Nature Medicine最新文献

{"title":"Full-spectrum extract from Cannabis sativa DKJ127 for chronic low back pain: a phase 3 randomized placebo-controlled trial.","authors":"Matthias Karst, Winfried Meissner, Sabine Sator, Jens Keßler, Volker Schoder, Winfried Häuser","doi":"10.1038/s41591-025-03977-0","DOIUrl":"https://doi.org/10.1038/s41591-025-03977-0","url":null,"abstract":"<p><p>Chronic low back pain (CLBP) affects over half a billion people worldwide. Current pharmacologic treatments offer limited efficacy and carry substantial risks, warranting the development of safe and effective alternatives. This multicenter, randomized, placebo-controlled phase 3 trial evaluated the efficacy and safety of VER-01 in CLBP. It enrolled 820 adults with CLBP (VER-01, n = 394; placebo, n = 426) and included a double-blind 12-week treatment phase (phase A), a 6-month open-label extension (phase B), followed by either a 6-month continuation (phase C) or randomized withdrawal (phase D). The primary endpoint of phase A was a change in mean numeric rating scale (NRS) pain intensity, with a change in total neuropathic pain symptom inventory (NPSI) score as a key secondary endpoint in participants with a neuropathic pain component (PainDETECT > 18). The primary endpoint for phase D was time to treatment failure. The study met its primary endpoint in phase A, with a mean pain reduction of -1.9 NRS points in the VER-01 group (mean difference (MD) versus placebo = -0.6, 95% confidence interval (CI) = -0.9 to -0.3; P < 0.001). Pain further decreased to -2.9 NRS points in phase B, with effects sustained through phase C. The study also met its key secondary endpoint of phase A, with a mean NPSI decrease of -14.4 (standard error, 3.3) points from baseline in the VER-01 arm (MD versus placebo = -7.3, 95% CI = -13.2 to -1.3; P = 0.017). Although phase D did not meet its primary endpoint (hazard ratio = 0.75, 95% CI = 0.44-1.27; P = 0.288), pain increased significantly more with placebo upon withdrawal (MD = 0.5, 95% CI = 0.0-1.0; P = 0.034). In phase A, the incidence of adverse events-mostly mild to moderate and transient-was higher with VER-01 than with placebo (83.3% versus 67.3%; P < 0.001). VER-01 was well-tolerated, with no signs of dependence or withdrawal. VER-01 shows potential as a new, safe and effective treatment for CLBP. ClinicalTrials.gov registration: NCT04940741 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192262","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":"Diffusing authority to make drug approval decisions at the US Food and Drug Administration.","authors":"Caleb Rhodes, Reshma Ramachandran, Holly Fernandez Lynch","doi":"10.1038/s41591-025-03948-5","DOIUrl":"https://doi.org/10.1038/s41591-025-03948-5","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192271","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":"Prevention of type 2 diabetes through prediabetes remission without weight loss.","authors":"Arvid Sandforth, Elsa Vazquez Arreola, Robert L Hanson, Nicolai J Wewer Albrechtsen, Jens Juul Holst, Robert Ahrends, Cristina Coman, Felicia Gerst, Estela Lorza-Gil, Yurong Cheng, Leontine Sandforth, Sarah Katzenstein, Marlene Ganslmeier, Jochen Seissler, Hans Hauner, Nikolaos Perakakis, Robert Wagner, Jürgen Machann, Fritz Schick, Andreas Peter, Rainer Lehmann, Cora Weigert, Jennifer Maurer, Hubert Preissl, Martin Heni, Julia Szendrödi, Stefan Kopf, Michele Solimena, Peter Schwarz, Matthias Blüher, Hans-Ulrich Häring, Martin Hrabé de Angelis, Annette Schürmann, Stefan Kabisch, Knut Mai, Andreas F H Pfeiffer, Stefan Bornstein, Michael Stumvoll, Michael Roden, Norbert Stefan, Andreas Fritsche, Andreas L Birkenfeld, Reiner Jumpertz von Schwartzenberg","doi":"10.1038/s41591-025-03944-9","DOIUrl":"https://doi.org/10.1038/s41591-025-03944-9","url":null,"abstract":"<p><p>Clinical practice guidelines recommend defined weight loss goals for the prevention of type 2 diabetes (T2D) in those individuals with increased risk, such as prediabetes. However, achieving prediabetes remission, that is, reaching normal glucose regulation according to American Diabetes Association criteria, is more efficient in preventing T2D than solely reaching weight loss goals. Here we present a post hoc analysis of the large, multicenter, randomized, controlled Prediabetes Lifestyle Intervention Study (PLIS), demonstrating that prediabetes remission is achievable without weight loss or even weight gain, and that it also protects against incident T2D. The underlying mechanisms include improved insulin sensitivity, β-cell function and increments in β-cell-GLP-1 sensitivity. Weight gain was similar in those achieving prediabetes remission (responders) compared with nonresponders; however, adipose tissue was differentially redistributed in responders and nonresponders when compared against each other-while nonresponders increased visceral adipose tissue mass, responders increased adipose tissue in subcutaneous depots. The findings were reproduced in the US Diabetes Prevention Program. These data uncover essential pathways for prediabetes remission without weight loss and emphasize the need to include glycemic targets in current clinical practice guidelines to improve T2D prevention.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192273","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":"New GLP-1 drug delivers weight loss in a pill.","authors":"Karen O'Leary","doi":"10.1038/d41591-025-00060-6","DOIUrl":"https://doi.org/10.1038/d41591-025-00060-6","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176846","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":"Targeting molecular vulnerabilities in glioblastoma.","authors":"Joshua D Bernstock","doi":"10.1038/s41591-025-03952-9","DOIUrl":"https://doi.org/10.1038/s41591-025-03952-9","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176828","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":"Antibody-mediated LOX-1 inhibition in patients with residual inflammation after myocardial infarction: a randomized phase 2 trial.","authors":"Michelle L O'Donoghue, David A Morrow, Andrea L Vavere, Dimitris Kardassis, Filipe A Moura, Antonio A De Paiva Fagundes, Diego Ardissino, Vladimir Blaha, Michael E Farkouh, Eri Kato, Takeshi Kimura, Robert Kiss, Ton Oude Ophuis, Joseph Selvanayagam, Jose Lopez-Sendon, Wojciech Wojakowski, Azfar Zaman, Joao A C Lima, Michael T Lu, Borek Foldyna, Julia Kuder, Jeong-Gun Park, Sabina A Murphy, Michelle Turton, Anna Collén, Anders Gabrielsen, Richard George, Marc S Sabatine","doi":"10.1038/s41591-025-03951-w","DOIUrl":"https://doi.org/10.1038/s41591-025-03951-w","url":null,"abstract":"<p><p>The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is a key scavenger receptor for oxidized low-density lipoprotein cholesterol (oxLDL), which promotes inflammation and atherosclerosis. Here we evaluated MEDI6570, an antibody that acts as a LOX-1 antagonist, in a randomized, double-blind, dose-finding study in patients with myocardial infarction (MI) and residual inflammation (high-sensitivity C-reactive protein ≥ 1 mg l^-1). At 30-365 days after MI, 423 patients (75 women, 348 men) were randomly allocated to 50 mg, 150 mg or 400 mg MEDI6570 or placebo treatment subcutaneously every 4 weeks for 32 weeks. The primary endpoint, the change in the noncalcified plaque volume in the most diseased coronary segment (NCPV_MD) by computed tomography angiography, was not significantly different between placebo and MEDI6570 at any dose. The secondary endpoints, global NCPV and low-attenuation plaque volume, were also not different between placebo and MEDI6570 at any dose (all placebo-adjusted comparisons, P > 0.05). With regard to exploratory endpoints, there were reductions in free soluble LOX-1 (sLOX-1) from baseline by 44.8%, 85.8%, 94.0% and 96.4% in the placebo, 50 mg, 150 mg and 400 mg dose arms, respectively (all placebo-adjusted comparisons P < 0.001). Interleukin-6 (IL-6) levels decreased by 2.9%, -3.0%, 18.9% and 21.5% in the placebo, 50 mg, 150 mg and 400 mg arms, respectively, with substantial placebo-adjusted reductions observed only at 150 mg and 400 mg (P < 0.05). MEDI6570 was well tolerated and rates of serious adverse events were similar in the MEDI6570 and placebo groups. In summary, despite favorable effects on sLOX-1 and IL-6, a LOX-1 inhibitor did not reduce noncalcified coronary plaque volume in patients with residual inflammation after acute MI. EudraCT registration: 2020-000840-75 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150154","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":"Health impacts of wildfires travel far and wide.","authors":"Karen O'Leary","doi":"10.1038/d41591-025-00059-z","DOIUrl":"https://doi.org/10.1038/d41591-025-00059-z","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138158","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":"Publisher Correction: Early-life serological profiles and the development of natural protective humoral immunity to Streptococcus pyogenes in a high-burden setting.","authors":"Alexander J Keeley, Fatoumata E Camara, Edwin P Armitage, Gabrielle de Crombrugghe, Jainaba Sillah, Modou Lamin Fofana, Victoria Rollinson, Elina Senghore, Musukoi Jammeh, Alana L Whitcombe, Amat Bittaye, Haddy Ceesay, Isatou Ceesay, Bunja Samateh, Muhammed Manneh, Martina Carducci, Luca Rovetini, Elena Boero, Luisa Massai, Lady Chilel Sanyang, Ousman Camara, Ebrima E Cessay, Miren Iturriza, Danilo Gomes Moriel, Adam Kucharski, Pierre R Smeesters, Anne Botteaux, Ya Jankey Jagne, Nicole J Moreland, Ed Clarke, Beate Kampmann, Michael Marks, Omar Rossi, Henrik Salje, Claire E Turner, Thushan I de Silva","doi":"10.1038/s41591-025-04017-7","DOIUrl":"10.1038/s41591-025-04017-7","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138105","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":"Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial.","authors":"Georgina V Long, Nitya Nair, Daniel Marbach, Richard A Scolyer, Sabine Wilson, Denise Cotting, Nicolas Staedler, Rodabe N Amaria, Paolo Antonio Ascierto, Ahmad A Tarhini, Caroline Robert, Omid Hamid, Caroline Gaudy-Marqueste, Celeste Lebbe, Eva Munoz-Couselo, Alexander M Menzies, Cecile Pages, Giuseppe Curigliano, Mario Mandala, Nikki Jessop, Uwe Bader, Maurizio Perdicchio, Volker Teichgräber, Merlind Muecke, Christoph Markert, Christian Blank","doi":"10.1038/s41591-025-03967-2","DOIUrl":"https://doi.org/10.1038/s41591-025-03967-2","url":null,"abstract":"<p><p>Patients with stage III melanoma are at high risk of relapse. The NADINA trial evaluating neoadjuvant nivolumab plus ipilimumab and the SWOG-1801 trial evaluating neoadjuvant pembrolizumab have demonstrated superior clinical outcomes with neoadjuvant versus adjuvant checkpoint inhibition. Morpheus-Melanoma was a phase 1b/2, randomized umbrella trial evaluating tobemstomig (anti-PD-1/anti-LAG-3 bispecific antibody; n = 40), tobemstomig plus tiragolumab (anti-TIGIT monoclonal antibody; n = 20) and atezolizumab (PD-L1-targeting monoclonal antibody) plus tiragolumab (n = 20) versus nivolumab (anti-PD-1 monoclonal antibody) plus ipilimumab (anti-CTLA-4 monoclonal antibody; n = 22) in stage III melanoma. The primary endpoint was pathological response by independent pathological review. Additional endpoints included safety and exploratory biomarkers. Here tobemstomig showed a similar pathological response rate (pRR) versus nivolumab plus ipilimumab (80.0% (32/40) versus 77.3% (17/22)); major pathological responses were less frequent with tobemstomig versus nivolumab plus ipilimumab treatment (62.5% (25/40) versus 72.7% (16/22)). Tobemstomig plus tiragolumab and atezolizumab plus tiragolumab showed a lower pRR versus nivolumab plus ipilimumab (60.0% (12/20) and 45.0% (9/20) versus 77.3% (17/22), respectively). Tobemstomig demonstrated improved safety versus nivolumab plus ipilimumab, with 2.5% (1/40) and 22.7% (5/22) of patients experiencing grade 3 or higher treatment-related adverse events (TRAEs), respectively, and 0% (0/40) and 13.6% (3/22) of patients discontinuing treatment due to TRAEs, respectively. Grade 3 or higher TRAEs were reported by 15% (3/20) of patients in the tobemstomig plus tiragolumab arm and by no patients in the atezolizumab plus tiragolumab arm. Baseline CD8⁺ and CD3⁺ tumor-infiltrating T cell density, IFNγ pathway and effector T cell gene expression, tumor mutational burden and pre-surgery circulating tumor DNA correlated with pathological response across treatments. In conclusion, in the Morpheus-Melanoma study, tobemstomig demonstrated a similar pathological response and improved safety profile versus nivolumab plus ipilimumab in patients with resectable stage III melanoma. ClinicalTrials.gov identifier: NCT05116202 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138163","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":"Co-infusion of CD19-targeting and BCMA-targeting CAR-T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial.","authors":"Jingjing Feng, Dawei Huo, Ruimin Hong, Xuexiao Jin, Heng Cao, Mi Shao, Rui Wen, Qiqi Zhang, Mingming Zhang, Shan Fu, Dongrui Wang, Huijun Xu, Guoqing Wei, Jiazhen Cui, Simao Huang, Dawei Cui, Alex Hongsheng Chang, Zhihong Liu, Linrong Lu, Jin Lin, Yongxian Hu, He Huang","doi":"10.1038/s41591-025-03937-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03937-8","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) remains refractory to conventional immunosuppression in a subset of patients. In treatment-refractory SLE, we show that peripheral CD19^⁺ B cells and bone marrow CD19⁻BCMA⁺ long-lived plasma cells are dominant autoantibody sources, motivating dual CD19 and BCMA targeting. Here we report results from a cohort of patients (14 female, one male) in an ongoing phase 1 dose-escalation trial of co-infused autologous anti-CD19 and anti-BCMA chimeric antigen receptor (CAR) T cells after fludarabine/cyclophosphamide lymphodepletion. Primary endpoints were dose-limiting toxicities (DLTs) within 28 days and adverse events within 12 weeks; key secondary endpoints comprised attainment of Lupus Low Disease Activity State (LLDAS) and DORIS remission within 12 weeks and in vivo CAR-T persistence within 24 weeks. Exploratory endpoints were the duration of post-infusion B cell depletion and time to recovery, the kinetics of immune reconstitution and longitudinal changes in autoantibody titers and serum immunoglobulin concentrations after CAR-T therapy. Over a median 712-day follow-up (range, 613-1,134), no DLTs occurred. Grade 1 cytokine release syndrome developed in 86.7% of patients, with no neurotoxicity or treatment-related deaths. The most common grade 3 or higher adverse events were neutropenia (100%), thrombocytopenia (40%) and anemia (13.3%), all of which were reversible with supportive care. By week 12, 12 of 15 patients (80%) fulfilled both the LLDAS and DORIS remission criteria. Multiomic analyses confirmed elimination of autoreactive CD19⁺BCMA⁺ clones, reconstitution of naive IgM/IgD B cells and durable downregulation of interferon-stimulated and BAFF-dependent signatures, indicating improved immune homeostasis. Longitudinal monitoring of three patients for 1 year demonstrated sustained eradication of pathogenic clones, suggesting potential cure. Dual anti-CD19/anti-BCMA CAR-T cell therapy demonstrates good safety and promising clinical efficacy in treatment-refractory SLE. This study supports the further development of this treatment approach for patients with rSLE. ClinicalTrials.gov identifier: NCT05030779 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138120","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}