Nature Medicine最新文献

{"title":"The traditional Chinese medicine Qiliqiangxin in heart failure with reduced ejection fraction: a randomized, double-blind, placebo-controlled trial","authors":"Iokfai Cheang, Wenming Yao, Yanli Zhou, Xu Zhu, Gehui Ni, Xinyi Lu, Shengen Liao, Rongrong Gao, Fang Zhou, Jiangang Shen, Alice Yeuk Lan Leung, Meng Jiang, Hong Kong, Ling Bai, Ailiman Mahemuti, Haitao Yuan, Yu-Gang Dong, Chun-Ka Wong, Qinghua Xu, Gaoxing Zhang, Jianhua Wu, Qi Lu, Junhai Zhang, Chunxi Cha, Qian Ren, Lu Fu, Bing Wang, Yongshun Xu, Houxiang Hu, Jing Dong, Zhuo Shang, Chaoping Yu, Songsen Li, Chen Yao, Lingling Gao, Haifeng Zhang, Anthony Rosenzweig, Zhenhua Jia, Xinli Li, QUEST Trial Committees and Investigators","doi":"10.1038/s41591-024-03169-2","DOIUrl":"10.1038/s41591-024-03169-2","url":null,"abstract":"Previous findings have indicated the potential benefits of the Chinese traditional medicine Qiliqiangxin (QLQX) in heart failure. Here we performed a double-blind, randomized controlled trial to evaluate the efficacy and safety of QLQX in patients with heart failure and reduced ejection fraction (HFrEF). This multicenter trial, conducted in 133 hospitals in China, enrolled 3,110 patients with HFrEF with NT-proBNP levels of ≥450 pg ml−1 and left ventricular ejection fraction of ≤40%. Participants were randomized to receive either QLQX capsules or placebo (four capsules three times daily) alongside standard heart failure therapy. The trial met its primary outcome, which was a composite of hospitalization for heart failure and cardiovascular death: over a median follow-up of 18.3 months, the primary outcome occurred in 389 patients (25.02%) in the QLQX group and 467 patients (30.03%) in the placebo group (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.68−0.90; P < 0.001). In an analysis of secondary outcomes, the QLQX group showed reductions in both hospitalization for heart failure (15.63% versus 19.16%; HR, 0.76; 95% CI, 0.64−0.90; P = 0.002) and cardiovascular death (13.31% versus 15.95%; HR, 0.83; 95% CI, 0.68−0.996; P = 0.045) compared to the placebo group. All-cause mortality did not differ significantly between the two groups (HR, 0.84; 95% CI, 0.70−1.01; P = 0.058) and adverse events were also comparable between the groups. The results of this trial indicate that QLQX may improve clinical outcomes in patients with HFrEF when added to conventional therapy. ChiCTR registration: ChiCTR1900021929 . In a randomized controlled trial involving patients with heart failure with reduced ejection fraction, treatment with Qiliqiangxin, a traditional Chinese medicine derived from 11 types of plants, decreased the incidence of cardiac events, as compared to placebo.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":58.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-024-03169-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells","authors":"Chirayu R. Chokshi, Muhammad Vaseem Shaikh, Benjamin Brakel, Martin A. Rossotti, David Tieu, William Maich, Alisha Anand, Shawn C. Chafe, Kui Zhai, Yujin Suk, Agata M. Kieliszek, Petar Miletic, Nicholas Mikolajewicz, David Chen, Jamie D. McNicol, Katherine Chan, Amy H. Y. Tong, Laura Kuhlmann, Lina Liu, Zahra Alizada, Daniel Mobilio, Nazanin Tatari, Neil Savage, Nikoo Aghaei, Shan Grewal, Anish Puri, Minomi Subapanditha, Dillon McKenna, Vladimir Ignatchenko, Joseph M. Salamoun, Jacek M. Kwiecien, Peter Wipf, Elizabeth R. Sharlow, John P. Provias, Jian-Qiang Lu, John S. Lazo, Thomas Kislinger, Yu Lu, Kevin R. Brown, Chitra Venugopal, Kevin A. Henry, Jason Moffat, Sheila K. Singh","doi":"10.1038/s41591-024-03138-9","DOIUrl":"https://doi.org/10.1038/s41591-024-03138-9","url":null,"abstract":"<p>Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. In this study, we investigated functional drivers of post-treatment recurrent GBM through integrative genomic analyses, genome-wide genetic perturbation screens in patient-derived GBM models and independent lines of validation. Specific genetic dependencies were found consistent across recurrent tumor models, accompanied by increased mutational burden and differential transcript and protein expression compared to its primary GBM predecessor. Our observations suggest a multi-layered genetic response to drive tumor recurrence and implicate <i>PTP4A2</i> (protein tyrosine phosphatase 4A2) as a modulator of self-renewal, proliferation and tumorigenicity in recurrent GBM. Genetic perturbation or small-molecule inhibition of PTP4A2 acts through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and its downstream molecular players, exploiting a functional dependency on ROBO signaling. Because a pan-PTP4A inhibitor was limited by poor penetrance across the blood–brain barrier in vivo, we engineered a second-generation chimeric antigen receptor (CAR) T cell therapy against ROBO1, a cell surface receptor enriched across recurrent GBM specimens. A single dose of ROBO1-targeted CAR T cells doubled median survival in cell-line-derived xenograft (CDX) models of recurrent GBM. Moreover, in CDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma, ROBO1 CAR T cells eradicated tumors in 50–100% of mice. Our study identifies a promising multi-targetable PTP4A–ROBO1 signaling axis that drives tumorigenicity in recurrent GBM, with potential in other malignant brain tumors.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877729","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":"Antifungal heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infections","authors":"Bing Zhai, Chen Liao, Siddharth Jaggavarapu, Yuanyuan Tang, Thierry Rolling, Yating Ning, Tianshu Sun, Sean A. Bergin, Mergim Gjonbalaj, Edwin Miranda, N. Esther Babady, Oliver Bader, Ying Taur, Geraldine Butler, Li Zhang, Joao B. Xavier, David S. Weiss, Tobias M. Hohl","doi":"10.1038/s41591-024-03183-4","DOIUrl":"https://doi.org/10.1038/s41591-024-03183-4","url":null,"abstract":"<p>Breakthrough fungal infections in patients on antimicrobial prophylaxis during allogeneic hematopoietic cell transplantation (allo-HCT) represent a major and often unexplained cause of morbidity and mortality. <i>Candida parapsilosis</i> is a common cause of invasive candidiasis and has been classified as a high-priority fungal pathogen by the World Health Organization. In high-risk allo-HCT recipients on micafungin prophylaxis, we show that heteroresistance (the presence of a phenotypically unstable, low-frequency subpopulation of resistant cells (~1 in 10,000)) underlies breakthrough bloodstream infections by <i>C. parapsilosis</i>. By analyzing 219 clinical isolates from North America, Europe and Asia, we demonstrate widespread micafungin heteroresistance in <i>C. parapsilosis</i>. Standard antimicrobial susceptibility tests, such as broth microdilution or gradient diffusion assays, which guide drug selection for invasive infections, fail to detect micafungin heteroresistance in <i>C. parapsilosis</i>. To facilitate rapid detection of micafungin heteroresistance in <i>C. parapsilosis</i>, we constructed a predictive machine learning framework that classifies isolates as heteroresistant or susceptible using a maximum of ten genomic features. These results connect heteroresistance to unexplained antifungal prophylaxis failure in allo-HCT recipients and demonstrate a proof-of-principle diagnostic approach with the potential to guide clinical decisions and improve patient care.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877730","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":"Integrating traditional and modern medicines to treat heart failure","authors":"Zhuang Tian,&nbsp;Shuyang Zhang","doi":"10.1038/s41591-024-03135-y","DOIUrl":"10.1038/s41591-024-03135-y","url":null,"abstract":"A large clinical trial supports the incorporation of qiliqiangxin, a traditional Chinese medicine, into standard treatment regimens for heart failure — highlighting a promising integration of ancient wisdom with modern medical practices through rigorous science.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":58.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877685","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 brain cell atlas integrating single-cell transcriptomes across human brain regions","authors":"Xinyue Chen,&nbsp;Yin Huang,&nbsp;Liangfeng Huang,&nbsp;Ziliang Huang,&nbsp;Zhao-Zhe Hao,&nbsp;Lahong Xu,&nbsp;Nana Xu,&nbsp;Zhi Li,&nbsp;Yonggao Mou,&nbsp;Mingli Ye,&nbsp;Renke You,&nbsp;Xuegong Zhang,&nbsp;Sheng Liu,&nbsp;Zhichao Miao","doi":"10.1038/s41591-024-03150-z","DOIUrl":"10.1038/s41591-024-03150-z","url":null,"abstract":"While single-cell technologies have greatly advanced our comprehension of human brain cell types and functions, studies including large numbers of donors and multiple brain regions are needed to extend our understanding of brain cell heterogeneity. Integrating atlas-level single-cell data presents a chance to reveal rare cell types and cellular heterogeneity across brain regions. Here we present the Brain Cell Atlas, a comprehensive reference atlas of brain cells, by assembling single-cell data from 70 human and 103 mouse studies of the brain throughout major developmental stages across brain regions, covering over 26.3 million cells or nuclei from both healthy and diseased tissues. Using machine-learning based algorithms, the Brain Cell Atlas provides a consensus cell type annotation, and it showcases the identification of putative neural progenitor cells and a cell subpopulation of PCDH9high microglia in the human brain. We demonstrate the gene regulatory difference of PCDH9high microglia between hippocampus and prefrontal cortex and elucidate the cell–cell communication network. The Brain Cell Atlas presents an atlas-level integrative resource for comparing brain cells in different environments and conditions within the Human Cell Atlas. A single-cell transcriptomic study from the Human Cell Atlas integrating over 11 million brain cells from 70 studies uncovers differences across human brain regions and identifies rare progenitor and microglia subtypes.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":58.7,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41591-024-03150-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141877686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determinants and inequities in healthy working life expectancy in China.","authors":"Chenshuang Li, Lingling Wang, Lieyun Ding, Ying Zhou","doi":"10.1038/s41591-024-03184-3","DOIUrl":"https://doi.org/10.1038/s41591-024-03184-3","url":null,"abstract":"<p><p>Many countries are raising the pension age to mitigate the challenges of population aging, but such a solution may ignore the disparities in health and working conditions across populations. Using large-scale longitudinal data from China, this study provides estimates of healthy working life expectancy (HWLE), defined as the average number of years expected to be spent healthy and in work from age 50 years, and highlights substantial inequities in HWLE by gender, socioeconomic status and geographical region. The HWLE from age 50 years was, on average, 6.87 (95% confidence interval: 6.70 to 7.04) years in China. Hypertension was the leading chronic condition for people working unhealthily (5.67 years for men and 4.85 years for women), and arthritis contributed the largest differences in unhealthy working years across people by occupation (agricultural laborer versus enterprise employee, 3.28 years). Moreover, adopting healthy lifestyles was associated with gains in HWLE (2.13 years for men and 1.61 years for women). Our findings suggest that increasing the pension age through a 'one-size-fits-all' approach may not effectively meet the goal of extending working lives. Inclusive initiatives aimed at targeted populations to promote health or work conditions and to facilitate the pension system will be essential to improve HWLE by reducing inequities.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":58.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875409","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 burden of diabetes-associated multiple long-term conditions on years of life spent and lost.","authors":"Edward W Gregg, Adrian Pratt, Alex Owens, Emma Barron, Rupert Dunbar-Rees, Eirion T Slade, Nasrin Hafezparast, Chirag Bakhai, Paul Chappell, Victoria Cornelius, Desmond G Johnston, Jacqueline Mathews, Jason Pickles, Ellie Bragan Turner, Gary Wainman, Kate Roberts, Kamlesh Khunti, Jonathan Valabhji","doi":"10.1038/s41591-024-03123-2","DOIUrl":"10.1038/s41591-024-03123-2","url":null,"abstract":"<p><p>Diabetes mellitus is a central driver of multiple long-term conditions (MLTCs), but population-based studies have not clearly characterized the burden across the life course. We estimated the age of onset, years of life spent and loss associated with diabetes-related MLTCs among 46 million English adults. We found that morbidity patterns extend beyond classic diabetes complications and accelerate the onset of severe MLTCs by 20 years earlier in life in women and 15 years earlier in men. By the age of 50 years, one-third of those with diabetes have at least three conditions, spend >20 years with them and die 11 years earlier than the general population. Each additional condition at the age of 50 years is associated with four fewer years of life. Hypertension, depression, cancer and coronary heart disease contribute heavily to MLTCs in older age and create the greatest community-level burden on years spent (813 to 3,908 years per 1,000 individuals) and lost (900 to 1,417 years per 1,000 individuals). However, in younger adulthood, depression, severe mental illness, learning disabilities, alcohol dependence and asthma have larger roles, and when they occur, all except alcohol dependence were associated with long periods of life spent (11-14 years) and all except asthma associated with many years of life lost (11-15 years). These findings provide a baseline for population monitoring and underscore the need to prioritize effective prevention and management approaches.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":58.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875410","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":"Western diets and chronic diseases","authors":"Timon E. Adolph,&nbsp;Herbert Tilg","doi":"10.1038/s41591-024-03165-6","DOIUrl":"10.1038/s41591-024-03165-6","url":null,"abstract":"‘Westernization’, which incorporates industrial, cultural and dietary trends, has paralleled the rise of noncommunicable diseases across the globe. Today, the Western-style diet emerges as a key stimulus for gut microbial vulnerability, chronic inflammation and chronic diseases, affecting mainly the cardiovascular system, systemic metabolism and the gut. Here we review the diet of modern times and evaluate the threat it poses for human health by summarizing recent epidemiological, translational and clinical studies. We discuss the links between diet and disease in the context of obesity and type 2 diabetes, cardiovascular diseases, gut and liver diseases and solid malignancies. We collectively interpret the evidence and its limitations and discuss future challenges and strategies to overcome these. We argue that healthcare professionals and societies must react today to the detrimental effects of the Western diet to bring about sustainable change and improved outcomes in the future. This Review outlines how Western-style diets contribute to the rising incidence of chronic, noncommunicable diseases by converging on key mechanisms, including gut microbial rarefaction and chronic inflammation.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":58.7,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857642","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":"Cranioencephalic functional lymphoid units in glioblastoma","authors":"Celia Dobersalske, Laurèl Rauschenbach, Yichao Hua, Christoph Berliner, Anita Steinbach, Anika Grüneboom, Konstantinos D. Kokkaliaris, Dieter H. Heiland, Pia Berger, Sarah Langer, Chin L. Tan, Martin Stenzel, Somaya Landolsi, Flora Weber, Marvin Darkwah Oppong, Rudolf A. Werner, Hanah Gull, Thomas Schröder, Thomas Linsenmann, Andreas K. Buck, Matthias Gunzer, Martin Stuschke, Kathy Keyvani, Michael Forsting, Martin Glas, Jonathan Kipnis, Dennis A. Steindler, Hans Christian Reinhardt, Edward W. Green, Michael Platten, Alpaslan Tasdogan, Ken Herrmann, Florian Rambow, Igor Cima, Ulrich Sure, Björn Scheffler","doi":"10.1038/s41591-024-03152-x","DOIUrl":"https://doi.org/10.1038/s41591-024-03152-x","url":null,"abstract":"<p>The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8⁺ T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8⁺ effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857643","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":"ADC superior to chemotherapy in recurrent cervical cancer","authors":"","doi":"10.1038/d41591-024-00054-w","DOIUrl":"https://doi.org/10.1038/d41591-024-00054-w","url":null,"abstract":"The antibody–drug conjugate (ADC) tisotumab vedotin resulted in improved progression-free and overall survival, leading to FDA approval and a new treatment option for patients.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":82.9,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794826","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}