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NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy. NDR2 通过调节 ULK1 介导的有丝分裂,对破骨细胞的形成至关重要。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.180409
Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiaojian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen
{"title":"NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy.","authors":"Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiaojian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen","doi":"10.1172/jci.insight.180409","DOIUrl":"10.1172/jci.insight.180409","url":null,"abstract":"<p><p>Bone homeostasis primarily stems from the balance between osteoblasts and osteoclasts, wherein an augmented number or heightened activity of osteoclasts is a prevalent etiological factor in the development of bone loss. Nuclear Dbf2-related kinase (NDR2), also known as STK38L, is a member of the Hippo family with serine/threonine kinase activity. We unveiled an upregulation of NDR2 expression during osteoclast differentiation. Manipulation of NDR2 levels through knockdown or overexpression facilitated or hindered osteoclast differentiation respectively, indicating a negative feedback role for NDR2 in the osteoclastogenesis. Myeloid NDR2-dificient mice (Lysm+NDR2f/f) showed lower bone mass and further exacerbated ovariectomy-induced or aging-related bone loss. Mechanically, NDR2 enhanced autophagy and mitophagy through mediating ULK1 instability. In addition, ULK1 inhibitor (ULK1-IN2) ameliorated NDR2 cKO-induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. In a word, NDR2-ULK1-mitophagy axis was a potential innovative therapeutic target for the prevention and management of bone loss.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667501","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}
引用次数: 0
Mutation of CRYAB encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy. 编码线粒体伴侣蛋白和抗凋亡蛋白的 CRYAB 基因突变会导致遗传性视神经萎缩。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.182209
Chenghui Wang, Liyao Zhang, Zhipeng Nie, Min Liang, Hanqing Liu, Qiuzi Yi, Chunyan Wang, Cheng Ai, Juanjuan Zhang, Yinglong Gao, Yanchun Ji, Min-Xin Guan
{"title":"Mutation of CRYAB encoding a conserved mitochondrial chaperone and anti-apoptotic protein causes hereditary optic atrophy.","authors":"Chenghui Wang, Liyao Zhang, Zhipeng Nie, Min Liang, Hanqing Liu, Qiuzi Yi, Chunyan Wang, Cheng Ai, Juanjuan Zhang, Yinglong Gao, Yanchun Ji, Min-Xin Guan","doi":"10.1172/jci.insight.182209","DOIUrl":"10.1172/jci.insight.182209","url":null,"abstract":"<p><p>The degeneration of retinal ganglion cells (RGC) due to mitochondrial dysfunctions manifests optic neuropathy. However, the molecular components of RGC linked to optic neuropathy manifestations remain largely unknown. Here, we identified a novel optic atrophy-causative CRYAB gene encoding a highly conserved major lens protein acting as mitochondrial chaperone and possessing anti-apoptotic activities. The heterozygous CRYAB mutation (c.313G>A, p. Glu105Lys) was cosegregated with autosomal dominant inheritance of optic atrophy in 3 Chinese families. The p.E105K mutation altered the structure and function of CRYAB, including decreased stability, reduced formation of oligomers and decreasing chaperone activity. Coimmunoprecipitation indicated that the p.E105K mutation reduced the interaction of CRYAB with apoptosis-associated cytochrome c and VDAC. The cell lines carrying the p.E105K mutation displayed promoting apoptosis, defective assembly, stability and activities of oxidative phosphorylation system and imbalance of mitochondrial dynamics. Involvement of CRYAB in optic atrophy was confirmed by phenotypic evaluations of Cryabp.E105K knock-in mice. These mutant mice exhibited ocular lesions including changing intra-retina layers, degeneration of RGCs, photoreceptor deficits and abnormal retinal vasculature. Furthermore, Cryab-deficient mice displayed elevated apoptosis and mitochondrial dysfunctions. Our findings provide new insight of pathophysiology of optic atrophy arising from RGC degeneration caused by CRYAB deficiency-induced elevated apoptosis and mitochondrial dysfunctions.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667500","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}
引用次数: 0
Aiolos promotes CXCR3 expression on TH1 cells via positive regulation of IFNγ/STAT1 signaling. Aiolos 通过正向调节 IFNγ/STAT1 信号,促进 TH1 细胞中 CXCR3 的表达。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-19 DOI: 10.1172/jci.insight.180287
Melissa R Leonard, Devin M Jones, Kaitlin A Read, Srijana Pokhrel, Jasmine A Tuazon, Robert T Warren, Jacob S Yount, Kenneth J Oestreich
{"title":"Aiolos promotes CXCR3 expression on TH1 cells via positive regulation of IFNγ/STAT1 signaling.","authors":"Melissa R Leonard, Devin M Jones, Kaitlin A Read, Srijana Pokhrel, Jasmine A Tuazon, Robert T Warren, Jacob S Yount, Kenneth J Oestreich","doi":"10.1172/jci.insight.180287","DOIUrl":"10.1172/jci.insight.180287","url":null,"abstract":"<p><p>CD4+ T helper 1 (TH1) cells coordinate adaptive immune responses to intracellular pathogens, including viruses. Key to this function is the ability of TH1 cells to migrate within secondary lymphoid tissues, as well as to sites of inflammation, which relies on signals received through the chemokine receptor CXCR3. CXCR3 expression is driven by the TH1 lineage-defining transcription factor T-bet, and the cytokine-responsive Signal Transducer and Activator of Transcription (STAT) family members STAT1 and STAT4. Here, we identify the Ikaros zinc finger (IkZF) transcription factor Aiolos (Ikzf3) as an additional positive regulator of CXCR3 both in vitro and in vivo using a murine model of influenza virus infection. Mechanistically, we find that Aiolos-deficient CD4+ T cells exhibit decreased expression of key components of the IFNγ/STAT1 signaling pathway, including JAK2 and STAT1. Consequently, Aiolos deficiency results in decreased levels of STAT1 tyrosine phosphorylation and reduced STAT1 enrichment at the Cxcr3 promoter. We further find that Aiolos and STAT1 form a positive feedback loop via reciprocal regulation of each other downstream of IFNγ signaling. Collectively, our study demonstrates that Aiolos promotes CXCR3 expression on TH1 cells by propagating the IFNγ/STAT1 cytokine signaling pathway.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667494","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}
引用次数: 0
Insulin mitigates acute ischemia induced atrial fibrillation and sinoatrial node dysfunction ex vivo. 胰岛素可减轻急性缺血诱发的体内心房颤动和中房结节功能障碍。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-14 DOI: 10.1172/jci.insight.185961
Huiliang Qiu, Fan Li, Hannah Prachyl, Alejandra Patino-Guerrero, Michael Rubart, Wuqiang Zhu
{"title":"Insulin mitigates acute ischemia induced atrial fibrillation and sinoatrial node dysfunction ex vivo.","authors":"Huiliang Qiu, Fan Li, Hannah Prachyl, Alejandra Patino-Guerrero, Michael Rubart, Wuqiang Zhu","doi":"10.1172/jci.insight.185961","DOIUrl":"10.1172/jci.insight.185961","url":null,"abstract":"<p><p>Acute atrial ischemia is a well-known cause of postoperative atrial fibrillation (POAF). However, mechanisms through which ischemia contributes to the development of POAF are not well understood. In this study, ex vivo Langendorff perfusion was used to induce acute ischemia and reperfusion in the heart in order to mimic POAF. Inducibility of atrial fibrillation (AF) was evaluated using programmed electrical stimulation and confirmed with open-atrium optical mapping. Compared to the control group without ischemia, 25 minutes of ischemia substantially increased the incidence of AF. The right atrium was more susceptible to AF than the left atrium. Administering insulin for 30 minutes before ischemia and during reperfusion with 25 minutes of ischemia greatly reduced the vulnerability to AF. However, insulin treatment during reperfusion only did not show substantial benefits against AF. Optical mapping studies showed that insulin mitigates ischemia-induced abnormal electrophysiology, including shortened action potential duration and effective refractory period, slowed conduction velocity, increased conduction heterogeneity, and altered calcium transients. In conclusion, insulin reduced the risk of acute ischemia/reperfusion-induced AF via improving the electrophysiology and calcium handling of atrial cardiomyocytes, which provides a potential therapy for POAF.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620638","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}
引用次数: 0
High-resolution multimodal profiling of human epileptic brain activity via explanted depth electrodes. 通过植入的深度电极对人类癫痫脑部活动进行高分辨率多模态分析。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-14 DOI: 10.1172/jci.insight.184518
Anuj Kumar Dwivedi, Arun Mahesh, Albert Sanfeliu, Julian Larkin, Rebecca A Siwicki, Kieron J Sweeney, Donncha F O'Brien, Peter Widdess-Walsh, Simone Picelli, David C Henshall, Vijay K Tiwari
{"title":"High-resolution multimodal profiling of human epileptic brain activity via explanted depth electrodes.","authors":"Anuj Kumar Dwivedi, Arun Mahesh, Albert Sanfeliu, Julian Larkin, Rebecca A Siwicki, Kieron J Sweeney, Donncha F O'Brien, Peter Widdess-Walsh, Simone Picelli, David C Henshall, Vijay K Tiwari","doi":"10.1172/jci.insight.184518","DOIUrl":"https://doi.org/10.1172/jci.insight.184518","url":null,"abstract":"<p><p>The availability and integration of electrophysiological and molecular data from the living brain is critical to understand and diagnose complex human disease. Intracranial stereo electroencephalography (SEEG) electrodes used for identifying the seizure focus on epilepsy patients could enable the integration of such multimodal data. Here, we report MoPEDE (Multimodal Profiling of Epileptic Brain Activity via Explanted Depth Electrodes), a method that recovers extensive protein-coding transcripts, including cell-type markers, DNA methylation and short variant profiles from explanted SEEG electrodes matched with electrophysiological and radiological data allowing for high-resolution reconstructions of brain structure and function. We find gene expression gradients that correspond with the neurophysiology-assigned epileptogenicity index but also outlier molecular fingerprints in some electrodes, potentially indicating seizure generation or propagation zones not detected during electroclinical assessments. Additionally, we identify DNA methylation profiles indicative of transcriptionally permissive or restrictive chromatin states and SEEG-adherent differentially expressed and methylated genes not previously associated with epilepsy. Together, these findings validate that RNA profiles and genome-wide epigenetic data from explanted SEEG electrodes offer high-resolution surrogate molecular landscapes of brain activity. The MoPEDE approach has the potential to enhance diagnostic decisions and deepen our understanding of epileptogenic network processes in the human brain.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620618","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}
引用次数: 0
Profound reduction of HIV-1 reservoir cells over three decades of antiretroviral therapy started in early infancy. 经过 30 年的抗逆转录病毒治疗,HIV-1 储库细胞的大幅减少始于婴儿期。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-14 DOI: 10.1172/jci.insight.186550
Liliana C Vela, Leah Carrere, Chloe Naasz, Sruthi Kalavacherla, Toong Seng Tan, Lesley de Armas, Ce Gao, Xu G Yu, Savita G Pahwa, Katherine Luzuriaga, Mathias Lichterfeld
{"title":"Profound reduction of HIV-1 reservoir cells over three decades of antiretroviral therapy started in early infancy.","authors":"Liliana C Vela, Leah Carrere, Chloe Naasz, Sruthi Kalavacherla, Toong Seng Tan, Lesley de Armas, Ce Gao, Xu G Yu, Savita G Pahwa, Katherine Luzuriaga, Mathias Lichterfeld","doi":"10.1172/jci.insight.186550","DOIUrl":"https://doi.org/10.1172/jci.insight.186550","url":null,"abstract":"<p><p>HIV-1 reservoir cells persist indefinitely during suppressive antiretroviral therapy (ART) in individuals who acquire infection in adulthood, but little is known about the longitudinal evolution of viral reservoir cells during long-term ART started during early infancy. We studied two fraternal twins who acquired HIV-1 perinatally, started ART at week 10 after birth and remained on ART for 28 years. We observed that the frequency of genome intact proviruses, determined by single-genome near full-length proviral sequencing, declined by approximately 4,000- to 13,000-fold during this period, indicating enhanced decay rates of intact proviruses even after adjusting for dilution effects from somatic growth. Despite analyzing more than one billion PBMC after 28 years of ART in each participant, no intact proviruses were detected in one participant, and one intact provirus was isolated in the other. The longitudinal decline of defective proviruses in the two participants was more similar to proviral decay kinetics reported in individuals who started ART during adulthood; moreover, clonal sequence clusters were readily detectable for defective proviruses but not for intact proviruses after 28 years of ART in the two twins. Together, these data suggest decreased long-term stability and increased immunological vulnerability of intact proviruses during long-term ART started in early infancy.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620659","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}
引用次数: 0
Integrated analysis of rectal mucosal microbiome and transcriptome reveals a distinct microenvironment among young MSM. 直肠粘膜微生物组和转录组的综合分析揭示了年轻 MSM 的独特微环境。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.181720
Cassie G Ackerley, S Abigail Smith, Phillip M Murray, Praveen K Amancha, Vanessa E Van Doren, Gregory K Tharp, Robert A Arthur, Rama R Amara, Yi-Juan Hu, Colleen F Kelley
{"title":"Integrated analysis of rectal mucosal microbiome and transcriptome reveals a distinct microenvironment among young MSM.","authors":"Cassie G Ackerley, S Abigail Smith, Phillip M Murray, Praveen K Amancha, Vanessa E Van Doren, Gregory K Tharp, Robert A Arthur, Rama R Amara, Yi-Juan Hu, Colleen F Kelley","doi":"10.1172/jci.insight.181720","DOIUrl":"10.1172/jci.insight.181720","url":null,"abstract":"<p><p>Crosstalk between the microbiome and gut mucosa-resident immune cells plays a pivotal role in modulating immune responses to pathogens, including responses to HIV infection. However, how these interactions may differ between young men who have sex with men (YMSM) disproportionately impacted by HIV, as compared with older adult MSM (AMSM), is not well understood. A broad analysis of associations between the microbiome and rectal transcriptome revealed 10 microbial families/genera correlated with immunologic gene pathways. Specifically, the rectal transcriptome of YMSM was characterized by upregulation of T cell activation/differentiation pathways and signaling from multiple cytokine families compared with AMSM. The microbiome of YMSM was enriched with pathogenic genera, including Peptostreptococcus, shown to be positively correlated with type I IFN pathways important for antiviral immunity. These findings demonstrate that YMSM have a unique immune phenotype and rectal microenvironment and support further evaluation of biological factors that influence rectal HIV transmission.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365270","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}
引用次数: 0
High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction. 对肾移植中的 NK 细胞进行高维分析,发现与抗体依赖性移植物功能障碍相关的亚群。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.185687
Dan Fu Ruan, Miguel Fribourg, Yuko Yuki, Yeon-Hwa Park, Maureen P Martin, Haocheng Yu, Geoffrey C Kelly, Brian Lee, Ronaldo M de Real, Rachel Lee, Daniel Geanon, Seunghee Kim-Schulze, Nicholas Chun, Paolo Cravedi, Mary Carrington, Peter S Heeger, Amir Horowitz
{"title":"High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction.","authors":"Dan Fu Ruan, Miguel Fribourg, Yuko Yuki, Yeon-Hwa Park, Maureen P Martin, Haocheng Yu, Geoffrey C Kelly, Brian Lee, Ronaldo M de Real, Rachel Lee, Daniel Geanon, Seunghee Kim-Schulze, Nicholas Chun, Paolo Cravedi, Mary Carrington, Peter S Heeger, Amir Horowitz","doi":"10.1172/jci.insight.185687","DOIUrl":"10.1172/jci.insight.185687","url":null,"abstract":"<p><p>Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400301","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}
引用次数: 0
SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma. SLC4A11介导氨的输入并促进肝细胞癌的癌干性。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.184826
Ameer L Elaimy, Marwa O El-Derany, Jadyn James, Zhuwen Wang, Ashley N Pearson, Erin A Holcomb, Amanda K Huber, Miguel Gijón, Hannah N Bell, Viraj R Sanghvi, Timothy L Frankel, Grace L Su, Elliot B Tapper, Andrew W Tai, Nithya Ramnath, Christopher P Centonze, Irina Dobrosotskaya, Julie A Moeller, Alex K Bryant, David A Elliott, Enid Choi, Joseph R Evans, Kyle C Cuneo, Thomas J Fitzgerald, Daniel R Wahl, Meredith A Morgan, Daniel T Chang, Max S Wicha, Theodore S Lawrence, Yatrik M Shah, Michael D Green
{"title":"SLC4A11 mediates ammonia import and promotes cancer stemness in hepatocellular carcinoma.","authors":"Ameer L Elaimy, Marwa O El-Derany, Jadyn James, Zhuwen Wang, Ashley N Pearson, Erin A Holcomb, Amanda K Huber, Miguel Gijón, Hannah N Bell, Viraj R Sanghvi, Timothy L Frankel, Grace L Su, Elliot B Tapper, Andrew W Tai, Nithya Ramnath, Christopher P Centonze, Irina Dobrosotskaya, Julie A Moeller, Alex K Bryant, David A Elliott, Enid Choi, Joseph R Evans, Kyle C Cuneo, Thomas J Fitzgerald, Daniel R Wahl, Meredith A Morgan, Daniel T Chang, Max S Wicha, Theodore S Lawrence, Yatrik M Shah, Michael D Green","doi":"10.1172/jci.insight.184826","DOIUrl":"10.1172/jci.insight.184826","url":null,"abstract":"<p><p>End-stage liver disease is marked by portal hypertension, systemic elevations in ammonia, and development of hepatocellular carcinoma (HCC). While these clinical consequences of cirrhosis are well described, it remains poorly understood whether hepatic insufficiency and the accompanying elevations in ammonia contribute to HCC carcinogenesis. Using preclinical models, we discovered that ammonia entered the cell through the transporter SLC4A11 and served as a nitrogen source for amino acid and nucleotide biosynthesis. Elevated ammonia promoted cancer stem cell properties in vitro and tumor initiation in vivo. Enhancing ammonia clearance reduced HCC stemness and tumor growth. In patients, elevations in serum ammonia were associated with an increased incidence of HCC. Taken together, this study forms the foundation for clinical investigations using ammonia-lowering agents as potential therapies to mitigate HCC incidence and aggressiveness.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287566","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}
引用次数: 0
Inhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors. 用 PD-1 阻断剂抑制布鲁顿酪氨酸激酶可调节实体瘤中 T 细胞的活化。
IF 6.3 1区 医学
JCI insight Pub Date : 2024-11-08 DOI: 10.1172/jci.insight.169927
Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A Shah, Anne M Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W Blaser, William E Carson
{"title":"Inhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors.","authors":"Emily Schwarz, Brooke Benner, Robert Wesolowski, Dionisia Quiroga, Logan Good, Steven H Sun, Himanshu Savardekar, Jianying Li, Kyeong Joo Jung, Megan C Duggan, Gabriella Lapurga, Jami Shaffer, Luke Scarberry, Bhavana Konda, Claire Verschraegen, Kari Kendra, Manisha Shah, Robert Rupert, Paul Monk, Hiral A Shah, Anne M Noonan, Kristin Bixel, John Hays, Lai Wei, Xueliang Pan, Gregory Behbehani, Yang Hu, Olivier Elemento, Dongjun Chung, Gang Xin, Bradley W Blaser, William E Carson","doi":"10.1172/jci.insight.169927","DOIUrl":"10.1172/jci.insight.169927","url":null,"abstract":"<p><p>BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"9 21","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11601564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604482","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}
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