Nature Medicine最新文献

{"title":"Broad rim lesions are a new pathological and imaging biomarker for rapid disease progression in multiple sclerosis","authors":"Luisa Klotz, Joost Smolders, Jussi Lehto, Markus Matilainen, Lukas Lütje, Luzia Buchholz, Stefanie Albrecht, Carolin Walter, Julian Varghese, Heinz Wiendl, Marjo Nylund, Christian Thomas, Maria Gardberg, Aletta M. R. van den Bosch, Laura Airas, Inge Huitinga, Tanja Kuhlmann","doi":"10.1038/s41591-025-03625-7","DOIUrl":"https://doi.org/10.1038/s41591-025-03625-7","url":null,"abstract":"<p>Current multiple sclerosis (MS) treatments reduce relapse activity but have limited impact on disease progression. Clinical trials targeting progression often fail because of insufficient understanding of its underlying mechanisms. This study analyzed a clinically well-characterized MS autopsy cohort from the Netherland Brain Bank (186 individuals) from which we selected donors exhibiting opposite disease trajectories of slow versus rapid progression. We performed extensive unbiased histology and spatial transcriptomics, which unveiled a distinct MS lesion type marked by an extensive myeloid cell rim with cellular and transcriptional signatures of innate immune activation, inflammatory cytokine production, unfolded protein response and apoptosis. Presence of this particular lesion type was linked to rapid disease progression. An independent translocator protein 18-kDa positron emission tomography study (114 individuals) validates the association between lesions with a broad myeloid cell rim and disease progression in individuals with MS. Our findings offer crucial insights into the mechanisms behind MS progression, identifying broad rim lesions as a biomarker for rapid disease progression and potentially guiding patient selection for future therapeutic trials targeting central nervous system intrinsic inflammation.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"45 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884916","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":"Author Correction: Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial","authors":"Martin Wermke, Dejka M. Araujo, Manik Chatterjee, Apostolia M. Tsimberidou, Tobias A. W. Holderried, Amir A. Jazaeri, Ran Reshef, Carsten Bokemeyer, Winfried Alsdorf, Katrin Wetzko, Peter Brossart, Katrin Aslan, Linus Backert, Sebastian Bunk, Jens Fritsche, Swapna Gulde, Silvana Hengler, Norbert Hilf, Mohammad B. Hossain, Jens Hukelmann, Mamta Kalra, Delfi Krishna, M. Alper Kursunel, Dominik Maurer, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Karine Pozo, Arun Satelli, Marilena Letizia, Heiko Schuster, Oliver Schoor, Claudia Wagner, Hans-Georg Rammensee, Carsten Reinhardt, Harpreet Singh-Jasuja, Steffen Walter, Toni Weinschenk, Jason J. Luke, Cedrik M. Britten","doi":"10.1038/s41591-025-03731-6","DOIUrl":"https://doi.org/10.1038/s41591-025-03731-6","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-025-03650-6, published online 9 April 2025.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"14 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885407","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":"Effect of felzartamab on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies","authors":"Matthias Diebold, Patrick T. Gauthier, Katharina A. Mayer, Martina Mackova, Christian Hinze, Jessica Chang, Uptal D. Patel, Ekkehard Schütz, Bernd Jilma, Eva Schrezenmeier, Klemens Budde, Georg A. Böhmig, Philip F. Halloran","doi":"10.1038/s41591-025-03653-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03653-3","url":null,"abstract":"<p>A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"9 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884915","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":"Personalized inhaled bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis","authors":"Benjamin K. Chan, Gail L. Stanley, Kaitlyn E. Kortright, Albert C. Vill, Mrinalini Modak, Isabel M. Ott, Ying Sun, Silvia Würstle, Casey N. Grun, Barbara I. Kazmierczak, Govindarajan Rajagopalan, Zachary M. Harris, Clemente J. Britto, Jill Stewart, Jaideep S. Talwalkar, Casey R. Appell, Nauman Chaudary, Sugeet K. Jagpal, Raksha Jain, Adaobi Kanu, Bradley S. Quon, John M. Reynolds, Charlotte C. Teneback, Quynh-Anh Mai, Veronika Shabanova, Paul E. Turner, Jonathan L. Koff","doi":"10.1038/s41591-025-03678-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03678-8","url":null,"abstract":"<p>Bacteriophage (phage) therapy, which uses lytic viruses as antimicrobials, is a potential strategy to address the antimicrobial resistance crisis. Cystic fibrosis, a disease complicated by recurrent <i>Pseudomonas aeruginosa</i> pulmonary infections, is an example of the clinical impact of antimicrobial resistance. Here, using a personalized phage therapy strategy that selects phages for a predicted evolutionary trade-off, nine adults with cystic fibrosis (eight women and one man) of median age 32 (range 22–46) years were treated with phages on a compassionate basis because their clinical course was complicated by multidrug-resistant or pan-drug-resistant <i>Pseudomonas</i> that was refractory to prior courses of standard antibiotics. The individuals received a nebulized cocktail or single-phage therapy without adverse events. Five to 18 days after phage therapy, sputum <i>Pseudomonas</i> decreased by a median of 10⁴ CFU ml⁻¹, or a mean difference of 10² CFU ml⁻¹ (<i>P</i> = 0.006, two-way analysis of variance with Dunnett’s multiple-comparisons test), without altering sputum microbiome, and an analysis of sputum <i>Pseudomonas</i> showed evidence of trade-offs that decreased antibiotic resistance or bacterial virulence. In addition, an improvement of 6% (median) and 8% (mean) predicted FEV₁ was observed 21–35 days after phage therapy (<i>P</i> = 0.004, Wilcoxon signed-rank <i>t</i>-test), which may reflect the combined effects of decreased bacterial sputum density and phage-driven trade-offs. These results show that a personalized, nebulized phage therapy trade-off strategy may affect clinical and microbiologic endpoints, which must be evaluated in larger clinical trials.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"13 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884919","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 biomarker predicts dementia onset and progression in Alzheimer’s disease","authors":"","doi":"10.1038/s41591-025-03700-z","DOIUrl":"https://doi.org/10.1038/s41591-025-03700-z","url":null,"abstract":"Proteomics analyses of thousands of proteins in human cerebrospinal fluid reveal that the ratio of two proteins can be used to predict future dementia or cognitive resilience among people with Alzheimer’s disease brain pathology.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"80 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880485","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":"Changing climate and socioeconomic factors contribute to global antimicrobial resistance","authors":"Weibin Li, Tingting Huang, Chaojie Liu, Haishaerjiang Wushouer, Xinyi Yang, Ruonan Wang, Haohai Xia, Xiying Li, Shengyue Qiu, Shanquan Chen, Hung Chak Ho, Cunrui Huang, Luwen Shi, Xiaodong Guan, Guobao Tian, Gordon Liu, Kristie L. Ebi, Lianping Yang","doi":"10.1038/s41591-025-03629-3","DOIUrl":"https://doi.org/10.1038/s41591-025-03629-3","url":null,"abstract":"<p>Climate change poses substantial challenges in containing antimicrobial resistance (AMR) from a One Health perspective. Using 4,502 AMR surveillance records involving 32 million tested isolates from 101 countries (1999–2022), we analyzed the impact of socioeconomic and environmental factors on AMR. We also established forecast models based on several scenarios, considering antimicrobial consumption reduction, sustainable development initiatives and different shared socioeconomic pathways under climate change. Our findings reveal growing AMR disparities between high-income countries and low- and middle-income countries under different shared socioeconomic pathway scenarios. By 2050, compared with the baseline, sustainable development efforts showed the most prominent effect by reducing AMR prevalence by 5.1% (95% confidence interval (CI): 0.0–26.6%), surpassing the effect of antimicrobial consumption reduction. Key contributors include reducing out-of-pocket health expenses (3.6% (95% CI: −0.5 to 21.4%)); comprehensive immunization coverage (1.2% (95% CI: −0.1% to 8.2%)); adequate health investments (0.2% (95% CI: 0.0–2.4%)) and universal access to water, sanitation and hygiene services (0.1% (95% CI: 0.0–0.4%)). These findings highlight the importance of sustainable development strategies as the most effective approach to help low- and middle-income countries address the dual challenges of climate change and AMR.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"24 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880445","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 risk score boosts prostate cancer detection","authors":"","doi":"10.1038/d41591-025-00027-7","DOIUrl":"https://doi.org/10.1038/d41591-025-00027-7","url":null,"abstract":"The polygenic score, based on analysis of DNA from a saliva sample, led to the detection of more cancers than would have been found with standard screening pathways.","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"31 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880483","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":"Author Correction: T cell malignancies after CAR T cell therapy in the DESCAR-T registry","authors":"Remy Dulery, Vincent Guiraud, Sylvain Choquet, Catherine Thieblemont, Emmanuel Bachy, Stéphane Barete, Ève Todesco, Bertrand Arnulf, Nicolas Boissel, André Baruchel, Jacques-Olivier Bay, Steven Le Gouill, Roch Houot","doi":"10.1038/s41591-025-03717-4","DOIUrl":"https://doi.org/10.1038/s41591-025-03717-4","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-024-03458-w, published online 8 January 2025.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"9 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876312","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":"Author Correction: Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers","authors":"Conan G. Kinsey, Soledad A. Camolotto, Amelie M. Boespflug, Katrin P. Guillen, Mona Foth, Amanda Truong, Sophia S. Schuman, Jill E. Shea, Michael T. Seipp, Jeffrey T. Yap, Lance D. Burrell, David H. Lum, Jonathan R. Whisenant, G. Weldon Gilcrease, Courtney C. Cavalieri, Kaitrin M. Rehbein, Stephanie L. Cutler, Kajsa E. Affolter, Alana L. Welm, Bryan E. Welm, Courtney L. Scaife, Eric L. Snyder, Martin McMahon","doi":"10.1038/s41591-025-03713-8","DOIUrl":"https://doi.org/10.1038/s41591-025-03713-8","url":null,"abstract":"<p>Correction to: <i>Nature Medicine</i> https://doi.org/10.1038/s41591-019-0367-9, published online 4 March 2019.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"45 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872500","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":"CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade","authors":"Gusztav Milotay, Martin Little, Robert A. Watson, Dylan Muldoon, Sophie MacKay, Ayako Kurioka, Orion Tong, Chelsea A. Taylor, Isar Nassiri, Louisa M. Webb, Oluwafemi Akin-Adigun, Julia Bremke, Weiyu Ye, Bo Sun, Piyush Kumar Sharma, Ros Cooper, Sara Danielli, Flavia Matos Santo, Alba Verge de Los Aires, Guangyi Niu, Lea Cohen, Esther Ng, James J. Gilchrist, Amanda Y. Chong, Alex Mentzer, Victoria Woodcock, Nicholas Coupe, Miranda J. Payne, Michael Youdell, Mark R. Middleton, Paul Klenerman, Benjamin P. Fairfax","doi":"10.1038/s41591-025-03647-1","DOIUrl":"https://doi.org/10.1038/s41591-025-03647-1","url":null,"abstract":"<p>Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV⁺ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8⁺ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8⁺ T cells from CMV⁻ patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV⁺ hazard ratio for death: 1.02, <i>P</i> = 0.92), whereas CMV⁺ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV⁺ hazard ratio for death: 0.37, <i>P</i> &lt; 0.01), a finding also seen in CMV⁺ adjuvant single-agent anti-PD-1 ICB recipients (CMV⁺ hazard ratio for recurrence: 0.19, <i>P</i> = 0.03). We identify <i>TBX21</i>, encoding T-bet, as a transcriptional driver of CMV-associated CD8⁺ T cell gene expression, finding that <i>TBX21</i> expression is predictive of overall survival (hazard ratio: 0.62, <i>P</i> = 0.026). CMV⁺ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, <i>P</i> = 2.2 × 10⁻⁵), with lower incidence of colitis (<i>P</i> = 7.8 × 10⁻⁴) and pneumonitis (<i>P</i> = 0.028), an effect replicated in non-melanoma ICB recipients (<i>n</i> = 58, <i>P</i> = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, <i>P</i> = 1.8 × 10⁻⁴), indicating CMV seropositivity may protect against MM. Specifically, patients with <i>BRAF</i>-mutated MM are less likely to be CMV⁺ (odds ratio = 2.2, <i>P</i> = 0.0054), while CMV⁻ patients present 9 yr earlier with <i>BRAF</i> wild-type MM (<i>P</i> = 1.3 × 10⁻⁴). This work reveals an interaction between CMV infection, MM development according to <i>BRAF</i> status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":"7 1","pages":""},"PeriodicalIF":82.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862721","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}