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Articles in this category appear as authors submitted them for publication, prior to copyediting and publication layout. </h6> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190850">Unveiling mechanisms underlying kidney function changes during sex hormone therapy</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45959-more' href='#'> <div class='article-abstract'> Background: Men with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as... </div> </a> <span class='article-published-at'> Published April 7, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI190850">https://doi.org/10.1172/JCI190850</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190850">Text</a> | <a href="/articles/view/190850/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/141"><span class='label-article-type'> Clinical Research and Public Health </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/20"><span class='label-specialty'> Endocrinology </span> </a><a href="/tags/31"><span class='label-specialty'> Nephrology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190850' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45959-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190850">Unveiling mechanisms underlying kidney function changes during sex hormone therapy</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190850">Text</a></li> <li><a class="button tiny" href="/articles/view/190850/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Background: Men with chronic kidney disease (CKD) experience faster kidney function decline than women. Studies in individuals undergoing sex hormone therapy suggest a role for sex hormones, as estimated glomerular filtration rate (eGFR) increases with feminizing therapy and decreases with masculinizing therapy. However, effects on measured GFR (mGFR), glomerular and tubular function, and involved molecular mechanisms remain unexplored. Methods: This prospective, observational study included individuals initiating feminizing (estradiol and antiandrogens; n=23) or masculinizing (testosterone; n=21) therapy. Baseline and three-month assessments included mGFR (Iohexol clearance), kidney perfusion (para-aminohippuric acid clearance), tubular injury biomarkers, and plasma proteomics. Results: During feminizing therapy, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; p<0.05), without increased glomerular pressure. Tubular injury biomarkers, including urine neutrophil gelatinase-associated lipocalin, EGF, monocyte chemoattractant protein-1, and chitinase 3-like protein 1 (YKL-40), decreased significantly (-53%, -42%, -45%, and -58%, respectively). During masculinizing therapy, mGFR and kidney perfusion remained unchanged, but urine YKL-40 and plasma TNFR-1 increased (+134% and +8%, respectively; p<0.05). Proteomic analysis revealed differential expression of 49 proteins during feminizing, and 356 proteins during masculinizing therapy. Many kidney-protective proteins were positively associated with estradiol and negatively associated with testosterone, including proteins involved in endothelial function (SFRP4, SOD3), inflammation reduction (TSG-6), and maintaining kidney tissue structure (agrin). Conclusion: Sex hormones influence kidney physiology, with estradiol showing protective effects on glomerular and tubular function, while testosterone predominantly exerts opposing effects. These findings emphasize the role of sex hormones in sexual dimorphism observed in kidney function and physiology and suggest new approaches for sex-specific precision medicine.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sarah A. van Eeghen, Laura Pyle, Phoom Narongkiatikhun, Ye Ji Choi, Wassim Obeid, Chirag R. Parikh, Taryn G. Vosters, Irene GM van Valkengoed, Merle M. Krebber, Daan J. Touw, Martin den Heijer, Petter Bjornstad, Daniël Raalte, Natalie J. Nokoff</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186432">Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45951-more' href='#'> <div class='article-abstract'> Neuronal hyperexcitability precedes synapse loss in certain neurodegenerative diseases, yet the synaptic membrane interactions and downstream signaling events remain unclear. The disordered amino... </div> </a> <span class='article-published-at'> Published April 4, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186432">https://doi.org/10.1172/JCI186432</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186432">Text</a> | <a href="/articles/view/186432/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/10"><span class='label-specialty'> Aging </span> </a><a href="/tags/32"><span class='label-specialty'> Neuroscience </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186432' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45951-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186432">Mutant prion protein enhances NMDA receptor activity, activates PKC, and triggers rapid excitotoxicity in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186432">Text</a></li> <li><a class="button tiny" href="/articles/view/186432/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Neuronal hyperexcitability precedes synapse loss in certain neurodegenerative diseases, yet the synaptic membrane interactions and downstream signaling events remain unclear. The disordered amino terminus of the prion protein (PrPC) has been implicated in aberrant signaling in prion and Alzheimer’s disease. To disrupt neuronal interactions and signaling linked to the amino terminus, here we CRISPR-engineered a knock-in mouse expressing mutant PrPC (G92N), generating an N-linked glycosylation site between two functional motifs. Mice developed seizures and necrosis of hippocampal pyramidal neurons, similar to prion-infected mice and consistent with excitotoxicity. Phosphoproteomics revealed phosphorylated glutamate receptors and calcium-sensitive kinases, including protein kinase C (PKC). Additionally, 92N-PrPC-expressing neurons show persistent calcium influx as well as dendritic beading, which was rescued by an NMDA receptor antagonist. Finally, survival of Prnp92N mice was prolonged by blocking active NMDA receptor channels. We propose dysregulated PrPC – NMDA receptor - induced signaling can trigger excitatory – inhibitory imbalance, spongiform degeneration, and neurotoxicity, and that calcium dysregulation is central to PrPC-linked neurodegeneration.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Joie Lin, Julia A. Callender, Joshua E. Mayfield, Daniel B. McClatchy, Daniel Ojeda-Juárez, Mahsa Pourhamzeh, Katrin Soldau, Timothy D. Kurt, Garrett A. Danque, Helen K. Khuu, Josephina E. Ronson, Donald P. Pizzo, Yixing Du, Maxwell A. Gruber, Alejandro M. Sevillano, Jin Wang, Christina D. Orrú, Joy Chen, Gail Funk, Patricia Aguilar-Calvo, Brent D. Aulston, Subhojit Roy, Jong M. Rho, Jack D. Bui, Alexandra C. Newton, Stuart A. Lipton, Byron Caughey, Gentry N. Patrick, Kim Doré, John R. Yates III, Christina J. Sigurdson</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181659">ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45940-more' href='#'> <div class='article-abstract'> Telomere biology disorders (TBD) are genetic diseases caused by defective telomere maintenance. TBD patients often develop bone marrow failure and have an increased risk of myeloid neoplasms. To... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI181659">https://doi.org/10.1172/JCI181659</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181659">Text</a> | <a href="/articles/view/181659/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/23"><span class='label-specialty'> Hematology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181659' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45940-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181659">ATM-dependent DNA damage response constrains cell growth and drives clonal hematopoiesis in telomere biology disorders</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181659">Text</a></li> <li><a class="button tiny" href="/articles/view/181659/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Telomere biology disorders (TBD) are genetic diseases caused by defective telomere maintenance. TBD patients often develop bone marrow failure and have an increased risk of myeloid neoplasms. To better understand the factors underlying hematopoietic outcomes in TBD, we comprehensively evaluated acquired genetic alterations in hematopoietic cells from 166 pediatric and adult TBD patients. 47.6% of patients (28.8% of children, 56.1% of adults) had clonal hematopoiesis. Recurrent somatic alterations involved telomere maintenance genes (7.6%), spliceosome genes (10.4%, mainly U2AF1 p.S34), and chromosomal alterations (20.2%), including 1q gain (5.9%). Somatic variants affecting the DNA damage response (DDR) were identified in 21.5% of patients, including 20 presumed loss-of-function variants in ATM. Using multimodal approaches, including single-cell sequencing, assays of ATM activation, telomere dysfunction-induced foci analysis, and cell growth assays, we demonstrate telomere dysfunction-induced activation of ATM-dependent DDR pathway with increased senescence and apoptosis in TBD patient cells. Pharmacologic ATM inhibition, modeling the effects of somatic ATM variants, selectively improved TBD cell fitness by allowing cells to bypass DDR-mediated senescence without detectably inducing chromosomal instability. Our results indicate that ATM-dependent DDR induced by telomere dysfunction is a key contributor to TBD pathogenesis and suggest dampening hyperactive ATM-dependent DDR as a potential therapeutic intervention.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Christopher M. Sande, Stone Chen, Dana V. Mitchell, Ping Lin, Diana M. Abraham, Jessie M. Cheng, Talia Gebhard, Rujul J. Deolikar, Colby Freeman, Mary Zhou, Sushant Kumar, Michael Bowman, Robert L. Bowman, Shannon Zheng, Bolormaa Munkhbileg, Qijun Chen, Natasha L. Stanley, Kathy Guo, Ajibike Lapite, Ryan Hausler, Deanne M. Taylor, James Corines, Jennifer J.D. Morrissette, David B. Lieberman, Guang Yang, Olga Shestova, Saar Gill, Jiayin Zheng, Kelcy Smith-Simmer, Lauren G. Banaszak, Kyle N. Shoger, Erica F. Reinig, Madilynn Peterson, Peter Nicholas, Amanda J. Walne, Inderjeet Dokal, Justin P. Rosenheck, Karolyn A. Oetjen, Daniel C. Link, Andrew E. Gelman, Christopher R. Reilly, Ritika Dutta, R. Coleman Lindsley, Karyn J. Brundige, Suneet Agarwal, Alison A. Bertuch, Jane E. Churpek, Laneshia K. Tague, F. Brad Johnson, Timothy S. Olson, Daria V. Babushok</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184115">SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45938-more' href='#'> <div class='article-abstract'> The Wnt/β-catenin pathway regulates expression of the SOX9 gene, which encodes SRY-box transcription factor 9, a differentiation factor and potential β-catenin regulator. Because APC tumor... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI184115">https://doi.org/10.1172/JCI184115</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184115">Text</a> | <a href="/articles/view/184115/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/21"><span class='label-specialty'> Gastroenterology </span> </a><a href="/tags/22"><span class='label-specialty'> Genetics </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184115' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45938-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184115">SOX9 suppresses colon cancer via inhibiting epithelial-mesenchymal transition and SOX2 induction</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184115">Text</a></li> <li><a class="button tiny" href="/articles/view/184115/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The Wnt/β-catenin pathway regulates expression of the SOX9 gene, which encodes SRY-box transcription factor 9, a differentiation factor and potential β-catenin regulator. Because APC tumor suppressor defects in ~80% of colorectal cancers (CRCs) activate the Wnt/β-catenin pathway, we studied SOX9 inactivation in CRC biology. Compared to effects of Apc inactivation in mouse colon tumors, combined Apc and Sox9 inactivation instigated more invasive tumors with epithelial-mesenchymal transition (EMT) and SOX2 stem cell factor upregulation. In an independent mouse CRC model with combined Apc, Kras, and Trp53 defects, Sox9 inactivation promoted SOX2 induction and distant metastases. About 20% of 171 human CRCs showed loss of SOX9 protein expression, which correlated with higher tumor grade. In an independent group of 376 CRC patients, low SOX9 gene expression was linked to poor survival, earlier age at diagnosis, and increased lymph node involvement. SOX9 expression reductions in human CRC were linked to promoter methylation. EMT pathway gene expression changes were prominent in human CRCs with low SOX9 expression and in a mouse cancer model with high SOX2 expression. Our results indicate SOX9 has tumor suppressor function in CRC; its loss may promote progression, invasion, and poor prognosis by enhancing EMT and stem cell phenotypes.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ying Feng, Ningxin Zhu, Karan Bedi, Jinju Li, Chamila Perera, Maranne Green, Naziheh Assarzadegan, Yali Zhai, Qingzhi Liu, Veerabhadran Baladandayuthapani, Jason R. Spence, Kathleen R. Cho, Eric R. Fearon</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181243">Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45937-more' href='#'> <div class='article-abstract'> Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that contributes to tumor progression and immunotherapy resistance. The gut microbiome produces diverse... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI181243">https://doi.org/10.1172/JCI181243</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181243">Text</a> | <a href="/articles/view/181243/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/21"><span class='label-specialty'> Gastroenterology </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181243' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45937-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181243">Gut microbial metabolite 4-hydroxybenzeneacetic acid drives colorectal cancer progression via accumulation of immunosuppressive PMN-MDSCs</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181243">Text</a></li> <li><a class="button tiny" href="/articles/view/181243/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Colorectal cancer (CRC) is characterized by an immune-suppressive microenvironment that contributes to tumor progression and immunotherapy resistance. The gut microbiome produces diverse metabolites that feature unique mechanisms of interaction with host targets, yet the role of many metabolites in CRC remains poorly understood. In this study, the microbial metabolite 4-hydroxybenzeneacetic acid (4-HPA) promoted the infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment, consequently inhibiting the anti-tumor response of CD8+ T cells and promoting CRC progression in vivo. Mechanistically, 4-HPA activates the JAK2/STAT3 pathway, which upregulates CXCL3 transcription, thereby recruiting PMN-MDSCs to the CRC microenvironment. Selective knockdown of CXCL3 re-sensitized tumors to anti-PD1 immunotherapy in vivo. Chlorogenic acid (CGA) reduces the production of 4-HPA by microbiota, likewise abolishing 4-HPA-mediated immunosuppression. The 4-HPA content in CRC tissues was notably increased in patients with advanced CRC. Overall, the gut microbiome uses 4-HPA as a messenger to control chemokine-dependent accumulation of PMN-MDSC cells and regulate anti-tumor immunity in CRC. Our findings provide a scientific basis for establishing clinical intervention strategies to reverse the tumor immune microenvironment and improve the efficacy of immunotherapy by reducing the interaction between intestinal microbiota, tumor cells and tumor immune cells.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Qing Liao, Ximing Zhou, Ling Wu, Yuyi Yang, Xiaohui Zhu, Hangyu Liao, Yujie Zhang, Weidong Lian, Feifei Zhang, Hui Wang, Yanqing Ding, Liang Zhao</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186939">Immune repertoire profiling uncovers pervasive T-cell clonal expansions in benign prostatic hyperplasia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45928-more' href='#'> <div class='article-abstract'> </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186939">https://doi.org/10.1172/JCI186939</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186939">Text</a> | <a href="/articles/view/186939/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/127"><span class='label-article-type'> Research Letter </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/27"><span class='label-specialty'> Inflammation </span> </a><a href="/tags/37"><span class='label-specialty'> Reproductive biology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186939' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45928-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186939">Immune repertoire profiling uncovers pervasive T-cell clonal expansions in benign prostatic hyperplasia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186939">Text</a></li> <li><a class="button tiny" href="/articles/view/186939/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p> </p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Anna S. Pollack, Christian A. Kunder, Chandler C. Ho, Josephine Chou, Andrew J. Pollack, Rachel L. P. Geisick, Bing M. Zhang, Robert B. West, James D. Brooks, Jonathan R. Pollack</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180570">Hyaluronan network remodeling by ZEB1 and ITIH2 enhances the motility and invasiveness of cancer cells</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45931-more' href='#'> <div class='article-abstract'> Hyaluronan (HA) in the extracellular matrix promotes epithelial-to-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI180570">https://doi.org/10.1172/JCI180570</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180570">Text</a> | <a href="/articles/view/180570/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/16"><span class='label-specialty'> Cell biology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180570' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45931-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180570">Hyaluronan network remodeling by ZEB1 and ITIH2 enhances the motility and invasiveness of cancer cells</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180570">Text</a></li> <li><a class="button tiny" href="/articles/view/180570/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Hyaluronan (HA) in the extracellular matrix promotes epithelial-to-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates cancer progression and metastasis in the tumor microenvironment (TME) remains largely unknown. In this study, inter-alpha-trypsin inhibitor heavy chain 2 (ITIH2), an HA-binding protein, was confirmed to be secreted from mesenchymal-like lung cancer cells when co-cultured with cancer-associated fibroblasts. ITIH2 expression is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1, along with HA synthase 2 (HAS2), which positively correlates with ZEB1 expression. Depletion of ITIH2 and HAS2 reduced HA matrix formation and the migration and invasion of lung cancer cells. Furthermore, ZEB1 facilitates alternative splicing and isoform expression of CD44, an HA receptor, and CD44 knockdown suppresses the motility and invasiveness of lung cancer cells. Using a deep learning-based drug-target interaction algorithm, we identified an ITIH2 inhibitor (sincalide) that inhibited HA matrix formation and migration of lung cancer cells, preventing metastatic colonization of lung cancer cells in mouse models. These findings suggest that ZEB1 remodels the HA network in the TME through the regulation of ITIH2, HAS2, and CD44, presenting a strategy for targeting this network to suppress lung cancer progression.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sieun Lee, Jihye Park, Seongran Cho, Eun Ju Kim, Seonyeong Oh, Younseo Lee, Sungsoo Park, Keunsoo Kang, Dong Hoon Shin, Song Yi Ko, Jonathan M. Kurie, Young-Ho Ahn</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186927">Safety and implementation of phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45932-more' href='#'> <div class='article-abstract'> BACKGROUND. The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186927">https://doi.org/10.1172/JCI186927</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186927">Text</a> | <a href="/articles/view/186927/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/141"><span class='label-article-type'> Clinical Research and Public Health </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/11"><span class='label-specialty'> AIDS/HIV </span> </a><a href="/tags/143"><span class='label-specialty'> Clinical Research </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186927' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45932-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186927">Safety and implementation of phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186927">Text</a></li> <li><a class="button tiny" href="/articles/view/186927/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND. The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a new-in-infants glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV. METHODS. HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants aged ≤ 5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks. RESULTS. 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, P = 0.25; 4, 40.0% systemic, P = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded. CONCLUSIONS. This study illustrates the feasibility of conducting trials of new-in-infants adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring. TRIAL REGISTRATION. ClinicalTrials.gov NCT04607408. FUNDING. The trial was funded through National Institute of Allergy and Infectious Disease of the National Institutes of Health under grants UM1 AI068614 (HVTN Leadership and Operations Center), UM1 AI068635 (HVTN Statistical and Data Management Center), and UM1 AI068618 (HVTN Laboratory Center).</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Avy Violari, Kennedy Otwombe, William Hahn, Shiyu Chen, Deirdre Josipovic, Vuyelwa Baba, Asimenia Angelidou, Kinga K. Smolen, Ofer Levy, Nonhlanhla N. Mkhize, Amanda S. Woodward Davis, Troy M. Martin, Barton F. Haynes, Wilton B. Williams, Zachary K. Sagawa, James G. Kublin, Laura Polakowski, Margaret Brewinski Isaacs, Catherine Yen, Georgia Tomaras, Lawrence Corey, Holly Janes, Glenda E. Gray</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190841">4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8<sup>+</sup> T cell antitumor response</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45934-more' href='#'> <div class='article-abstract'> Activating the immune co-stimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the antitumor... </div> </a> <span class='article-published-at'> Published April 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI190841">https://doi.org/10.1172/JCI190841</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190841">Text</a> | <a href="/articles/view/190841/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190841' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45934-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190841">4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8<sup>+</sup> T cell antitumor response</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190841">Text</a></li> <li><a class="button tiny" href="/articles/view/190841/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Activating the immune co-stimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the antitumor responses of CD8 T cells. However, the underlying in-depth mechanisms remain to be defined. Here, we show that agonistic 4-1BB treatment of activated CD8+ T cells under continuous antigenic stimulation are more metabolically vulnerable to redox perturbation by ablation of intracellular glutathione (GSH) and glutathione peroxidase 4 (GPX4) inhibition. Further, genetic deletion of adenosine A2B receptor (A2BR) induces superior survival and expansion advantage of competent CD8+ T cells with agonistic 4-1BB costimulation, leading to more effective antitumor efficacy of adoptive cell therapy (ACT). Mechanistically, A2BR deletion helps sustain the increased energy and biosynthetic requirements through the GSH-GPX4 axis upon 4-1BB costimulation. A2BR deletion in combination with agonistic 4-1BB costimulation displays a greater ability to promote antitumor CD8+ effector T cell survival and expansion while mitigating T cell exhaustion. Thus, the A2BR pathway plays an important role in metabolic reprogramming with potentiation of the GSH-GPX4 cascade upon agonistic 4-1BB costimulation that allows the fine-tuning of the antitumor responses of CD8+ T cells.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jihae Ahn, Ping Xie, Siqi Chen, Guilan Shi, Jie Fan, Minghui Zhang, Hui Tang, Amanda R. Zuckerman, Deyu Fang, Yong Wan, Timothy M. Kuzel, Yi Zhang, Bin Zhang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/189202">Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45918-more' href='#'> <div class='article-abstract'> The physiological impact of ultradian temporal feeding patterns remains a major unanswered question in nutritional science. We have employed automated and nasogastric feeding to address this... </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI189202">https://doi.org/10.1172/JCI189202</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/189202">Text</a> | <a href="/articles/view/189202/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/20"><span class='label-specialty'> Endocrinology </span> </a><a href="/tags/28"><span class='label-specialty'> Metabolism </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI189202' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45918-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/189202">Meal-feeding promotes skeletal growth by ghrelin-dependent enhancement of growth hormone rhythmicity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/189202">Text</a></li> <li><a class="button tiny" href="/articles/view/189202/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The physiological impact of ultradian temporal feeding patterns remains a major unanswered question in nutritional science. We have employed automated and nasogastric feeding to address this question in male rodents and human volunteers. While grazing and meal-feeding reduced food intake in parallel (compared to ad libitum-fed rodents), body length and tibial epiphysial plate width were maintained in meal-fed rodents via the action of ghrelin and its receptor, GHS-R. Grazing and meal-feeding initially suppressed elevated pre-prandial ghrelin levels in rats, followed by either a sustained elevation in ghrelin in grazing rats or pre-prandial ghrelin surges in meal-fed rats. Episodic growth hormone (GH) secretion was largely unaffected in grazing rats, but meal-feeding tripled GH secretion, with burst height augmented and two additional bursts of GH per day. Continuous nasogastric infusion of enteral feed in humans failed to suppress circulating ghrelin, producing continuously elevated circulating GH with minimal rhythmicity. In contrast, bolus enteral infusion elicited post-prandial ghrelin troughs accompanied by reduced circulating GH, with enhanced ultradian rhythmicity. Taken together, our data imply that the contemporary shift from regular meals to snacking behaviour may be detrimental to optimal skeletal growth outcomes by sustaining circulating GH at levels associated with undernourishment and diminishing GH pulsatility.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Amanda K.E. Hornsby, Richard C. Brown, Thomas W. Tilston, Harry A. Smith, Alfonso Moreno-Cabañas, Bradley Arms-Williams, Anna L. Hopkins, Katie D. Taylor, Simran K.R. Rogaly, Lois H.M. Wells, Jamie J. Walker, Jeffrey S. Davies, Yuxiang Sun, Jeffrey M. Zigman, James A. Betts, Timothy Wells</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184036">Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45923-more' href='#'> <div class='article-abstract'> The anti-metastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of anti-tumor characteristics... </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI184036">https://doi.org/10.1172/JCI184036</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184036">Text</a> | <a href="/articles/view/184036/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184036' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45923-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184036">Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184036">Text</a></li> <li><a class="button tiny" href="/articles/view/184036/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The anti-metastatic activity of NK cells is well established in several cancer types, but the mechanisms underlying NK cell metastasis infiltration and acquisition of anti-tumor characteristics remain unclear. Herein, we investigated the cellular and molecular factors required to facilitate the generation of an ILC1-like CD49a+NK cell population within the liver metastasis (LM) environment of colorectal cancer (CRC). We show that CD49a+NK cells had the highest cytotoxic capacity among metastasis-infiltrating NK cells in the MC38 mouse model. Furthermore, the chemokine receptor CXCR3 promoted CD49a+NK cell accumulation and persistence in metastasis where NK cells co-localize with macrophages in CXCL9 and CXCL10 rich areas. By mining a published scRNA-seq dataset of a cohort of treatment-naïve CRC patients, we confirmed the accumulation of CXCR3+NK cells in metastatic samples. Conditional deletion of Cxcr3 in NKp46+ cells and antibody-mediated depletion of metastasis-associated macrophages impaired CD49a+NK cell development, indicating that CXCR3 and macrophages contribute to efficient NK cell localization and polarization in LM. Conversely, CXCR3neg NK cells maintained a CD49a- phenotype in metastasis with reduced parenchymal infiltration and tumor killing capacity. Furthermore, CD49a+NK cell accumulation was impaired in an independent SL4-induced CRC metastasis model, which fails to accumulate CXCL9+ macrophages. Together, our results highlight a role for CXCR3/ligand axis in promoting macrophage-dependent NK cell accumulation and functional sustenance in CRC LM.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Eleonora Russo, Chiara D'Aquino, Chiara Di Censo, Mattia Laffranchi, Luana Tomaipitinca, Valerio Licursi, Stefano Garofalo, Johann Promeuschel, Giovanna Peruzzi, Francesca Sozio, Anna Kaffke, Cecilia Garlanda, Ulf Panzer, Cristina Limatola, Christian A. J. Vosshenrich, Silvano Sozzani, Giuseppe Sciumè, Angela Santoni, Giovanni Bernardini</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181164">Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45920-more' href='#'> <div class='article-abstract'> Aberrant O-glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury.... </div> </a> <span class='article-published-at'> Published March 28, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI181164">https://doi.org/10.1172/JCI181164</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181164">Text</a> | <a href="/articles/view/181164/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/22"><span class='label-specialty'> Genetics </span> </a><a href="/tags/31"><span class='label-specialty'> Nephrology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181164' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45920-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181164">Loss of GalNAc-T14 links O-glycosylation defects to alterations in B cell homing in IgA nephropathy</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181164">Text</a></li> <li><a class="button tiny" href="/articles/view/181164/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Aberrant O-glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury. Other studies have suggested that abnormalities in mucosal immunity and lymphocyte homing are major contributors to disease. We identified a family with IgAN segregating a heterozygous predicted loss-of-function (LOF) variant in GALNT14, the gene encoding N-acetylgalactosaminyltransferase 14, one of the enzymes involved in mucin-type protein O-glycosylation. While GALNT14 is expressed in IgA1-producing cells, carriers of the LOF variant did not have altered levels of poorly glycosylated IgA1, suggesting other disease mechanisms. Investigation of Galnt14 null mice revealed elevated serum IgA levels and ex vivo IgA production by B cells. These mice developed glomerular IgA deposition with aging and after induction of sterile colitis. Galnt14 null mice also displayed an attenuated mucin layer in the colon and redistribution of IgA-producing cells from mucosal to systemic sites. Adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14 deficient B lymphocytes, resulting in increased retention in peripheral blood. These findings suggest that abnormalities in O-glycosylation alter mucosal immunity and B lymphocyte homing, pointing to an expanded role of aberrant O-glycosylation in the pathogenesis of IgAN.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sindhuri Prakash, Nicholas J. Steers, Yifu Li, Elena Sanchez-Rodriguez, Miguel Verbitsky, Isabel Robbins, Jenna Simpson, Sharvari Pathak, Milan Raska, Colin Reily, Anna Ng, Judy Liang, Natalia DeMaria, Amanda Katiraei, Kelsey O'Stevens, Clara Fischman, Samantha Shapiro, Swetha Kodali, Jason McCutchan, Heekuk Park, Djamila Eliby, Marco Delsante, Landino Allegri, Enrico Fiaccadori, Monica Bodria, Maddalena Marasa, Elizabeth Raveche, Bruce A. Julian, Anne-Catrin Uhlemann, Krzysztof Kiryluk, Hong Zhang, Vivette D. D'Agati, Simone Sanna-Cherchi, Jan Novak, Ali G. Gharavi</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179881">Prefrontal correlates of fear generalization during endocannabinoid depletion</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45894-more' href='#'> <div class='article-abstract'> Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation... </div> </a> <span class='article-published-at'> Published March 27, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI179881">https://doi.org/10.1172/JCI179881</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179881">Text</a> | <a href="/articles/view/179881/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/143"><span class='label-specialty'> Clinical Research </span> </a><a href="/tags/32"><span class='label-specialty'> Neuroscience </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179881' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45894-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179881">Prefrontal correlates of fear generalization during endocannabinoid depletion</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179881">Text</a></li> <li><a class="button tiny" href="/articles/view/179881/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Maladaptive fear generalization is one of the hallmarks of trauma-related disorders. The endocannabinoid 2-arachidonoylglycerol (2-AG) is crucial for modulating anxiety, fear, and stress adaptation but its role in balancing fear discrimination versus generalization is not known. To address this, we used a combination of plasma endocannabinoid measurement and neuroimaging from a childhood maltreatment-exposed and non-exposed mixed population combined with human and rodent fear conditioning models. Here we show that 2-AG levels are inversely associated with fear generalization at the behavioral level in both mice and humans. In mice, 2-AG depletion increases the proportion of neurons, and the similarity between neuronal representations, of threat-predictive and neutral stimuli within prelimbic prefrontal cortex neuronal ensembles. In humans, increased dorsolateral prefrontal cortical-amygdala resting state connectivity is inversely correlated with fear generalization. These data provide convergent cross-species evidence that 2-AG is a key regulator of fear generalization and further support the notion that 2-AG deficiency could represent a trauma-related disorder susceptibility endophenotype.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Luis E. Rosas-Vidal, Saptarnab Naskar, Leah M. Mayo, Irene Perini, Rameen Masroor, Megan Altemus, Liorimar Ramos-Medina, S. Danyal Zaidi, Hilda Engelbrektsson, Puja Jagasia, Markus Heilig, Sachin Patel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186146">Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45905-more' href='#'> <div class='article-abstract'> Long-standing hypertension (HTN) affects multiple organs and leads to pathologic arterial remodeling, which is driven by smooth muscle cell (SMC) plasticity. To identify relevant genes regulating... </div> </a> <span class='article-published-at'> Published March 27, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186146">https://doi.org/10.1172/JCI186146</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186146">Text</a> | <a href="/articles/view/186146/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/15"><span class='label-specialty'> Cardiology </span> </a><a href="/tags/22"><span class='label-specialty'> Genetics </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186146' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45905-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186146">Epigenetic alteration of smooth muscle cells regulates endothelin-dependent blood pressure and hypertensive arterial remodeling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186146">Text</a></li> <li><a class="button tiny" href="/articles/view/186146/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Long-standing hypertension (HTN) affects multiple organs and leads to pathologic arterial remodeling, which is driven by smooth muscle cell (SMC) plasticity. To identify relevant genes regulating SMC function in HTN, we considered Genome Wide Association Studies (GWAS) of blood pressure, focusing on genes encoding epigenetic enzymes, which control SMC fate in cardiovascular disease. Using statistical fine mapping of the KDM6 (JMJD3) locus, we found that rs62059712 is the most likely casual variant, with each major T allele copy associated with a 0.47 mmHg increase in systolic blood pressure. We show that the T allele decreased JMJD3 transcription in SMCs via decreased SP1 binding to the JMJD3 promoter. Using our unique SMC-specific Jmjd3-deficient murine model (Jmjd3flox/floxMyh11CreERT), we show that loss of Jmjd3 in SMCs results in HTN due to decreased EDNRB expression and increased EDNRA expression. Importantly, the Endothelin Receptor A antagonist, BQ-123, reversed HTN after Jmjd3 deletion in vivo. Additionally, single cell RNA-sequencing (scRNA-seq) of human arteries revealed strong correlation between JMJD3 and EDNRB in SMCs. Further, JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs increased HTN-induced arterial remodeling. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing targets that may be used in personalized management of HTN.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kevin D Mangum, Qinmengge Li, Katherine Hartmann, Tyler M Bauer, Sonya J. Wolf, James Shadiow, Jadie Y. Moon, Emily Barrett, Amrita Joshi, Gabriela Saldana de Jimenez, Sabrina A. Rocco, Zara Ahmed, Rachael Bogle, Kylie Boyer, Andrea Obi, Frank M Davis, Lin Chang, Lam Tsoi, Johann Gudjonsson, Scott M. Damrauer, Katherine Gallagher</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184609">Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45896-more' href='#'> <div class='article-abstract'> Background: Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an... </div> </a> <span class='article-published-at'> Published March 25, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI184609">https://doi.org/10.1172/JCI184609</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184609">Text</a> | <a href="/articles/view/184609/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/141"><span class='label-article-type'> Clinical Research and Public Health </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/11"><span class='label-specialty'> AIDS/HIV </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/26"><span class='label-specialty'> Infectious disease </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184609' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45896-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184609">Bacterial vaginosis associates with dysfunctional T cells and altered soluble immune factors in the cervicovaginal tract</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184609">Text</a></li> <li><a class="button tiny" href="/articles/view/184609/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Background: Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent among reproductive-age females worldwide. Adverse health outcomes associated with BV include an increased risk of sexually-acquired HIV, yet the immunological mechanisms underlying this association are not well understood. Methods: To investigate BV-driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, Kinga Study participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and PBMC samples. Results: High-parameter flow cytometry revealed an increased frequency of cervical conventional CD4+ T cells (Tconv) expressing CCR5. However, we found no difference in number of CD3+CD4+CCR5+ cells in the CX or VT of BV+ versus BV- individuals, suggesting that BV-driven increased HIV susceptibility may not be solely attributed to increased CVT HIV target cell abundance. Flow cytometry also revealed that individuals with BV have an increased frequency of dysfunctional CX and VT CD39+ Tconv and CX tissue-resident CD69+CD103+ Tconv, reported to be implicated in HIV acquisition risk and replication. Many soluble immune factor differences in the CVT further support that BV elicits diverse and complex CVT immune alterations. Conclusion: Our comprehensive analysis expands on potential immunological mechanisms that may underlie the adverse health outcomes associated with BV including increased HIV susceptibility.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Finn MacLean, Adino Tesfahun Tsegaye, Jessica B. Graham, Jessica L. Swarts, Sarah C. Vick, Nicole B. Potchen, Irene Cruz Talavera, Lakshmi Warrier, Julien Dubrulle, Lena K. Schroeder, Ayumi Saito, Corinne Mar, Katherine K. Thomas, Matthias Mack, Michelle C. Sabo, Bhavna H. Chohan, Kenneth Ngure, Nelly Rwamba Mugo, Jairam R. Lingappa, Jennifer M. Lund</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186034">Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45895-more' href='#'> <div class='article-abstract'> Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment (TME) and play critical roles in promoting tumor progression and... </div> </a> <span class='article-published-at'> Published March 25, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI186034">https://doi.org/10.1172/JCI186034</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186034">Text</a> | <a href="/articles/view/186034/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/25"><span class='label-specialty'> Immunology </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186034' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45895-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186034">Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186034">Text</a></li> <li><a class="button tiny" href="/articles/view/186034/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment (TME) and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3b-STAT3 pathway. Moreover, TAM-derived LGMN activated the integrin aV-AKT-P65 signaling to drive GBM cell proliferation and survival. Targeting LGMN-directed macrophage (inhibiting GSK3b and STAT3) and GBM cell (inhibiting integrin aV) mechanisms resulted in an anti-tumor effect in immunocompetent GBM mouse models that was further enhanced when combined with anti-PD1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN in promoting GBM progression and immunosuppression, providing effective therapeutic targets for improving immunotherapy in GBM.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Lizhi Pang, Songlin Guo, Yuyun Huang, Fatima Khan, Yang Liu, Fei Zhou, Justin D. Lathia, Peiwen Chen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179262">Long non-coding RNA BCYRN1 promotes cardioprotection by enhancing human and murine regulatory T cell dynamics</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45837-more' href='#'> <div class='article-abstract'> Regulatory T (Treg) cells modulate immune responses and attenuate inflammation. Extracellular vesicles from human cardiosphere-derived cells (CDC-EVs) enhance Treg proliferation and IL10... </div> </a> <span class='article-published-at'> Published March 25, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI179262">https://doi.org/10.1172/JCI179262</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179262">Text</a> | <a href="/articles/view/179262/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/15"><span class='label-specialty'> Cardiology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179262' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45837-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179262">Long non-coding RNA BCYRN1 promotes cardioprotection by enhancing human and murine regulatory T cell dynamics</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179262">Text</a></li> <li><a class="button tiny" href="/articles/view/179262/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Regulatory T (Treg) cells modulate immune responses and attenuate inflammation. Extracellular vesicles from human cardiosphere-derived cells (CDC-EVs) enhance Treg proliferation and IL10 production, but the mechanisms remain unclear. Here we focus on BCYRN1, a long noncoding RNA (lncRNA) highly abundant in CDC-EVs, and its role in Treg cell function. BCYRN1 acts as a "microRNA sponge," inhibiting miR-138, miR-150, and miR-98. Suppression of these miRs leads to increased Treg cell proliferation via ATG7-dependent autophagy, CCR6-dependent Treg migration, and enhanced Treg IL10 production. In a mouse model of myocardial infarction, CDC-EVs, particularly those overexpressing BCYRN1, were cardioprotective, reducing infarct size and troponin I levels even when administered after reperfusion. Underlying the cardioprotection, we verified that CDC-EVs overexpressing BCYRN1 increased cardiac Treg infiltration, proliferation, and IL10 production in vivo. These salutary effects were negated when BCYRN1 levels were reduced in CDC-EVs, or when Tregs were depleted systemically. Thus, we have identified BCYRN1 as a booster of Treg number and bioactivity, rationalizing its cardioprotective efficacy. While here we studied BCYRN1 overexpression in the context of ischemic injury, the same approach merits testing in other disease processes (e.g., autoimmunity or transplant rejection) where increased Treg activity is a recognized therapeutic goal.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ke Liao, Jiayi Yu, Akbarshakh Akhmerov, Zahra Mohammadigoldar, Liang Li, Weixin Liu, Natasha Anders, Ahmed G.E. Ibrahim, Eduardo Marbán</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/181609">Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45889-more' href='#'> <div class='article-abstract'> Allosteric inhibitors of the tyrosine phosphatase SHP2 hold therapeutic promise in cancers with overactive RAS/ERK signaling but “adaptive resistance” to SHP2 inhibitors may limit benefits. Here,... </div> </a> <span class='article-published-at'> Published March 25, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI181609">https://doi.org/10.1172/JCI181609</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181609">Text</a> | <a href="/articles/view/181609/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/12"><span class='label-specialty'> Angiogenesis </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181609' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45889-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181609">Induced clustering of SHP2-depleted tumor cells in vascular islands restores sensitivity to MEK/ERK inhibition</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181609">Text</a></li> <li><a class="button tiny" href="/articles/view/181609/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Allosteric inhibitors of the tyrosine phosphatase SHP2 hold therapeutic promise in cancers with overactive RAS/ERK signaling but “adaptive resistance” to SHP2 inhibitors may limit benefits. Here, we utilized tumor cells that proliferate similarly with or without endogenous SHP2 to explore means to overcome this growth-independence from SHP2. We found that SHP2 depletion profoundly alters output of vascular regulators, cytokines, chemokines, and other factors from SHP2 growth-resistant cancer cells. Tumors derived from inoculation of SHP2-depleted, but SHP2 growth-independent, mouse melanoma and colon carcinoma cell lines display a typically subverted architecture where proliferative tumor cells cluster in distinct “vascular islands” centered by remodeled vessels, each limited by surrounding hypoxic and dead tumor tissue, where inflammatory blood cells are limited. Although vascular islands generally reflect protected sanctuaries for tumor cells, we found that vascular island-resident, highly proliferative, SHP2-depleted tumor cells acquire an increased sensitivity to blocking MEK/ERK signaling resulting in reduced tumor growth. Our results show that response to targeted therapies in resistant tumor cells is controlled by tumor cell-induced vascular changes and tumor architectural reorganization providing a compelling approach to eliciting tumor response by exploiting tumor and endothelial-dependent biochemical changes.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yuyi Wang, Hidetaka Ohnuki, Andy D. Tran, Dunrui Wang, Taekyu Ha, Jing-Xin Feng, Minji Sim, Raymond Barnhill, Claire Lugassy, Michael R. Sargen, Emanuel Salazar-Cavazos, Michael Kruhlak, Giovanna Tosato</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180900">Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45885-more' href='#'> <div class='article-abstract'> Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the vessel is unknown. This study tested the hypothesis that... </div> </a> <span class='article-published-at'> Published March 20, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI180900">https://doi.org/10.1172/JCI180900</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180900">Text</a> | <a href="/articles/view/180900/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/15"><span class='label-specialty'> Cardiology </span> </a><a href="/tags/42"><span class='label-specialty'> Vascular biology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180900' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45885-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180900">Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180900">Text</a></li> <li><a class="button tiny" href="/articles/view/180900/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the vessel is unknown. This study tested the hypothesis that extracellular vesicles (EVs) secreted by RBCs act as mediators of endothelial dysfunction in T2D. Despite a lower production of EVs derived from RBCs of T2D patients (T2D RBC-EVs), their uptake by endothelial cells was greater than that of EVs derived from RBCs of healthy individuals (H RBC-EVs). T2D RBC-EVs impaired endothelium-dependent relaxation and this effect was attenuated following inhibition of arginase in EVs. Inhibition of vascular arginase or oxidative stress also attenuated endothelial dysfunction induced by T2D RBC-EVs. Arginase-1 was detected in RBC-derived EVs, and arginase-1 and oxidative stress were increased in endothelial cells following co-incubation with T2D RBC-EVs. T2D RBC-EVs also increased arginase-1 protein in endothelial cells following mRNA silencing and in the endothelium of aortas from endothelial cell arginase 1 knockout mice. It is concluded that T2D-RBCs induce endothelial dysfunction through increased uptake of EVs that transfer arginase-1 from RBCs to the endothelium to induce oxidative stress and endothelial dysfunction. These results shed important light on the mechanism underlying endothelial injury mediated by RBCs in T2D.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Aida Collado, Rawan Humoud, Eftychia Kontidou, Maria Eldh, Jasmin Swaich, Allan Zhao, Jiangning Yang, Tong Jiao, Elena Domingo, Emelie Carlestål, Ali Mahdi, John Tengbom, Ákos Végvári, Qiaolin Deng, Michael Alvarsson, Susanne Gabrielsson, Per Eriksson, Zhichao Zhou, John Pernow</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/184021"><i>TP53</i> mutations and <i>TET2</i> deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class='hide-for-small show-more' data-reveal-id='article45886-more' href='#'> <div class='article-abstract'> Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies and developing improved therapies for TP53-mutant leukemias is of urgent need. Here we... </div> </a> <span class='article-published-at'> Published March 20, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025. <a href="https://doi.org/10.1172/JCI184021">https://doi.org/10.1172/JCI184021</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184021">Text</a> | <a href="/articles/view/184021/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/106"><span class='label-article-type'> Research </span> </a><a href="/tags/113"><span class='label-in-press-preview'> In-Press Preview </span> </a><a href="/tags/23"><span class='label-specialty'> Hematology </span> </a><a href="/tags/27"><span class='label-specialty'> Inflammation </span> </a><a href="/tags/33"><span class='label-specialty'> Oncology </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184021' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45886-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184021"><i>TP53</i> mutations and <i>TET2</i> deficiency cooperate to drive leukemogenesis and establish an immunosuppressive environment</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184021">Text</a></li> <li><a class="button tiny" href="/articles/view/184021/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Mutations and deletions in TP53 are associated with adverse outcomes in patients with myeloid malignancies and developing improved therapies for TP53-mutant leukemias is of urgent need. Here we identify mutations in TET2 as the most common co-occurring mutation in TP53 mutant acute myeloid leukemia (AML) patients. In mice, combined hematopoietic-specific deletion of TET2 and TP53 resulted in enhanced self-renewal compared to deletion of either gene alone. Tp53/Tet2 double knockout mice developed serially transplantable AML. Both mice and AML patients with combined TET2/TP53 alterations upregulated innate immune signaling in malignant granulocyte-monocyte progenitors (GMPs), which had leukemia-initiating capacity. A20 governs the leukemic maintenance by triggering aberrant non-canonical NF-κB signaling. Mice with Tp53/Tet2 loss had expansion of monocytic myeloid-derived suppressor cells (MDSCs), which impaired T cell proliferation and activation. Moreover, mice and AML patients with combined TP53/TET2 alterations displayed increased expression of the TIGIT ligand, CD155, on malignant cells. TIGIT blocking antibodies augmented NK cell-mediated killing of Tp53/Tet2 double-mutant AML cells, reduced leukemic burden, and prolonged survival in Tp53/Tet2 double knockout mice. These findings uncover a leukemia-promoting link between TET2 and TP53 mutations and highlight therapeutic strategies to overcome the immunosuppressive bone marrow environment in this adverse subtype of AML.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Pu Zhang, Ethan C. Whipp, Sarah J. Skuli, Mehdi Gharghabi, Caner Saygin, Steven A. Sher, Martin Carroll, Xiangyu Pan, Eric D. Eisenmann, Tzung-Huei Lai, Bonnie K. Harrington, Wing Keung Chan, Youssef Youssef, Bingyi Chen, Alex Penson, Alexander M. Lewis, Cynthia R. Castro, Nina Fox, Ali Cihan, Jean-Benoit Le Luduec, Susan DeWolf, Tierney Kauffman, Alice S. Mims, Daniel Canfield, Hannah Phillips, Katie E. Williams, Jami Shaffer, Arletta Lozanski, Tzyy-Jye Doong, Gerard Lozanski, Charlene Mao, Christopher J. Walker, James S. Blachly, Anthony F. Daniyan, Lapo Alinari, Robert A. Baiocchi, Yiping Yang, Nicole R. Grieselhuber, Moray J. Campbell, Sharyn D. Baker, Bradley W. Blaser, Omar Abdel-Wahab, Rosa Lapalombella</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <p> <div role="navigation" aria-label="Pagination" class="pagination"><span class="previous_page disabled" aria-disabled="true">← Previous</span> <em class="current" aria-label="Page 1" aria-current="page">1</em> <a rel="next" aria-label="Page 2" href="/in-press-preview?page=2">2</a> <a aria-label="Page 3" href="/in-press-preview?page=3">3</a> <span class="gap">…</span> <a aria-label="Page 99" href="/in-press-preview?page=99">99</a> <a aria-label="Page 100" href="/in-press-preview?page=100">100</a> <a class="next_page" rel="next" href="/in-press-preview?page=2">Next →</a></div> </p> </div> </div> </div> </div> </div> <div id='footer'> <div class='row panel-padding'> <div class='small-6 columns'> <div id='social-links'> <a onclick="trackOutboundLink('/twitter?ref=footer');" href="/twitter"><img title="Twitter" src="/assets/social/twitter-round-blue-78025a92064e3594e44e4ccf5446aefeafba696cd3c8e4a7be1850c7c9f62aba.png" /></a> <a onclick="trackOutboundLink('/facebook?ref=footer');" href="/facebook"><img title="Facebook" src="/assets/social/facebook-round-blue-2787910d46dcbdbee4bd34030fee044e5a77cfda2221af9191d437b2f5fadeb1.png" /></a> <a href="/rss"><img title="RSS" src="/assets/social/rss-round-color-6f5fa8e93dc066ee4923a36ba6a7cb97d53c5b77de78a2c7b2a721adc603f342.png" /></a> </div> <br> Copyright © 2025 <a href="http://www.the-asci.org">American Society for Clinical Investigation</a> <br> ISSN: 0021-9738 (print), 1558-8238 (online) </div> <div class='small-6 columns'> <div class='row'> <div class='small-12 columns'> <h4 class='notices-signup'>Sign up for email alerts</h4> <form action='https://notices.jci.org/subscribers/new' method='get'> <input name='utm_source' type='hidden' value='jci'> <input name='utm_medium' type='hidden' value='web'> <input name='utm_campaign' type='hidden' value='email_signup'> <input name='utm_content' type='hidden' value='footer'> <div class='row'> <div class='small-12 medium-9 columns'> <input name='email_address' placeholder='Your email address' required type='text'> </div> <div class='small-12 medium-3 columns'> <input class='button tiny orange' type='submit' value='Sign up'> </div> </div> </form> </div> </div> </div> </div> </div> </div> <script src="/assets/application-27f18b5fe3b7302e5b3e3c6d7cf9bb3f54759fad32679209f5aef429b89f3aef.js"></script>  <script src="//s7.addthis.com/js/300/addthis_widget.js#pubid=ra-4d8389db4b0bb592" async="async"></script> <script src="//d1bxh8uas1mnw7.cloudfront.net/assets/embed.js" async="async"></script>  </body> </html>