Nature Medicine最新文献

{"title":"Nivolumab plus chemotherapy or ipilimumab in gastroesophageal cancer: exploratory biomarker analyses of a randomized phase 3 trial","authors":"Kohei Shitara, Yelena Y. Janjigian, Jaffer Ajani, Markus Moehler, Jin Yao, Xuya Wang, Aparna Chhibber, Dimple Pandya, Lin Shen, Marcelo Garrido, Carlos Gallardo, Lucjan Wyrwicz, Kensei Yamaguchi, Tomasz Skoczylas, Arinilda Bragagnoli, Tianshu Liu, Michael Schenker, Patricio Yañez, Ruben Kowalyszyn, Michalis Karamouzis, Thomas Zander, Kynan Feeney, Elena Elimova, Parul Doshi, Mingshun Li, Ming Lei","doi":"10.1038/s41591-025-03575-0","DOIUrl":"https://doi.org/10.1038/s41591-025-03575-0","url":null,"abstract":"<p>First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein–Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"23 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569910","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":"Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease","authors":"Lynn van Olst, Brooke Simonton, Alex J. Edwards, Anne V. Forsyth, Jake Boles, Pouya Jamshidi, Thomas Watson, Nate Shepard, Talia Krainc, Benney MR Argue, Ziyang Zhang, Joshua Kuruvilla, Lily Camp, Mengwei Li, Hang Xu, Jeanette L. Norman, Joshua Cahan, Robert Vassar, Jinmiao Chen, Rudolph J. Castellani, James AR Nicoll, Delphine Boche, David Gate","doi":"10.1038/s41591-025-03574-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03574-1","url":null,"abstract":"<p>Alzheimer’s disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (<i>TREM2</i>) and apolipoprotein E (<i>APOE</i>) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"50 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561256","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":"Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: overall survival and exploratory analyses of the NRG GY018 phase 3 randomized trial","authors":"Ramez N. Eskander, Michael W. Sill, Lindsey Beffa, Richard G. Moore, Joanie M. Hope, Fernanda B. Musa, Robert S. Mannel, Mark S. Shahin, Guilherme H. Cantuaria, Eugenia Girda, Elizabeth Lokich, Juraj Kavecansky, Charles A. Leath, Lilian T. Gien, Emily M. Hinchcliff, Shashikant B. Lele, Lisa M. Landrum, Floor Backes, Roisin E. O’Cearbhaill, Tareq Al Baghdadi, Emily K. Hill, Premal H. Thaker, Veena S. John, Stephen Welch, Amanda N. Fader, Matthew A. Powell, Carol Aghajanian","doi":"10.1038/s41591-025-03566-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03566-1","url":null,"abstract":"<p>Historically, the treatment of patients with advanced stage or recurrent endometrial cancer included paclitaxel plus carboplatin. Immunotherapy in combination with chemotherapy resulted in improved clinical outcomes in several solid tumors. In the phase 3 NRG GY018 study, pembrolizumab plus chemotherapy significantly improved investigator-assessed progression-free survival (PFS; primary endpoint) versus placebo plus chemotherapy in patients with advanced/metastatic/recurrent endometrial cancer regardless of mismatch repair status. Here we report on key secondary endpoints and exploratory analyses. Patients were women ≥18 years old with newly diagnosed stage III or IVA endometrial cancer with measurable disease, or stage IVB or recurrent endometrial cancer with or without measurable disease. Patients (<i>n</i> = 810) were randomized (1:1) to pembrolizumab or placebo plus paclitaxel–carboplatin followed by maintenance pembrolizumab or placebo for up to 24 months. Overall survival was a secondary endpoint and PFS per RECIST v.1.1 by blinded independent central review was an exploratory endpoint. Overall survival data were immature; hazard ratios favored pembrolizumab (mismatch repair-proficient: 0.79 (0.53–1.17); 1-sided nominal <i>P</i> = 0.1157; mismatch repair-deficient: 0.55 (0.25–1.19); 1-sided nominal <i>P</i> = 0.0617). Hazard ratios (95% confidence intervals) for PFS per blinded independent central review favored pembrolizumab (mismatch repair-proficient: 0.64 (0.49–0.85); <i>P</i> = 0.0008; mismatch repair-deficient: 0.45 (0.27–0.73); <i>P</i> = 0.0005). These findings further support the use of pembrolizumab plus chemotherapy as first-line treatment for patients with advanced stage or recurrent endometrial cancer regardless of mismatch repair status. ClinicalTrials.gov identifier: NCT03914612.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"52 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545881","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":"Prediction of mental health risk in adolescents","authors":"Elliot D. Hill, Pratik Kashyap, Elizabeth Raffanello, Yun Wang, Terrie E. Moffitt, Avshalom Caspi, Matthew Engelhard, Jonathan Posner","doi":"10.1038/s41591-025-03560-7","DOIUrl":"https://doi.org/10.1038/s41591-025-03560-7","url":null,"abstract":"<p>Prospective prediction of mental health risk in adolescence can facilitate early preventive interventions. Here, using psychosocial questionnaires and neuroimaging measures from over 11,000 children in the Adolescent Brain and Cognitive Development Study, we trained neural network models to stratify general psychopathology risk. The model trained on current symptoms accurately predicted which participants would convert into the highest psychiatric illness risk group in the following year (area under the receiver operating characteristic curve = 0.84). The model trained solely on potential etiologies or disease mechanisms achieved an area under the receiver operating characteristic curve of 0.75 without relying on the child’s current symptom burden. Sleep disturbances emerged as the most influential predictor of high-risk status, surpassing adverse childhood experiences and family mental health history. Including neuroimaging measures did not enhance predictive performance. These findings suggest that artificial intelligence models trained on readily available psychosocial questionnaires can effectively predict future psychiatric risk while highlighting potential targets for intervention. This is a promising step toward artificial intelligence-based mental health screening for clinical decision support systems.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"40 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545882","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 new newborn screening","authors":"Wendy K. Chung","doi":"10.1038/s41591-025-03567-0","DOIUrl":"https://doi.org/10.1038/s41591-025-03567-0","url":null,"abstract":"DNA sequencing offers opportunities for enhancing and expanding newborn screening for treatable conditions that affect children; pilot studies will be critical to refining key parameters for scalability and optimal outcomes.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"40 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545850","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":"Leveraging implementation science in clinical trials of vaccines in the global south","authors":"Abdu A. Adamu, Duduzile Ndwandwe, Charles S. Wiysonge","doi":"10.1038/s41591-025-03546-5","DOIUrl":"https://doi.org/10.1038/s41591-025-03546-5","url":null,"abstract":"<p>Infectious diseases have a major impact on the global economy and politics, as exemplified by the COVID-19 pandemic, so investigational vaccines and immunization technologies often need to be rapidly developed and adopted for use in humans within the shortest possible time.</p><p>One way to achieve this is by proactively leveraging implementation science from the early stages of clinical development through to regulatory approval and clinical use. The need for implementation science applies to vaccines, as well as to innovations or technologies that can improve vaccination coverage, such as the microneedle patch¹, for which an early stage clinical trial in The Gambia has demonstrated safety and immunogenicity in delivering the vaccine against measles and rubella¹. There is always a risk in biomedical science that investigational products such as vaccines and immunization-related innovations become trapped in the chasm between research and practice. Implementation science, defined as “the scientific study of methods to promote the systematic uptake of research findings and other evidence-based practices into routine practice, and, hence, to improve the quality and effectiveness of health services”², emerged out of the need to shorten the know–do gaps of health interventions³. This field of study promotes a better understanding of context and how it affects implementation outcomes, and has several multidisciplinary and theory-informed frameworks and models for navigating multifaceted complex processes³. Although implementation science research has been mostly focused on the T3 phase (translation to practice) and T4 phase (translation to community) of the translational science continuum, it can also be applied in the early stages of a clinical trial in the T1 phase (translation to humans) and T2 phase (translation to patients) to improve successful and timely trial execution.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"194 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545880","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":"Smartwatch- and smartphone-based remote assessment of brain health and detection of mild cognitive impairment","authors":"Paul Monroe Butler,&nbsp;Jenny Yang,&nbsp;Roland Brown,&nbsp;Matt Hobbs,&nbsp;Andrew Becker,&nbsp;Joaquin Penalver-Andres,&nbsp;Philippe Syz,&nbsp;Sofia Muller,&nbsp;Gautier Cosne,&nbsp;Adrien Juraver,&nbsp;Han Hee Song,&nbsp;Paramita Saha-Chaudhuri,&nbsp;Daniel Roggen,&nbsp;Alf Scotland,&nbsp;Natalia Silveira,&nbsp;Gizem Demircioglu,&nbsp;Audrey Gabelle,&nbsp;Richard Hughes,&nbsp;Michael G. Erkkinen,&nbsp;Jessica B. Langbaum,&nbsp;Jennifer H. Lingler,&nbsp;Pamela Price,&nbsp;Yakeel T. Quiroz,&nbsp;Sharon J. Sha,&nbsp;Marty Sliwinski,&nbsp;Anton P. Porsteinsson,&nbsp;Rhoda Au,&nbsp;Matt T. Bianchi,&nbsp;Hanson Lenyoun,&nbsp;Hung Pham,&nbsp;Mithun Patel,&nbsp;Shibeshih Belachew","doi":"10.1038/s41591-024-03475-9","DOIUrl":"10.1038/s41591-024-03475-9","url":null,"abstract":"Consumer-grade mobile devices are used by billions worldwide. Their ubiquity provides opportunities to robustly capture everyday cognition. ‘Intuition’ was a remote observational study that enrolled 23,004 US adults, collecting 24 months of longitudinal multimodal data via their iPhones and Apple Watches using a custom research application that captured routine device use, self-reported health information and cognitive assessments. The study objectives were to classify mild cognitive impairment (MCI), characterize cognitive trajectories and develop tools to detect and track cognitive health at scale. The study addresses sources of bias in current cognitive health research, including limited representativeness (for example, racial/ethnic, geographic) and accuracy of cognitive measurement tools. We describe study design and provide baseline cohort characteristics. Next, we present foundational proof-of-concept MCI classification modeling results using interactive cognitive assessment data. Initial findings support the reliability and validity of remote MCI detection and the usefulness of such data in describing at-risk cognitive health trajectories in demographically diverse aging populations. ClinicalTrials.gov identifier: NCT05058950 . A study using iPhones and Apple Watches to track and analyze cognitive health over 18 months in more than 23,000 US adults demonstrates the feasibility of remote cognitive health monitoring and uncovers potential methods for early detection of cognitive decline.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 3","pages":"829-839"},"PeriodicalIF":58.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-024-03475-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538565","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":"Advancing clinical genomics with Middle Eastern and South Asian pangenomes","authors":"Nasna Nassir,&nbsp;Mohamed A. Almarri,&nbsp;Hosneara Akter,&nbsp;Hamda Hassan Khansaheb,&nbsp;K. M. Furkan Uddin,&nbsp;Ahmad Abou Tayoun,&nbsp;Stefan S. Du Plessis,&nbsp;Marc Haber,&nbsp;Alawi Alsheikh-Ali,&nbsp;Mohammed Uddin","doi":"10.1038/s41591-025-03544-7","DOIUrl":"10.1038/s41591-025-03544-7","url":null,"abstract":"The creation of pangenome references for the 2.5 billion people in the Middle East and South Asia will advance precision medicine and promote global health equity.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 3","pages":"725-727"},"PeriodicalIF":58.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-025-03544-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538467","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":"Endothelial cell-mediated risk of CAD could be used to target lipid-lowering therapy","authors":"","doi":"10.1038/s41591-025-03553-6","DOIUrl":"10.1038/s41591-025-03553-6","url":null,"abstract":"We developed an endothelial cell-specific polygenic risk score for coronary artery disease (CAD), which quantifies a currently immeasurable axis of CAD risk. This tool identifies patients who are more susceptible to LDL-C entering the cell wall and will benefit from aggressive lipid-lowering therapy, providing an opportunity to guide earlier and more-personalized preventive therapies.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 3","pages":"747-748"},"PeriodicalIF":58.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538563","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":"Task-sharing and telemedicine delivery of psychotherapy to treat perinatal depression: a pragmatic, noninferiority randomized trial","authors":"Daisy R. Singla, Richard K. Silver, Simone N. Vigod, Nour Schoueri-Mychasiw, J. Jo Kim, Laura M. La Porte, Paula Ravitz, Crystal E. Schiller, Andrea S. Lawson, Alex Kiss, Steven D. Hollon, Cindy-Lee Dennis, Tara S. Berenbaum, Holly A. Krohn, Jamie E. Gibori, Jaime Charlebois, David M. Clark, Ariel K. Dalfen, Wendy Davis, Bradley N. Gaynes, Molyn Leszcz, Sarah Rachel Katz, Kellie E. Murphy, John A. Naslund, Mae Lynn Reyes-Rodríguez, Alison M. Stuebe, Claire Zlobin, Benoit H. Mulsant, Vikram Patel, Samantha Meltzer-Brody","doi":"10.1038/s41591-024-03482-w","DOIUrl":"https://doi.org/10.1038/s41591-024-03482-w","url":null,"abstract":"<p>Task-sharing and telemedicine can increase access to effective psychotherapies. Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) is pragmatic, multisite, noninferiority, four-arm trial that tested the non-inferiority of provider (non-specialist vs. specialist providers) and modality (telemedicine vs. in-person) in delivering psychotherapy for perinatal depressive symptoms. Across three university-affiliated networks in the United States and Canada, pregnant and postpartum adult participants were randomized 1:1:1:1 to each arm (472 nonspecialist telemedicine, 145 nonspecialist in-person, 469 specialist telemedicine and 144 specialist in-person) and offered weekly behavioral activation treatment sessions. The primary outcome was depressive symptoms (Edinburgh Postnatal Depression Scale (EPDS)) and the secondary outcome was anxiety (Generalized Anxiety Disorder (GAD-7)) symptoms at 3 months post-randomization. Between 8 January 2020 and 4 October 2023, 1,230 participants were recruited. Noninferiority was met for the primary outcome comparing provider (EPDS: nonspecialist 9.27 (95% CI 8.85–9.70) versus specialist 8.91 (95% CI 8.49–9.33)) and modality (EPDS: telemedicine 9.15 (95% CI 8.79–9.50) versus in-person 8.92 (95% CI 8.39–9.45)) for both intention-to-treat and per protocol analyses. Noninferiority was also met for anxiety symptoms in both comparisons. There were no serious or adverse events related to the trial. This trial suggests compelling evidence for task-sharing and telemedicine to improve access to psychotherapies for perinatal depressive and anxiety symptoms. ClinicalTrials.gov NCT04153864</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"72 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532336","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}