首页 > 最新文献

Nature Medicine最新文献

英文 中文
High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial 大剂量nusinersen治疗脊髓性肌萎缩症:一项3期随机试验
IF 82.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-03 DOI: 10.1038/s41591-025-04193-6
Richard S. Finkel, Thomas O. Crawford, Eugenio Mercuri, Charlotte J. Sumner, Maria del Mar Garcia Romero, John W. Day, Jacqueline Montes, Peng Sun, Ben Tichler, Angela D. Paradis, Emily Boesch, Jennifer Inra, Ross Littauer, Jihee Sohn, Michael Monine, Giulia Gambino, Richard Foster, Raechel Farewell, Stephanie Fradette
Despite the remarkable benefits of nusinersen and other disease-modifying therapies in spinal muscular atrophy (SMA), patients may still experience clinical manifestations of the disease. Here we assessed the potential for high-dose nusinersen to rapidly slow neurodegeneration and lead to improved outcomes for patients. The global, three-part, phase 2/3 DEVOTE trial evaluated the efficacy and safety of high-dose nusinersen (50-mg loading dose; 28-mg maintenance dose) in individuals with SMA. In Part B, treatment-naive individuals (n = 75) were randomized 2:1 to 50/28 mg or 12/12 mg nusinersen. In a supportive open-label cohort (Part C), nusinersen-experienced individuals (12/12 mg for more than 1 year) were enrolled. The primary endpoint (Part B infantile-onset participants) was a 6-month change in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score comparing 50/28 mg with matched ENDEAR participants (n = 20) who received sham. DEVOTE met its primary endpoint: at day 183, the CHOP-INTEND total score significantly improved (+15.1 points) in those who received 50/28 mg nusinersen and worsened (−11.1 points) in matched ENDEAR participants who received sham (difference, 26.19 (95% confidence interval = 20.7 to 31.74); statistical testing was performed using the joint-rank test where the difference in ranks was 26.06 (95% confidence interval = 17.9 to 34.2; P < 0.0001). The safety profile of 50/28 mg nusinersen was similar to the 12/12 mg regimen. The data support that high-dose nusinersen provides benefit in patients with SMA, with a generally well-tolerated safety profile. ClinicalTrials.gov registration: https://clinicaltrials.gov/study/NCT04089566. EudraCT no: 2019-002663-10.
尽管nusinersen和其他疾病改善疗法对脊髓性肌萎缩症(SMA)有显著的益处,但患者仍可能出现该疾病的临床表现。在这里,我们评估了高剂量nusinersen快速减缓神经退行性变并改善患者预后的潜力。这项全球性的三部分2/3期临床试验评估了高剂量nusinersen (50mg负荷剂量,28mg维持剂量)对SMA患者的疗效和安全性。在B部分中,未接受治疗的个体(n = 75)被2:1随机分配至50/28 mg或12/12 mg nusinersen。在一个支持性开放标签队列(C部分)中,招募了有用药经验的个体(12/12毫克,持续1年以上)。主要终点(B部分婴儿发病参与者)是费城儿童医院婴儿神经肌肉疾病测试(chop - intention)总分的6个月变化,将50/28 mg与接受假药的匹配ENDEAR参与者(n = 20)进行比较。emit达到了主要终点:在第183天,接受50/28 mg nusinersen的患者chop - intention总分显著提高(+15.1分),而接受sham的匹配ENDEAR参与者的chop - intention总分恶化(- 11.1分)(差异为26.19(95%置信区间= 20.7至31.74);采用联合秩检验进行统计学检验,秩差为26.06(95%置信区间= 17.9 ~ 34.2,P < 0.0001)。50/28 mg nusinersen的安全性与12/12 mg方案相似。数据支持高剂量nusinersen对SMA患者有益,具有良好的耐受性。ClinicalTrials.gov注册:https://clinicaltrials.gov/study/NCT04089566。草案编号:2019-002663-10。
{"title":"High-dose nusinersen for spinal muscular atrophy: a phase 3 randomized trial","authors":"Richard S. Finkel, Thomas O. Crawford, Eugenio Mercuri, Charlotte J. Sumner, Maria del Mar Garcia Romero, John W. Day, Jacqueline Montes, Peng Sun, Ben Tichler, Angela D. Paradis, Emily Boesch, Jennifer Inra, Ross Littauer, Jihee Sohn, Michael Monine, Giulia Gambino, Richard Foster, Raechel Farewell, Stephanie Fradette","doi":"10.1038/s41591-025-04193-6","DOIUrl":"https://doi.org/10.1038/s41591-025-04193-6","url":null,"abstract":"Despite the remarkable benefits of nusinersen and other disease-modifying therapies in spinal muscular atrophy (SMA), patients may still experience clinical manifestations of the disease. Here we assessed the potential for high-dose nusinersen to rapidly slow neurodegeneration and lead to improved outcomes for patients. The global, three-part, phase 2/3 DEVOTE trial evaluated the efficacy and safety of high-dose nusinersen (50-mg loading dose; 28-mg maintenance dose) in individuals with SMA. In Part B, treatment-naive individuals (n = 75) were randomized 2:1 to 50/28 mg or 12/12 mg nusinersen. In a supportive open-label cohort (Part C), nusinersen-experienced individuals (12/12 mg for more than 1 year) were enrolled. The primary endpoint (Part B infantile-onset participants) was a 6-month change in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score comparing 50/28 mg with matched ENDEAR participants (n = 20) who received sham. DEVOTE met its primary endpoint: at day 183, the CHOP-INTEND total score significantly improved (+15.1 points) in those who received 50/28 mg nusinersen and worsened (−11.1 points) in matched ENDEAR participants who received sham (difference, 26.19 (95% confidence interval = 20.7 to 31.74); statistical testing was performed using the joint-rank test where the difference in ranks was 26.06 (95% confidence interval = 17.9 to 34.2; P < 0.0001). The safety profile of 50/28 mg nusinersen was similar to the 12/12 mg regimen. The data support that high-dose nusinersen provides benefit in patients with SMA, with a generally well-tolerated safety profile. ClinicalTrials.gov registration: https://clinicaltrials.gov/study/NCT04089566. EudraCT no: 2019-002663-10.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"1 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102152","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}
引用次数: 0
Scaling medical AI across clinical contexts. 在临床环境中扩展医疗人工智能。
IF 5 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-03 DOI: 10.1038/s41591-025-04184-7
Michelle M Li, Ben Y Reis, Adam Rodman, Tianxi Cai, Noa Dagan, Ran D Balicer, Joseph Loscalzo, Isaac S Kohane, Marinka Zitnik

Medical artificial intelligence (AI) tools, including clinical language models, vision-language models and multimodal health record models, are used to summarize clinical notes, answer questions and support decisions. Their adaptation to new populations, specialties or care settings often relies on fine-tuning, prompting or retrieval from external knowledge bases. These strategies can scale poorly and risk contextual errors-outputs that appear plausible but miss critical patient or situational information. We envision context switching as an emergent solution. Context switching adjusts model reasoning at inference, without retraining. Generative models can tailor outputs to patient biology, care setting or disease. Multimodal models can switch between notes, laboratory results, imaging and genomics, even when some data are missing or delayed. Agent models can coordinate tools and roles based on task and user context. In each case, context switching enables medical AI to adapt across specialties, populations and geographies. This approach requires advances in data design, model architectures and evaluation frameworks, and establishes a foundation for medical AI that scales to an infinite number of contexts, while remaining reliable and suited to real-world care.

医疗人工智能(AI)工具,包括临床语言模型、视觉语言模型和多模态健康记录模型,用于总结临床笔记、回答问题和支持决策。它们对新的人群、专业或护理环境的适应往往依赖于微调、提示或从外部知识库中检索。这些策略的可扩展性很差,并且有可能出现上下文错误——输出看似合理,但忽略了关键的患者或情境信息。我们认为上下文切换是一种紧急解决方案。上下文切换在推理时调整模型推理,而无需重新训练。生成模型可以根据患者生物学、护理环境或疾病定制输出。多模式模型可以在笔记、实验室结果、成像和基因组学之间切换,即使有些数据丢失或延迟。代理模型可以根据任务和用户上下文协调工具和角色。在每种情况下,上下文切换使医疗人工智能能够适应不同的专业、人群和地理位置。这种方法需要在数据设计、模型架构和评估框架方面取得进展,并为医疗人工智能奠定基础,使其能够扩展到无限多的环境,同时保持可靠并适合现实世界的护理。
{"title":"Scaling medical AI across clinical contexts.","authors":"Michelle M Li, Ben Y Reis, Adam Rodman, Tianxi Cai, Noa Dagan, Ran D Balicer, Joseph Loscalzo, Isaac S Kohane, Marinka Zitnik","doi":"10.1038/s41591-025-04184-7","DOIUrl":"https://doi.org/10.1038/s41591-025-04184-7","url":null,"abstract":"<p><p>Medical artificial intelligence (AI) tools, including clinical language models, vision-language models and multimodal health record models, are used to summarize clinical notes, answer questions and support decisions. Their adaptation to new populations, specialties or care settings often relies on fine-tuning, prompting or retrieval from external knowledge bases. These strategies can scale poorly and risk contextual errors-outputs that appear plausible but miss critical patient or situational information. We envision context switching as an emergent solution. Context switching adjusts model reasoning at inference, without retraining. Generative models can tailor outputs to patient biology, care setting or disease. Multimodal models can switch between notes, laboratory results, imaging and genomics, even when some data are missing or delayed. Agent models can coordinate tools and roles based on task and user context. In each case, context switching enables medical AI to adapt across specialties, populations and geographies. This approach requires advances in data design, model architectures and evaluation frameworks, and establishes a foundation for medical AI that scales to an infinite number of contexts, while remaining reliable and suited to real-world care.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113699","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}
引用次数: 0
Fault lines in a global promise. 全球承诺中的断层线。
IF 5 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-03 DOI: 10.1038/s41591-026-04199-8
Paul Adepoju
{"title":"Fault lines in a global promise.","authors":"Paul Adepoju","doi":"10.1038/s41591-026-04199-8","DOIUrl":"https://doi.org/10.1038/s41591-026-04199-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113586","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}
引用次数: 0
Integration of health check-ups into school and healthcare systems can improve adolescent health in LMICs. 将健康检查纳入学校和卫生保健系统可以改善中低收入国家的青少年健康。
IF 5 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1038/s41591-026-04200-4
{"title":"Integration of health check-ups into school and healthcare systems can improve adolescent health in LMICs.","authors":"","doi":"10.1038/s41591-026-04200-4","DOIUrl":"https://doi.org/10.1038/s41591-026-04200-4","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106303","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}
引用次数: 0
Implementation and evaluation of the Y-Check comprehensive adolescent health check-up intervention in Zimbabwe: a pre−post mixed-methods study 津巴布韦Y-Check综合青少年健康检查干预措施的实施和评价:一项前后混合方法研究
IF 82.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1038/s41591-025-04156-x
Aoife M. Doyle, Farirai Nzvere, Salome Manyau, Victoria Simms, Ines Li Lin, Faith R. Kandiye, Chipo Ashley Nyamayaro, Michaela Takawira, Rudo M. S. Chingono, Mandikudza Tembo, Ronald Manhibi, Ethel Dauya, Chido Dziva Chikwari, Giulia Greco, Sarah Bernays, Valentina Baltag, Hannah Maisiri, Tonderai Kasu, Wenceslas Nyamayaro, Tsitsi Bandason, Constance R. S. Mackworth-Young, Prerna Banati, Helen A. Weiss, David A. Ross, Rashida A. Ferrand
Routine adolescent health check-ups can support healthy development and well-being, but evidence on the feasibility, acceptability and effectiveness of contextually relevant comprehensive check-ups in low- and middle-income settings is limited. We conducted a hybrid implementation-effectiveness study incorporating a mixed-methods pre−post design of Y-Check, a comprehensive health check-up intervention in Zimbabwe, as part of a multicountry study developed and coordinated by the World Health Organization. Eligible participants were 10–19-year-old adolescents attending school or community venues. We used self-administered digital questionnaires, provider-led clinical tests and nurse reviews to screen for 25 conditions/behaviors. We provided health promotion, on-site care and referral to relevant providers. From October 2022 to September 2023, 2,097 adolescents were enrolled, of whom 1,843 (87.9%) were seen at 6 months. The primary outcome of appropriate care and/or referral(s) for all identified issues was achieved for 70.8% (95% confidence interval: 68.7–72.9%) of 1,865 participants with at least one issue. At follow-up, there were improvements in nutrition, health-related quality of life, self-esteem, behaviors and educational outcomes. The intervention was feasible and largely acceptable. Uptake of referral services varied by issue. Y-Check cost US$47 per participant. Through Y-Check, we identified untreated conditions and risk behaviors and successfully treated and linked adolescents to services. Here we provide evidence on the potential of the intervention to positively impact health and well-being.
青少年常规健康检查可以促进健康发展和福祉,但在低收入和中等收入环境中开展与具体情况相关的全面检查的可行性、可接受性和有效性方面的证据有限。作为世界卫生组织制定和协调的多国研究的一部分,我们开展了一项实施-有效性混合研究,采用混合方法设计津巴布韦的全面健康检查干预措施Y-Check。符合条件的参与者是在学校或社区活动的10 - 19岁青少年。我们使用自我管理的数字问卷、提供者主导的临床测试和护士评论来筛选25种情况/行为。我们提供健康促进、现场护理和转介给相关提供者。从2022年10月至2023年9月,共纳入2097名青少年,其中1843名(87.9%)在6个月时随访。在1,865名至少有一个问题的参与者中,70.8%(95%置信区间:68.7-72.9%)达到了针对所有确定问题的适当护理和/或转诊的主要结局。在随访中,营养、健康相关生活质量、自尊、行为和教育成果都有所改善。这种干预是可行的,而且在很大程度上是可以接受的。接受转诊服务的情况因问题而异。Y-Check每位参与者的费用为47美元。通过Y-Check,我们确定了未经治疗的状况和危险行为,并成功地治疗了青少年,并将其与服务联系起来。在这里,我们提供了证据,证明干预可能对健康和福祉产生积极影响。
{"title":"Implementation and evaluation of the Y-Check comprehensive adolescent health check-up intervention in Zimbabwe: a pre−post mixed-methods study","authors":"Aoife M. Doyle, Farirai Nzvere, Salome Manyau, Victoria Simms, Ines Li Lin, Faith R. Kandiye, Chipo Ashley Nyamayaro, Michaela Takawira, Rudo M. S. Chingono, Mandikudza Tembo, Ronald Manhibi, Ethel Dauya, Chido Dziva Chikwari, Giulia Greco, Sarah Bernays, Valentina Baltag, Hannah Maisiri, Tonderai Kasu, Wenceslas Nyamayaro, Tsitsi Bandason, Constance R. S. Mackworth-Young, Prerna Banati, Helen A. Weiss, David A. Ross, Rashida A. Ferrand","doi":"10.1038/s41591-025-04156-x","DOIUrl":"https://doi.org/10.1038/s41591-025-04156-x","url":null,"abstract":"Routine adolescent health check-ups can support healthy development and well-being, but evidence on the feasibility, acceptability and effectiveness of contextually relevant comprehensive check-ups in low- and middle-income settings is limited. We conducted a hybrid implementation-effectiveness study incorporating a mixed-methods pre−post design of Y-Check, a comprehensive health check-up intervention in Zimbabwe, as part of a multicountry study developed and coordinated by the World Health Organization. Eligible participants were 10–19-year-old adolescents attending school or community venues. We used self-administered digital questionnaires, provider-led clinical tests and nurse reviews to screen for 25 conditions/behaviors. We provided health promotion, on-site care and referral to relevant providers. From October 2022 to September 2023, 2,097 adolescents were enrolled, of whom 1,843 (87.9%) were seen at 6 months. The primary outcome of appropriate care and/or referral(s) for all identified issues was achieved for 70.8% (95% confidence interval: 68.7–72.9%) of 1,865 participants with at least one issue. At follow-up, there were improvements in nutrition, health-related quality of life, self-esteem, behaviors and educational outcomes. The intervention was feasible and largely acceptable. Uptake of referral services varied by issue. Y-Check cost US$47 per participant. Through Y-Check, we identified untreated conditions and risk behaviors and successfully treated and linked adolescents to services. Here we provide evidence on the potential of the intervention to positively impact health and well-being.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"87 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102154","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}
引用次数: 0
Time-of-day immunochemotherapy in nonsmall cell lung cancer: a randomized phase 3 trial 非小细胞肺癌的每日免疫化疗:一项随机3期试验
IF 82.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-02-02 DOI: 10.1038/s41591-025-04181-w
Zhe Huang, Liang Zeng, Zhaohui Ruan, Qun Zeng, Huan Yan, Wenjuan Jiang, Yi Xiong, Chunhua Zhou, Haiyan Yang, Li Liu, Jiacheng Dai, Nachuan Zou, Shidong Xu, Ya Wang, Zhan Wang, Jun Deng, Xue Chen, Jing Wang, Hua Xiang, Xiaomei Li, Boris Duchemann, Guoqiang Chen, Yang Xia, Tony Mok, Christoph Scheiermann, Francis Lévi, Nong Yang, Yongchang Zhang
Retrospective studies suggest that early time-of-day (ToD) infusions of immunochemotherapy may improve efficacy. However, prospective randomized controlled trials are needed to validate it. In this randomized phase 3 LungTIME-C01 trial, 210 patients with treatment naive stage IIIC–IV nonsmall cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a 1:1 ratio to either an early or late ToD group, defined by the administration of the first four cycles of an anti-PD-1 agent before or after 15:00 h. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS) and objective response rate (ORR). After a median follow-up of 28.7 months, the median PFS was 11.3 months (95% confidence interval (CI) = 9.2–13.4) in the early ToD group and 5.7 months (95% CI = 5.2–6.2) in the late ToD group, corresponding to a hazard ratio (HR) for earlier disease progression of 0.40 (95% CI = 0.29–0.55; P < 0.001). The median OS was 28.0 months (95% CI = not estimable (NE)–NE) in the early ToD group and 16.8 months (95% CI = 13.7–19.9) in the late ToD group, corresponding to an HR of an earlier death of 0.42 (95% CI = 0.29–0.60; P < 0.001). Treatment-related adverse events were consistent with the established safety profile, with no new safety signals observed. No significant differences in immune-related adverse events were observed between the two groups. Over the first four cycles, morning circulating CD8+ T cells increased in the early ToD group, whereas they declined in the late ToD group (P < 0.001). Furthermore, the ratio of activated (CD38+ HLA-DR+) versus exhausted (TIM-3+PD-1+) CD8+ T cells was higher in the early ToD group (P < 0.001) compared with the late ToD group (P < 0.001). In summary, our study indicates that early ToD immunochemotherapy substantially improves PFS and OS and is associated with enhanced antitumor CD8+ T cell characteristics compared with late ToD treatment. ClinicalTrials.gov registration: NCT05549037.
回顾性研究表明,每天早时间(ToD)输注免疫化疗可提高疗效。然而,需要前瞻性随机对照试验来验证它。在这项随机的3期临床试验中,210例缺乏驱动突变的初始IIIC-IV期非小细胞肺癌(NSCLC)患者被按1:1的比例随机分配到早期或晚期ToD组,通过在15:00之前或之后施用抗pd -1药物的前四个周期来定义。主要终点是无进展生存期(PFS),次要终点包括总生存期(OS)和客观缓解率(ORR)。中位随访28.7个月后,ToD早期组的中位PFS为11.3个月(95%可信区间(CI) = 9.2-13.4), ToD晚期组的中位PFS为5.7个月(95% CI = 5.2-6.2),对应于早期疾病进展的风险比(HR)为0.40 (95% CI = 0.29-0.55; P < 0.001)。ToD早期组的中位OS为28.0个月(95% CI =不可估计(NE) -NE), ToD晚期组的中位OS为16.8个月(95% CI = 13.7-19.9),对应于早期死亡的HR为0.42 (95% CI = 0.29-0.60; P < 0.001)。与治疗相关的不良事件与既定的安全性一致,未观察到新的安全性信号。两组之间免疫相关不良事件无显著差异。在前四个周期中,ToD早期组的晨循环CD8+ T细胞增加,而ToD晚期组的晨循环CD8+ T细胞减少(P < 0.001)。此外,与ToD晚期组相比,ToD早期组活化(CD38+ HLA-DR+)和耗尽(TIM-3+PD-1+) CD8+ T细胞的比例(P < 0.001)更高。综上所述,我们的研究表明,与晚期ToD治疗相比,早期ToD免疫化疗显著改善了PFS和OS,并与增强的抗肿瘤CD8+ T细胞特征相关。ClinicalTrials.gov注册:NCT05549037。
{"title":"Time-of-day immunochemotherapy in nonsmall cell lung cancer: a randomized phase 3 trial","authors":"Zhe Huang, Liang Zeng, Zhaohui Ruan, Qun Zeng, Huan Yan, Wenjuan Jiang, Yi Xiong, Chunhua Zhou, Haiyan Yang, Li Liu, Jiacheng Dai, Nachuan Zou, Shidong Xu, Ya Wang, Zhan Wang, Jun Deng, Xue Chen, Jing Wang, Hua Xiang, Xiaomei Li, Boris Duchemann, Guoqiang Chen, Yang Xia, Tony Mok, Christoph Scheiermann, Francis Lévi, Nong Yang, Yongchang Zhang","doi":"10.1038/s41591-025-04181-w","DOIUrl":"https://doi.org/10.1038/s41591-025-04181-w","url":null,"abstract":"Retrospective studies suggest that early time-of-day (ToD) infusions of immunochemotherapy may improve efficacy. However, prospective randomized controlled trials are needed to validate it. In this randomized phase 3 LungTIME-C01 trial, 210 patients with treatment naive stage IIIC–IV nonsmall cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a 1:1 ratio to either an early or late ToD group, defined by the administration of the first four cycles of an anti-PD-1 agent before or after 15:00 h. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS) and objective response rate (ORR). After a median follow-up of 28.7 months, the median PFS was 11.3 months (95% confidence interval (CI) = 9.2–13.4) in the early ToD group and 5.7 months (95% CI = 5.2–6.2) in the late ToD group, corresponding to a hazard ratio (HR) for earlier disease progression of 0.40 (95% CI = 0.29–0.55; P < 0.001). The median OS was 28.0 months (95% CI = not estimable (NE)–NE) in the early ToD group and 16.8 months (95% CI = 13.7–19.9) in the late ToD group, corresponding to an HR of an earlier death of 0.42 (95% CI = 0.29–0.60; P < 0.001). Treatment-related adverse events were consistent with the established safety profile, with no new safety signals observed. No significant differences in immune-related adverse events were observed between the two groups. Over the first four cycles, morning circulating CD8+ T cells increased in the early ToD group, whereas they declined in the late ToD group (P < 0.001). Furthermore, the ratio of activated (CD38+ HLA-DR+) versus exhausted (TIM-3+PD-1+) CD8+ T cells was higher in the early ToD group (P < 0.001) compared with the late ToD group (P < 0.001). In summary, our study indicates that early ToD immunochemotherapy substantially improves PFS and OS and is associated with enhanced antitumor CD8+ T cell characteristics compared with late ToD treatment. ClinicalTrials.gov registration: NCT05549037.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"67 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146102153","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}
引用次数: 0
Base editing enables off-the-shelf CAR T cells for leukemia. 碱基编辑使现成的CAR - T细胞能够治疗白血病。
IF 82.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-30 DOI: 10.1038/d41591-026-00004-8
Karen O'Leary
{"title":"Base editing enables off-the-shelf CAR T cells for leukemia.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00004-8","DOIUrl":"https://doi.org/10.1038/d41591-026-00004-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"37 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089091","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}
引用次数: 0
Babies share microbiomes at nursery. 婴儿在托儿所共享微生物群。
IF 5 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-30 DOI: 10.1038/d41591-026-00006-6
Karen O'Leary
{"title":"Babies share microbiomes at nursery.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00006-6","DOIUrl":"https://doi.org/10.1038/d41591-026-00006-6","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106254","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}
引用次数: 0
New analysis shows no link between autism and paracetamol. 新的分析显示自闭症和扑热息痛之间没有联系。
IF 82.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-30 DOI: 10.1038/d41591-026-00005-7
Karen O'Leary
{"title":"New analysis shows no link between autism and paracetamol.","authors":"Karen O'Leary","doi":"10.1038/d41591-026-00005-7","DOIUrl":"https://doi.org/10.1038/d41591-026-00005-7","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"3 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089005","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}
引用次数: 0
Author Correction: Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. 作者更正:联合抑制BET家族蛋白和组蛋白去乙酰化酶作为一种潜在的基于表观遗传学的胰腺导管腺癌治疗方法。
IF 5 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2026-01-29 DOI: 10.1038/s41591-026-04234-8
Pawel K Mazur, Alexander Herner, Stephano S Mello, Matthias Wirth, Simone Hausmann, Francisco J Sánchez-Rivera, Shane M Lofgren, Timo Kuschma, Stephan A Hahn, Deepak Vangala, Marija Trajkovic-Arsic, Aayush Gupta, Irina Heid, Peter B Noël, Rickmer Braren, Mert Erkan, Jörg Kleeff, Bence Sipos, Leanne C Sayles, Mathias Heikenwalder, Elisabeth Heßmann, Volker Ellenrieder, Irene Esposito, Tyler Jacks, James E Bradner, Purvesh Khatri, E Alejandro Sweet-Cordero, Laura D Attardi, Roland M Schmid, Guenter Schneider, Julien Sage, Jens T Siveke
{"title":"Author Correction: Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.","authors":"Pawel K Mazur, Alexander Herner, Stephano S Mello, Matthias Wirth, Simone Hausmann, Francisco J Sánchez-Rivera, Shane M Lofgren, Timo Kuschma, Stephan A Hahn, Deepak Vangala, Marija Trajkovic-Arsic, Aayush Gupta, Irina Heid, Peter B Noël, Rickmer Braren, Mert Erkan, Jörg Kleeff, Bence Sipos, Leanne C Sayles, Mathias Heikenwalder, Elisabeth Heßmann, Volker Ellenrieder, Irene Esposito, Tyler Jacks, James E Bradner, Purvesh Khatri, E Alejandro Sweet-Cordero, Laura D Attardi, Roland M Schmid, Guenter Schneider, Julien Sage, Jens T Siveke","doi":"10.1038/s41591-026-04234-8","DOIUrl":"https://doi.org/10.1038/s41591-026-04234-8","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":" ","pages":""},"PeriodicalIF":50.0,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086482","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}
引用次数: 0
期刊
Nature Medicine
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1