The Journal of Clinical Investigation最新文献_第8页

Disruption of Ataxia-telangiectasia mutated kinase enhances radiation therapy efficacy in spatially-directed diffuse midline glioma models. 破坏共济失调-毛细血管扩张突变激酶可增强放射治疗在空间定向弥漫性中线胶质瘤模型中的疗效。

The Journal of Clinical Investigation Pub Date : 2025-04-17 DOI: 10.1172/jci179395

Avani Mangoli,Vennesa Valentine,Spencer Maingi,Sophie R Wu,Harrison Q Liu,Michael Aksu,Vaibhav Jain,Bronwen E Foreman,Joshua A Regal,Loren B Weidenhammer,Connor E Stewart,Maria E Guerra Garcia,Emily Hocke,Karen Abramson,Tal Michaeli,Nerissa T Williams,Lixia Luo,Megan Romero,Katherine Deland,Samantha Gadd,Eita Uchida,Laura Attardi,Kouki Abe,Rintaro Hashizume,David M Ashley,Oren J Becher,David G Kirsch,Simon G Gregory,Zachary J Reitman

{"title":"Disruption of Ataxia-telangiectasia mutated kinase enhances radiation therapy efficacy in spatially-directed diffuse midline glioma models.","authors":"Avani Mangoli,Vennesa Valentine,Spencer Maingi,Sophie R Wu,Harrison Q Liu,Michael Aksu,Vaibhav Jain,Bronwen E Foreman,Joshua A Regal,Loren B Weidenhammer,Connor E Stewart,Maria E Guerra Garcia,Emily Hocke,Karen Abramson,Tal Michaeli,Nerissa T Williams,Lixia Luo,Megan Romero,Katherine Deland,Samantha Gadd,Eita Uchida,Laura Attardi,Kouki Abe,Rintaro Hashizume,David M Ashley,Oren J Becher,David G Kirsch,Simon G Gregory,Zachary J Reitman","doi":"10.1172/jci179395","DOIUrl":"https://doi.org/10.1172/jci179395","url":null,"abstract":"Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce native H3.3K27M mutations in a lineage- and spatially-directed manner. We generated primary mouse tumors that recapitulate human DMG. Disrupting ataxia-telangiectasia mutated kinase (ATM) enhanced the efficacy of radiation therapy in murine and patient-derived DMG models which increased survival. Microscopy-based in situ sequencing was used to spatially resolve transcriptional profiles in >750,000 single cells with or without ATM disruption and radiation therapy, revealing altered immune-neoplastic and endothelial cell interactions after treatment. An allelic series of primary murine DMG models with different p53 mutations confirmed that transactivation-independent p53 activity is a key mediator of radiosensitivity after ATM disruption. Our findings contribute primary DMG mouse models with deep profiling and reveal the mechanisms of treatment response to an actionable therapeutic strategy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"137 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849373","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}

引用次数: 0

Deficiency of the Fanconi anemia core complex protein FAAP100 results in severe Fanconi anemia. 范可尼贫血核心复合蛋白FAAP100缺乏可导致严重的范可尼贫血。

The Journal of Clinical Investigation Pub Date : 2025-04-17 DOI: 10.1172/jci185126

Benjamin A Harrison,Emma Mizrahi-Powell,John Pappas,Kristen Thomas,Subrahmanya Vasishta,Shripad Hebbar,Anju Shukla,Shalini S Nayak,Tina K Truong,Amy Woroch,Yara Kharbutli,Bruce D Gelb,Cassie S Mintz,Gilad D Evrony,Agata Smogorzewska

{"title":"Deficiency of the Fanconi anemia core complex protein FAAP100 results in severe Fanconi anemia.","authors":"Benjamin A Harrison,Emma Mizrahi-Powell,John Pappas,Kristen Thomas,Subrahmanya Vasishta,Shripad Hebbar,Anju Shukla,Shalini S Nayak,Tina K Truong,Amy Woroch,Yara Kharbutli,Bruce D Gelb,Cassie S Mintz,Gilad D Evrony,Agata Smogorzewska","doi":"10.1172/jci185126","DOIUrl":"https://doi.org/10.1172/jci185126","url":null,"abstract":"Fanconi anemia (FA) is a rare genetic disease characterized by loss-of-function variants in any of the 22 previously identified genes (FANCA-FANCW) that encode proteins participating in the repair of DNA interstrand crosslinks (ICLs). Patient phenotypes are variable, but may include developmental abnormalities, early onset pancytopenia, and predisposition to hematologic and solid tumors. Here, we describe two unrelated families with multiple pregnancy losses and offspring presenting with severe developmental and hematologic abnormalities leading to death in utero or in early life. Homozygous loss-of-function variants in FAAP100 were identified in affected children of both families. The FAAP100 protein associates with FANCB and FANCL, the E3 ubiquitin ligase responsible for the monoubiquitination of FANCD2 and FANCI, which is necessary for FA pathway function. Patient-derived cells exhibited phenotypes consistent with FA. Expression of the wild-type FAAP100 cDNA, but not the patient-derived variants, rescued the observed cellular phenotypes. This establishes FAAP100 deficiency as a cause of Fanconi anemia, with FAAP100 gaining an alias as FANCX. The extensive developmental malformations of individuals with FAAP100 loss-of-function variants are among the most severe across previously described FA phenotypes, indicating that the FA pathway is essential for human development.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849476","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}

引用次数: 0

Transcriptome-guided GLP-1 receptor therapy rescues metabolic and behavioral disruptions in a Bardet-Biedl Syndrome mouse model. 转录组引导GLP-1受体治疗在Bardet-Biedl综合征小鼠模型中拯救代谢和行为中断。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci184636

Arashdeep Singh,Naila Haq,Mingxin Yang,Shelby Luckey,Samira Mansouri,Martha Campbell-Thompson,Lei Jin,Sofia Christou-Savina,Guillaume de Lartigue

{"title":"Transcriptome-guided GLP-1 receptor therapy rescues metabolic and behavioral disruptions in a Bardet-Biedl Syndrome mouse model.","authors":"Arashdeep Singh,Naila Haq,Mingxin Yang,Shelby Luckey,Samira Mansouri,Martha Campbell-Thompson,Lei Jin,Sofia Christou-Savina,Guillaume de Lartigue","doi":"10.1172/jci184636","DOIUrl":"https://doi.org/10.1172/jci184636","url":null,"abstract":"Bardet-Biedl Syndrome (BBS), a ciliopathy characterized by obesity, hyperphagia, and learning deficits, arises from mutations in BBS genes. More exacerbated symptoms occur with mutations in genes encoding the BBSome, a complex regulating primary cilia function. We investigated the mechanisms underlying BBS-induced obesity using a novel BBS5 knockout (BBS5-/-) mouse model. BBS5-/- mice displayed hyperphagia, learning deficits, glucose/insulin intolerance, and disrupted metabolic hormones, phenocopying human BBS. They displayed an unique immunophenotype in white adipose tissue with increased proinflammatory macrophages and dysfunctional regulatory T cells, suggesting a distinct mechanism for adiposity compared to typical obesity models. Additionally, BBS5-/- mice exhibited pancreatic islet hyperplasia but failed to normalize blood glucose, suggesting defective insulin action. Hypothalamic transcriptomics revealed dysregulated endocrine signaling pathways with functional analyses confirming defects in insulin, leptin, and cholecystokinin (CCK) signalling, while preserving glucagon-like peptide-1 receptor (GLP-1R) responsiveness. Notably, treatment with a GLP-1R agonist effectively alleviated hyperphagia, body weight gain, improved glucose tolerance, and circulating metabolic hormones in BBS5-/- mice. This study establishes BBS5-/- mice as a valuable translational model of BBS to understand the pathogenesis and develop novel treatments. Our findings highlight the therapeutic potential of GLP-1R agonists for managing BBS-associated metabolic dysregulation, warranting further investigation for clinical application.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841048","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}

引用次数: 0

Clinical evidence for independent regulation of vitamin D by intestinal CYP24A1. 肠道CYP24A1独立调节维生素D的临床证据

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci190972

Sandrine Lemoine,Arnaud Molin,Alice Koenig,Justine Bacchetta

引用次数: 0

Precision screening facilitates clinical classification of BRCA2-PALB2 binding variants with benign and pathogenic functional effects. 精准筛选有助于临床对BRCA2-PALB2结合变异进行良性和致病性功能作用的分类。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci181879

Muthiah Bose,Manika Indrajit Singh,Morten Frödin,Bent Ejlertsen,Claus S Sørensen,Maria Rossing

{"title":"Precision screening facilitates clinical classification of BRCA2-PALB2 binding variants with benign and pathogenic functional effects.","authors":"Muthiah Bose,Manika Indrajit Singh,Morten Frödin,Bent Ejlertsen,Claus S Sørensen,Maria Rossing","doi":"10.1172/jci181879","DOIUrl":"https://doi.org/10.1172/jci181879","url":null,"abstract":"BACKGROUNDDecoding the clinical impact of genetic variants is particularly important for precision medicine in cancer. Genetic screening of mainly breast and ovarian cancer patients has identified numerous BRCA1/BRCA2 'variants of uncertain significance' (VUS) that remain unclassified due to a lack of pedigrees and functional data.METHODSHere, we used CRISPR-Select - a technology that exploits unique inbuilt controls at the endogenous locus - to assess 54 rare ClinVar VUS located in the PALB2-binding domain (PBD) of BRCA2. Variant deleteriousness was examined in the absence and presence of PARPi, Cisplatin, or Mitomycin C.RESULTSMarked functional deficiency was observed for variants in the exon 2-donor splice region (A22 = (c.66A>C), A22 = (c.66A>G), A22 = (c.66A>T), and D23H) and Trp31 amino acid (W31G, W31L, and W31C), both critical for BRCA2 function. Moreover, T10K and G25R resulted in an intermediate phenotype, suggesting these variants are hypomorphic in nature. Combining our functional results with the latest ClinGen BRCA1/2 Variant Curation Expert Panel recommendations, we could classify 49 of the 54 VUS as either likely benign (n = 45) or likely pathogenic (n = 4).CONCLUSIONHence, CRISPR-Select is an important tool for efficient variant clinical classification. Application of this technology in the future will ultimately improve patient care.FUNDINGDanish Cancer Society, Novo Nordisk Foundation, Sygeforsikring Danmark, Børnecancerfonden, Neye-Fonden, Roche, Novartis, Pfizer, AstraZeneca, MSD, and Daiichi Sankyo Europe GmbH.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841118","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}

引用次数: 0

Immunotherapeutic strategies in head and neck cancer: challenges and opportunities. 头颈癌的免疫治疗策略：挑战与机遇。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci188128

Xia Liu,R Alex Harbison,Mark A Varvares,Sidharth V Puram,Guangyong Peng

{"title":"Immunotherapeutic strategies in head and neck cancer: challenges and opportunities.","authors":"Xia Liu,R Alex Harbison,Mark A Varvares,Sidharth V Puram,Guangyong Peng","doi":"10.1172/jci188128","DOIUrl":"https://doi.org/10.1172/jci188128","url":null,"abstract":"HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%-22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836495","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}

引用次数: 0

A dominant-negative IFNGR1 variant reveals broad immune cell sequestering of IFN-γ. IFNGR1显性阴性变异揭示了IFN-γ广泛的免疫细胞隔离。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci186799

Samantha Chan,Mai B Margetts,Longfei Wang,Jack Godsell,Josh Chatelier,Belinda Liu,Charlotte A Slade,Andrew Brett,Kasha P Singh,Vanessa L Bryant,Lauren J Howson

引用次数: 0

Transient pain and long-term gain: adjuvant dose directs immune memory. 短暂疼痛和长期获益：佐剂剂量指导免疫记忆。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci190524

Pabitra B Pal,Smita S Iyer

引用次数: 0

Targeting melanocortin 4 receptor to treat sleep disordered breathing in mice. 靶向黑素皮质素4受体治疗小鼠睡眠呼吸障碍。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci177823

Mateus R Amorim,Noah R Williams,O Aung,Melanie Alexis Ruiz,Frederick Anokye-Danso,Junia Lara de Deus,Jiali Xiong,Olga Dergacheva,Shannon Bevans-Fonti,Sean M Lee,Jeffrey S Berger,Mark N Wu,Rexford S Ahima,David Mendelowitz,Vsevolod Y Polotsky

{"title":"Targeting melanocortin 4 receptor to treat sleep disordered breathing in mice.","authors":"Mateus R Amorim,Noah R Williams,O Aung,Melanie Alexis Ruiz,Frederick Anokye-Danso,Junia Lara de Deus,Jiali Xiong,Olga Dergacheva,Shannon Bevans-Fonti,Sean M Lee,Jeffrey S Berger,Mark N Wu,Rexford S Ahima,David Mendelowitz,Vsevolod Y Polotsky","doi":"10.1172/jci177823","DOIUrl":"https://doi.org/10.1172/jci177823","url":null,"abstract":"Weight loss medications are emerging candidates for pharmacotherapy of sleep disordered breathing (SDB). A melanocortin receptor 4 (MC4R) agonist, setmelanotide (SET), is used to treat obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that SET can treat SDB in diet induced obese mice. We performed a proof-of-concept randomized crossover trial of a single dose of SET vs vehicle and a two-week daily SET vs vehicle trial, examined co-localization of Mc4r mRNAs with markers of CO2 sensing neurons Phox2b and neuromedin-B in the brainstem, and expressed Cre-dependent designer receptors exclusively activated by designer drugs or caspase in obese Mc4r-Cre mice. SET increased minute ventilation across sleep/wake states, enhanced the hypercapnic ventilatory response (HCVR) and abolished apneas during sleep. Phox2b+ neurons in the nucleus of the solitary tract (NTS) and the parafacial region expressed Mc4r. Chemogenetic stimulation of the MC4R+ neurons in the parafacial region, but not in the NTS, augmented HCVR without any changes in metabolism. Caspase elimination of the parafacial MC4R+ neurons abolished effects of SET on HCVR. Parafacial MC4R+ neurons projected to the respiratory pre-motor neurons retrogradely labeled from C3-C4. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R+ neurons.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841051","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}

引用次数: 0

A small-molecule inhibitor of BCL10-MALT1 interaction abrogates progression of diffuse large B cell lymphoma. BCL10-MALT1相互作用的小分子抑制剂可消除弥漫性大B细胞淋巴瘤的进展。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci164573

Heejae Kang,Lisa M Maurer,Jing Cheng,Mei Smyers,Linda R Klei,Dong Hu,Juliana Hofstatter Azambuja,Marcelo J Murai,Ahmed Mady,Ejaz Ahmad,Matthew Trotta,Hanna B Klei,Minda Liu,Prasanna Ekambaram,Zaneta Nikolovska-Coleska,Bill B Chen,Linda M McAllister-Lucas,Peter C Lucas

{"title":"A small-molecule inhibitor of BCL10-MALT1 interaction abrogates progression of diffuse large B cell lymphoma.","authors":"Heejae Kang,Lisa M Maurer,Jing Cheng,Mei Smyers,Linda R Klei,Dong Hu,Juliana Hofstatter Azambuja,Marcelo J Murai,Ahmed Mady,Ejaz Ahmad,Matthew Trotta,Hanna B Klei,Minda Liu,Prasanna Ekambaram,Zaneta Nikolovska-Coleska,Bill B Chen,Linda M McAllister-Lucas,Peter C Lucas","doi":"10.1172/jci164573","DOIUrl":"https://doi.org/10.1172/jci164573","url":null,"abstract":"Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the activated B cell-like subtype (ABC-DLBCL) is associated with particularly poor outcome. Many ABC-DLBCLs harbor gain-of-function mutations that cause inappropriate assembly of the CARMA1-BCL10-MALT1 (CBM) signalosome, a cytoplasmic complex that drives downstream NF-κB signaling. MALT1 is the effector protein of the CBM signalosome such that its recruitment to the signalosome via interaction with BCL10 allows it to exert both protease and scaffolding activities that together synergize in driving NF-κB. Here, we demonstrate that a molecular groove located between two adjacent immunoglobulin-like domains within MALT1 represents a binding pocket for BCL10. Leveraging this discovery, we performed an in silico screen to identify small molecules that dock within this MALT1 groove and act as BCL10-MALT1 protein-protein interaction (PPI) inhibitors. We report the identification of M1i-124 as a first-in-class compound that blocks BCL10-MALT1 interaction, abrogates MALT1 scaffolding and protease activities, promotes degradation of BCL10 and MALT1 proteins, and specifically targets ABC-DLBCLs characterized by dysregulated MALT1. Our findings demonstrate that small-molecule inhibitors of BCL10-MALT1 interaction can function as potent agents to block MALT1 signaling in selected lymphomas, and provide a road map for clinical development of a new class of precision-medicine therapeutics.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836494","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}

引用次数: 0