Science Translational Medicine最新文献

{"title":"Serial multiomics uncovers anti-glioblastoma responses not evident by routine clinical analyses","authors":"Alexander L. Ling,&nbsp;Jennifer Gantchev,&nbsp;Michael C. Prabhu,&nbsp;Sreyashi Basu,&nbsp;Ryuhjin Ahn,&nbsp;Alicia D’Souza,&nbsp;Nafisa Masud,&nbsp;Anna Ball,&nbsp;Odysseas Nikas,&nbsp;Genaro R. Villa,&nbsp;Michael S. Regan,&nbsp;Gerard Baquer,&nbsp;Georges Ayoub,&nbsp;Charles A. Whittaker,&nbsp;Zaki Abou-Mrad,&nbsp;Andres Santos,&nbsp;Charles P. Couturier,&nbsp;Dina Elharouni,&nbsp;Jayne Vogelzang,&nbsp;Kenny K. H. Yu,&nbsp;Hong Chen,&nbsp;Zhong He,&nbsp;Wen Jiang,&nbsp;Calixto Hope Lucas,&nbsp;Haley E. Sax,&nbsp;Frederick F. Lang,&nbsp;Vinay K. Puduvalli,&nbsp;Viviane Tabar,&nbsp;Cameron W. Brennan,&nbsp;Adrienne Boire,&nbsp;Matthias Holdhoff,&nbsp;Chetan Bettegowda,&nbsp;Michael Cima,&nbsp;Isaac H. Solomon,&nbsp;Ying Yuan,&nbsp;Paul P. Tak,&nbsp;Accelerating GBM Therapies TeamLab,&nbsp;Padmanee Sharma,&nbsp;Forest M. White,&nbsp;Keith L. Ligon,&nbsp;Nathalie Y.R. Agar,&nbsp;David A. Reardon,&nbsp;Giacomo Oliveira,&nbsp;E. Antonio Chiocca","doi":"10.1126/scitranslmed.adv2881","DOIUrl":"10.1126/scitranslmed.adv2881","url":null,"abstract":"<div >Recurrent glioblastoma (rGBM) remains incurable. One barrier to the development of effective rGBM therapies is the difficulty in collecting posttreatment tumor tissue. Serial multiomic assays from longitudinal rGBM biopsies may uncover tumor responses to a treatment. Here, we obtained 97 serial rGBM biopsy cores over 4 months from the first two patients participating in a clinical trial of repeated intratumoral dosing of the immunotherapeutic agent CAN-3110. Multiomic analysis of the biopsy cores revealed therapeutic effects, including longitudinal and spatial reshaping of the rGBM’s microenvironment, expansion of new T cell tissue-resident effector memory clonotypes against CAN-3110 epitopes and other undetermined antigens, and expression of human leukocyte antigen (HLA)–presented immunopeptides, including cancer testis antigens. Moreover, serial integrated multimodal analyses provided evidence of therapeutic responses to CAN-3110 despite traditional magnetic resonance imaging indicating progression. Clinically, the two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand rGBM’s evolution during administration of an investigational therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243244","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":"Sprayable extracellular matrix hydrogel reduces postoperative adhesion formation and protects healing tissues in preclinical models","authors":"Lucía Pascual-Antón,&nbsp;Pilar Sandoval,&nbsp;Henar Tomero-Sanz,&nbsp;Michela Terri,&nbsp;Raffaele Strippoli,&nbsp;Íñigo García-Sanz,&nbsp;Cristina Marín-Campos,&nbsp;Miguel Ángel del Pozo,&nbsp;Maryam Obaid,&nbsp;Valentina Garcia,&nbsp;Peter Alex Smith,&nbsp;Timothy J. Keane,&nbsp;Molly M. Stevens,&nbsp;Manuel López-Cabrera","doi":"10.1126/scitranslmed.adn3179","DOIUrl":"10.1126/scitranslmed.adn3179","url":null,"abstract":"<div >Tissue trauma initiates inflammation that can lead to fibrotic complications such as postoperative peritoneal adhesions, which contribute to chronic pain, infertility, and bowel obstruction. Despite their prevalence and impact, effective interventions to prevent adhesion formation remain limited. In this study, we evaluated a sprayable extracellular matrix (ECM) hydrogel as a barrier to protect healing tissues and reduce adhesion formation after abdominal surgery. In both mouse and rabbit models of colorectal and gynecologic procedures, ECM hydrogel application resulted in a substantial reduction in adhesion severity. Mechanistic studies demonstrated that the hydrogel promotes preservation or restoration of the mesothelial lining while modulating early local inflammation. Treated tissues exhibited reduced expression of inflammatory cytokines, including IL-1β, and maintained an intact mesothelial surface with fewer activated myofibroblasts compared with synthetic hydrogel and controls. Immunohistochemical analysis, transcriptomic profiling of mesothelial cells, and in vitro mechanical stretch experiments revealed that the ECM hydrogel mitigates mesothelial-to-mesenchymal transition. These findings suggest that the hydrogel not only provides a physical barrier but also serves as a biological modulator, shielding tissue from mechanical and inflammatory cues that drive adhesion formation. Overall, this study identifies a dual-function, biologically active ECM hydrogel capable of protecting healing tissues and reducing adhesion development in preclinical surgical models. These results support the potential of ECM hydrogel as a clinically translatable, biocompatible strategy for improving postsurgical healing outcomes and reducing adhesion-related complications.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241881","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":"Deletion of murine Sarm1 results in a microenvironment that delays peripheral nerve regeneration after injury","authors":"Ligia B. Schmitd,&nbsp;Hannah Hafner,&nbsp;Ayobami Ward,&nbsp;Elham Asghari Adib,&nbsp;Natalia P. Biscola,&nbsp;Rafi Kohen,&nbsp;Mitre Athaiya,&nbsp;Meghan Tuttle,&nbsp;Manav Patel,&nbsp;Rachel E. Williamson,&nbsp;Emily Desai,&nbsp;Julianna Bennett,&nbsp;Grace Saxman,&nbsp;David Wilborn,&nbsp;Jaisha Shumpert,&nbsp;Xiao-Feng Zhao,&nbsp;Riki Kawaguchi,&nbsp;Daniel H. Geschwind,&nbsp;Ahmet Hoke,&nbsp;Peter Shrager,&nbsp;Catherine A. Collins,&nbsp;Leif A. Havton,&nbsp;Ashley L. Kalinski,&nbsp;Roman J. Giger","doi":"10.1126/scitranslmed.adp9155","DOIUrl":"10.1126/scitranslmed.adp9155","url":null,"abstract":"<div >Upon injury to the mammalian peripheral nervous system (PNS), severed axons undergo rapid SARM1-dependent programmed axon death (Wallerian degeneration), but a potential role for <i>Sarm1</i> in PNS regeneration remains unclear. We show that in mouse dorsal root ganglia with their axons cut, <i>Sarm1</i> delayed the activation of injury-induced transcriptional programs associated with axon outgrowth and immune function. After sciatic nerve crush in <i>Sarm1^−/−</i> mice, axons rapidly extended through the nerve injury site, but growth stalled more distally. Slow axon regeneration in the distal nerve was accompanied by delayed induction of the nerve repair response by Schwann cells and delayed clearance of disintegrating myelin. Nerve fibers did regenerate in <i>Sarm1^−/−</i> mice, but regeneration was delayed, and axons exhibited reduced caliber and aberrant target innervation. Tibial nerve action potentials were weaker, and recovery of hind paw function was delayed but ultimately not impaired. Grafting of mouse <i>Sarm1^−/−</i> nerves into wild-type mice and mouse wild-type nerves into <i>Sarm1^−/−</i> mice revealed that the <i>Sarm1^−/−</i> nerve microenvironment was hostile to wild-type axon regeneration and, conversely, that <i>Sarm1^−/−</i> axons robustly grew into mouse wild-type nerve grafts. Ex vivo, the appearance of c-Jun–labeled Schwann cells in cultured mouse <i>Sarm1^−/−</i> nerves was delayed but could be accelerated by pharmacological inhibition of ErbB kinase. Our study highlights the opposing functions of <i>Sarm1</i> deficiency in dorsal root ganglia and distal nerves in mice, the consequence of which is delayed PNS regeneration.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241880","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":"CRISPR activation of the ribosome-associated quality control factor ASCC3 ameliorates fragile X syndrome phenotypes in mice","authors":"Ji Geng,&nbsp;Xiying Wang,&nbsp;Jie Pan,&nbsp;Danish Khan,&nbsp;Sopida Pimcharoen,&nbsp;Yongjie Zhang,&nbsp;Nima Mosammaparast,&nbsp;Susumu Hirose,&nbsp;Leonard Petrucelli,&nbsp;Onn Brandman,&nbsp;Lei S. Qi,&nbsp;Bingwei Lu","doi":"10.1126/scitranslmed.adq3551","DOIUrl":"10.1126/scitranslmed.adq3551","url":null,"abstract":"<div >Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), an inherited neurodevelopmental disorder resulting in intellectual disability and autism spectrum disorder; however, the molecular function of FMRP remains uncertain. Here, using cell lines and fibroblasts and induced pluripotent stem cell–derived neurons from healthy individuals and patients with FXS, we showed that FMRP regulates collided ribosomes by recruiting activating signal cointegrator 1 complex subunit 3 (ASCC3), an early-acting ribosome-associated quality control (RQC) factor to collided ribosomes, and either positively or negatively regulating translation, depending on transcript context. Disease-associated <i>ASCC3</i> variants that perturbed ASCC3-FMRP interaction were also found to be defective in ribosome association and handling of collided ribosomes. In cells of a patient with FXS and the <i>Fmr1</i> KO mouse model, ASCC3 abundance was reduced, and overexpression of ASCC3 in the brains of fetal <i>Fmr1</i> KO mice promoted neuronal migration. In addition, CRISPR-mediated activation of ASCC3 by lateral ventricular injection of adeno-associated virus (AAV) ameliorated synaptic defects and improved locomotor activity, cognitive deficits, obsessive-compulsive–like behavior, and social interaction deficits after 1 month in 2-month-old <i>Fmr1</i> KO mice compared with untreated <i>Fmr1</i> KO controls. In conclusion, these data implicated FMRP in the handling of collided ribosomes to maintain protein homeostasis during neurodevelopment and synaptogenesis and demonstrated proof of concept that targeting RQC may offer alternative treatment strategies for FXS.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241878","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":"Immune signatures link myelin oligodendrocyte glycoprotein antibody–associated disease to other autoantibody-mediated conditions","authors":"Jonas Schmid,&nbsp;Chiara Alberti,&nbsp;Laura Power,&nbsp;Nicolás G. Nuñez,&nbsp;Donatella De Feo,&nbsp;Sofia Tyystjärvi,&nbsp;Laila Kulsvehagen,&nbsp;Victor Kreiner,&nbsp;Ana Beatriz Ayroza Bleher,&nbsp;Patrick Lipps,&nbsp;Stijn Swinnen,&nbsp;Florian Ingelfinger,&nbsp;Can Ulutekin,&nbsp;Camille Chaubet,&nbsp;Susanne Unger,&nbsp;Stefanie Kreutmair,&nbsp;Romain Marignier,&nbsp;Thomas Korn,&nbsp;Anne-Katrin Pröbstel,&nbsp;Roland Liblau,&nbsp;Burkhard Becher","doi":"10.1126/scitranslmed.adw0358","DOIUrl":"10.1126/scitranslmed.adw0358","url":null,"abstract":"<div >Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) is a recently defined neurological autoimmune condition. The pathogenesis of the disease remains poorly understood, and no specific therapies are currently approved. Here, a comprehensive single-cell immunophenotyping of peripheral blood mononuclear cells from two independent cohorts of patients with MOGAD revealed pronounced immune perturbations in MOGAD when compared with healthy controls and patients with multiple sclerosis. Patients with MOGAD displayed an expansion of CXCR5⁻CD21⁻ activated naïve and double-negative B cell subsets, a feature shared with patients with systemic lupus erythematosus. In addition, we observed altered Fc gamma receptor expression in natural killer cells, monocytes, and dendritic cells. Within the T cell compartment, CXCR3⁺CD4⁺ memory T cells were reduced in the circulation of patients with MOGAD compared with healthy controls, and this result was mirrored in a transgenic mouse model that showed retention of these cells in the inflamed central nervous system. Together, these results demonstrate profound systemic immune cell alterations in MOGAD and contribute to a better understanding of this distinct disease entity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adw0358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241876","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":"Now you see me; now you don’t","authors":"Pedro R. Lowenstein","doi":"10.1126/scitranslmed.adz1286","DOIUrl":"10.1126/scitranslmed.adz1286","url":null,"abstract":"<div >Multiomics on serial glioblastoma biopsies can enable differentiation of pseudoprogression from true tumor progression (see Ling <i>et al</i>.).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241879","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 replicating RNA vaccine protects cynomolgus macaques against lethal clade 2.3.4.4b influenza A H5N1 virus challenge","authors":"David W. Hawman,&nbsp;Amanda Griffin,&nbsp;Natalie McCarthy,&nbsp;Atsushi Okumura,&nbsp;Shanna S. Leventhal,&nbsp;Mahati Agumamidi,&nbsp;Michael Chorabik Jr.,&nbsp;Ekaterina Altynova,&nbsp;Matthew Lewis,&nbsp;Troy Hinkley,&nbsp;E. Taylor Stone,&nbsp;Nikole Warner,&nbsp;Stephanie Park,&nbsp;Jamie Lovaglio,&nbsp;Brian J. Smith,&nbsp;Patrick Hanley,&nbsp;Greg Saturday,&nbsp;Carl Shaia,&nbsp;Chad Clancy,&nbsp;Kyle Rosenke,&nbsp;Jesse H. Erasmus,&nbsp;Heinz Feldmann","doi":"10.1126/scitranslmed.adw4646","DOIUrl":"10.1126/scitranslmed.adw4646","url":null,"abstract":"<div >In early 2024, clade 2.3.4.4b highly pathogenic avian influenza (HPAI) A H5N1 virus was detected in United States dairy cattle. Although so far the public health threat of contemporary clade 2.3.4.4b H5N1 virus strains remains low, continued circulation in mammals and frequent spillover into humans poses a threat of pandemic H5N1. The United States and other countries have stockpiled vaccines and have plans in place to rapidly produce additional vaccine doses should a pandemic H5N1 virus emerge. However, the continued antigenic drift of clade 2.3.4.4b H5N1 antigens compared with historical antigens used by stockpiled vaccines has raised questions of whether these vaccines will confer protection or whether stockpiles need to be updated. We recently evaluated a replicating RNA (repRNA) vaccine against lethal contemporary 2.3.4.4b H5N1 virus challenge in mice and found that a homologous, but not historical, H5 hemagglutinin (HA)–based vaccine conferred protection. Here, we further evaluated the protective capacity of a repRNA expressing the contemporary 2.3.4.4b HA or a repRNA expressing a historical H5 HA (A/Vietnam/1203/2004) in a recently developed lethal nonhuman primate (NHP) challenge model. We found that both vaccines conferred robust protection against lethal 2.3.4.4b H5N1 virus challenge, reducing viral loads and signs of respiratory illness. Our data show that the repRNA platform can elicit protective immunity against lethal influenza virus challenge in NHPs and that historical H5 HAs can elicit cross-protective immunity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 819","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241882","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":"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}