Nature Medicine最新文献

{"title":"Intravenous hyaluronidase-expressing oncolytic adenovirus with chemotherapy in metastatic pancreatic cancer: a randomized phase 2b trial","authors":"Rocio Garcia-Carbonero, Roberto Pazo Cid, Teresa Macarulla, Berta Laquente, Alana Nguyen, Carmen Guillén-Ponce, Andrés Muñoz, Edward J. Kim, Mireya Cazorla, Tara Seery, Miriam Lobo de Mena, Chris Nevala-Plagemann, Vivek Sharma, Eva Martínez de Castro, Mohammad Hojouj, Charles Le, Ana Mato-Berciano, Sheila Connelly, Mike Kaleko, Luis A. Rojas, Vincent J. Wacher, Mary Ann Shallcross, Carmen Blasco, Manel Cascallo, Manuel Hidalgo","doi":"10.1038/s41591-026-04705-y","DOIUrl":"https://doi.org/10.1038/s41591-026-04705-y","url":null,"abstract":"Zabilugene almadenorepvec (VCN-01) is a hyaluronidase-expressing oncolytic adenovirus with a favorable safety profile and encouraging antitumor activity in patients with pancreatic ductal adenocarcinoma. This randomized phase 2b trial evaluated the efficacy and safety of two doses of intravenous VCN-01 with gemcitabine and nab-paclitaxel (GnP) versus GnP alone as first-line therapy in metastatic pancreatic ductal adenocarcinoma. The primary endpoints were overall survival (OS) in the intent-to-treat and full analysis set (FAS) populations, and safety and tolerability in the safety population. In the intent-to-treat population (VCN-01 + GnP, n = 53; GnP, n = 48), median OS in the VCN-01 + GnP versus GnP group was 10.6 versus 8.6 months (hazard ratio (HR) = 0.69 (95% confidence interval (CI) 0.42–1.12), P = 0.196) and progression-free survival was 5.6 versus 4.6 months (HR = 0.63 (95% CI 0.4–1.00), P = 0.046). In the FAS population (n = 48 per group), median OS was 10.8 months in the VCN-01 + GnP group versus 8.6 months in the GnP group (HR = 0.57 (95% CI 0.34-0.96), P = 0.055) and progression-free survival was 7.0 versus 4.6 months (HR = 0.55 (95% CI, 0.34-0.88), P = 0.011). The primary efficacy endpoint of OS was met in the FAS population. Duration of response was 11.2 versus 5.4 months (HR = 0.22 (95% CI 0.08–0.63), P = 0.004). No statistically significant differences were observed in overall response rate, disease control rate or carbohydrate antigen 19-9 levels between treatment groups. In addition, survival rates in the VCN-01 + GnP group versus the GnP group were 35.5% versus 12.8% at 15 months, and 31.1% versus 8.5% at 18 months. Patients receiving two VCN-01 doses 14 weeks apart showed greater survival benefit, with sustained circulating viral genomes indicating ongoing viral replication and preserved second-dose bioactivity despite persistent neutralizing antibodies. More frequent VCN-01-related events included pyrexia, flu-like symptoms, elevation in liver enzymes and decreases in platelet counts, with serious events occurring in 22.6% of patients. Milder toxicity was observed after the second administration. Two fatal events occurred, one in each treatment group; neither was considered related to study treatment. These results further support VCN-01 combined with GnP as a first-line therapy for metastatic pancreatic ductal adenocarcinoma and warrant evaluation in a blinded phase 3 trial. ClinicalTrials.gov identifier: NCT05673811.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149087686","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 synthetic lethal drug for microsatellite instability cancers.","authors":"Jia Liu","doi":"10.1038/s41591-026-04693-z","DOIUrl":"https://doi.org/10.1038/s41591-026-04693-z","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081590","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":"Werner helicase inhibitor for advanced microsatellite instability solid tumors: a phase 1 trial.","authors":"Timothy A Yap, Elisa Fontana, Natalie Cook, Marwan Fakih, Oliver Bechter, Erica S Tsang, Emiliano Calvo, Kristoffer S Rohrberg, Javier Ros, Ignacio Matos, John H Strickler, Malaka Ameratunga, Meredith Pelster, Adam Sharp, Jaspreet Grewal, Susanna Ulahannan, Rajesh Belani, Matthew P Patricelli, Sophia M Blake, David Dejardin, Stephen Fowler, Christina Godfried Sie, Astrid Heller, Nina Henkel, Michael Hettich, Angelika Lahr, David Lamparter, Charlotte Lane, Ting Liu, Hélène Meistermann, Christophe Meille, Neil Parrott, Sotirios K Sotiriou, Denise Reeves, Barbara Romagnoli, Piergiorgio Pettazzoni, Daniel Waterkamp, Matthias Wittwer, Yali Fu, Sophie Postel-Vinay","doi":"10.1038/s41591-026-04657-3","DOIUrl":"https://doi.org/10.1038/s41591-026-04657-3","url":null,"abstract":"<p><p>Werner syndrome helicase (WRN) is a synthetic lethal target for microsatellite instability (MSI) cancers. In part 1 of this ongoing first-in-human, phase 1 trial, escalating doses of RO7589831 (VVD-133214), a first-in-class, WRN covalent inhibitor, were evaluated in 88 patients with MSI and/or deficient DNA mismatch repair advanced solid tumors. RO7589831 was administered once daily (150 mg), twice daily (BID; 150-1,000 mg) or three-times daily (TID; 200-600 mg). Primary objectives were to evaluate safety and tolerability, and identify the recommended phase 2 dose and schedule (RP2D). Secondary objectives included evaluation of antitumor activity (end points: disease control rate (DCR), objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS)). One dose-limiting toxicity of grade 2 nausea occurred in the 600-mg TID cohort; however, the maximum tolerated dose was not identified per protocol. Treatment-emergent adverse events (TEAEs) occurring in ≥10% were mostly grade 1-2; events in ≥30% were nausea (54.5%, 48/88; grade 3+: 2.3%, 2/88), diarrhea (43.2%, 38/88; grade 3+: 1.1%, 1/88), fatigue (39.8%, 35/88; grade 3+: 2.3%, 2/88), anemia (37.5%, 33/88; grade 3+: 11.4%, 10/88), and vomiting (30.7%, 27/88, grade 3+: 1.1%, 1/88). TEAEs leading to RO7589831 discontinuation were uncommon (3.4%, 3/88). No grade 5 TEAEs occurred. The DCR among MSI efficacy-evaluable patients was 74.2% (49/66). Seven patients achieved confirmed RECIST v.1.1 partial responses (ORR 10.6%, 7/66); median DOR was 10.2+ months. Among MSI efficacy-evaluable patients, median PFS was 6.7 months (95% CI 4.1-8.5); median OS was 17.6 months (95% CI 17.6-not estimable). Although direct target engagement in tumor tissue could not be demonstrated, exploratory analyses of ctDNA molecular response and FDG-PET metabolic response supported biological activity. The 150-mg and 600-mg BID doses were selected as RP2Ds for dose optimization. These data suggest that RO7589831 has a manageable safety profile and warrants further clinical testing. ClinicalTrials.gov identifier: NCT06004245 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081537","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":"Oral small-molecule GLP-1 receptor agonist safiglipron in early type 2 diabetes: a randomized, double-blind, placebo-controlled trial.","authors":"Miao Yu, Liang Peng, Chengyan Jiang, Xianghua Zhang, Qifu Li, Lihui Zhang, Xiuhai Su, Zhaoyang Zeng, Shuang Yan, Jinyang Wang, Debin Huang, Sihong Wang, Na Liu, Yimei Xu, Guo Tang, Fangli Dong, Yanlin Ma, Zi Ye, Xinhua Xiao","doi":"10.1038/s41591-026-04651-9","DOIUrl":"https://doi.org/10.1038/s41591-026-04651-9","url":null,"abstract":"<p><p>Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety in OUTSTAND-1, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 46 sites in China. We randomized 284 adults with type 2 diabetes managed with diet and exercise alone (mean baseline HbA1c 7.95%, median diabetes duration 1.6 years, 33.1% women) to once-daily safiglipron 30 mg (n = 70), 60 mg (n = 70), 90 mg (n = 72) or placebo (n = 72) for 32 weeks, followed by a 20-week active-treatment extension. For the primary endpoint, placebo-adjusted treatment differences in HbA1c change from baseline to week 32 were -1.22% (95% CI, -1.53 to -0.91), -1.20% (95% CI, -1.52 to -0.89) and -1.45% (95% CI, -1.75 to -1.14) for 30 mg, 60 mg and 90 mg, respectively (all P < 0.0001; treatment policy estimand). Secondary outcomes showed HbA1c < 7.0% in 71.4-77.8% versus 25.0%, HbA1c ≤ 6.5% in 58.6-68.1% versus 16.7% and placebo-adjusted fasting plasma glucose differences of -1.58, -1.68 and -2.08 mmol l^-¹, respectively (all P < 0.0001). Body weight differences were modest (-0.65%, -2.23% and -3.56% versus placebo). Other secondary outcomes generally favored safiglipron for HbA1c < 5.7% attainment, postprandial glycemia, homeostatic model assessment of β cell function (HOMA-β), homeostatic model assessment of insulin resistance (HOMA-IR), disposition index and waist circumference, with less rescue therapy use. Insulin and C-peptide responses varied by dose, and changes in treatment satisfaction were limited. Gastrointestinal adverse events were most common and mostly mild or moderate. Adverse events led to treatment discontinuation in 1.4%, 2.9%, 6.9% and 0% of participants receiving safiglipron 30 mg, 60 mg, 90 mg and placebo, respectively. These findings support once-daily oral safiglipron as an effective treatment option for type 2 diabetes. ClinicalTrials.gov identifier: NCT06672172 .</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081600","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":"Reproducibility in biomedical research","authors":"Judy Zhong,&nbsp;Debra D’Angelo,&nbsp;Chen Lyu,&nbsp;Ian Xu,&nbsp;Peter K. Enns,&nbsp;Fei Wang,&nbsp;Rainu Kaushal","doi":"10.1038/s41591-026-04667-1","DOIUrl":"10.1038/s41591-026-04667-1","url":null,"abstract":"Reproducibility has long been considered a foundation of trustworthy science, yet practices that enable reproducible research remain inconsistently implemented, despite widespread awareness and establishment of policies and guidelines. Biomedical research that cannot be reproduced can lead to resource waste and adversely impact patient safety, public health outcomes, scientific progress and public trust. Rapid advances in technology, scientific dissemination and clinical translation have prompted renewed emphasis on validating research methods and findings to ensure transparency, rigor and credibility. Here we provide an overview of the current landscape of reproducible research in the biomedical sciences, summarize current efforts to harmonize terminology and implementation, and highlight the persistent barriers to adoption of best practices. We outline a practical framework to promote more uniform implementation and explore future directions for advancing reproducibility across stakeholders in the research process, including researchers, institutions, journals and funders. Reproducibility is a foundational principle of trustworthy science, but reproducible research practices are not consistently implemented. This Review summarizes the current landscape including efforts to harmonize terminology and implementation, persistent barriers and ecosystem responses.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"32 10","pages":"3564-3577"},"PeriodicalIF":52.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081582","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":"Biography of an inherited lung cancer risk gene.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00048-w","DOIUrl":"https://doi.org/10.1038/d41591-026-00048-w","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075265","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":"When detecting Ebola is not enough: closing the response interval in DRC.","authors":"Justin Kambale Kahingi, Benny Bebedi Nkamba, Jonas Belanga Bola, Clovis Mbokolo Bolima, Eric Ilonga Mpeti, Claudia Mbanda Mpunza, Héritier Bekoka Wanga, Relindis Mpembe Ngila, Jean Belito Nyimi, Lionel Shotsha Asamboa, Nelly Kola Nsimba, Rosie Mubindukila Nzamba, Max Seke Vangu, Gédéon Bongo Ngiala, Odette Kabena Ngandu, Roland Muhindo Muyisa","doi":"10.1038/s41591-026-04698-8","DOIUrl":"https://doi.org/10.1038/s41591-026-04698-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075323","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":"Prime editing goes large.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00049-9","DOIUrl":"https://doi.org/10.1038/d41591-026-00049-9","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":52.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149075325","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":"Polygenic scores in the NHS: the debate is not primarily about the evidence","authors":"Hayley Wilson,Chantal Babb de Villiers,Peter Mills","doi":"10.1038/s41591-026-04684-0","DOIUrl":"https://doi.org/10.1038/s41591-026-04684-0","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"34 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049622","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 next phase of translational medicine must bridge the gap between innovation to impact","authors":"Giulio Cavalli,Vicky Seyfert-Margolis,Charles Cairns,Carol Gregorio,Scott Compton,Berent Prakken,Salvatore Albani","doi":"10.1038/s41591-026-04681-3","DOIUrl":"https://doi.org/10.1038/s41591-026-04681-3","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"14 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049624","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}