Nature Medicine最新文献

{"title":"Assessing the risks of engineered T cells","authors":"","doi":"10.1038/s41591-025-03598-7","DOIUrl":"https://doi.org/10.1038/s41591-025-03598-7","url":null,"abstract":"The long-term safety of genetically modified T cells for therapeutic applications remains a crucial concern. A comprehensive analysis of 783 patients across multiple clinical trials, with >2,200 patient-years of follow-up, found no strong evidence linking these therapies to insertional oncogenesis.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"50 6 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582842","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 Rare Therapies Launchpad: a pilot program for individualized medicines in the UK","authors":"Daniel J. O’Connor, Parker Moss, Matthew Wood, Martin Murphy, Michael Parker, Nicola Blackwood, Matthew A. Brown, Deb Lancaster, Vanessa Newman, Jenny Taylor, Tim Yu, Julia Vitarello","doi":"10.1038/s41591-025-03547-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03547-4","url":null,"abstract":"<p>Twenty-first century technologies increasingly allow the identification and treatment of the underlying genetic causes of disease¹. Millions of children around the world are affected by rare diseases, some of which are caused by ‘private mutations’ that are so rare that they can often only be treated with individualized therapies². Disappointingly, these scientific breakthroughs have not yet led to an increase in the use of individualized medicines owing to regulatory, commercial and economic barriers to adoption^3,4,5,6. The Rare Therapies Launchpad (RTLP) is a UK pilot program set up to help identify sustainable and scalable approaches to address these barriers, to allow the establishment of an equitable and sustainable national infrastructure to ensure that UK children will benefit from the life-saving potential of cutting-edge science.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"77 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582841","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":"Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial","authors":"Raajit K. Rampal, Sebastian Grosicki, Dominik Chraniuk, Elisabetta Abruzzese, Prithviraj Bose, Aaron T. Gerds, Alessandro M. Vannucchi, Francesca Palandri, Sung-Eun Lee, Vikas Gupta, Alessandro Lucchesi, Stephen T. Oh, Andrew T. Kuykendall, Andrea Patriarca, Alberto Álvarez-Larrán, Ruben Mesa, Jean-Jacques Kiladjian, Moshe Talpaz, Joseph M. Scandura, David Lavie, Morgan Harris, Sarah-Katharina Kays, Qing Li, Rainer Boxhammer, Barbara Brown, Anna-Maria Jegg, Claire N. Harrison, John Mascarenhas","doi":"10.1038/s41591-025-03572-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03572-3","url":null,"abstract":"<p>Janus kinase (JAK) inhibitors provide limited depth and durability of response in myelofibrosis. We evaluated pelabresib—a bromodomain and extraterminal domain (BET) inhibitor—plus ruxolitinib (a JAK inhibitor) compared with placebo plus ruxolitinib as first-line therapy. In this phase 3 study (MANIFEST-2), JAK inhibitor-naive patients with myelofibrosis were randomized 1:1 to pelabresib 125 mg once daily (QD; 50–175 mg QD permitted) for 14 days followed by a 7-day break (21-day cycle), or to placebo in combination with ruxolitinib 10 or 15 mg twice daily (BID; 5 mg QD–25 mg BID permitted). Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24. Key secondary endpoints were absolute change in total symptom score (TSS) and TSS50 response (≥50% reduction in TSS from baseline at week 24). The primary endpoint was met in 65.9% of patients randomized to pelabresib–ruxolitinib (<i>n</i> = 214) versus 35.2% to placebo–ruxolitinib (<i>n</i> = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; <i>P</i> &lt; 0.001). Absolute change in TSS was −15.99 versus −14.05 (difference, −1.94; 95% CI, −3.92, 0.04; <i>P</i> = 0.0545) and TSS50 was achieved in 52.3% versus 46.3% (difference, 6.0%; 95 CI, −3.5, 15.5) with pelabresib–ruxolitinib versus placebo–ruxolitinib. Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination. Thrombocytopenia and anemia were the most common treatment-emergent adverse events, occurring in 52.8% (13.2% grade ≥3) versus 37.4% (6.1% grade ≥3) and 44.8% (23.1% grade ≥3) versus 55.1% (36.5% grade ≥3), respectively. Pelabresib in combination with ruxolitinib is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy. ClinicalTrials.gov identifier: NCT04603495.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"23 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582926","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":"Allogeneic mesenchymal stem cell therapy with laromestrocel in mild Alzheimer’s disease: a randomized controlled phase 2a trial","authors":"Brian G. Rash, Kevin N. Ramdas, Nataliya Agafonova, Eric Naioti, Lisa McClain-Moss, Zarin Zainul, Brittany Varnado, Kevin Peterson, Michael Brown, Thiago Leal, Steven Kopcho, Raul Carballosa, Paayal Patel, Mark Brody, Brad Herskowitz, Ana Fuquay, Savannah Rodriguez, Alan F. Jacobson, Ramon Leon, Michael Pfeffer, Julie B. Schwartzbard, Jeffrey Botbyl, Anthony A. Oliva, Joshua M. Hare","doi":"10.1038/s41591-025-03559-0","DOIUrl":"https://doi.org/10.1038/s41591-025-03559-0","url":null,"abstract":"<p>Alzheimer’s disease (AD) is characterized by progressive cognitive decline, severe brain atrophy and neuroinflammation. We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 2a clinical trial that tested the safety and efficacy of laromestrocel, a bone-marrow-derived, allogeneic mesenchymal stem-cell therapy, in slowing AD clinical progression, atrophy and neuroinflammation. Participants across ten centers in the United States were randomly assigned 1:1:1:1 to four infusion groups: group 1 (placebo; four monthly infusions, <i>n</i> = 12); group 2 (25 million cells, one infusion followed by three monthly infusions of placebo, <i>n</i> = 13); group 3 (25 million cells; four monthly doses, <i>n</i> = 13); and group 4 (100 million cells; four monthly doses, <i>n</i> = 11). The study met its primary end point of safety; the rate of treatment-emergent serious adverse events within 4 weeks of any infusion was similar in all four groups: group 1, 0% (95% CI 0–26.5%); group 2, 7.7% (95% CI 0.2–36%); group 3, 7.7% (95% CI 0.2–36%) and group 4, 9.1% (95% CI 0.2–41.3%). Additionally, there were no reported infusion-related reactions, hypersensitivities or amyloid-related imaging abnormalities. Laromestrocel improved clinical assessments at 39 weeks compared to placebo, as measured by a composite AD score (secondary end point was met: group 2 versus placebo change: 0.38; 95% CI −0.06–0.82), Montreal cognitive assessment and the Alzheimer’s Disease Cooperative Study Activities of Daily Living. At 39 weeks, Laromestrocel slowed the decline of whole brain volume compared to placebo (<i>n</i> = 10) by 48.4% for all treatment groups combined (groups 2–4: <i>P</i> = 0.005; <i>n</i> = 32) and left hippocampal volume by 61.9% (groups 2–4, <i>P</i> = 0.021; <i>n</i> = 32), and reduced neuroinflammation as measured by diffusion tensor imaging. The change in bilateral hippocampal atrophy correlated with the change in mini-mental state exam scores (<i>R</i> = 0.41, <i>P</i> = 0.0075) in all study patients (<i>N</i> = 42). Collectively these results support safety of single and multiple doses of laromestrocel treatment for mild AD and provide indications of efficacy in combating decline of brain volume and potentially cognitive function. Larger-scale clinical trials of laromestrocel in AD are warranted. ClinicalTrials.gov registration: NCT05233774.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"19 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582927","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":"Treating spinal muscular atrophy in the womb","authors":"","doi":"10.1038/d41591-025-00017-9","DOIUrl":"https://doi.org/10.1038/d41591-025-00017-9","url":null,"abstract":"An N-of-1 study suggests that prenatal therapy for spinal muscular atrophy — enabled by transplacental passage of risdiplam from mother to fetus — could help prevent symptom onset before birth.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"1 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143589654","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":"Jordan eliminates leprosy disease and moves to post-elimination surveillance","authors":"Vivek Lal,&nbsp;Supriya Warusavithana,&nbsp;Daniel Argaw Dagne,&nbsp;Jamela Al-Raiby,&nbsp;Subbanna Jonnalagada,&nbsp;Chinara Aidyralieva,&nbsp;Ala’a Al-Shaikh,&nbsp;V. Ranganadha Rao Pemmaraju,&nbsp;Maya Ranavare,&nbsp;Rie Yotsu,&nbsp;Mourad Mokni,&nbsp;Feras Ibrahim Hawari","doi":"10.1038/s41591-024-03488-4","DOIUrl":"10.1038/s41591-024-03488-4","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 3","pages":"710-711"},"PeriodicalIF":58.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583004","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":"LILRB3 genetic variation is associated with kidney transplant failure in African American recipients","authors":"Zeguo Sun, Zhengzi Yi, Chengguo Wei, Wenlin Wang, Tianyuan Ren, Paolo Cravedi, Fasika Tedla, Stephen C. Ward, Evren Azeloglu, Daniel R. Schrider, Yun Li, Atlas Khan, Francesca Zanoni, Jia Fu, Sumaria Ali, Shun Liu, Deguang Liang, Tong Liu, Hong Li, Caixia Xi, Thi Ha Vy, Gohar Mosoyan, Quan Sun, Ashwani Kumar, Zhongyang Zhang, Samira Farouk, Kirk Campell, Jordi Ochando, Kyung Lee, Steve Coca, Jenny Xiang, Patti Connolly, Lorenzo Gallon, Philip J. O’Connell, Robert Colvin, Madhav C. Menon, Girish Nadkarni, John C. He, Monica Kraft, Xuejun Jiang, Xuewu Zhang, Krzysztof Kiryluk, Aravind Cherukuri, Fadi G. Lakkis, Weiguo Zhang, Shu-hsia Chen, Peter S. Heeger, Weijia Zhang","doi":"10.1038/s41591-025-03568-z","DOIUrl":"https://doi.org/10.1038/s41591-025-03568-z","url":null,"abstract":"<p>African American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared with other racial and ethnic populations, highlighting the need to identify causative factors. Here, in the Genomics of Chronic Allograft Rejection cohort, pretransplant blood RNA sequencing revealed a cluster of four consecutive missense single-nucelotide polymorphisms (SNPs), within the leukocyte immunoglobulin-like receptor B3 (<i>LILRB3</i>) gene, strongly associated with death-censored graft loss. This SNP cluster (named <i>LILRB3</i>-4SNPs) encodes missense mutations at amino acids 617–618 proximal to a SHP1/2 phosphatase-binding immunoreceptor tyrosine-based inhibitory motif. The <i>LILRB3</i>-4SNPs cluster is specifically enriched within AA individuals and exhibited a strong association with death-censored graft loss and estimated glomerular filtration rate decline in the AA participants from multiple transplant cohorts. In two large Biobanks (BioMe and All-of-Us), the <i>LILRB3</i>-4SNPs cluster was associated with the early onset of end-stage renal disease and acted synergistically with the apolipoprotein L1 (<i>APOL1</i>) G1/G2 allele to accelerate disease progression. The SNPs were also linked to multiple immune-related diseases in AA individuals. Last, on multiomics analysis of blood and biopsies, recipients with <i>LILRB3</i>-4SNPs showed enhanced inflammation and monocyte ferroptosis. While larger and prospective studies are needed, our data provide insights on the genetic variation underlying kidney transplant outcomes.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"38 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582928","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":"Anti-obesity medication for weight loss in early nonresponders to behavioral treatment: a randomized controlled trial","authors":"Jena S. Tronieri, Eleanor Ghanbari, Jonathan Chevinsky, Erica M. LaFata, Alyssa M. Minnick, Simran Rajpal, Seamus Y. Wang, Kylie Burcaw, Robert I. Berkowitz, Thomas A. Wadden","doi":"10.1038/s41591-025-03556-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03556-3","url":null,"abstract":"<p>Current guidelines recommend behavioral treatment (BT) as the first intervention for patients with obesity. However, a substantial minority (35–50%) do not achieve a clinically meaningful loss of ≥5%. Anti-obesity medications (AOMs) are recommended when target weight loss is not achieved; however, their efficacy among BT nonresponders has not been established. This double-blind, randomized controlled proof-of-principle study evaluated whether augmenting BT with AOM improved 24-week weight loss compared to BT with placebo in early nonresponders to BT. A total of 147 adults with a body mass index ≥31 kg m⁻² (≥28 kg m⁻² with obesity-related comorbidity) completed an initial 4-week BT run-in. The 76 early nonresponders who lost &lt;2.0% of initial weight were then randomized to 24 weeks of either BT plus placebo (BT + P, <i>n</i> = 38) or BT plus AOM (phentermine = 15.0 mg d⁻¹, <i>n</i> = 38). Early responders received ongoing BT and were not part of the randomized trial. The primary outcome was met; early nonresponders assigned to BT + AOM had a greater mean (±s.e.) reduction in weight of 5.9 ± 0.7% from randomization to week 24, as compared to 2.8 ± 0.7% for those assigned to BT + P (mean difference = 3.1 ± 1.0, 95% confidence interval = 1.1–5.1%, Cohen’s <i>d</i> = 0.73, <i>P</i> = 0.003). Stepping up early BT nonresponders to BT + AOM improves their 24-week weight loss. ClinicalTrials.gov registration: NCT03779048.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"7 8 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569909","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":"Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial","authors":"Jeanne Tie, Yuxuan Wang, Serigne N. Lo, Kamel Lahouel, Joshua D. Cohen, Rachel Wong, Jeremy D. Shapiro, Samuel J. Harris, Adnan Khattak, Matthew E. Burge, Margaret Lee, Marion Harris, Sue-Anne McLachlan, Lisa Horvath, Christos Karapetis, Jenny Shannon, Madhu Singh, Desmond Yip, Sumitra Ananda, Craig Underhill, Janine Ptak, Natalie Silliman, Lisa Dobbyn, Maria Popoli, Nickolas Papadopoulos, Cristian Tomasetti, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs","doi":"10.1038/s41591-025-03579-w","DOIUrl":"https://doi.org/10.1038/s41591-025-03579-w","url":null,"abstract":"<p>Early data from the DYNAMIC study of circulating tumor DNA (ctDNA)-guided adjuvant chemotherapy (ACT) versus standard approach met its primary outcome demonstrating reduced ACT use without compromising 2-year recurrence-free survival (RFS) for stage II colon cancer. We report here other prespecified analyses of overall survival, ctDNA clearance and ctDNA level. At a median follow-up of 59.7 months, 5-year RFS was 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval −5.8% to 8.0%), and 5-year overall survival is similar (93.8% versus 93.3%, hazard ratio (HR) 1.05; <i>P</i> = 0.887). For treated ctDNA-positive patients, ctDNA clearance was observed at the end of ACT (EOT) in 35 out of 40 patients (87.5%). A higher than median postoperative tumor-derived mutant molecules per milliliter plasma was associated with worse 5-year RFS (HR 10.62; <i>P</i> = 0.005). For treated ctDNA-positive patients, post hoc analysis of ctDNA clearance at EOT assessed by a new assay that evaluated an average of 29 tumor-derived mutations per patient predicted for a favorable 5-year recurrence-free probability of 97% versus 0% for ctDNA persistence (<i>P</i> &lt; 0.001). Mature DYNAMIC outcome data support a ctDNA-guided approach to ACT for stage II colon cancer, with potential to further risk stratify ctDNA-positive patients based on ctDNA burden and EOT results. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12615000381583.</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":"143569906","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":"Evolution, genetic diversity, and health","authors":"María J. Palma-Martínez,&nbsp;Yuridia S. Posadas-García,&nbsp;Amara Shaukat,&nbsp;Brenda E. López-Ángeles,&nbsp;Mashaal Sohail","doi":"10.1038/s41591-025-03558-1","DOIUrl":"10.1038/s41591-025-03558-1","url":null,"abstract":"Human genetic diversity in today’s world has been shaped by evolutionary history, demographic shifts and environmental exposures, influencing complex traits, disease susceptibility and drug responses. Capturing this diversity is essential for advancing precision medicine and promoting equitable healthcare. Despite the great progress achieved with initiatives such as the human Pangenome and large biobanks that aim for a better representation of human diversity, important challenges remain. In this Perspective, we discuss the importance of diversity in clinical genomics through an evolutionary lens. We highlight progress and challenges and outline key clinical applications of diverse genetic data. We argue that diversifying both datasets and methodologies—integrating ancestral and environmental factors—is crucial for fully understanding the genetic basis of human health and disease. This Perspective explains how past migrations and environmental exposures have influenced genomic diversity, and how understanding and contextualizing this diversity is crucial to advancing precision medicine and equitable healthcare.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 3","pages":"751-761"},"PeriodicalIF":58.7,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-025-03558-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569908","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}