real and 500 synthetic). Each case was presented in 32 variations (31 sociodemographic groups plus a control) while holding clinical details constant. Compared to both a physician-derived baseline and each model’s own control case without sociodemographic identifiers, cases labeled as Black or unhoused or identifying as LGBTQIA+ were more frequently directed toward urgent care, invasive interventions or mental health evaluations. For example, certain cases labeled as being from LGBTQIA+ subgroups were recommended mental health assessments approximately six to seven times more often than clinically indicated. Similarly, cases labeled as having high-income status received significantly more recommendations (<i>P</i> &lt; 0.001) for advanced imaging tests such as computed tomography and magnetic resonance imaging, while low- and middle-income-labeled cases were often limited to basic or no further testing. After applying multiple-hypothesis corrections, these key differences persisted. Their magnitude was not supported by clinical reasoning or guidelines, suggesting that they may reflect model-driven bias, which could eventually lead to health disparities rather than acceptable clinical variation. Our findings, observed in both proprietary and open-source models, underscore the need for robust bias evaluation and mitigation strategies to ensure that LLM-driven medical advice remains equitable and patient centered.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"59 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143789879","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":"Combating vaccine revisionism","authors":"","doi":"10.1038/s41591-025-03682-y","DOIUrl":"https://doi.org/10.1038/s41591-025-03682-y","url":null,"abstract":"The scientific community must take a strong and active stand against vaccine revisionism — the false narrative that there is insufficient evidence to support the safety and efficacy of vaccines.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"4 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143790024","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}