Science Translational Medicine最新文献

{"title":"S-nitrosoglutathione reductase as a therapeutic target for diabetic vascular complications in rodent models","authors":"Shuang Zhao,&nbsp;Tianyu Song,&nbsp;Xin Tang,&nbsp;Chenglin Fan,&nbsp;Yuhao Yang,&nbsp;Zhiren Zhang,&nbsp;Ying Xia,&nbsp;Yan Zhang,&nbsp;Jiawei Cao,&nbsp;Ziyu Wang,&nbsp;Zhiguang Shi,&nbsp;Xinlong Tang,&nbsp;Dongjin Wang,&nbsp;Guoyong Yin,&nbsp;Shaohua Zhang,&nbsp;Yuanqing Gao,&nbsp;Hongshan Chen,&nbsp;Liansheng Wang,&nbsp;Feng Chen,&nbsp;Hong Wang,&nbsp;Bo Yu,&nbsp;Yu Cao,&nbsp;Kangyun Sun,&nbsp;Xin Liu,&nbsp;Xiujie Wang,&nbsp;Chenghui Yan,&nbsp;Yaling Han,&nbsp;Yi Han,&nbsp;Liping Xie,&nbsp;Yong Ji","doi":"10.1126/scitranslmed.adn9216","DOIUrl":"10.1126/scitranslmed.adn9216","url":null,"abstract":"<div >Endothelial dysfunction is one of the earliest processes in diabetes and a major contributor to diabetic vascular complications, which often exhibit limited response to glucose-lowering therapies. We identified up-regulated <i>S</i>-nitrosoglutathione reductase (GSNOR) as a critical factor associated with diabetic vascular complications by unbiased proteomics. Elevated GSNOR expression was observed in the endothelium of patients with type 2 diabetes and in streptozotocin (STZ)–induced type 1 diabetes mice as well as in <i>db/db</i> type 2 diabetes mouse models. Genetic ablation of endothelial <i>Gsnor</i> promoted angiogenesis, maintained vascular permeability, and improved vasodilation in type 1 diabetes mice induced by STZ. GSNOR deficiency protected against high glucose–induced endothelial dysfunction in vitro, as evidenced by rescued tube formation, enhanced spheroid sprouting, maintained barrier integrity, and reduced permeability. Mechanistically, GSNOR orchestrated endothelial dysfunction independently of its enzymatic activity by binding the transcription factor ETS-related gene (ERG) and triggered its nuclear export through chromosome region maintenance 1. We synthesized NYY-001, an oral agent, that selectively blocks the GSNOR-ERG interaction. The direct targeting of NYY-001 to GSNOR was determined by resolving the crystal structure of their complex using cryo–electron microscopy. NYY-001 treatment enhanced postischemic neovascularization and restored vascular permeability in the peripheral vasculature in STZ-induced type 1 diabetes and <i>db/db</i> type 2 diabetes mouse models. These findings reveal a mechanistic role for the GSNOR-ERG complex in diabetic vascular complications and highlight NYY-001 as a promising therapeutic candidate.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195413","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":"SV2A-PET imaging uncovers cortical synapse loss in multiple sclerosis","authors":"Emily M. Ullrich Gavilanes,&nbsp;Laura M. Bartos,&nbsp;Jonathan A. Gernert,&nbsp;Carla Ares Carral,&nbsp;Diego Ruiz Navarro,&nbsp;Joachim Havla,&nbsp;Lisa-Ann Gerdes,&nbsp;Johannes S. Gnörich,&nbsp;Lea H. Kunze,&nbsp;Julia S. Dorneich,&nbsp;Vanessa Pakula,&nbsp;Lisa Tagnin,&nbsp;Hanna Zimmermann,&nbsp;Klaus Seelos,&nbsp;Nicolai Franzmeier,&nbsp;Lukas Frontzkowski,&nbsp;Nuno Pedrosa de Barros,&nbsp;Annemie Ribbens,&nbsp;Rachel Maria Zwergal,&nbsp;Andreas Zwergal,&nbsp;Christian Vollmar,&nbsp;Jan Remi,&nbsp;Carmen Picon,&nbsp;Richard Reynolds,&nbsp;Doron Merkler,&nbsp;Mike P. Wattjes,&nbsp;Tania Kümpfel,&nbsp;Matthias Brendel,&nbsp;Martin Kerschensteiner","doi":"10.1126/scitranslmed.adt5585","DOIUrl":"10.1126/scitranslmed.adt5585","url":null,"abstract":"<div >Gray matter pathology, including the formation of cortical lesions, predicts progression in people with multiple sclerosis (PwMS). Here, we investigated whether positron emission tomography (PET) imaging using the synaptic vesicle protein 2A (SV2A)–targeting radioligand [¹⁸F]UCB-H could help to detect and monitor synapse loss, an early feature of gray matter pathology in MS. First, we confirmed that SV2A is a suitable marker of synapse density in MS by analyzing SV2A mRNA and protein expression in cortical gray matter. We then used a mouse model of cortical MS pathology to demonstrate that SV2A-PET imaging can detect synapse loss in cortical lesions and that synapse densities measured by PET imaging correspond to the densities of genetically and immunohistochemically labeled synapses in the same lesions. Last, we performed SV2A-PET imaging in a total of 31 PwMS at different stages of the disease process, showing that PET imaging can detect synapse loss in cortical MS lesions in vivo. Moreover, we found that interhemispheric asymmetries in SV2A-PET tracer uptake can be leveraged to uncover further cortical alterations, the volume of which was more than 20-fold larger than the cortical lesion area detected by MRI. The extent of these PET-defined areas of cortical synapse pathology was larger in the progressive stage of the disease and correlated with the disability and cognitive performance of the same individuals. SV2A-PET imaging thus unmasked clinically relevant cortical pathology in MS thereby providing a promising tool to detect and monitor disease progression.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195384","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":"Cholesterol desensitizes the response of endometrial cancer to progestin by attenuating progestin signaling","authors":"Jiali Hu,&nbsp;Lulu Wang,&nbsp;Bingyi Yang,&nbsp;Shimin Zhao,&nbsp;Xiaoping Wan,&nbsp;Wei Liu,&nbsp;Qiaoying Lv,&nbsp;Wei Xu,&nbsp;Xiaojun Chen","doi":"10.1126/scitranslmed.adp0064","DOIUrl":"10.1126/scitranslmed.adp0064","url":null,"abstract":"<div >Progestin is the primary fertility-preserving treatment for patients with endometrial cancer (EC) and its precursor lesions, endometrial atypical hyperplasia (EAH); however, a subset of patients exhibits a poor response. In this study, through the analysis of serum lipid differences, we found that progestin-resistant patients with EC/EAH exhibited reduced serum apolipoprotein A-I concentrations and increased cholesterol accumulation in endometrial tissue. Mechanistically, molecular docking simulations and cellular models confirmed that cellular cholesterol interfered with progestin-driven signaling by competing with progestin for binding to progesterone receptor B (PRB), thereby impairing its phosphorylation, nuclear translocation, and downstream gene activation. Substitution of leucine⁸⁸⁷ with alanine⁸⁸⁷ in PRB disrupted cholesterol binding but preserved progestin responsiveness. Furthermore, cholesterol-lowering therapy with rosuvastatin calcium restored progestin sensitivity in animal models and in a single-arm, open-label phase 2 clinical trial. Our work shows that cholesterol accumulation contributes to progestin resistance and that combining progestin with statins may enhance therapeutic efficacy in EC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195415","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":"Genetic and structural aspects of amyloid diseases","authors":"Gregory M. Rosenberg,&nbsp;Kevin A. Murray,&nbsp;Michael R. Sawaya,&nbsp;Yi Xiao Jiang,&nbsp;Daniel H. Geschwind,&nbsp;David S. Eisenberg","doi":"10.1126/scitranslmed.adp3378","DOIUrl":"10.1126/scitranslmed.adp3378","url":null,"abstract":"<div >The conversion of proteins into insoluble fibrillar aggregates known as amyloid occurs in a wide variety of diseases, e.g., Alzheimer’s disease, amyotrophic lateral sclerosis, systemic transthyretin amyloidosis, and multisystem atrophy. There are more than 60 disease-associated amyloid-forming proteins, and amyloid formation can occur sporadically or can be induced or accelerated by genetic mutations. This Review discusses structural mechanisms by which genetic changes promote amyloid formation and thereby influence disease outcomes. By dividing amyloid-forming proteins into six types according to the genetic mutations they carry and analyzing mutation-induced structural changes in amyloid fibrils, a better understanding of inheritance patterns of amyloid diseases (amyloidoses) can be obtained.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195416","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":"An inactivated trivalent virion-based vaccine protects against aerosol challenge with encephalitic alphaviruses in mice and macaques","authors":"L. K. Metthew Lam,&nbsp;Theron Gilliland Jr.,&nbsp;Matthew Dunn,&nbsp;Maria D. Alcorn-Burckhardt,&nbsp;Yutaka Terada,&nbsp;Chengqun Sun,&nbsp;Shauna Vasilatos,&nbsp;Morgan Midgett,&nbsp;Connor Williams,&nbsp;Amanda Laughlin,&nbsp;Jeneveve Lundy,&nbsp;Christina L. Gardner,&nbsp;Archana Thomas,&nbsp;Hans-Peter Raué,&nbsp;Hans P. Gertje,&nbsp;Aoife K. O’Connell,&nbsp;Nicholas A. Crossland,&nbsp;Douglas S. Reed,&nbsp;Michael S. Diamond,&nbsp;Mark K. Slifka,&nbsp;William B. Klimstra","doi":"10.1126/scitranslmed.adv7079","DOIUrl":"10.1126/scitranslmed.adv7079","url":null,"abstract":"<div >Venezuelan (VEEV), Eastern (EEEV), and Western (WEEV) equine encephalitis viruses are mosquito-transmitted alphaviruses in the family <i>Togaviridae</i> with the potential to cause fatal neuroinvasive disease in humans. These viruses can also be infectious when aerosolized and, thus, are potential biothreat agents. Human infection can progress rapidly to encephalitis, with fatality rates of 1 to 10% in symptomatic VEEV and WEEV infections and 30 to 70% in symptomatic EEEV infections. Currently, there are no antiviral agents or vaccines approved for encephalitic alphaviruses. An investigational live-attenuated VEEV vaccine was generated more than 40 years ago but is highly reactogenic, poorly immunogenic, and causes disease in up to 20% of recipients. Formalin-inactivated vaccines for EEEV and WEEV are also poorly immunogenic and no longer available. Here, we developed a trivalent vaccine against VEEV, EEEV, and WEEV using a combination of attenuated chimeric Sindbis-VEEV/EEEV/WEEV viruses to streamline production and an H₂O₂ inactivation treatment for enhanced safety and virion surface epitope preservation. The vaccines were adjuvanted with alum and tested for immunogenicity and protection in mouse and nonhuman primate models of lethal, aerosolized alphavirus infection. Two doses conferred complete protection in mice, and a similar regimen showed substantial or complete protection in nonhuman primates when administered at low and high doses, respectively. These results suggest that this inactivated vaccine is effective against the three encephalitogenic alphaviruses and may meet the need to counter the public health threat and biothreat posed by these viruses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195419","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":"Severe asthma is characterized by a sex-specific ILC landscape and aberrant airway profile that is suppressed by anti–IL-5/5Rα biologics","authors":"Kyle T. Mincham,&nbsp;Lola E. Loewenthal,&nbsp;Garance F. M. Meyer,&nbsp;Sara Fontanella,&nbsp;Martina Marfia,&nbsp;Minerva Garcia Martin,&nbsp;Viola Kaygusuz,&nbsp;Charlotte Goss,&nbsp;Simone A. Walker,&nbsp;Franz Puttur,&nbsp;Andrew Menzies-Gow,&nbsp;Pujan Patel,&nbsp;Clare M. Lloyd,&nbsp;Robert J. Snelgrove","doi":"10.1126/scitranslmed.adu4913","DOIUrl":"10.1126/scitranslmed.adu4913","url":null,"abstract":"<div >Innate lymphoid cells (ILCs) fulfill critical roles in maintenance of tissue-specific homeostasis but have also been implicated in disease pathology when dysregulated. Although they are broadly classified into three core subsets, it is increasingly apparent that ILCs exhibit plasticity in response to microenvironmental factors. Accurate and holistic evaluation of the ILC landscape is critical to understanding the contribution of ILCs to disease pathology. Using high-parameter flow cytometry, we comprehensively interrogated the phenotypic and functional diversity of ILCs in healthy volunteers and patients with severe asthma (SA), assessing the reciprocity between peripheral blood and airway compartments and dissecting the impact of anti–IL-5/5Rα biologics on these responses. We identified substantial heterogeneity and putative plasticity in human ILC responses, highlighting inherent limitations of conventional enumeration strategies. Deep phenotypic and functional profiling demonstrated a distinct sexual dimorphism in ILC responses in patients with SA. Females displayed an elevated abundance of circulating ILC progenitors, ILC1s, and ILC3s, whereas males presented with diminished ILC2s compared with respective healthy controls. Circulating ILC progenitors inversely correlated with testosterone concentrations. Moreover, we identified a reciprocal influx of all core ILC subsets into the airways of patients with SA, with unbiased multisource clustering identifying a relationship between elevated airway ILC2s and reduced lung function. Last, we showed that anti–IL-5/5Rα biologics largely ablated airway ILC type 2 cytokine production without affecting core ILC subset abundance in the peripheral blood or airways, identifying a potential mechanism whereby anti–IL-5/5Rα biologics alleviate clinical disease in patients with SA.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 818","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adu4913","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195417","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":"Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice","authors":"Fangyuan Gao,&nbsp;Emily Tom,&nbsp;Cezary Rydz,&nbsp;William Cho,&nbsp;Alexander V. Kolesnikov,&nbsp;Yutong Sha,&nbsp;Anastasios Papadam,&nbsp;Samantha Jafari,&nbsp;Andrew Joseph,&nbsp;Ava Ahanchi,&nbsp;Nika Balalaei Someh Saraei,&nbsp;David C. Lyon,&nbsp;Andrzej Foik,&nbsp;Qing Nie,&nbsp;Felix Grassmann,&nbsp;Vladimir J. Kefalov,&nbsp;Dorota Skowronska-Krawczyk","doi":"10.1126/scitranslmed.ads5769","DOIUrl":"10.1126/scitranslmed.ads5769","url":null,"abstract":"<div >The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), primarily localized in cell membranes, where they govern membrane biophysical properties. During aging, alterations in lipid metabolism lead to reduced content of very long–chain PUFAs (VLC-PUFAs) in the retina, which is associated with normal age-related reductions in contrast sensitivity, diminished photoreceptor function and delayed rod-mediated dark adaptation recovery, and pathological age-related macular degeneration (AMD). <i>ELOVL2</i> (<i>elongation of very long chain fatty acids-like 2</i>) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs. The methylation status of the <i>ELOVL2</i> promoter is currently one of the best predictors of chronological age. Here, we show that lower VLC-PUFA abundance in the aged mouse retina is accompanied by a reduction in visual function. Similarly, mice lacking ELOVL2-specific enzymatic activity (<i>Elovl2^C234W</i>) demonstrate reduced contrast sensitivity and slower rod-mediated dark adaptation. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals improved visual function for up to 4 weeks and reduced accumulation of APOE- and C3d-positive sub-RPE deposits. The gene expression pattern observed in supplemented retinas exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature resembling younger retinas. Last, human genetic data from the IAMDGC and UK Biobank linked two variants in the <i>ELOVL2</i> locus with the onset of intermediate AMD, underlining the translational importance of our findings. Our work highlights VLC-PUFA supplementation as a potential therapeutic opportunity and defines ELOVL2 as a promising target for interventions to prevent age-related vision loss.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129540","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":"Afucosylation of anti-dengue IgG is associated with enhanced susceptibility to dengue virus infection postvaccination","authors":"Usama Ashraf,&nbsp;Saborni Chakraborty,&nbsp;Courtney Scallan,&nbsp;Nathan C. Lo,&nbsp;Maria Theresa Alera,&nbsp;Aaron Farmer,&nbsp;Mary Noreen Cabalfin-Chua,&nbsp;Nelson L. Michael,&nbsp;Alan L. Rothman,&nbsp;Taia T. Wang","doi":"10.1126/scitranslmed.adx7231","DOIUrl":"10.1126/scitranslmed.adx7231","url":null,"abstract":"<div >Dengue viruses (DENVs) cause 390 million infections annually, although only ~25% of these infections are symptomatic. Whereas antibody features linked to severe DENV disease are well studied, factors influencing infection susceptibility remain less clear. Here, we examined immunoglobulin G (IgG) characteristics before and after DENV vaccination (Dengvaxia) in individuals with a history of prior DENV exposure, comparing those who developed postvaccination infections to those who remained infection free. Elevated anti-DENV afucosylation, present before or after vaccination, was associated with increased likelihood of infection after vaccination. These data were further supported by mechanistic studies, which revealed that nonneutralizing, afucosylated, post-Dengvaxia IgG enhanced DENV replication in mice. This enhancement was dependent on CD16, the receptor for the afucosylated IgG Fc domain. Together, these findings support a model in which the presence of afucosylated IgG promotes virus replication, increasing the likelihood of productive infection upon DENV exposure. Moreover, these results highlight that IgG1 fucosylation is a predictor of risk for breakthrough DENV infection despite vaccination and support the importance of investigating strategies to regulate Fc fucosylation during vaccination.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129542","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":"Spatial profiling of human pancreatic ductal adenocarcinoma reveals molecular alterations associated with venous invasion","authors":"Alexander T. F. Bell,&nbsp;Peter Chianchiano,&nbsp;Katsuya Hirose,&nbsp;Daniel Salas-Escabillas,&nbsp;Doreen M. Zucha,&nbsp;Jacob T. Mitchell,&nbsp;Ludmila Danilova,&nbsp;Alexander I. Damanakis,&nbsp;Joseph A. Tandurella,&nbsp;Jeanette Johnson,&nbsp;Jing Zhu,&nbsp;James R. Eshleman,&nbsp;Qingfeng Zhu,&nbsp;Robert A. Anders,&nbsp;Luciane T. Kagohara,&nbsp;Elana J. Fertig,&nbsp;Laura D. Wood","doi":"10.1126/scitranslmed.ady7524","DOIUrl":"10.1126/scitranslmed.ady7524","url":null,"abstract":"<div >In pancreatic ductal adenocarcinoma (PDAC), venous invasion (VI) is a critical step in metastasis and is associated with poor survival. However, little is known about the molecular features of VI. To investigate, we performed spatial transcriptomic analysis of 95 human PDAC tissue samples from eight treatment-naïve patients. Our analysis revealed that, compared with PDAC in stroma, PDAC with VI demonstrated up-regulation of genes associated with epithelial differentiation, classical subtype, and benign exocrine function. Conversely, PDAC with VI demonstrated down-regulation of genes associated with mesenchymal differentiation, basal-like subtype, and disease aggression. Additionally, we uncovered characteristics of VI morphology that correlated with these molecular features. VI–intraepithelial neoplasia–like foci had preserved venous architecture and had a classical, epithelial molecular phenotype, whereas VI-destructive foci had destroyed venous architecture and had a more basal-like, mesenchymal phenotype. We contextualized our findings using public RNA-seq data and observed that metastatic PDAC had greater similarity to PDAC in stroma than to PDAC with VI, whereas circulating tumor cells showed no preferential association. We confirmed our findings by spatial proteomic analysis of VI in an independent cohort of 19 treatment-naïve patients with PDAC. Overall, our work provides a reference atlas of spatial transcriptomics and proteomics of VI in PDAC and reveals unexpected increases in molecular features associated with better patient outcomes.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129544","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":"CAR T cell–mediated bone marrow inflammation causes hematotoxicity and favors clonal hematopoiesis","authors":"Myriam Ben Khelil,&nbsp;Ahmadreza Arbab,&nbsp;Janesa Srikanthan,&nbsp;Laura Marcos Kovandzic,&nbsp;Véronique Vergé,&nbsp;Arnaud Pagès,&nbsp;Jessica Rengassamy,&nbsp;Roula Amine-Hneineh,&nbsp;Marine Aglave,&nbsp;Rémy Jelin,&nbsp;Vincent Ribrag,&nbsp;Wassila Rahali,&nbsp;Paul-Auguste Goutebroze,&nbsp;Stéphane de Botton,&nbsp;Laurie Menger,&nbsp;Ileana Antony-Debré,&nbsp;Jean-Baptiste Micol,&nbsp;Christophe Marzac,&nbsp;Cristina Castilla Llorente,&nbsp;Camille Bigenwald","doi":"10.1126/scitranslmed.adu9790","DOIUrl":"10.1126/scitranslmed.adu9790","url":null,"abstract":"<div >Although chimeric antigen receptor (CAR) T cells have shown excellent results in treating hematological malignancies, they also cause side effects. Patients treated with CAR T cells experience persistent cytopenia or hematotox. Here, using a fully immunocompetent mouse model, we recapitulated hematotox and demonstrated that a lymphodepleting regimen alone was insufficient to induce hematotox and required CAR T cell injection. Analysis of bone marrow (BM) samples from patients experiencing hematotox revealed a correlation between BM CAR T cells and hematotox severity. CAR T cells exhibited an activated program, leading to intense inflammation. In addition, we observed a high rate of clonal hematopoiesis in our patient cohort and the emergence of distinct hematopoietic clones in the months after CAR T cell injection. Our study provides insights into the pathophysiology of hematotox and highlights the need for long-term follow-up studies to determine the relevance of this intense BM inflammation in clonal selection.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127731","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}