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Melanocortin-4 receptor antagonist TCMCB07 alleviates chemotherapy-induced anorexia and weight loss in rats. 黑色素皮质素-4受体拮抗剂 TCMCB07 可减轻化疗引起的大鼠厌食和体重减轻。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-07 DOI: 10.1172/JCI181305
Xinxia Zhu, Russell Potterfield, Kenneth A Gruber, Emma Zhang, Samuel D Newton, Mason A Norgard, Peter R Levasseur, Peng Bai, Xu Chen, Qingyang Gu, Aaron J Grossberg, Daniel L Marks
{"title":"Melanocortin-4 receptor antagonist TCMCB07 alleviates chemotherapy-induced anorexia and weight loss in rats.","authors":"Xinxia Zhu, Russell Potterfield, Kenneth A Gruber, Emma Zhang, Samuel D Newton, Mason A Norgard, Peter R Levasseur, Peng Bai, Xu Chen, Qingyang Gu, Aaron J Grossberg, Daniel L Marks","doi":"10.1172/JCI181305","DOIUrl":"https://doi.org/10.1172/JCI181305","url":null,"abstract":"<p><p>Cancer patients undergoing chemotherapy often experience anorexia and weight loss that substantially deteriorates overall health, reduces treatment tolerance and quality of life, and worsens oncologic outcomes. There are currently few effective therapeutic options to mitigate these side effects. The central melanocortin system, which plays a pivotal role in regulating appetite and energy homeostasis, presents a logical target for treating anorexia and weight loss. In this preclinical study, we evaluated the efficacy of TCMCB07, a synthetic antagonist of the melanocortin-4 receptor, in mitigating anorexia and weight loss in several rat models of chemotherapy: cisplatin, 5-fluorouracil, cyclophosphamide, vincristine, doxorubicin, and a combination of irinotecan and 5-fluorouracil. Our results indicate that peripheral administration of TCMCB07 improved appetite, stabilized body weight, preserved fat and heart mass, and slightly protected lean mass after multiple cycles of chemotherapy. Furthermore, combining TCMCB07 with a growth differentiation factor 15 antibody enhanced treatment effectiveness. Similar effects from TCMCB07 treatment were observed in a rat tumor model following combination chemotherapy. No notable adverse effects nor increased chemotherapy-related toxicities were observed with TCMCB07 treatment. These findings suggest that peripheral administration of TCMCB07 holds promise as a therapeutic approach for alleviating chemotherapy-induced anorexia and weight loss, potentially benefiting numerous patients undergoing chemotherapy.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604942","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
More T cell receptors to the RAScue in cancer? 癌症中 RAScue 的更多 T 细胞受体？
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI184782
Eric Tran
{"title":"More T cell receptors to the RAScue in cancer?","authors":"Eric Tran","doi":"10.1172/JCI184782","DOIUrl":"10.1172/JCI184782","url":null,"abstract":"<p><p>Treatment with T cells genetically engineered to express tumor-reactive T cell receptors (TCRs), known as TCR-gene therapy (TCR-T), is a promising immunotherapeutic approach for patients with cancer. The identification of optimal TCRs to use and tumor antigens to target are key considerations for TCR-T. In this issue of the JCI, Bear and colleagues report on their use of in vitro assays to characterize four HLA-A*03:01- or HLA-A*11:01-restricted TCRs targeting the oncogenic KRAS G12V mutation. The TCRs were derived from healthy donors or patients with pancreatic cancer who had received a vaccine against mutant KRAS. The most promising TCRs warrant testing in patients with KRAS G12V-positive cancers.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557915","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
Targeting TET3 in macrophages provides a concept strategy for the treatment of endometriosis. 靶向巨噬细胞中的 TET3 为治疗子宫内膜异位症提供了一种概念性策略。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI185421
Hossein Hosseinirad, Md Saidur Rahman, Jae-Wook Jeong
{"title":"Targeting TET3 in macrophages provides a concept strategy for the treatment of endometriosis.","authors":"Hossein Hosseinirad, Md Saidur Rahman, Jae-Wook Jeong","doi":"10.1172/JCI185421","DOIUrl":"10.1172/JCI185421","url":null,"abstract":"<p><p>Endometriosis, characterized by the presence of endometrial-like tissue outside the uterus, is a condition associated with pain and infertility. In this issue of the JCI, Lv et al. illuminate the critical pathophysiological role of the ten-eleven translocation 3 (TET3) in endometriosis. TET3 expression levels were higher in macrophages of endometriotic lesions compared with control endometrial tissue, implicating TET3 as a contributing factor in the chronic inflammation that occurs in endometriosis. TGF-β1 and MCP1 are present in the peritoneal cavity of women with endometriosis, and macrophage exposure to these factors resulted in upregulation of TET3, thereby promoting their survival. Notably, Bobcat339, a selective TET inhibitor, induced apoptosis in these macrophages. Further, myeloid-specific TET3 loss reduced endometriosis in mice. RNA-Seq analysis following TET3 knockdown revealed alterations in cytokine signaling and cell-death pathways, underscoring the therapeutic potential of targeting TET3 in macrophages as a strategy for managing endometriosis.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557916","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
Accumulation of Epstein-Barr virus-induced cross-reactive immune responses is associated with multiple sclerosis. Epstein-Barr 病毒诱导的交叉反应性免疫反应的累积与多发性硬化症有关。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI184481
Hannes Vietzen, Laura M Kühner, Sarah M Berger, Philippe L Furlano, Gabriel Bsteh, Thomas Berger, Paulus Rommer, Elisabeth Puchhammer-Stöckl
{"title":"Accumulation of Epstein-Barr virus-induced cross-reactive immune responses is associated with multiple sclerosis.","authors":"Hannes Vietzen, Laura M Kühner, Sarah M Berger, Philippe L Furlano, Gabriel Bsteh, Thomas Berger, Paulus Rommer, Elisabeth Puchhammer-Stöckl","doi":"10.1172/JCI184481","DOIUrl":"10.1172/JCI184481","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557894","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
Hidradenitis suppurativa: key insights into treatment success and failure. 化脓性扁平湿疹：治疗成功与失败的关键因素。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI186744
Kelsey R van Straalen, Vincent Piguet, Johann E Gudjonsson
{"title":"Hidradenitis suppurativa: key insights into treatment success and failure.","authors":"Kelsey R van Straalen, Vincent Piguet, Johann E Gudjonsson","doi":"10.1172/JCI186744","DOIUrl":"10.1172/JCI186744","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557914","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
TET3-overexpressing macrophages promote endometriosis. TET3表达过高的巨噬细胞会促进子宫内膜异位症。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI181839
Haining Lv, Beibei Liu, Yangyang Dai, Feng Li, Stefania Bellone, Yuping Zhou, Ramanaiah Mamillapalli, Dejian Zhao, Muthukumaran Venkatachalapathy, Yali Hu, Gordon G Carmichael, Da Li, Hugh S Taylor, Yingqun Huang
{"title":"TET3-overexpressing macrophages promote endometriosis.","authors":"Haining Lv, Beibei Liu, Yangyang Dai, Feng Li, Stefania Bellone, Yuping Zhou, Ramanaiah Mamillapalli, Dejian Zhao, Muthukumaran Venkatachalapathy, Yali Hu, Gordon G Carmichael, Da Li, Hugh S Taylor, Yingqun Huang","doi":"10.1172/JCI181839","DOIUrl":"10.1172/JCI181839","url":null,"abstract":"<p><p>Endometriosis is a debilitating, chronic inflammatory disease affecting approximately 10% of reproductive-age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we report identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We show that factors from the disease microenvironment upregulated TET3 expression, transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated proinflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival and hence were vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation in both human and mouse macrophages. This degradation was dependent on a von Hippel-Lindau (VHL) E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982426","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
The importance of diverse multiomics datasets and analyses. 多样化多组学数据集和分析的重要性。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI184350
Laura J Rasmussen-Torvik
{"title":"The importance of diverse multiomics datasets and analyses.","authors":"Laura J Rasmussen-Torvik","doi":"10.1172/JCI184350","DOIUrl":"10.1172/JCI184350","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557992","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
Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus. 激活 STAT3 介导的纤毛细胞存活可防止呼吸道合胞病毒的严重感染。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI183978
Caiqi Zhao, Yan Bai, Wei Wang, Gaurang M Amonkar, Hongmei Mou, Judith Olejnik, Adam J Hume, Elke Mühlberger, Nicholas W Lukacs, Rachel Fearns, Paul H Lerou, Xingbin Ai
{"title":"Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus.","authors":"Caiqi Zhao, Yan Bai, Wei Wang, Gaurang M Amonkar, Hongmei Mou, Judith Olejnik, Adam J Hume, Elke Mühlberger, Nicholas W Lukacs, Rachel Fearns, Paul H Lerou, Xingbin Ai","doi":"10.1172/JCI183978","DOIUrl":"10.1172/JCI183978","url":null,"abstract":"<p><p>Respiratory syncytial virus (RSV) selectively targets ciliated cells in human bronchial epithelium and can cause bronchiolitis and pneumonia, mostly in infants. To identify molecular targets of intervention during RSV infection in infants, we investigated how age regulates RSV interaction with the bronchial epithelium barrier. Employing precision-cut lung slices and air-liquid interface cultures generated from infant and adult human donors, we found robust RSV virus spread and extensive apoptotic cell death only in infant bronchial epithelium. In contrast, adult bronchial epithelium showed no barrier damage and limited RSV infection. Single nuclear RNA-Seq revealed age-related insufficiency of an antiapoptotic STAT3 activation response to RSV infection in infant ciliated cells, which was exploited to facilitate virus spread via the extruded apoptotic ciliated cells carrying RSV. Activation of STAT3 and blockade of apoptosis rendered protection against severe RSV infection in infant bronchial epithelium. Lastly, apoptotic inhibitor treatment of a neonatal mouse model of RSV infection mitigated infection and inflammation in the lung. Taken together, our findings identify a STAT3-mediated antiapoptosis pathway as a target to battle severe RSV disease in infants.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557895","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
Experimental West Nile virus infection provides lessons for recovery from enteric neuropathies. 西尼罗河病毒感染实验为肠道神经病的康复提供了借鉴。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI185865
Joel C Bornstein
{"title":"Experimental West Nile virus infection provides lessons for recovery from enteric neuropathies.","authors":"Joel C Bornstein","doi":"10.1172/JCI185865","DOIUrl":"10.1172/JCI185865","url":null,"abstract":"<p><p>Loss of enteric neurons leading to long-term gastrointestinal dysfunction is common to many diseases, and the path to functional recovery is unclear. In this issue of the JCI, Janova et al. report that West Nile virus killed enteric neurons and glia via CD4+ and CD8+ T cells acting through the perforin and Fas ligand pathways. Enteric glial cells contributed to neurogenesis and at least partial replacement of affected neurons. While neurogenesis is important for recovery, dysmotility and disruptions to the network structure persisted. Following enteric injury, the contribution of neurogenesis and the conditions that support restoration of enteric neural circuits for functional recovery remain for further investigation.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557913","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
The convergence of genomic medicine and translational omics in transforming breast cancer patient care. 基因组医学和转化 omics 在改变乳腺癌患者护理方面的融合。
IF 13.3 1区 医学
Journal of Clinical Investigation Pub Date : 2024-11-01 DOI: 10.1172/JCI187520
Sulin Wu, Yonglan Zheng, Olufunmilayo I Olopade
{"title":"The convergence of genomic medicine and translational omics in transforming breast cancer patient care.","authors":"Sulin Wu, Yonglan Zheng, Olufunmilayo I Olopade","doi":"10.1172/JCI187520","DOIUrl":"10.1172/JCI187520","url":null,"abstract":"","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":"134 21","pages":""},"PeriodicalIF":13.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557917","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
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