Nature Medicine最新文献

{"title":"The unseen climate health risks of antimicrobial resistance in urban informal settlements","authors":"Karin Leder, Brett Davis, S. Fiona Barker, Fiona Lynch, Rebekah Henry","doi":"10.1038/s41591-025-03548-3","DOIUrl":"10.1038/s41591-025-03548-3","url":null,"abstract":"","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 3","pages":"712-714"},"PeriodicalIF":58.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518536","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":"Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases","authors":"Somnath Tagore, Lindsay Caprio, Amit Dipak Amin, Kresimir Bestak, Karan Luthria, Edridge D’Souza, Irving Barrera, Johannes C. Melms, Sharon Wu, Sinan Abuzaid, Yiping Wang, Viktoria Jakubikova, Peter Koch, D. Zack Brodtman, Banpreet Bawa, Sachin K. Deshmukh, Leon Ebel, Miguel A. Ibarra-Arellano, Abhinav Jaiswal, Carino Gurjao, Jana Biermann, Neha Shaikh, Priyanka Ramaradj, Yohanna Georgis, Galina G. Lagos, Matthew I. Ehrlich, Patricia Ho, Zachary H. Walsh, Meri Rogava, Michelle Garlin Politis, Devanik Biswas, Azzurra Cottarelli, Nikhil Rizvi, Catherine A. Shu, Benjamin Herzberg, Niroshana Anandasabapathy, George Sledge, Emmanuel Zorn, Peter Canoll, Jeffrey N. Bruce, Naiyer A. Rizvi, Alison M. Taylor, Anjali Saqi, Hanina Hibshoosh, Gary K. Schwartz, Brian S. Henick, Fei Chen, Denis Schapiro, Parin Shah, Benjamin Izar","doi":"10.1038/s41591-025-03530-z","DOIUrl":"https://doi.org/10.1038/s41591-025-03530-z","url":null,"abstract":"<p>Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CIN^high cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"25 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506888","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 triplet immune checkpoint blockade in newly diagnosed glioblastoma","authors":"Georgina V. Long, Elena Shklovskaya, Laveniya Satgunaseelan, Yizhe Mao, Inês Pires da Silva, Kristen A. Perry, Russell J. Diefenbach, Tuba N. Gide, Brindha Shivalingam, Michael E. Buckland, Maria Gonzalez, Nicole Caixeiro, Ismael A. Vergara, Xinyu Bai, Robert V. Rawson, Edward Hsiao, Umaimainthan Palendira, Tri Giang Phan, Alexander M. Menzies, Matteo S. Carlino, Camelia Quek, Sean M. Grimmond, Joseph H. A. Vissers, Dannel Yeo, John E. J. Rasko, Mustafa Khasraw, Bart Neyns, David A. Reardon, David M. Ashley, Helen Wheeler, Michael Back, Richard A. Scolyer, James Drummond, James S. Wilmott, Helen Rizos","doi":"10.1038/s41591-025-03512-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03512-1","url":null,"abstract":"<p>Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH<i>-</i>wild-type, <i>MGMT</i> promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927).</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"25 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506966","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":"Cerebrospinal fluid circulating tumor DNA profiling for risk stratification and matched treatment of central nervous system metastases","authors":"Mei-Mei Zheng, Qing Zhou, Hua-Jun Chen, Ben-Yuan Jiang, Li-Bo Tang, Guang-Ling Jie, Hai-Yan Tu, Kai Yin, Hao Sun, Si-Yang Liu, Jia-Tao Zhang, Fa-Man Xiao, Jin-Ji Yang, Xu-Chao Zhang, Wen-Zhao Zhong, Yi Pan, Bin-Chao Wang, Hong-Hong Yan, Wei-Bang Guo, Zhi-Hong Chen, Zhen Wang, Chong-Rui Xu, Su-Yun Li, Si-Yang Maggie Liu, Lu Zeng, Shang-Li Cai, Guo-Qiang Wang, Dong-Qin Zhu, Yang-Si Li, Yi-Long Wu","doi":"10.1038/s41591-025-03538-5","DOIUrl":"https://doi.org/10.1038/s41591-025-03538-5","url":null,"abstract":"<p>Genomic profiling of central nervous system (CNS) metastases has the potential to guide treatments. In the present study, we included 584 patients with non-small-cell lung cancer and CNS metastases and performed a comprehensive analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) with clinicopathological annotation. CSF ctDNA-positive detection was independently associated with shorter survival than negative detection (hazard ratio (HR) = 1.9, 95% confidence interval (CI) = 1.56–2.39; <i>P</i> &lt; 0.0001). Matched tumor–CSF analysis characterized the CSF private molecular features causing poor survival (HR = 1.64, 95% CI = 1.15–2.32, <i>P</i> = 0.006). A multimetric CSF ctDNA prognostic model integrating CSF ctDNA features and clinical factors was developed for risk-stratifying CNS metastases and validated in an independent cohort. Among patients with treatment histories available, those positive for a driver alteration by CSF ctDNA showed a survival benefit from CSF-matched therapy (HR = 0.78, 95% CI = 0.65–0.92, <i>P</i> = 0.003). Longitudinal monitoring by CSF identified CNS-specific resistant mechanisms and a second matched targeted therapy indicating improved survival (HR = 0.56, 95% CI = 0.35–0.91, <i>P</i> = 0.018). These findings support the clinical value of CSF ctDNA for risk-stratifying CNS metastases and guiding therapy.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"28 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506950","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":"How to measure biological aging in humans","authors":"Luigi Ferrucci, Nir Barzilai, Daniel W. Belsky, Vadim N. Gladyshev","doi":"10.1038/s41591-025-03550-9","DOIUrl":"https://doi.org/10.1038/s41591-025-03550-9","url":null,"abstract":"<p>We were intrigued by the article by M. Arfan Ikram regarding the purported ‘misuse’ of biological aging, recently published in <i>Nature Medicine</i>¹. We are grateful to the author for raising this important issue but would like to offer a counterpoint to enrich the scientific dialogue on this topic.</p><p>When Peto and Doll stated “There is no such thing as aging”², they could not have anticipated the remarkable advancements in the understanding of the biology of aging over the subsequent two decades, including the development of various types of aging biomarkers. Although we concur that aging does not equal changes over time (but involves the accumulation of negative consequences of life, such as damage to macromolecules and organelles), dismissing the idea of any biomarkers based on calendar age as an approximate measure of aging seems counterproductive. Calendar age is deeply rooted in human life, science and society; it is reasonable to think that the accumulation of damage over time must come with consequences for health. It is also important to clarify how aging, biological age and disease are defined, because there is wide difference of opinion on these terms and concepts.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"54 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495303","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":"Endothelial cell-related genetic variants identify LDL cholesterol-sensitive individuals who derive greater benefit from aggressive lipid lowering","authors":"Nicholas A. Marston,&nbsp;Frederick K. Kamanu,&nbsp;Giorgio E. M. Melloni,&nbsp;Gavin Schnitzler,&nbsp;Aaron Hakim,&nbsp;Rosa X. Ma,&nbsp;Helen Kang,&nbsp;Daniel I. Chasman,&nbsp;Robert P. Giugliano,&nbsp;Patrick T. Ellinor,&nbsp;Paul M. Ridker,&nbsp;Jesse M. Engreitz,&nbsp;Marc S. Sabatine,&nbsp;Christian T. Ruff,&nbsp;Rajat M. Gupta","doi":"10.1038/s41591-025-03533-w","DOIUrl":"10.1038/s41591-025-03533-w","url":null,"abstract":"The role of endothelial cell (EC) dysfunction in contributing to an individual’s susceptibility to coronary atherosclerosis and how low-density lipoprotein cholesterol (LDL-C) concentrations might modify this relationship have not been previously studied. Here, from an examination of genome-wide significant single nucleotide polymorphisms associated with coronary artery disease (CAD), we identified variants with effects on EC function and constructed a 35 single nucleotide polymorphism polygenic risk score comprising these EC-specific variants (EC PRS). The association of the EC PRS with the risk of incident cardiovascular disease was tested in 3 cohorts: a primary prevention population in the UK Biobank (UKBB; n = 348,967); a primary prevention cohort from a trial that tested a statin (JUPITER, n = 8,749); and a secondary prevention cohort that tested a PCSK9 inhibitor (FOURIER, n = 14,298). In the UKBB, the EC PRS was independently associated with the risk of incident CAD (adjusted hazard ratio (aHR) per 1 s.d. of 1.24 (95% CI 1.21–1.26), P &lt; 2 × 10−16). Moreover, LDL-C concentration significantly modified this risk: the aHR per 1 s.d. was 1.26 (1.22–1.30) when LDL-C was 150 mg dl−1 but 1.00 (0.85–1.16) when LDL-C was 50 mg dl−1 (Pinteraction = 0.004). The clinical benefit of LDL-C lowering was significantly greater in individuals with a high EC PRS than in individuals with low or intermediate EC PRS, with relative risk reductions of 68% (HR 0.32 (0.18–0.59)) versus 29% (HR 0.71 (0.52–0.95)) in the primary prevention cohort (Pinteraction = 0.02) and 33% (HR 0.67 (0.53–0.83)) versus 8% (HR 0.92 (0.82–1.03)) in the secondary prevention cohort (Pinteraction = 0.01). We conclude that EC PRS quantifies an independent axis of CAD risk that is not currently captured in medical practice and identifies individuals who are more sensitive to the atherogenic effects of LDL-C and who would potentially derive substantially greater benefit from aggressive LDL-C lowering. From an analysis of participants in lipid-lowering trials for primary and secondary prevention of coronary artery disease, a polygenic risk score comprising 35 single nucleotide variants with predicted effects on endothelial cell function identified patients who benefited most from aggressive lipid-lowering therapy.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 3","pages":"963-969"},"PeriodicalIF":58.7,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495304","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":"AI tool reads immune signatures to detect disease","authors":"","doi":"10.1038/d41591-025-00016-w","DOIUrl":"https://doi.org/10.1038/d41591-025-00016-w","url":null,"abstract":"A machine learning framework — trained on B cell and T cell receptor sequences from thousands of people — can detect a range of infectious and autoimmune diseases.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"6 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506889","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 bispecific antibody delivers new treatment for NRG1 fusion–positive cancers","authors":"","doi":"10.1038/d41591-025-00015-x","DOIUrl":"https://doi.org/10.1038/d41591-025-00015-x","url":null,"abstract":"In a phase 2 registrational trial, zenocutuzumab showed durable anti-tumor activity across a variety of NRG1 fusion-positive cancer types, providing a new treatment for patients with few alternative options.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"8 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485855","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":"Epigenetic editing of PCSK9 for a durable reduction in cholesterol","authors":"","doi":"10.1038/s41591-025-03583-0","DOIUrl":"https://doi.org/10.1038/s41591-025-03583-0","url":null,"abstract":"A sustained decrease in low-density lipoprotein cholesterol (LDL-C) is key to reducing the risk of atherosclerotic cardiovascular disease; however, achieving this goal can be hampered by low adherence to standard of care and the sub-maximal efficacy of currently available long-acting therapeutics. We developed an epigenetic editor that targets PCSK9 and robustly and durably decreases LDL-C.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"15 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485851","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":"Nanoplastics in the human brain and their change in abundance over time","authors":"","doi":"10.1038/s41591-025-03571-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03571-4","url":null,"abstract":"Nanoplastics were identified in human brain samples from cadavers. Concentrations were higher in the brain than in the liver or kidneys, and appeared to increase over time between 2016 and 2024. Visualization of the plastics using a variety of approaches provided insights into the anatomical distribution and physical characteristics of nanoplastics.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"30 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477679","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}