The Journal of Clinical Investigation最新文献_第9页

Haptenization as the missing link between vasculitis and myeloperoxidase. 血管炎与髓过氧化物酶之间缺失的一环--合滕化。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci191587

Laura Santambrogio

引用次数: 0

Off-the-shelf invariant NKT cells expressing anti-PSCA CAR and IL-15 promote pancreatic cancer regression in mice. 现成的表达抗psca CAR和IL-15的不变NKT细胞促进小鼠胰腺癌的消退。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci179014

Zhenyu Dai,Zheng Zhu,Zhiyao Li,Lei Tian,Kun-Yu Teng,Hanyu Chen,Li-Shu Wang,Jianying Zhang,Laleh Melstrom,Michael A Caligiuri,Jianhua Yu

{"title":"Off-the-shelf invariant NKT cells expressing anti-PSCA CAR and IL-15 promote pancreatic cancer regression in mice.","authors":"Zhenyu Dai,Zheng Zhu,Zhiyao Li,Lei Tian,Kun-Yu Teng,Hanyu Chen,Li-Shu Wang,Jianying Zhang,Laleh Melstrom,Michael A Caligiuri,Jianhua Yu","doi":"10.1172/jci179014","DOIUrl":"https://doi.org/10.1172/jci179014","url":null,"abstract":"Pancreatic ductal adenocarcinoma cancer (PDAC) continues to pose a significant health burden, with a 5-year survival rate of only 10%. Prostate stem cell antigen (PSCA) is highly expressed on the surface of tumor cells of most PDAC patients, with minimum expression in most normal tissues. Here, we generated cryopreserved, off-the-shelf, allogeneic PSCA chimeric antigen receptor (CAR) invariant NKT (iNKT) cells using human peripheral blood mononuclear cells as a cell source. In multiple in vitro and in vivo PDAC models, freshly manufactured PSCA CAR_sIL-15 iNKT cells and frozen-thawed, off-the-shelf PSCA CAR_sIL-15 iNKT cells demonstrate comparable efficacies, and both show remarkable suppression of PSCA-positive and gemcitabine-resistant PDAC. Importantly, off-the-shelf cryopreserved PSCA CAR_sIL-15 iNKT cells show equivalent efficacy when compared with PSCA CAR T cells using the same PSCA CAR and in the same PDAC model; however, PSCA CAR_sIL-15 iNKT cells do not appear to induce systemic toxicity or graft-versus-host disease, thus allowing for multiple infusions to control recurrent disease. Collectively, our study suggests that PSCA CAR_sIL-15 iNKT cells merit clinical investigation for PDAC patients exhibiting positive PSCA expression. The therapy could be given as a single agent or in combination with established therapeutic modalities for PDAC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836558","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

Developing cell-based therapies for pancreatic ductal adenocarcinoma. 发展胰腺导管腺癌的细胞疗法。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci189513

Rachel Elizabeth Ann Fincham,Joe Poh Sheng Yeong,Hemant Mahendrakumar Kocher

引用次数: 0

Cell-intrinsic insulin signaling defects in human iPS cell-derived hepatocytes in type 2 diabetes. 2型糖尿病人iPS细胞源性肝细胞的细胞内胰岛素信号缺陷

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci183513

Arijeet K Gattu,Maria Tanzer,Tomer M Yaron-Barir,Jared L Johnson,Ashok Kumar Jayavelu,Hui Pan,Jonathan M Dreyfuss,Lewis C Cantley,Matthias Mann,C Ronald Kahn

{"title":"Cell-intrinsic insulin signaling defects in human iPS cell-derived hepatocytes in type 2 diabetes.","authors":"Arijeet K Gattu,Maria Tanzer,Tomer M Yaron-Barir,Jared L Johnson,Ashok Kumar Jayavelu,Hui Pan,Jonathan M Dreyfuss,Lewis C Cantley,Matthias Mann,C Ronald Kahn","doi":"10.1172/jci183513","DOIUrl":"https://doi.org/10.1172/jci183513","url":null,"abstract":"Hepatic insulin resistance is central to type 2 diabetes (T2D) and metabolic syndrome, but defining the molecular basis of this defect in humans is challenging because of limited tissue access. Utilizing inducible pluripotent stem cells differentiated into hepatocytes from control individuals and patients with T2D and liquid chromatography with tandem mass spectrometry-based (LC-MS/MS-based) phosphoproteomics analysis, we identified a large network of cell-intrinsic alterations in signaling in T2D. Over 300 phosphosites showed impaired or reduced insulin signaling, including losses in the classical insulin-stimulated PI3K/AKT cascade and their downstream targets. In addition, we identified over 500 phosphosites of emergent, i.e., new or enhanced, signaling. These occurred on proteins involved in the Rho-GTPase pathway, RNA metabolism, vesicle trafficking, and chromatin modification. Kinome analysis indicated that the impaired phosphorylation sites represented reduced actions of AKT2/3, PKCθ, CHK2, PHKG2, and/or STK32C kinases. By contrast, the emergent phosphorylation sites were predicted to be mediated by increased action of the Rho-associated kinases 1 and 2 (ROCK1/2), mammalian STE20-like protein kinase 4 (MST4), and/or branched-chain α-ketoacid dehydrogenase kinase (BCKDK). Inhibiting ROCK1/2 activity in T2D induced pluripotent stem cell-derived hepatocytes restored some of the alterations in insulin action. Thus, insulin resistance in the liver in T2D did not simply involve a loss of canonical insulin signaling but the also appearance of new phosphorylations representing a change in the balance of multiple kinases. Together, these led to altered insulin action in the liver and identified important targets for the therapy of hepatic insulin resistance.","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":"143836496","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

Serotonin sets up neutrophil extracellular traps to promote neuroendocrine prostate cancer metastasis in the liver. 血清素建立中性粒细胞胞外陷阱，促进前列腺癌在肝脏的神经内分泌转移。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci191687

Dean G Tang

引用次数: 0

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

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci191585

Michaela Aa Fuchs,Myles Wolf

引用次数: 0

Genetic inactivation of FAAP100 causes Fanconi anemia due to disruption of the monoubiquitin ligase core complex. 由于单泛素连接酶核心复合物的破坏，FAAP100基因失活导致范可尼贫血。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci187323

Julia Kuehl,Yutong Xue,Fenghua Yuan,Ramanagouda Ramanagoudr-Bhojappa,Simone Pickel,Reinhard Kalb,Settara C Chandrasekharappa,Weidong Wang,Yanbin Zhang,Detlev Schindler

{"title":"Genetic inactivation of FAAP100 causes Fanconi anemia due to disruption of the monoubiquitin ligase core complex.","authors":"Julia Kuehl,Yutong Xue,Fenghua Yuan,Ramanagouda Ramanagoudr-Bhojappa,Simone Pickel,Reinhard Kalb,Settara C Chandrasekharappa,Weidong Wang,Yanbin Zhang,Detlev Schindler","doi":"10.1172/jci187323","DOIUrl":"https://doi.org/10.1172/jci187323","url":null,"abstract":"The Fanconi anemia (FA)/BRCA DNA repair network promotes the removal of DNA interstrand crosslinks (ICLs) to counteract their devastating consequences, including oncogenesis. Network signaling is initiated by the FA core complex, which consists of seven authentic FA proteins and an FA-associated protein, FAAP100, with incompletely characterized roles and unknown disease associations. Upon activation, the FA core complex functions as a multiprotein E3 ubiquitin ligase centered on its catalytic module, the FANCB-FANCL-FAAP100 (BLP100) subcomplex, for FANCD2 and FANCI monoubiquitylation. Here, we identified a homozygous variant in FAAP100, c.1642A>C, predicting p.(T542P), in a fetus with malformations suggestive of FA. The mutation causes sensitivity to ICL-inducing agents in cells from the affected individual and genetically engineered, FAAP100-inactivated human, avian, zebrafish, and mouse cells. All FAAP100-deficient cell types were rescued by ectopic expression of wild-type FAAP100, but not FAAP100T542P. In a confirmatory animal model, customized Faap100-/- mice exhibit embryonic lethality, microsomia, malformations, and gonadal atrophy resembling mice with established FA subtypes. Mechanistically, FAAP100T542P impairs ligase activity by preventing BLP100 subcomplex formation, resulting in defective FAAP100T542P nuclear translocation and chromatin recruitment. FAAP100 dysfunction that disrupts the FA pathway and impairs genomic maintenance, together with FAconsistent human manifestations, recommends FAAP100 as a legitimate FA gene, FANCY.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"270 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841049","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

Addiction of primary cutaneous γδ T cell lymphomas to JAK/STAT signaling. 原发性皮肤γδT细胞淋巴瘤对JAK/STAT信号的依赖。

The Journal of Clinical Investigation Pub Date : 2025-04-15 DOI: 10.1172/jci180417

Yue Zhang,Julia A Yescas,Kristy Tefft,Spencer Ng,Kevin Qiu,Erica B Wang,Shifa Akhtar,Addie Walker,Macartney Welborn,Martin Zaiac,Joan Guitart,Aamir M Qureshi,Youn H Kim,Michael S Khodadoust,Naiem T Issa,Jaehyuk Choi

引用次数: 0

Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension. 单核细胞和间质巨噬细胞有助于低氧性肺动脉高压。

The Journal of Clinical Investigation Pub Date : 2025-01-30 DOI: 10.1172/jci176865

Rahul Kumar,Kevin Nolan,Biruk Kassa,Neha Chanana,Tsering Palmo,Kavita Sharma,Kanika Singh,Claudia Mickael,Dara Fonseca Balladares,Julia Nilsson,Amit Prabhakar,Aastha Mishra,Michael H Lee,Linda Sanders,Sushil Kumar,Ari B Molofsky,Kurt R Stenmark,Dean Sheppard,Rubin M Tuder,Mohit D Gupta,Tashi Thinlas,Qadar Pasha,Brian B Graham

{"title":"Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension.","authors":"Rahul Kumar,Kevin Nolan,Biruk Kassa,Neha Chanana,Tsering Palmo,Kavita Sharma,Kanika Singh,Claudia Mickael,Dara Fonseca Balladares,Julia Nilsson,Amit Prabhakar,Aastha Mishra,Michael H Lee,Linda Sanders,Sushil Kumar,Ari B Molofsky,Kurt R Stenmark,Dean Sheppard,Rubin M Tuder,Mohit D Gupta,Tashi Thinlas,Qadar Pasha,Brian B Graham","doi":"10.1172/jci176865","DOIUrl":"https://doi.org/10.1172/jci176865","url":null,"abstract":"Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2+ macrophages through recruitment, which express the protein thrombospondin-1 that functionally activates TGF-beta to cause vascular disease. Blockade of monocyte recruitment with either CCL2 neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who travelled from low (225m) to high (3500m) elevation, revealing an increase in thrombospondin-1 and TGF-beta expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2+ monocyte recruitment. These data suggest a pathologic cross-talk between two discrete interstitial macrophage populations, which can be therapeutically targeted.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"121 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062014","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

Passive transfer of patient-derived anti-nephrin autoantibodies causes a podocytopathy with minimal change lesions. 患者源性抗肾素自身抗体的被动转移引起足细胞病，病变变化极小。

The Journal of Clinical Investigation Pub Date : 2025-01-16 DOI: 10.1172/jci186769

Felicitas E Hengel,Silke Dehde,Oliver Kretz,Jonas Engesser,Tom Zimmermann,Tobias B Huber,Nicola M Tomas

引用次数: 0