Science Translational Medicine最新文献

{"title":"Erratum for the Research Article “Treatment of otitis media by transtympanic delivery of antibiotics” by R. Yang et al.","authors":"","doi":"10.1126/scitranslmed.ady2642","DOIUrl":"10.1126/scitranslmed.ady2642","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 797","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920018","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 phase 1/2a clinical trial to assess safety and immunogenicity of an adenoviral-vectored capsular group B meningococcal vaccine","authors":"Christina Dold,&nbsp;Blanché Oguti,&nbsp;Laura Silva-Reyes,&nbsp;Anna Stanzelova,&nbsp;Meriel Raymond,&nbsp;Catherine C. Smith,&nbsp;Maria Moore,&nbsp;Anna Barton,&nbsp;Edward M. Choi,&nbsp;Emma Plested,&nbsp;Kiarash Tanha,&nbsp;Jennifer Louth,&nbsp;Ann Holland,&nbsp;Robert Cook,&nbsp;Jessica King,&nbsp;Jay Lucidarme,&nbsp;Ray Borrow,&nbsp;Adrian V. S. Hill,&nbsp;Peter T. Beernink,&nbsp;Xinxue Liu,&nbsp;Andrew J. Pollard,&nbsp;Christine S. Rollier","doi":"10.1126/scitranslmed.adn1441","DOIUrl":"10.1126/scitranslmed.adn1441","url":null,"abstract":"<div >Capsular group B meningococcus (MenB) remains an important cause of disease globally, and additional vaccines against MenB would aid in reducing the incidence of infection. Previous work has demonstrated that a MenB adenoviral-vectored vaccine, ChAdOx1 MenB.1, elicited high serum bactericidal responses in preclinical models after a single dose, supporting further clinical development of this vaccine. Here, we report the results of a trial designed to assess the safety and immunogenicity of ChAdOx1 MenB.1 in healthy adults aged 18 to 50. In this phase 1/2a, single-center trial, participants received one or two doses of ChAdOx1 MenB.1 at days 0 and 180. One dose of ChAdOx1 MenB.1 was also given at day 180 to some individuals primed with one dose of 4CMenB at day 0. Participants recorded their symptoms in an electronic diary after vaccination, and safety blood readouts were monitored. Serum bactericidal antibody (SBA) assays were performed against a panel of MenB target strains. ChAdOx1 MenB.1 was well tolerated with no safety concerns and elicited protective SBA titers against a MenB strain expressing a homologous factor H–binding protein (fHbp) variant in 100% of participants after two doses. However, cross-reactivity analysis indicated a low SBA response to strains expressing heterologous fHbp, suggesting that a multivalent vaccine may be needed. In sum, ChAdOx1 MenB.1 is immunogenic in humans, and addition of another fHbp variant or of another antigen in this platform could provide an approach to extend protection against endemic MenB disease.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 797","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The inhibitory receptor Siglec-E controls antigen-presenting cell activation and T cell–mediated transplant rejection","authors":"Thiago J. Borges,&nbsp;Karina Lima,&nbsp;Rodrigo B. Gassen,&nbsp;Kaifeng Liu,&nbsp;Yoshikazu Ganchiku,&nbsp;Guilherme T. Ribas,&nbsp;Minxue Liao,&nbsp;Joao I. B. Goncalves,&nbsp;Isadora T. Lape,&nbsp;Ivy A. Rosales,&nbsp;Yunlong Zhao,&nbsp;Enfu Hui,&nbsp;Robert L. Fairchild,&nbsp;Christian LeGuern,&nbsp;Cristina Bonorino,&nbsp;Stuart K. Calderwood,&nbsp;Joren C. Madsen,&nbsp;Leonardo V. Riella","doi":"10.1126/scitranslmed.ads2694","DOIUrl":"10.1126/scitranslmed.ads2694","url":null,"abstract":"<div >After transplantation, inflammation and tissue injury release danger signals that activate myeloid cells, driving adaptive immune responses and acute rejection. Current immunosuppressants primarily target T cells but inadequately control innate immunity. Regulatory signals controlling innate responses in transplantation remain elusive. The sialic acid–binding immunoglobulin-like lectin-E (Siglec-E, or SigE) binds sialylated ligands to suppress inflammation. In mouse heart transplants, SigE is up-regulated in graft-infiltrating myeloid cells, including dendritic cells (DCs). SigE deficiency in recipients, but not donors, accelerates acute rejection by enhancing DC activation, nuclear factor κB (NF-κB) signaling, and tumor necrosis factor–α (TNF-α) production, thereby boosting alloreactive T cell responses. Conversely, SigE overexpression on DCs reduces activation by danger signals and their T cell allostimulatory capacity. The human homologs Siglecs-7 and -9 were up-regulated in rejecting allograft biopsies, and their higher expression correlated with improved allograft survival. Thus, SigE/7/9 is a crucial inhibitory receptor controlling antigen-presenting cell activation and T cell–mediated transplant rejection, offering therapeutic potential.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 797","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916086","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":"Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues","authors":"Helen Chen,&nbsp;Christy W. LaFlamme,&nbsp;Yong-Dong Wang,&nbsp;Aidan W. Blan,&nbsp;Nikki Koehler,&nbsp;Renata Mendonca Moraes,&nbsp;Athena R. Olszewski,&nbsp;Edith P. Almanza Fuerte,&nbsp;Emily S. Bonkowski,&nbsp;Richa Bajpai,&nbsp;Alfonso Lavado,&nbsp;Shondra M. Pruett-Miller,&nbsp;Heather C. Mefford","doi":"10.1126/scitranslmed.adn8417","DOIUrl":"10.1126/scitranslmed.adn8417","url":null,"abstract":"<div ><i>UBA5</i> encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in endoplasmic reticulum (ER) homeostasis. The clinical phenotypes of <i>UBA5</i>-associated encephalopathy include developmental delays, epilepsy, and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences of <i>UBA5</i> pathogenic variants. We developed and characterized patient-derived cortical organoid cultures from two patients with compound heterozygous variants in <i>UBA5</i>. Both shared the same missense variant, which encodes a hypomorphic allele (p.A371T), along with a nonsense variant (p.G267* or p.A123fs*4). Single-cell RNA sequencing of 100-day organoids identified defects in GABAergic interneuron development. We demonstrated aberrant neuronal firing and reduction in size of patient-derived organoids. Mechanistically, we showed that ER homeostasis is perturbed along with an exacerbated unfolded protein response pathway in engineered U87-MG cells and patient-derived organoids expressing <i>UBA5</i> pathogenic variants. We also assessed two potential therapeutic modalities that augmented UBA5 protein abundance to rescue aberrant molecular and cellular phenotypes. We assessed SINEUP, a long noncoding RNA that augments translation efficiency, and CRISPRa, a modified CRISPR-Cas9 approach to augment transcription efficiency to increase UBA5 protein production. Our study provides a humanized model that allows further investigations of <i>UBA5</i> variants in the brain and highlights promising approaches to alleviate cellular aberrations for this rare, developmental disorder.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 797","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916019","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":"PET imaging of antisense oligonucleotide distribution in rat and nonhuman primate brains using click chemistry","authors":"Brendon E. Cook,&nbsp;Thomas C. Pickel,&nbsp;Sangram Nag,&nbsp;Philippe N. Bolduc,&nbsp;Rouaa Beshr,&nbsp;Anton Forsberg Morén,&nbsp;Cathy Muste,&nbsp;Giulia Boscutti,&nbsp;Di Jiang,&nbsp;Long Yuan,&nbsp;Prodip Datta,&nbsp;Piotr Ochniewicz,&nbsp;Yasir Khani Meynaq,&nbsp;Sac-Pham Tang,&nbsp;Christophe Plisson,&nbsp;Mario Amatruda,&nbsp;Qize Zhang,&nbsp;Jonathan M. DuBois,&nbsp;Armin Delavari,&nbsp;Stephanie K. Klein,&nbsp;Ildiko Polyak,&nbsp;Adebowale Shoroye,&nbsp;Sara Girmay,&nbsp;Christer Halldin,&nbsp;Laurent Martarello,&nbsp;Emily A. Peterson,&nbsp;Maciej Kaliszczak","doi":"10.1126/scitranslmed.adl1732","DOIUrl":"10.1126/scitranslmed.adl1732","url":null,"abstract":"<div >Determination of a drug’s biodistribution is critical to ensure that it reaches the target tissue of interest. This is particularly challenging in the brain, where invasive sampling methods may not be possible. Here, we present a pretargeted positron emission tomography (PET) imaging methodology that uses bioorthogonal click chemistry to determine the distribution of an antisense oligonucleotide (ASO) in the brains of rats and nonhuman primates after intrathecal dosing of ASO. A PET tracer, [¹⁸F]BIO-687, bearing a click-reactive <i>trans</i>-cyclooctene was developed and tested in conjunction with a test Malat1 ASO conjugated with a methyltetrazine group. PET imaging in rats demonstrated that the tracer had good kinetic properties for PET imaging in the rodent central nervous system and could react to form a covalent linkage with high specificity to the methyltetrazine-conjugated ASO in vivo. Furthermore, the amount of PET tracer reacted by cycloaddition with the methyltetrazine was determined to be dependent on the concentration of ASO-methyltetrazine in rat brain tissue, as determined by comparing the PET imaging signal with the liquid chromatography–mass spectrometry signal in the tissue homogenates. The approach was evaluated in cynomolgus macaques using both the Malat1 test ASO and a candidate therapeutic ASO, BIIB080, targeting the microtubule-associated protein tau (<i>MAPT</i>) gene. PET imaging showed favorable tracer kinetics and specific binding to both ASOs in nonhuman primate (NHP) brain in vivo. These results suggest that the PET imaging tracer [¹⁸F]BIO-687 could show the distribution of intrathecally delivered ASOs in the rat and NHP brains.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 797","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916025","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":"Brain-wide microglia replacement using a nonconditioning strategy ameliorates pathology in mouse models of neurological disorders","authors":"Dadian Chen,&nbsp;Chen Wang,&nbsp;Xi Chen,&nbsp;Jiayu Li,&nbsp;Shuai Chen,&nbsp;Yanzhong Li,&nbsp;Fangling Ma,&nbsp;Tingting Li,&nbsp;Mengling Zou,&nbsp;Xin Li,&nbsp;Xiaohua Huang,&nbsp;Yun-wu Zhang,&nbsp;Yingjun Zhao,&nbsp;Guojun Bu,&nbsp;Honghua Zheng,&nbsp;Xiao-Fen Chen,&nbsp;Jie Zhang,&nbsp;Li Zhong","doi":"10.1126/scitranslmed.ads6111","DOIUrl":"10.1126/scitranslmed.ads6111","url":null,"abstract":"<div >Growing genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy. Traditional bone marrow transplantation (BMT) methods for replenishing brain microglia have limitations, including low efficiency and the potential for brain injury because of preconditioning regimens, such as irradiation or chemotherapy. Moreover, BM-derived cells that migrate to the brain do not recapitulate the phenotypic and functional properties of resident microglia. Here, we present a microglia transplantation strategy devoid of any conditioning, termed “tricyclic microglial depletion for transplantation” (TCMDT). This approach leverages three cycles of microglial depletion using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, creating an optimal window for efficient engraftment of exogenous microglia. Transplantation of primary cultured microglia by TCMDT successfully restored the identity and functions of endogenous microglia. To evaluate the therapeutic potential of TCMDT, we applied this strategy to two distinct mouse models of neurologic disorder. In a Sandhoff disease model, a neurodegenerative lysosomal storage disorder caused by hexosaminidase subunit beta (<i>Hexb</i>) deficiency, TCMDT effectively replaced deficient microglia, attenuating neurodegeneration and improving motor performance. Similarly, in an Alzheimer’s disease (AD)–related amyloid mouse model carrying the triggering receptor expressed on myeloid cells 2 (Trem2) R47H mutation, our transplantation strategy rescued microglial dysfunction and mitigated AD-related pathology. Overall, our study introduces TCMDT as a practical, efficient, and safe approach for microglia replacement, suggesting therapeutic potential for treating neurological disorders associated with microglial dysfunction.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 796","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893036","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":"Hypoxia-inducible factors link poor glycemic control to diabetic retinopathy","authors":"Yusuke Ichiyama,&nbsp;Przemyslaw Sapieha","doi":"10.1126/scitranslmed.adu7718","DOIUrl":"10.1126/scitranslmed.adu7718","url":null,"abstract":"<div >Hypoglycemic episodes exacerbate diabetic eye disease, which is targetable by dual-HIF inhibition (Guo <i>et al.</i>, this issue).</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 796","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893076","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":"Inclusion of a retroviral protease enhances the immunogenicity of VLP-forming mRNA vaccines against HIV-1 or SARS-CoV-2 in mice","authors":"Peng Zhang,&nbsp;Mamta Singh,&nbsp;Vada A. Becker,&nbsp;Jacob Croft,&nbsp;Yaroslav Tsybovsky,&nbsp;Vinay Gopan,&nbsp;Yuna Seo,&nbsp;Qingbo Liu,&nbsp;Denise Rogers,&nbsp;Huiyi Miao,&nbsp;Yin Lin,&nbsp;Daniel Rogan,&nbsp;Courtney Shields,&nbsp;Sayda M. Elbashir,&nbsp;Samantha Calabrese,&nbsp;Isabella Renzi,&nbsp;Vladimir Preznyak,&nbsp;Elizabeth Narayanan,&nbsp;Guillaume Stewart-Jones,&nbsp;Sunny Himansu,&nbsp;Mark Connors,&nbsp;Kelly Lee,&nbsp;Andrea Carfi,&nbsp;Paolo Lusso","doi":"10.1126/scitranslmed.adt9576","DOIUrl":"10.1126/scitranslmed.adt9576","url":null,"abstract":"<div >Messenger RNA (mRNA) has emerged as a highly effective and versatile platform for vaccine delivery. We previously designed a virus-like particle (VLP)–forming <i>env-gag</i> mRNA vaccine against human immunodeficiency virus–1 (HIV-1) that elicited envelope-specific neutralizing antibodies and protection from heterologous simian-human immunodeficiency virus (SHIV) infection in rhesus macaques. Here, we introduce a key technological advance to this platform by inclusion of mRNA encoding a retroviral protease to process Gag and produce mature VLPs. Appropriately dosed and timed expression of the protease was achieved using a full-length <i>gag-pol</i> mRNA transcript. Addition of <i>gag-pol</i> mRNA to an HIV-1 <i>env-gag</i> mRNA vaccine resulted in enhanced titers of envelope trimer-binding and neutralizing antibodies in a mouse model. Analogous results were obtained with a hybrid Gag-based, VLP-forming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine expressing an engineered spike protein. Thus, inclusion of a retroviral protease can increase the immunogenicity of Gag-based, VLP-forming mRNA vaccines against human pathogens.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 796","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893035","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 thin cryobiopsy device compatible with transnasal endoscopy for the gastrointestinal tract","authors":"David O. Otuya,&nbsp;Hamid Farrokhi,&nbsp;Yogesh Verma,&nbsp;Jing Dong,&nbsp;Peter Choy,&nbsp;Aditya Kumar,&nbsp;Rachel E. Shore,&nbsp;Sarah K. Zemlok,&nbsp;Evan Sevieri,&nbsp;Mason Schellenberg,&nbsp;Graham Spicer,&nbsp;Dan Rolando Lopez,&nbsp;Hany A. Osman,&nbsp;Joseph A. Gardecki,&nbsp;Alfred A. F. Kyrollos Kelada,&nbsp;Anna H. Gao,&nbsp;Anita Chung,&nbsp;Catriona N. Grant,&nbsp;Nitasha G. M. Bhat,&nbsp;Mireille Rosenberg,&nbsp;Brian C. Jacobson,&nbsp;Norman S. Nishioka,&nbsp;Yolonda Colson,&nbsp;Guillermo J. Tearney","doi":"10.1126/scitranslmed.ado9609","DOIUrl":"10.1126/scitranslmed.ado9609","url":null,"abstract":"<div >Luminal organ biopsies are critical for disease diagnosis and are obtained using single-bite forceps inserted through the working channel of large endoscopes. Procedures using these endoscopes frequently require patient sedation or anesthesia and may not be feasible for use in pediatric patients. Additionally, forceps-derived biopsies can suffer from difficulty maintaining tissue orientation, crush artifacts, and lack of precise control of biopsy depth. The high cost and risks of anesthesia and sedation have driven the development of smaller endoscopes for unsedated procedures. However, reduced endoscope size limits working-channel dimensions, restricting biopsy forceps to sizes that may yield insufficient or nondiagnostic samples. To address these limitations, we developed an image-guided, depth-controlled, ultrasmall-diameter (1.2-millimeters) cryobiopsy device (μCryoProbe). We optimized the coolant flow profile into the device to enhance tissue freezing, optimizing device-tissue contact time and freezing depth. We tested the device for gastrointestinal biopsy collection in ex vivo preclinical tissues, in an in vivo porcine model, and in sedated human participants. Dimensions and quality of mucosal cryobiopsies from esophagus, stomach, and duodenum were compared with those of forceps-derived biopsies, and it was found that the μCryoProbe device consistently produced high-quality biopsies with optimal tissue orientation and no evidence of crush artifacts. We also demonstrated the ability to capture gastrointestinal biopsies from sedated human participants. By capturing large, well-oriented samples using a small-diameter biopsy tool, this technology has the potential to shift procedures from large to small endoscopes, reducing the need for sedation and improving patient diagnosis through the acquisition of tissue samples with better quality.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 796","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893034","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":"Somatic mosaicism in the buccal mucosa reflects lifestyle and germline risk factors for esophageal squamous cell carcinoma","authors":"Akira Yokoyama,&nbsp;Koichi Watanabe,&nbsp;Yoshikage Inoue,&nbsp;Tomonori Hirano,&nbsp;Masashi Tamaoki,&nbsp;Kenshiro Hirohashi,&nbsp;Shun Kawaguchi,&nbsp;Yoshihiro Ishida,&nbsp;Yasuhide Takeuchi,&nbsp;Yo Kishimoto,&nbsp;Soo Ki Kim,&nbsp;Chikatoshi Katada,&nbsp;Yasuhito Nannya,&nbsp;Hiroshi Seno,&nbsp;Seishi Ogawa,&nbsp;Manabu Muto,&nbsp;Nobuyuki Kakiuchi","doi":"10.1126/scitranslmed.adq6740","DOIUrl":"10.1126/scitranslmed.adq6740","url":null,"abstract":"<div >Clones harboring cancer driver mutations can expand in normal tissues, known as somatic mosaicism, and can be influenced by age and environmental and germline factors. Somatic mosaicism in the blood predicts the risk of hematological malignancies; however, the relevance of somatic mosaicism to solid tumors remains unclear, in part because of limited sample availability. Lifestyle habits, including alcohol consumption and tobacco smoking, and pathogenic germline variants increase the risk of developing esophageal squamous cell carcinoma (ESCC). Because somatic mosaicism in the esophagus is known to be associated with aging and lifestyle habits and considering the contiguity of squamous epithelium from the esophagus to the oral cavity, we noninvasively collected buccal mucosa samples from patients with and without ESCC using swabs of different sizes and conducted deep error-corrected sequencing of 26 cancer driver genes to obtain comprehensive landscapes of tissue remodeling by driver-mutant clones. We found that the number of mutations increased with drinking, but only in individuals with germline risks. Moreover, across positively selected genes in the buccal mucosa, mutations increased with age and smoking regardless of germline risks, whereas drinking affected only those with germline risks. The buccal mucosa of patients with ESCC was extensively remodeled, and models predicting the presence of ESCC demonstrated high accuracy with smaller swab sizes, possibly because of their higher sensitivity in detecting small mutant clones. In conclusion, we showed that buccal mucosal remodeling reflects lifestyle and germline risks, as well as age, which might be exploited for noninvasive risk assessment of ESCC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 796","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893039","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}