JCI insight最新文献

{"title":"Dipeptidase-1-knockout mice develop invasive tumors with features of microsatellite-unstable colorectal cancer.","authors":"Sarah E Glass, Matthew E Bechard, Zheng Cao, Radhika Aramandla, Ping Zhao, Samuel T Ellis, Emily H Green, Elizabeth G Fisher, Ryan T Smith, Chelsie K Sievers, Maria Johnson Irudayam, Frank Revetta, M Kay Washington, Gregory D Ayers, Cody N Heiser, Alan J Simmons, Yanwen Xu, Yu Wang, Annika Windon, Martha J Shrubsole, Nicholas O Markham, Qi Liu, Ken S Lau, Robert J Coffey","doi":"10.1172/jci.insight.186938","DOIUrl":"10.1172/jci.insight.186938","url":null,"abstract":"<p><p>Dipeptidase-1 (DPEP1) is highly upregulated in colorectal cancer (CRC), with its enzymatic function linked to invasion and metastasis. More recently, DPEP1 was found to serve as a receptor for neutrophils when expressed by activated endothelial cells. It is unknown whether neutrophils bind to DPEP1-expressing CRC cells and whether this impacts features of CRC. Neutrophils have been shown to be tumor promoting in cancers including CRC, where they act to exclude CD8+ T cells. Herein, we show that neutrophils bind DPEP1-expressing CRC cells. In addition, DPEP1 is preferentially expressed in microsatellite-stable (MSS) CRCs, in which there are a paucity of CD8+ T cells, whereas DPEP1 is negatively correlated with microsatellite-unstable (MSI-H) CRCs, which are T cell rich and are more responsive to immunotherapy. Remarkably, carcinogen-treated Dpep1-null mice develop multiple, large, plaque-like, locally invasive adenocarcinomas and squamous cell cancers in the distal colon. These adenocarcinomas exhibit a marked reduction in neutrophils and an influx CD8+ T cells, along with reduced expression of mismatch repair proteins, consistent with features of MSI-H CRC. These results establish DPEP1's importance in maintaining MSS CRC and its ability to shape the tumor microenvironment.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780165","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}

{"title":"Enhanced durability of a Zika virus self-amplifying RNA vaccine through combinatorial OX40 and 4-1BB agonism.","authors":"Hsueh-Han Lu, Rúbens Prince Dos Santos Alves, Qin Hui Li, Luke Eder, Julia Timis, Henry Madany, Kantinan Chuensirikulchai, Krithik V Varghese, Aditi Singh, Linda Le Tran, Audrey Street, Annie Elong Ngono, Michael Croft, Sujan Shresta","doi":"10.1172/jci.insight.187405","DOIUrl":"10.1172/jci.insight.187405","url":null,"abstract":"<p><p>The SARS-CoV-2 pandemic highlighted the potential of mRNA vaccines in rapidly responding to emerging pathogens. However, immunity induced by conventional mRNA vaccines wanes quickly, requiring frequent boosters. Self-amplifying RNA (saRNA) vaccines, which extend antigen expression via self-replication, offer a promising strategy to induce more durable immune responses. In this study, we developed an saRNA vaccine encoding Zika virus (ZIKV) membrane and envelope proteins and evaluated its efficacy in mice. A single vaccination elicited strong humoral and cellular immune responses and reduced viral loads but only for 28 days. By day 84, antibody titers and T cell responses had significantly declined, resulting in reduced efficacy. To address this, we evaluated agonist antibodies targeting the T cell costimulatory molecules OX40 and 4-1BB. Coadministration of agonist antibodies enhanced CD8+ T cell responses to vaccination, resulting in sustained immunity and reduced viral loads at day 84. Depletion and passive transfer studies verified that long-term antiviral immunity was primarily CD8+ T cell dependent, with minimal contributions from antibody responses. These findings suggest that agonists targeting members of the tumor necrosis receptor superfamily, such as OX40 and 4-1BB, might enhance the durability of saRNA vaccine-induced protection, addressing a key limitation of current mRNA vaccine platforms.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780168","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}

{"title":"Germline mutations in PPP2R1B in patients with a personal and family history of cancer.","authors":"Sahar Mazhar, Caitlin M O'Connor, Alexis Harold, Amanda C Dowdican, Peter J Ulintz, Erika N Hanson, Yuping Zhang, Michelle F Jacobs, Sofia D Merajver, Mark W Jackson, Anthony Scott, Anieta M Sieuwerts, Arul M Chinnaiyan, Goutham Narla","doi":"10.1172/jci.insight.186288","DOIUrl":"10.1172/jci.insight.186288","url":null,"abstract":"<p><p>An estimated 5%-10% of cancer results from an underlying genetic predisposition. For the majority of familial cases, the genes in question remain unknown, suggesting a critical need to identify new cancer predisposition genes. Members of the protein phosphatase 2A (PP2A) family exist as trimeric holoenzymes and are vital negative regulators of multiple oncogenic pathways. PP2A inhibition by somatic mutation, loss of expression, and upregulation of its exogenous inhibitors in tumors has been well described. However, it remains unknown whether germline loss of any PP2A subunits results in a predisposition to cancer in humans. In this study, we identified 9 cancer patients with germline loss-of-function (LOF) variants in PPP2R1B (Aβ), the β isoform of the PP2A scaffold subunit. All 4 patients for whom documentation was available also had a family history of cancer, including multiple indicators of hereditary cancer. Overexpression of these mutant forms of Aβ resulted in truncated proteins that were rapidly turned over. Characterization of an additional missense germline Aβ variant, R233C, which is also recurrently mutated at the somatic level, showed disruption of PP2A catalytic subunit binding, resulting in loss of phosphatase activity. An analysis of Aβ expression among multiple breast cancer cohorts (the most highly represented cancer among the Aβ germline patients) revealed that somatic, heterozygous loss of Aβ was a frequent event in this disease, and decreased Aβ expression correlated with shorter disease-free and overall survival. Furthermore, Aβ levels were significantly lower in multiple histological subtypes of both in situ and malignant breast cancer compared with adjacent normal breast tissue, suggesting that Aβ loss is an early event in breast cancer development. Together, these results highlight a role for Aβ as a predisposition gene in breast cancer and potentially additional cancers.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780170","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}

{"title":"Loss of GATA2 promotes invasion and predicts cancer recurrence and survival in uterine serous carcinoma.","authors":"Usha S Polaki, Trey E Gilpin, Apoorva T Patil, Emily Chiu, Ruth Baker, Peng Liu, Tatiana S Pavletich, Morteza Seifi, Paula M Mañán-Mejías, Jordan Morrissey, Jenna Port, Rene Welch Schwartz, Irene M Ong, Dina El-Rayes, Mahmoud A Khalifa, Pei Hui, Vanessa L Horner, María Virumbrales-Muñoz, Britt K Erickson, Lisa Barroilhet, Stephanie M McGregor, Emery H Bresnick, Daniel R Matson","doi":"10.1172/jci.insight.187073","DOIUrl":"10.1172/jci.insight.187073","url":null,"abstract":"<p><p>BACKGROUNDA priori knowledge of recurrence risk in patients with nonmetastatic (International Federation of Gynecology and Obstetrics [FIGO] stage I) uterine serous carcinoma (USC) would enable a risk-stratified approach to the use of adjuvant chemotherapy. This would greatly reduce treatment-related morbidity and be predicted to improve survival.METHODSGATA2 expression was scored by IHC across a retrospective multiinstitutional cohort of 195 primary USCs. Associations between GATA2 levels and clinicopathologic metrics were evaluated using Student's t test, Fisher's exact test, Kaplan-Meier method, and Cox proportional hazard ratio. Invasion in patient-derived USC cells was assessed by Student's t test. RNA-Seq, anti-GATA2 ChIP-Seq, and confirmatory Western blotting enabled identification of GATA2 targets.RESULTSPatients with FIGO stage I GATA2hi USCs had 100% recurrence-free and 100% cancer-related survival, which was significantly better than patients with GATA2lo USCs. In patients for whom adjuvant chemotherapy was omitted, patients with GATA2hi USC had 100% recurrence-free 5-year survival compared with 60% recurrence-free survival in patients with GATA2lo USC. Depletion of GATA2 in patient-derived USC cells increased invasion in vitro.CONCLUSIONRoutine GATA2 IHC identifies 33% of patients with FIGO stage I USC who have a greatly reduced risk of posthysterectomy USC recurrence. Our results suggest that a GATA2-guided personalized medicine approach could be rapidly implemented in most hospital settings, would reduce treatment-related morbidity, and would likely improve outcomes in patients with USC.FUNDINGNIH grants R01 DK068634, P30 CA014520, S10 OD023526, K08 DK127244, T32 HL007899, the UW-Madison Department of Pathology and Laboratory Medicine, the UW-Madison Centennial Scholars Program, the Diane Lindstrom Foundation, the American Cancer Society, the V Foundation, The Hartwell Foundation, and the UMN Department of Obstetrics, Gynecology, and Women's Health.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143752810","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}

{"title":"Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection.","authors":"Pei-Suen Tsou, Ramadan A Ali, Chenyang Lu, Gautam Sule, Carmelo Carmona-Rivera, Serena Lucotti, Yuzo Ikari, Qi Wu, Phillip L Campbell, Mikel Gurrea-Rubio, Kohei Maeda, Sharon E Fox, William D Brodie, Megan N Mattichak, Caroline Foster, Ajay Tambralli, Srilakshmi Yalavarthi, M Asif Amin, Katarina Kmetova, Bruna Mazetto Fonseca, Emily Chong, Yu Zuo, Michael D Maile, Luisa Imberti, Arnaldo Caruso, Francesca Caccuri, Virginia Quaresima, Alessandra Sottini, Douglas B Kuhns, Danielle Fink, Riccardo Castagnoli, Ottavia M Delmonte, Heather Kenney, Yu Zhang, Mary Magliocco, Helen Su, Luigi Notarangelo, Rachel L Zemans, Yang Mao-Draayer, Irina R Matei, Mirella Salvatore, David Lyden, Yogendra Kanthi, Mariana J Kaplan, Jason S Knight, David A Fox","doi":"10.1172/jci.insight.184975","DOIUrl":"10.1172/jci.insight.184975","url":null,"abstract":"<p><p>The soluble variant of the ectopeptidase CD13 (sCD13), released from the cell surface by matrix metalloproteinase 14 (MMP14), is a potent pro-inflammatory mediator, displaying chemotactic, angiogenic, and arthritogenic properties through bradykinin receptor B1 (B1R). We revealed a link between sCD13 and amplified neutrophil-mediated inflammatory responses in SARS-CoV-2 infection. sCD13 was markedly elevated in patients with COVID-19 and correlated with disease severity and variants, ethnicity, inflammation markers, and neutrophil extracellular trap formation (NETosis). Neutrophils treated with sCD13 showed heightened NETosis and chemotaxis, which were inhibited by sCD13 receptor blockade. Meanwhile sCD13 did not induce platelet aggregation. Single-cell analysis of COVID-19 lungs revealed coexpression of CD13 and MMP14 by various cell types, and higher CD13 expression compared with controls. Neutrophils with high CD13 mRNA were enriched for genes associated with immaturity, though CD13 protein expression was lower. Histological examination of COVID-19 lungs revealed CD13-positive leukocytes trapped in vessels with fibrin thrombi. Flow cytometry verified the presence of B1R and a second sCD13 receptor, protease-activated receptor 4, on monocytes and neutrophils. These findings identify sCD13 as a potential instigator of COVID-19-associated NETosis, potentiating vascular stress and thromboembolic complications. The potent pro-inflammatory effects of sCD13 may contribute to severe COVID-19, suggesting that sCD13 and its receptors might be therapeutic targets.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763877","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}

{"title":"SEC24C deficiency causes trafficking and glycosylation abnormalities in an epileptic encephalopathy with cataracts and dyserythropoeisis.","authors":"Nina Bögershausen, Büsranur Cavdarli, Taylor H Nagai, Miroslav P Milev, Alexander Wolff, Mahsa Mehranfar, Julia Schmidt, Dharmendra Choudhary, Óscar Gutiérrez-Gutiérrez, Lukas Cyganek, Djenann Saint-Dic, Arne Zibat, Karl Köhrer, Tassilo E Wollenweber, Dagmar Wieczorek, Janine Altmüller, Tatiana Borodina, Dilek Kaçar, Göknur Haliloğlu, Yun Li, Christian Thiel, Michael Sacher, Ela W Knapik, Gökhan Yigit, Bernd Wollnik","doi":"10.1172/jci.insight.173484","DOIUrl":"10.1172/jci.insight.173484","url":null,"abstract":"<p><p>As a major component of intracellular trafficking, the coat protein complex II (COPII) is indispensable for cellular function during embryonic development and throughout life. The 4 SEC24 proteins (A-D) are essential COPII components involved in cargo selection and packaging. A human disorder corresponding to alterations of SEC24 function is currently known only for SEC24D. Here, we reported that biallelic loss of SEC24C leads to a syndrome characterized by primary microcephaly, brain anomalies, epilepsy, hearing loss, liver dysfunction, anemia, and cataracts in an extended consanguineous family with 4 affected individuals. We showed that knockout of sec24C in zebrafish recapitulated important aspects of the human phenotype. SEC24C-deficient fibroblasts displayed alterations in the expression of several COPII components as well as impaired anterograde trafficking to the Golgi, indicating a severe impact on COPII function. Transcriptome analysis revealed that SEC24C deficiency also affected the proteasome and autophagy pathways. Moreover, a shift in the N-glycosylation pattern and deregulation of the N-glycosylation pathway suggested a possible secondary alteration of protein glycosylation, linking the described disorder with the congenital disorders of glycosylation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709806","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}

{"title":"Vitamin A retinoic acid contributes to muscle stem cell and mitochondrial function loss in old age.","authors":"Paula M Fraczek, Pamela Duran, Benjamin A Yang, Valeria Ferre, Leanne Alawieh, Jesus A Castor-Macias, Vivian T Wong, Steve D Guzman, Celeste Piotto, Klimentini Itsani, Jacqueline A Larouche, Carlos A Aguilar","doi":"10.1172/jci.insight.183706","DOIUrl":"10.1172/jci.insight.183706","url":null,"abstract":"<p><p>Adult stem cells decline in number and function in old age, and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining a healthy lifespan. Here we show that vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected that the receptor for vitamin A-derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709807","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}

{"title":"IFN-γ and donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation.","authors":"Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Erika M Moore, Scott Furlan, Warren D Shlomchik","doi":"10.1172/jci.insight.190655","DOIUrl":"10.1172/jci.insight.190655","url":null,"abstract":"<p><p>BACKGROUNDThe graft-versus-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-γ is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-γ combined with donor leukocyte infusions (DLIs) in myeloblastic malignancies that relapsed after HLA-matched alloSCT.METHODSPatients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-γ for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-γ for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNA-Seq) to assess in vivo responses to IFN-γ by malignant myeloblasts.RESULTSIFN-γ monotherapy was well tolerated by all participants (n = 7). Treatment-related toxicities after DLI included grade I-II graft-versus-host disease (n = 5), immune effector cell-associated neurotoxicity syndrome (n = 2), and idiopathic pulmonary syndrome (n = 1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97-906) in responders. scRNA-Seq validated in vivo activation of the IFN-γ response pathway in hematopoietic stem cell-like or myeloid progenitor cells after IFN-γ in analyzed samples.CONCLUSIONIFN-γ was safe and well tolerated in this phase I study of IFN-γ for relapsed acute myeloid leukemia and myelodysplastic syndrome after alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach.TRIAL REGISTRATIONClinicalTrials.gov NCT04628338.FUNDINGUPMC Hillman Cancer Center Cancer Immunology and Immunotherapy Program Pilot Award and Cure Within Reach: Drug Repurposing Clinical Trials to Impact Blood Cancers.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709805","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}

{"title":"CFTR negatively reprograms Th2 cell responses, and CFTR potentiation restrains allergic airway inflammation.","authors":"Mark Rusznak, Christopher M Thomas, Jian Zhang, Shinji Toki, Weisong Zhou, Masako Abney, Danielle M Yanda, Allison E Norlander, Craig A Hodges, Dawn C Newcomb, Mark H Kaplan, R Stokes Peebles, Daniel P Cook","doi":"10.1172/jci.insight.191098","DOIUrl":"10.1172/jci.insight.191098","url":null,"abstract":"<p><p>Type 2 inflammatory diseases, including asthma, sinusitis, and allergic bronchopulmonary aspergillosis, are common in cystic fibrosis (CF). CD4+ Th2 cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the CF transmembrane conductance regulator (CFTR), the mutated protein in CF, has a direct effect on Th2 development is unknown. Using murine models of CFTR deficiency and human CD4+ T cells, we show that CD4+ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared with control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared with control mice. Culture of CFTR-deficient Th2 cells demonstrated increased IL-4Rα expression and increased sensitivity to IL-4 with greater induction of GATA3 and IL-13 compared with control Th2 cell cultures. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine secretion in bronchoalveolar lavage of humanized CFTR mice following Alternaria alternata extract challenge and decreased Th2 development in human T cell culture. These data support a direct role of CFTR in regulating T cell sensitivity to IL-4 and demonstrate a potential CFTR-specific therapeutic strategy for Th2 cell-mediated allergic disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709804","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}

{"title":"Reduced high-density lipoprotein antioxidant function in patients with coronary artery disease and acute coronary syndrome.","authors":"Benjamin Sasko, Linda Scharow, Rhea Mueller, Monique Jaensch, Werner Dammermann, Felix S Seibert, Philipp Hillmeister, Ivo Buschmann, Martin Christ, Oliver Ritter, Nazha Hamdani, Christian Ukena, Timm H Westhoff, Theodoros Kelesidis, Nikolaos Pagonas","doi":"10.1172/jci.insight.187889","DOIUrl":"10.1172/jci.insight.187889","url":null,"abstract":"<p><strong>Results: </strong>Participants with CAD (n = 723) had 12% higher mean relative levels of nHDLox compared with those with invasively excluded CAD (n = 502, P < 0.001). Patients presenting with symptoms of an ACS had the highest nHDLox values when compared with the elective cohort (median 1.35, IQR 0.97 to 1.85, P < 0.001). In multivariate analysis adjusted for age, sex, body mass index, and hypertension, nHDLox was a strong independent predictor of ACS (P < 0.001) but not of CAD (P > 0.05).</p><p><strong>Conclusion: </strong>HDL antioxidant function is reduced in patients with CAD. nHDLox is strongly associated with ACS.</p><p><strong>Trial registration: </strong>German Clinical Trials Register DRKS00014037.</p><p><strong>Funding: </strong>Brandenburg Medical School Theodor Fontane, the BIOX Stiftung, and NIH grants R01AG059501 and R03AG059462.</p><p><strong>Background: </strong>High-density lipoprotein (HDL) function rather than its concentration plays an important role in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to determine whether reduced antioxidant function of HDL is associated with the presence of a stable CAD or acute coronary syndrome (ACS).</p><p><strong>Methods: </strong>HDL function was measured in 2 cohorts: 1225 patients admitted electively for coronary angiography and 196 patients with ACS. A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function, as assessed by increased HDL-lipid peroxide content (HDLox), which was normalized by HDL-C levels and the mean value of a pooled serum control from healthy participants (nHDLox; unitless). Results are expressed as median with interquartile range (IQR).</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 6","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692006","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}