The Journal of Clinical Investigation最新文献

{"title":"Multiomic assessments of LNCaP and derived cell strains reveal determinants of prostate cancer pathobiology.","authors":"Arnab Bose,Armand Bankhead Iii,Ilsa Coleman,Thomas Persse,Wanting Han,Patricia Galipeau,Brian Hanratty,Tony Chu,Jared Lucas,Dapei Li,Rabeya Bilkis,Pushpa Itagi,Sajida Hassan,Mallory Beightol,Minjeong Ko,Ruth Dumpit,Michael Haffner,Colin Pritchard,Gavin Ha,Peter S Nelson","doi":"10.1172/jci194727","DOIUrl":"https://doi.org/10.1172/jci194727","url":null,"abstract":"A cornerstone of research to improve cancer outcomes involves studies of model systems to identify causal drivers of oncogenesis, understand mechanisms leading to metastases, and develop new therapeutics. While most cancer types are represented by large cell line panels that reflect diverse neoplastic genotypes and phenotypes found in patients, prostate cancer is notable for a very limited repertoire of models that recapitulate the pathobiology of human disease. Of these, Lymph node carcinoma of the prostate (LNCaP) has served as the major resource for basic and translational studies. Here, we delineated the molecular composition of LNCaP and multiple substrains through analyses of whole genome sequences, transcriptomes, chromatin structure, AR cistromes, and functional studies. Our results determined that LNCaP exhibits substantial subclonal diversity, ongoing genomic instability and phenotype plasticity. While several oncogenic features were consistently present across strains, others were unexpectedly variable such as ETV1 expression, Y chromosome loss, a reliance on WNT and glucocorticoid receptor activity, and distinct AR alterations maintaining AR pathway activation. These results document the inherent molecular heterogeneity and ongoing genomic instability that drive diverse prostate cancer phenotypes and provide a foundation for the accurate interpretation and reproduction of research findings.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"83 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Open-label phase 4 trial evaluating nusinersen after onasemnogene abeparvovec in children with spinal muscular atrophy.","authors":"Crystal M Proud,Richard S Finkel,Julie A Parsons,Riccardo Masson,John F Brandsema,Nancy L Kuntz,Richard Foster,Wenjing Li,Ross Littauer,Jihee Sohn,Stephanie Fradette,Bora Youn,Angela D Paradis","doi":"10.1172/jci193956","DOIUrl":"https://doi.org/10.1172/jci193956","url":null,"abstract":"BACKGROUNDSpinal muscular atrophy (SMA) is a rare genetic neuromuscular disease caused by deletions or mutations of the survival motor neuron 1 gene. Despite the availability of genetically-based treatments for SMA, functional impairments and weakness persist in treated symptomatic individuals. This study addresses whether additional treatment after gene transfer therapy could provide further clinical benefits.METHODSInterim Day 302 findings are described from the phase 4 open-label RESPOND trial evaluating nusinersen in participants aged ≤ 36 months who had suboptimal clinical status following onasemnogene abeparvovec (OA) treatment, as determined by the investigator.RESULTSThirty-seven participants included in the interim analysis were symptomatic at the time of OA administration. Most (92%) had two survival motor neuron 2 gene copies. Age at first nusinersen dose (median [range]) was 9.1 (3-33) months for participants with two SMN2 copies and 34.2 (31-36) months for those with three SMN2 copies, while time from OA dose to first nusinersen dose (median [range]) was 6.3 (3-31) and 13.3 (10-22) months, respectively. Participants had elevated neurofilament light chain (NfL) levels and low compound muscle action potential (CMAP) amplitudes at baseline, suggesting active neurodegeneration and severe denervation at study entry. Improvements from baseline were observed across a range of outcomes at Day 302, including motor function outcomes (HINE-2 and CHOP-INTEND total score), achievement of independent sitting, NfL levels, CMAP, and investigator- and caregiver-reported outcomes. Mean NfL levels decreased rapidly from baseline to Day 183 and remained low at Day 302. Mean ulnar and peroneal CMAP amplitudes increased. No safety concerns were identified.CONCLUSIONImprovements in clinical and biomarker outcomes support the benefit of nusinersen treatment in infants and children with suboptimal clinical status following OA.TRIAL REGISTRATIONCLINICALTRIALSgov ID, NCT04488133; EudraCT number, 2020-003492-18.FUNDINGThis study was sponsored by Biogen (Cambridge, MA, USA).","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of function of T-box 3 in the liver protects against MASLD.","authors":"Jacquelyn J Maher","doi":"10.1172/jci197143","DOIUrl":"https://doi.org/10.1172/jci197143","url":null,"abstract":"The hallmark feature of metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic lipid accumulation. A recent search for genes impacting MASLD in mice uncovered the transcriptional repressor T-box 3 (Tbx3) as a top hit. In this issue of the JCI, Mannino et al. investigated the mechanism of action of TBX3 in murine MASLD. Tbx3 deletion protected against MASLD by inducing high density lipoprotein binding protein and stimulating hepatic VLDL secretion. Loss-of-function mutations in human TBX3 identified in MASLD patients displayed a similar protective effect. Collectively, these findings highlight the importance of lipid export in the prevention of MASLD and identify a transcriptional pathway controlling hepatic lipid secretion that is poised for further investigation.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maintenance DNA methylation is required for induced Treg reparative function following viral pneumonia in mice.","authors":"Anthony M Joudi,Jonathan K Gurkan,Qianli Liu,Elizabeth M Steinert,Manuel A Torres Acosta,Kathryn A Helmin,Luisa Morales-Nebreda,Nurbek Mambetsariev,Carla Patricia Reyes Flores,Hiam Abdala-Valencia,Samuel E Weinberg,Benjamin D Singer","doi":"10.1172/jci192925","DOIUrl":"https://doi.org/10.1172/jci192925","url":null,"abstract":"FOXP3+ natural regulatory T cells (nTregs) promote resolution of inflammation and repair of epithelial damage following viral pneumonia-induced lung injury, thus representing a cellular therapy for patients with severe viral pneumonia and the acute respiratory distress syndrome (ARDS). Whether in vitro induced Tregs (iTregs), which can be rapidly generated in substantial numbers from conventional T cells, also promote lung recovery is unknown. nTregs require specific DNA methylation patterns maintained by the epigenetic regulator, ubiquitin-like with PHD and RING finger domains 1 (UHRF1). Here, we tested whether iTregs promote recovery following viral pneumonia and whether iTregs require UHRF1 for their pro-recovery function. We found that adoptive transfer of iTregs to mice with influenza virus pneumonia promotes lung recovery and that loss of UHRF1-mediated maintenance DNA methylation in iTregs leads to reduced engraftment and a delayed repair response. Transcriptional and DNA methylation profiling of adoptively transferred UHRF1-deficient iTregs that had trafficked to influenza-injured lungs demonstrated transcriptional instability with gain of effector T cell lineage-defining transcription factors. Strategies to promote the stability of iTregs could be leveraged to further augment their pro-recovery function during viral pneumonia and other causes of severe lung injury.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial threads in the tapestry of rheumatoid arthritis.","authors":"Jing Li,Kristine A Kuhn","doi":"10.1172/jci195374","DOIUrl":"https://doi.org/10.1172/jci195374","url":null,"abstract":"Rheumatoid arthritis (RA) has a preclinical period of 5-10 years preceding the appearance of joint pain and swelling characteristic of clinical RA. Preclinical RA has been characterized by circulating IgA and IgG classes of autoantibodies targeting citrullinated protein antigens (ACPAs) that are highly specific for future clinical RA, circulating IgA plasmablasts, and autoantibody production at mucosal sites, all of which point toward mucosal tissues as the origin of immune dysregulation. In individuals at risk for developing and with established RA, oral and gut microbial shifts correlate with immune activation. Specific bacterial taxa such as Segatella copri, Subdoligranulum didolesgii, Eggerthella lenta, and Streptococcal species have been shown to contribute to the development and/or perpetuation of RA through mechanisms that include molecular mimicry, antigen citrullination, and disruption of mucosal immunity. Furthermore, microbial metabolites, including short-chain fatty acids, bile acids, and tryptophan derivatives, regulate immune homeostasis and offer potential therapeutic avenues. The gut microbiome also influences therapeutic responses by modulating conventional disease-modifying antirheumatic drugs. This Review synthesizes current knowledge on the bacterial microbiome's role in RA pathogenesis and treatment responses, highlighting microbiome-targeted interventions as potential strategies for disease prevention and management.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"83 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIE2 activation by antibody-clustered endogenous angiopoietin-2 prevents capillary loss and fibrosis in experimental kidney disease.","authors":"Riikka Pietilä,Amanda M Marks-Hultström,Liqun He,Sami Nanavazadeh,Susan E Quaggin,Christer Betsholtz,Marie Jeansson","doi":"10.1172/jci190286","DOIUrl":"https://doi.org/10.1172/jci190286","url":null,"abstract":"The role of endothelial dysfunction in tubulointerstitial fibrosis associated with chronic kidney disease (CKD) is not well understood. In this study, we demonstrate that the activation of the endothelial tyrosine kinase TIE2 alleviates renal pathology in experimental CKD in mice. TIE2 activation was achieved using a human angiopoietin-2 (ANGPT2)-binding and TIE2-activating antibody (ABTAA), or through adult-induced endothelial-specific knockout of the vascular endothelial protein tyrosine phosphatase gene (Veptp). Both methods significantly protected CKD mice from endothelial dysfunction, peritubular capillary loss, tubular epithelial injury, and tubulointerstitial fibrosis. Conversely, silencing TIE2 through adult-induced endothelial-specific knockout of the Tie2 gene exacerbated CKD pathology. Additionally, we found that endothelial dysfunction promotes renal fibrosis not through endothelial-to-mesenchymal transition as previously expected, but by inducing the expression of pro-fibrotic PDGFB in tubular epithelial cells, a process that is inhibited by TIE2 activation. Our findings suggest that TIE2 activation via ABTAA warrants investigation as a therapy in human CKD, where there is a substantial unmet medical need.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting peroxiredoxin 2 prevents hepatocarcinogenesis in metabolic liver disease.","authors":"Emilie Crouchet,Eugénie Schaeffer,Marine A Oudot,Julien Moehlin,Cloé Gadenne,Frank Jühling,Hussein El Saghire,Naoto Fujiwara,Shijia Zhu,Fahmida Akter Rasha,Sarah C Durand,Anouk Charlot,Clara Ponsolles,Romain Martin,Nicolas Brignon,Fabio Del Zompo,Laura Meiss Heydmann,Marie Parnot,Nourdine Hamdane,Danijela Heide,Jenny Hetzer,Mathias Heikenwälder,Emanuele Felli,Patrick Pessaux,Nathalie Pochet,Joffrey Zoll,Brian Cunniff,Yujin Hoshida,Laurent Mailly,Thomas F Baumert,Catherine Schuster","doi":"10.1172/jci169395","DOIUrl":"https://doi.org/10.1172/jci169395","url":null,"abstract":"Treatment options for advanced liver disease and hepatocellular carcinoma (HCC) are limited and strategies to prevent HCC development are lacking. Aiming to discover novel therapeutic targets, we combined genome wide transcriptomic analysis of liver tissues from patients with advanced liver disease and HCC and a cell-based system predicting liver disease progression and HCC risk. Computational analysis predicted peroxiredoxin 2 (PRDX2) as a candidate gene mediating hepatocarcinogenesis and HCC risk. Analysis of HCC patient tissues confirmed a perturbed expression of PRDX2 in cancer. In vivo perturbation studies in mouse models for MASH driven hepatocarcinogenesis showed that specific Prdx2 knockout in hepatocytes significantly improved metabolic liver functions, restored AMPK activity and prevented HCC development by suppressing oncogenic signaling. Perturbations studies in HCC cell lines, a CDX mouse model and patient-derived HCC spheroids unraveled that PRDX2 also mediates cancer initiation, cancer cell proliferation and survival through its antioxidant activity. Targeting PRDX2 may therefore be a valuable strategy to prevent HCC development in metabolic liver disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recessive TMEM167A variants cause neonatal diabetes, microcephaly and epilepsy syndrome.","authors":"Enrico Virgilio,Sylvia Tielens,Georgia Bonfield,Fang-Shin Nian,Toshiaki Sawatani,Chiara Vinci,Molly Govier,Hossam Montaser,Romane Lartigue,Anoop Arunagiri,Alexandrine Liboz,Flavia Natividade da Silva,Maria Lytrivi,Theodora Papadopoulou,Matthew N Wakeling,James Russ-Silsby,Pamela Bowman,Matthew B Johnson,Thomas W Laver,Anthony Piron,Xiaoyan Yi,Federica Fantuzzi,Sirine Hendrickx,Mariana Igoillo-Esteve,Bruno J Santacreu,Jananie Suntharesan,Radha Ghildiyal,Darshan G Hegde,Nikhil Avnish Shah,Sezer Acar,Beyhan Özkaya Dönmez,Behzat Özkan,Fauzia Mohsin,Iman M Talaat,Mohamed Tarek Abbas,Omar Saied Abbas,Hamed Ali Alghamdi,Nurgun Kandemir,Sarah E Flanagan,Raphael Scharfmann,Peter Arvan,Matthieu Raoux,Laurent Nguyen,Andrew T Hattersley,Miriam Cnop,Elisa De Franco","doi":"10.1172/jci195756","DOIUrl":"https://doi.org/10.1172/jci195756","url":null,"abstract":"Understanding the genetic causes of diseases affecting pancreatic β cells and neurons can give insights into pathways essential for both cell types. Microcephaly, epilepsy and diabetes syndrome (MEDS) is a congenital disorder with two known aetiological genes, IER3IP1 and YIPF5. Both genes encode proteins involved in endoplasmic reticulum (ER) to Golgi trafficking. We used genome sequencing to identify 6 individuals with MEDS caused by biallelic variants in the novel disease gene, TMEM167A. All had neonatal diabetes (diagnosed <6 months) and severe microcephaly, five also had epilepsy. TMEM167A is highly expressed in developing and adult human pancreas and brain. To gain insights into the mechanisms leading to diabetes, we silenced TMEM167A in EndoC-βH1 cells and knocked-in one patient's variant, p.Val59Glu, in induced pluripotent stem cells (iPSCs). Both TMEM167A depletion in EndoC-βH1 cells and the p.Val59Glu variant in iPSC-derived β cells sensitized β cells to ER stress. The p.Val59Glu variant impaired proinsulin trafficking to the Golgi and induced iPSC-β cell dysfunction. The discovery of TMEM167A variants as a new genetic cause of MEDS highlights a critical role of TMEM167A in the ER to Golgi pathway in β cells and neurons.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XP-J, a ninth xeroderma pigmentosum complementation group, results from mutations in GTF2H4, encoding TFIIH-p52 subunit.","authors":"Hiva Fassihi,Shehla Mohammed,Yuka Nakazawa,Heather Fawcett,Sally Turner,Joanne Palfrey,Isabel Garrood,Adesoji Abiona,Ana Ms Morley,Mayuko Shimada,Kana Kato,Alan R Lehmann,Tomoo Ogi","doi":"10.1172/jci195731","DOIUrl":"https://doi.org/10.1172/jci195731","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statin-dependent and -independent pathways are associated with major adverse cardiovascular events in people with HIV.","authors":"Márton Kolossváry,Irini Sereti,Markella V Zanni,Carl J Fichtenbaum,Judith A Aberg,Gerald S Bloomfield,Carlos D Malvestutto,Judith S Currier,Sarah M Chu,Marissa R Diggs,Alex B Lu,Christopher deFilippi,Borek Foldyna,Sara McCallum,Craig A Sponseller,Michael T Lu,Pamela S Douglas,Heather J Ribaudo,Steven K Grinspoon","doi":"10.1172/jci196021","DOIUrl":"https://doi.org/10.1172/jci196021","url":null,"abstract":"BACKGROUNDStatin therapy lowers the risk of major adverse cardiovascular events (MACE) among people with HIV (PWH). Residual risk pathways contributing to excess MACE beyond low-density lipoprotein cholesterol (LDL-C) are not well understood. Our objective was to evaluate the association of statin responsive and other inflammatory and metabolic pathways to MACE in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE).METHODSCox proportional hazards models were used to assess the relationship between MACE and proteomic measurements at study entry and year 2 adjusting for time-updated statin use and baseline 10-year atherosclerotic cardiovascular disease risk score. We built a machine learning (ML) model to predict MACE using baseline proteins values with significant associations.RESULTSIn 765 individuals (age: 50.8±5.9 years, 82% males) among 7 proteins changing with statin vs. placebo, angiopoietin-related protein 3 (ANGPTL3) related most strongly to MACE (aHR: 2.31 per 2-fold higher levels; 95%CI: 1.11-4.80; p=0.03), such that lower levels of ANGPTL3 achieved with statin therapy were associated with lower MACE risk. Among 248 proteins not changing in response to statin therapy, 26 were associated with MACE at FDR<0.05. These proteins represented predominantly humoral immune response, leukocyte chemotaxis, and cytokine pathways. Our proteomic ML model achieved a 10-fold cross-validated c-index of 0.74±0.11 to predict MACE, improving on models using traditional risk prediction scores only (c-index: 0.61±0.18).CONCLUSIONSANGPTL3, as well as key inflammatory pathways may contribute to residual risk of MACE among PWH, beyond LDL-C.TRIAL REGISTRATIONCLINICALTRIALSgov: NCT02344290.FUNDINGNIH, Kowa, Gilead Sciences, ViiV.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}