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<div class='row cover-caption'> <div class='small-12 columns'> <h3 class='issue'> Issue published March 17, 2025 <span class='browse'> <a id="issue#show_previous_issue" href="/135/5">Previous issue</a> | <a id="issue#show_next_issue" href="/135/7">Next issue</a> </span> </h3> </div> </div> <div class='row'> <div class='large-3 medium-4 columns'> <img class="issue-cover" src="//dm5migu4zj3pb.cloudfront.net/volumes/135/6/135-6-cover.jpg" /> </div> <div class='large-9 medium-8 columns'> <ul class='no-bullet'> <li> Volume 135, Issue 6 </li> </ul> <h5>Go to section:</h5> <ul class='no-bullet'> <li> <a href='#review'> Reviews </a> </li> <li> <a href='#editor_s_note'> Editor's note </a> </li> <li> <a href='#commentary'> Commentaries </a> </li> <li> <a href='#research_letter'> Research Letter </a> </li> <li> <a href='#research_article'> Research Articles </a> </li> <li> <a href='#corrigendum'> Corrigenda </a> </li> </ul> </div> </div> <div class='row'> <div class='small-12 columns'> <h4 class='cover-story-headline'> On the cover: RNase L restrains regeneration in response to tissue injury </h4> <div><p><a href="/articles/view/172595">Kirby et al.</a> show that the oligoadenylate synthetase (OAS)/RNase L pathway, which regulates the innate immune response to viral RNA, represses wound healing and epithelial regeneration. Loss of Rnase L or pharmacological inhibition of downstream signaling enhances regenerative capacity in mice. The cover shows Xenium spatial transcriptomics of <i>Rnasel6</i>-knockout mouse skin captured in Xenium Explorer using graph-based clustering.</p> </div> </div> </div> <a class='in-page' name='review'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel0' name='review'> <strong></strong> <span class='toggle-icon'></span> Reviews </a> <div class='content active' id='panel0'> <div class='row'> <div class='small-12 columns'> <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/172837">Extracranial arteriovenous malformations: towards etiology-based therapeutic management</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/172837">Julien Coulie, … , Miikka Vikkula, Laurence M. Boon</a> <a class='hide-for-small show-more' data-reveal-id='article45839-more' href='#'> <div class='article-authors'> Julien Coulie, … , Miikka Vikkula, Laurence M. Boon </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e172837. <a href="https://doi.org/10.1172/JCI172837">https://doi.org/10.1172/JCI172837</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/172837">Text</a> | <a href="/articles/view/172837/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI172837' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/172837/figure/1' ref='group' title='Clinical aspects of AVMs illustrating the Schöbinger’s staging system. Stage I: cutaneous blush with warmth; a localized left ear AVM (A) and a left temporal AVM (D). Stage II: bruit, audible pulsations, expanding lesion; a growing left earlobe AVM (B) and a right frontal AVM with an important glabellar draining vein (E). Stage III: pain, ulceration, bleeding, infection; a left ear AVM causing pain and severe deformation (C) and an ulcerated left ankle AVM (F). Stage IV: cardiac failure; an extensive ulcerated AVM of the entire right lower limb causing cardiac insufficiency and pulmonary hypertension (G). All photos are shown with patient consent.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/172000/172837/small/JCI172837.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45839-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/172837">Extracranial arteriovenous malformations: towards etiology-based therapeutic management</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/172837">Text</a></li> <li><a class="button tiny" href="/articles/view/172837/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Anomalies during angiogenesis can initiate the formation of arteriovenous malformations (AVMs), characterized by aberrant connections between arteries and veins and fast lesional blood flow. These anomalies can manifest anywhere in the body, including the brain, and they typically appear at birth and evolve alongside growth of the individual. Depending on their location and size, AVMs can induce progressive deformation, chronic pain, functional impairment, and ulceration and pose life-threatening risks such as hemorrhage and organ dysfunction. The primary treatment modalities entail surgical intervention or embolization followed by surgery. However, these approaches are often challenging and seldom offer definitive resolution. In addition, inadequately performed surgery may trigger angiogenic rebound, fostering AVM recurrence. Advancements in comprehending the molecular pathways underlying AVMs have sparked interest in repurposing targeted therapies initially devised for cancer treatment. The first results are promising, giving new hope to the patients affected with these often devastating and debilitating lesions, the management of which presents major clinical challenges.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Julien Coulie, Emmanuel Seront, Miikka Vikkula, Laurence M. Boon</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/188127">Nonvesicular cholesterol transport in physiology</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188127">Alessandra Ferrari, Peter Tontonoz</a> <a class='hide-for-small show-more' data-reveal-id='article45864-more' href='#'> <div class='article-authors'> Alessandra Ferrari, Peter Tontonoz </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e188127. <a href="https://doi.org/10.1172/JCI188127">https://doi.org/10.1172/JCI188127</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188127">Text</a> | <a href="/articles/view/188127/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188127' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/188127/figure/1' ref='group' title='Overview of whole-body cholesterol transport in mice. Diet-derived cholesterol is absorbed by enterocytes in small intestine and incorporated into chylomicrons and HDL. Liver and intestine synthesize cholesterol de novo. Hepatic cholesterol is packaged into VLDL and HDL. Chylomicrons and VLDL are enriched in triglycerides (TAG), which are delivered to periphery tissues, including adipose and muscle. TAG-depleted chylomicrons, called chylomicron remnants, are delivered back to liver, where they bind LRP1 and LDLR. TAG-depleted VLDLs are called intermediate-density lipoproteins (IDLs). When IDLs are further depleted of TAG, they become LDL. LDL is taken up by LDLR in liver and by scavenger receptors in macrophages. Efflux of cholesterol from macrophages to HDL initiates reverse cholesterol transport (RCT) to the liver for excretion. HDL-cholesterol is taken up by hepatic SR-BI in the liver and is converted to bile acids for elimination. In mice HDL is the most abundant lipoprotein and delivers cholesterol to steroidogenic organs. ApoA1, apolipoprotein A-I; ApoB, apolipoprotein B.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/188000/188127/small/JCI188127.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45864-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188127">Nonvesicular cholesterol transport in physiology</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188127">Text</a></li> <li><a class="button tiny" href="/articles/view/188127/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Alessandra Ferrari, Peter Tontonoz</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/188358">Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188358">Megan L. Baker, Lloyd G. Cantley</a> <a class='hide-for-small show-more' data-reveal-id='article45860-more' href='#'> <div class='article-authors'> Megan L. Baker, Lloyd G. Cantley </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e188358. <a href="https://doi.org/10.1172/JCI188358">https://doi.org/10.1172/JCI188358</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188358">Text</a> | <a href="/articles/view/188358/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188358' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/188358/figure/1' ref='group' title='Patterns of epithelial cell injury in response to distinct injury stimuli. Defined classes of tubular insults can induce distinct initial mechanisms and distributions of cellular injury. From left to right, macrocirculatory insufficiency in ischemic injury results in mitochondrial dysfunction and cellular metabolic and energy disturbances. In toxin-mediated AKI, the cellular mechanisms of injury are dependent on toxin characteristics and toxin handling within the tubule (i.e., secretion or filtration and accumulation within tubular space or TEC absorption and intracellular accumulation). Septic AKI is characterized by endothelial injury and activation along with TEC injury resulting from both pattern recognition receptor activation on TECs as well as cellular energy and metabolic derangements from macro-and microcirculatory insufficiency. In immune-mediated injury such as AIN, antigens elicit a cell-mediated T cell hypersensitivity immune response either directly or after hydrolysis and processing by tubular cells to form a hapten bridge. PCT, proximal convoluted tubule; PST, proximal straight tubule.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/188000/188358/small/JCI188358.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45860-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188358">Adding insult to injury: the spectrum of tubulointerstitial responses in acute kidney injury</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188358">Text</a></li> <li><a class="button tiny" href="/articles/view/188358/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Acute kidney injury (AKI) encompasses pathophysiology ranging from glomerular hypofiltration to tubular cell injury and outflow obstruction. This Review will focus on the tubulointerstitial processes that underlie most cases of AKI. Tubular epithelial cell (TEC) injury can occur via distinct insults, including ischemia, nephrotoxins, sepsis, and primary immune-mediated processes. Following these initial insults, tubular cells can activate survival and repair responses or they can develop mitochondrial dysfunction and metabolic reprogramming, cell-cycle arrest, and programmed cell death. Developing evidence suggests that the fate of individual tubular cells to survive and proliferate or undergo cell death or senescence is frequently determined by a biphasic immune response with initial proinflammatory macrophage, neutrophil, and lymphocyte infiltration exacerbating injury and activating programmed cell death, while alternatively activated macrophages and specific lymphocyte subsets subsequently modulate inflammation and promote repair. Functional recovery requires that this reparative phase supports proteolytic degradation of tubular casts, proliferation of surviving TECs, and restoration of TEC differentiation. Incomplete resolution or persistence of inflammation can lead to failed tubular repair, fibrosis, and chronic kidney disease. Despite extensive research in animal models, translating preclinical findings to therapies remains challenging, emphasizing the need for integrated multiomic approaches to advance AKI understanding and treatment.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Megan L. Baker, Lloyd G. Cantley</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='editor_s_note'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel1' name='editor_s_note'> <strong></strong> <span class='toggle-icon'></span> Editor's note </a> <div class='content active' id='panel1'> <div class='row'> <div class='small-12 columns'> <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/188611">Expanding the bandwidth of checkpoint inhibitors for cancer using epigenetic regulators</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188611">Daniel J. Brat</a> <a class='hide-for-small show-more' data-reveal-id='article45870-more' href='#'> <div class='article-authors'> Daniel J. Brat </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e188611. <a href="https://doi.org/10.1172/JCI188611">https://doi.org/10.1172/JCI188611</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188611">Text</a> | <a href="/articles/view/188611/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188611' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45870-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188611">Expanding the bandwidth of checkpoint inhibitors for cancer using epigenetic regulators</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188611">Text</a></li> <li><a class="button tiny" href="/articles/view/188611/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>Daniel J. Brat</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='commentary'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel2' name='commentary'> <strong></strong> <span class='toggle-icon'></span> Commentaries </a> <div class='content active' id='panel2'> <div class='row'> <div class='small-12 columns'> <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/190230">Sensing mycobacteria through unconventional pathways</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190230">Catarina F. Almeida, Jennifer A. Juno</a> <a class='hide-for-small show-more' data-reveal-id='article45861-more' href='#'> <div class='article-authors'> Catarina F. Almeida, Jennifer A. Juno </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e190230. <a href="https://doi.org/10.1172/JCI190230">https://doi.org/10.1172/JCI190230</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190230">Text</a> | <a href="/articles/view/190230/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190230' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/190230/figure/1' ref='group' title='Mycobacterial lipids play a dual role in stimulating the immune system. The mycobacterial cell wall contains numerous MAs with immunostimulatory activity. Mycolate lipids such as TMM, TDM, and diacyltrehalose (DAT) bind to the C-type lectin receptor Mincle on myeloid cells, stimulating downstream inflammatory processes. Others such as LAM and PIM bind TLR2, which triggers GM-CSF secretion and CD1 upregulation on antigen-presenting cells, including myeloid cells, monocytes, and macrophages. These and other lipid-based molecules, such as MA or its ester derivatives GMM, DAT, and SGL, can also be captured by CD1b and presented to unconventional T cells that recognize such CD1b-lipid complexes via their TCR. The CD1b-TMM–specific T cell populations revealed by Sakai and colleagues (3) expand upon M. tuberculosis infection and exhibited conserved features shared across different individuals. Some of these characteristics are also common among other CD1b-restricted T cell subsets, including expression of the CD4 coreceptor and cytotoxicity-associated effector molecules, such as IFN, TNF, granzyme B (GzmB), and perforin. They also share a previously described TRBV4-1 usage for CD1b-restricted cells (albeit with long and flexible CDR3β loops to accommodate a complex lipid headgroup that protrudes from CD1b) and positively charged amino acids comprising the CDR3α (similar to CD1b-GMM–reactive cells), which define the TCR specificity for CD1b-TMM.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/190000/190230/small/JCI190230.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45861-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190230">Sensing mycobacteria through unconventional pathways</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190230">Text</a></li> <li><a class="button tiny" href="/articles/view/190230/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Approximately one-quarter of the global population is estimated to be infected with Mycobacterium tuberculosis. New developments in vaccine design and therapeutics are urgently needed, particularly in the face of multidrug-resistant tuberculosis (TB). In this issue of the JCI, Sakai and colleagues used a multidisciplinary approach to determine that trehalose-6-monomycolate (TMM), a mycobacterial cell wall lipid, serves as a T cell antigen presented by CD1b. CD1b-TMM–specific T cells were characterized by conserved T cell receptor features and were present at elevated frequencies in individuals with active TB disease. These findings highlight the dual role of TMM in stimulating both innate and adaptive immunity and broaden our understanding of CD1-mediated lipid recognition by unconventional T cells.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Catarina F. Almeida, Jennifer A. Juno</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/190955">Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190955">Selket Delafontaine, Isabelle Meyts</a> <a class='hide-for-small show-more' data-reveal-id='article45847-more' href='#'> <div class='article-authors'> Selket Delafontaine, Isabelle Meyts </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e190955. <a href="https://doi.org/10.1172/JCI190955">https://doi.org/10.1172/JCI190955</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190955">Text</a> | <a href="/articles/view/190955/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190955' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/190955/figure/1' ref='group' title='Autosomal recessive OSM deficiency causes an isolated phenotype of IBMFS through an alteration of the BMM. OSM is a pleiotropic cytokine, secreted by activated immune cells such as T cells, monocytes, macrophages, and neutrophils. Upon binding to its receptors, composed of gp130 and LIFR and/or gp130 and OSMRb, which are widely expressed in hematopoietic and nonhematopoietic tissue, OSM activates the JAK/STAT, the RAS/MAPK, and the PI3K/AKT signaling pathways. Garrigue, Kermasson, and colleagues (1) demonstrated how a homozygous LoF mutation, found in three children from a consanguineous family, leads to the production of a neopeptide, impeding the interaction with both OSM receptors on HSPCs, which ultimately underlies an IBMFS characterized by profound anemia, neutropenia, and thrombocytopenia. This discovery demonstrates that genetic causes of IBMFS extend beyond HSPC intrinsic defects, as alterations of the BMM and inflammatory cytokines can play a pathogenic role in the development of IBMFS.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/190000/190955/small/JCI190955.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45847-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190955">Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190955">Text</a></li> <li><a class="button tiny" href="/articles/view/190955/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Inherited bone marrow failure syndromes (IBMFSs) encompass a diverse group of hematological disorders characterized by a progressive single-lineage cytopenia or pancytopenia. Despite their heterogeneity, these syndromes often result from genetic errors affecting key biological mechanisms, including telomere maintenance, DNA repair and chromosomal stability, and ribosome assembly, generally leading to accelerated apoptosis of hematopoietic cells. Nevertheless, a genetic diagnosis remains elusive in more than half of the cases. The increased risk of myelodysplastic syndrome (MDS), acute leukemia, and solid tumors associated with IBMFS frequently prompts early hematopoietic stem cell transplantation (HSCT). In this issue of the JCI, Garrigue, Kermasson, and colleagues identified a homozygous variant in Oncostatin M (OSM) in 3 children from a consanguineous family presenting with IBMFS characterized by profound anemia, thrombocytopenia, and neutropenia. The findings suggest that the loss-of-function OSM variant affected hematopoietic stem cell function through changes to the bone marrow microenvironment (BMM).</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Selket Delafontaine, Isabelle Meyts</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/190957">Macrophages: key conductors behind perivascular inflammation and vascular remodeling in hypoxia-induced pulmonary hypertension</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190957">Edda Spiekerkoetter</a> <a class='hide-for-small show-more' data-reveal-id='article45854-more' href='#'> <div class='article-authors'> Edda Spiekerkoetter </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e190957. <a href="https://doi.org/10.1172/JCI190957">https://doi.org/10.1172/JCI190957</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190957">Text</a> | <a href="/articles/view/190957/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190957' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45854-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190957">Macrophages: key conductors behind perivascular inflammation and vascular remodeling in hypoxia-induced pulmonary hypertension</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190957">Text</a></li> <li><a class="button tiny" href="/articles/view/190957/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Pulmonary hypertension (PH) encompasses a heterogenous group of disorders with the common feature of increased pulmonary arterial pressures. Patients with PH associated with lung disease and/or hypoxia undergo immune-mediated vascular remodeling that includes thickening of the muscular layer surrounding arteries and arterioles. In this issue of the JCI, Kumar and colleagues examined the role of interstitial macrophages in a model of high-altitude PH. Resident interstitial macrophages increased, proliferated, and expressed CCL2, a monocyte chemoattractant ligand. There was also a rise in CCR2+ macrophages expressing thrombospondin-1, which is known to activate vascular remodeling through TGF-β. Blocking monocyte recruitment partially reduced hypoxic PH, and corticosteroid treatment effectively reduced CCL2 expression and CCR2+ monocyte recruitment. Further, plasma samples collected from individuals ascending from low to high altitudes showed increased thrombospondin-1 and TGF-β levels, which were reduced with dexamethasone. These findings reveal interstitial macrophage populations as potential therapeutic targets in hypoxic PH.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Edda Spiekerkoetter</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='research_letter'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel3' name='research_letter'> <strong></strong> <span class='toggle-icon'></span> Research Letter </a> <div class='content active' id='panel3'> <div class='row'> <div class='small-12 columns'> <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/187376">Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/187376">Evi J.C. Koene, … , Patrick Schrauwen, Martijn C.G.J. Brouwers</a> <a class='hide-for-small show-more' data-reveal-id='article45863-more' href='#'> <div class='article-authors'> Evi J.C. Koene, … , Patrick Schrauwen, Martijn C.G.J. Brouwers </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e187376. <a href="https://doi.org/10.1172/JCI187376">https://doi.org/10.1172/JCI187376</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/187376">Text</a> | <a href="/articles/view/187376/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI187376' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/187376/figure/1' ref='group' title='Fructose metabolism in MASLD and fructose tolerance in HFI upon PF-06835919. (A) Fructose can serve as a substrate for gluconeogenesis, oxidation, and de novo lipogenesis in the liver. Upon fructose ingestion in HFI, ALDOB deficiency results in the accumulation of Fru-1P and depletion of ATP and Pi. These conditions impair gluconeogenesis and glycogenolysis and consequently induce hypoglycemia. It is hypothesized that pharmacological inhibition of KHK by PF-06835919 will mitigate these biochemical derangements. Created in BioRender. Brouwers, M. (2025) https:// BioRender.com/q91c888. (B and C) In vivo changes in hepatic PME and Pi concentrations in response to a 60-gram oral fructose load after placebo and PF-06835919 treatment in participants with MASLD (n = 14). Data are presented as mean ± SEM. (D–O) Changes in urinary fructose, urinary glucose, phosphate and pH, and serum phosphate and blood glucose after an oral fructose load (2.5 g [blue], 5.0 g [green], 7.5 g [orange]) in patients A (D–G), B (H–K), and C (L–O) treated with PF-06835919. Gray lines represent upper, lower, and mean reference ranges obtained from five healthy individuals (not treated with PF-06835919) after 7.5 g oral fructose. Black lines/dots represent fasted samples.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/187000/187376/small/JCI187376.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45863-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/187376">Safety and efficacy of pharmacological inhibition of ketohexokinase in hereditary fructose intolerance</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/187376">Text</a></li> <li><a class="button tiny" href="/articles/view/187376/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>Evi J.C. Koene, Amée M. Buziau, David Cassiman, Timothy M. Cox, Judith Bons, Jean L.J.M. Scheijen, Casper G. Schalkwijk, Steven J.R. Meex, Aditi R. Saxena, William P. Esler, Vera B. Schrauwen-Hinderling, Patrick Schrauwen, Martijn C.G.J. Brouwers</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='research_article'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel4' name='research_article'> <strong></strong> <span class='toggle-icon'></span> Research Articles </a> <div class='content active' id='panel4'> <div class='row'> <div class='small-12 columns'> <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/172595">RNase L represses hair follicle regeneration through altered innate immune signaling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/172595">Charles S. Kirby, … , Robert H. Silverman, Luis A. Garza</a> <a class='hide-for-small show-more' data-reveal-id='article45879-more' href='#'> <div class='article-authors'> Charles S. Kirby, … , Robert H. Silverman, Luis A. Garza </div> </a> <span class='article-published-at'> Published February 4, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e172595. <a href="https://doi.org/10.1172/JCI172595">https://doi.org/10.1172/JCI172595</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/172595">Text</a> | <a href="/articles/view/172595/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI172595' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/172595/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/172000/172595/small/JCI172595.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45879-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/172595">RNase L represses hair follicle regeneration through altered innate immune signaling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/172595">Text</a></li> <li><a class="button tiny" href="/articles/view/172595/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Mammalian injury responses are predominantly characterized by fibrosis and scarring rather than functional regeneration. This limited regenerative capacity in mammals could reflect a loss of proregeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we screened transcripts in human participants following laser rejuvenation treatment and compared them with mice with enhanced wound-induced hair neogenesis (WIHN), a rare example of mammalian organogenesis. We found that Rnasel–/– mice exhibit an increased regenerative capacity, with elevated WIHN through enhanced IL-36α. Consistent with RNase L’s known role to stimulate caspase-1, we found that pharmacologic inhibition of caspases promoted regeneration in an IL-36–dependent manner in multiple epithelial tissues. We identified a negative feedback loop, where RNase L–activated caspase-1 restrains the proregenerative dsRNA-TLR3 signaling cascade through the cleavage of toll-like adaptor protein TRIF. Through integrated single-cell RNA-seq and spatial transcriptomic profiling, we confirmed OAS & IL-36 genes to be highly expressed at the site of wounding and elevated in Rnasel–/– mouse wounds. This work suggests that RNase L functions as a regeneration repressor gene, in a functional trade off that tempers immune hyperactivation during viral infection at the cost of inhibiting regeneration.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Charles S. Kirby, Nasif Islam, Eric Wier, Martin P. Alphonse, Evan Sweren, Gaofeng Wang, Haiyun Liu, Dongwon Kim, Ang Li, Sam S. Lee, Andrew M. Overmiller, Yingchao Xue, Sashank Reddy, Nathan K. Archer, Lloyd S. Miller, Jianshi Yu, Weiliang Huang, Jace W. Jones, Sooah Kim, Maureen A. Kane, Robert H. Silverman, Luis A. Garza</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/176865">Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176865">Rahul Kumar, … , Qadar Pasha, Brian B. Graham</a> <a class='hide-for-small show-more' data-reveal-id='article45849-more' href='#'> <div class='article-authors'> Rahul Kumar, … , Qadar Pasha, Brian B. Graham </div> </a> <span class='article-published-at'> Published January 30, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e176865. <a href="https://doi.org/10.1172/JCI176865">https://doi.org/10.1172/JCI176865</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176865">Text</a> | <a href="/articles/view/176865/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI176865' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/176865/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/176000/176865/small/JCI176865.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45849-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176865">Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176865">Text</a></li> <li><a class="button tiny" href="/articles/view/176865/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2+ macrophages through recruitment, which express the protein thrombospondin-1, which functionally activates TGF-β to cause vascular disease. Blockade of monocyte recruitment with either CCL2-neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who traveled from low (225 m) to high (3500 m) elevation, revealing an increase in thrombospondin-1 and TGF-β expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2+ monocyte recruitment. These data suggest a pathologic cross talk between 2 discrete interstitial macrophage populations, which can be therapeutically targeted.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Rahul Kumar, Kevin Nolan, Biruk Kassa, Neha Chanana, Tsering Palmo, Kavita Sharma, Kanika Singh, Claudia Mickael, Dara Fonseca Balladares, Julia Nilsson, Amit Prabhakar, Aastha Mishra, Michael H. Lee, Linda Sanders, Sushil Kumar, Ari B. Molofsky, Kurt R. Stenmark, Dean Sheppard, Rubin M. Tuder, Mohit D. Gupta, Tashi Thinlas, Qadar Pasha, Brian B. Graham</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/179137">Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179137">Tanvi Potluri, … , Hong Zhao, Serdar E. Bulun</a> <a class='hide-for-small show-more' data-reveal-id='article45857-more' href='#'> <div class='article-authors'> Tanvi Potluri, … , Hong Zhao, Serdar E. Bulun </div> </a> <span class='article-published-at'> Published February 4, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e179137. <a href="https://doi.org/10.1172/JCI179137">https://doi.org/10.1172/JCI179137</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179137">Text</a> | <a href="/articles/view/179137/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI179137' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/179137/figure/1' ref='group' title='Fibroblast-specific ablation of ESR1 in Aromhum mice prevents herniation. (A) Representative images of WT and Aromhum mice, and an illustration depicting scrotal hernia and LAMs. Created with BioRender (biorender.com). (B) Measurement of scrotal hernia size with age in fibroblast-specific Esr1-knockout mice (fEsr1–/– Aromhum) and fEsr1+/+ Aromhum and fEsr1+/+ WT littermate controls (n = 3–4 per group, mean ± SEM, repeated-measures ANOVA with Bonferroni multiple comparisons). (C) Flow cytometry dot plots showing the percentage of PDGFRA+ estrogen receptor-α–positive HAFs in LAMs from fEsr1–/– Aromhum and control fEsr1+/+ Aromhum mice (n = 3). (D) Representative images of scrotal hernias (top) and Masson’s trichrome–stained LAMs (bottom). Red arrows point to scrotal hernia, while yellow arrows point to atrophied myofibers. Scale bars: 100 μm. (E) Quantification of the fibrotic area in fEsr1–/– Aromhum, fEsr1+/+ Aromhum, and fEsr1+/+ WT mice (n = 3–4 per group, median ± interquartile range, 1-way ANOVA with Bonferroni multiple comparisons).'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/179000/179137/small/JCI179137.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45857-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179137">Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179137">Text</a></li> <li><a class="button tiny" href="/articles/view/179137/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment that affects a noteworthy 50% of men by age 75 and necessitates surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Using a humanized mouse model that replicates the elevated skeletal muscle tissue estrogen concentrations seen in aging men, we identified estrogen receptor-α (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomics analyses of in vitro LAM fibroblasts from humanized mice unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and present non-surgical avenues for addressing inguinal hernias.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Tanvi Potluri, Tianming You, Ping Yin, John Coon V, Jonah J. Stulberg, Yang Dai, David J. Escobar, Richard L. Lieber, Hong Zhao, Serdar E. Bulun</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/180242">ZDHHC18 promotes renal fibrosis development by regulating HRAS palmitoylation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180242">Di Lu, … , Yuhang Jiang, Qi Wang</a> <a class='hide-for-small show-more' data-reveal-id='article45842-more' href='#'> <div class='article-authors'> Di Lu, … , Yuhang Jiang, Qi Wang </div> </a> <span class='article-published-at'> Published February 6, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e180242. <a href="https://doi.org/10.1172/JCI180242">https://doi.org/10.1172/JCI180242</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180242">Text</a> | <a href="/articles/view/180242/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180242' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180242/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180242/small/JCI180242.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45842-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180242">ZDHHC18 promotes renal fibrosis development by regulating HRAS palmitoylation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180242">Text</a></li> <li><a class="button tiny" href="/articles/view/180242/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Fibrosis is the final common pathway leading to end-stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and the underlying mechanisms remain unclear. In this study, we observed that expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid–induced (FA-induced) renal fibrosis mouse models and was significantly upregulated in fibrotic kidneys of patients with CKD. Functionally, tubule-specific deletion of ZDHHC18 attenuated tubular epithelial cells’ partial epithelial-mesenchymal transition (EMT) and then reduced the production of profibrotic cytokines and alleviated tubulointerstitial fibrosis. In contrast, ZDHHC18 overexpression exacerbated progressive renal fibrosis. Mechanistically, ZDHHC18 catalyzed the palmitoylation of HRAS, which was pivotal for its translocation to the plasma membrane and subsequent activation. HRAS palmitoylation promoted downstream phosphorylation of MEK/ERK and further activated Ras-responsive element–binding protein 1 (RREB1), enhancing SMAD binding to the Snai1 cis-regulatory regions. Taken together, our findings suggest that ZDHHC18 plays a crucial role in renal fibrogenesis and represents a potential therapeutic target for combating kidney fibrosis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Di Lu, Gulibositan Aji, Guanyu Li, Yue Li, Wenlin Fang, Shuai Zhang, Ruiqi Yu, Sheng Jiang, Xia Gao, Yuhang Jiang, Qi Wang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/180981">Human oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180981">Alexandrine Garrigue, … , Chantal Lagresle-Peyrou, Patrick Revy</a> <a class='hide-for-small show-more' data-reveal-id='article45843-more' href='#'> <div class='article-authors'> Alexandrine Garrigue, … , Chantal Lagresle-Peyrou, Patrick Revy </div> </a> <span class='article-published-at'> Published January 23, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e180981. <a href="https://doi.org/10.1172/JCI180981">https://doi.org/10.1172/JCI180981</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180981">Text</a> | <a href="/articles/view/180981/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180981' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180981/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180981/small/JCI180981.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45843-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180981">Human oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180981">Text</a></li> <li><a class="button tiny" href="/articles/view/180981/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukemia inhibitory factor receptor (LIFR). On the other hand, OSMR interacts with IL31RA to form the interleukin-31 receptor. This intricate network of cytokines and receptors makes it difficult to understand the specific function of OSM. While monoallelic loss-of-function (LoF) mutations in OSMR underlie autosomal dominant familial primary localized cutaneous amyloidosis, the in vivo consequences of human OSM deficiency have never been reported so far. Here, we identified 3 young individuals from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Genetic analysis revealed a homozygous 1 base-pair insertion in the sequence of OSM associated with the disease. Structural and functional analyses showed that this variant causes a frameshift that replaces the C-terminal portion of OSM, which contains the FxxK motif that interacts with both OSMR and LIFR, with a neopeptide. The lack of detection and signaling of the mutant OSM suggests a LoF mutation. Analysis of zebrafish models further supported the role of the OSM/OSMR signaling in erythroid progenitor proliferation and neutrophil differentiation. Our study provides the previously uncharacterized and unexpectedly limited in vivo consequence of OSM deficiency in humans.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Alexandrine Garrigue, Laëtitia Kermasson, Sandrine Susini, Ingrid Fert, Christopher B. Mahony, Hanem Sadek, Sonia Luce, Myriam Chouteau, Marina Cavazzana, Emmanuelle Six, Marie-Caroline Le Bousse-Kerdilès, Adrienne Anginot, Jean-Baptiste Souraud, Valérie Cormier-Daire, Marjolaine Willems, Anne Sirvent, Jennifer Russello, Isabelle Callebaut, Isabelle André, Julien Y. Bertrand, Chantal Lagresle-Peyrou, Patrick Revy</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/181136">Post-transfusion activation of coagulation pathways during severe COVID-19 correlates with COVID-19 convalescent plasma antibody profiles</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181136">Svenja Weiss, … , Raymond A. Alvarez, Benjamin K. Chen</a> <a class='hide-for-small show-more' data-reveal-id='article45874-more' href='#'> <div class='article-authors'> Svenja Weiss, … , Raymond A. Alvarez, Benjamin K. Chen </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e181136. <a href="https://doi.org/10.1172/JCI181136">https://doi.org/10.1172/JCI181136</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181136">Text</a> | <a href="/articles/view/181136/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181136' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/181136/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/181000/181136/small/JCI181136.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45874-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181136">Post-transfusion activation of coagulation pathways during severe COVID-19 correlates with COVID-19 convalescent plasma antibody profiles</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181136">Text</a></li> <li><a class="button tiny" href="/articles/view/181136/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from “higher-risk” units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. “Higher-risk” CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with “lower-risk” units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex–activated coagulopathy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Svenja Weiss, Hung-Mo Lin, Eric Acosta, Natalia L. Komarova, Ping Chen, Dominik Wodarz, Ian Baine, Ralf Duerr, Ania Wajnberg, Adrian Gervais, Paul Bastard, Jean-Laurent Casanova, Suzanne A. Arinsburg, Talia H. Swartz, Judith A. Aberg, Nicole M. Bouvier, Sean T.H. Liu, Raymond A. Alvarez, Benjamin K. Chen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/181671">Epigenetic therapy sensitizes anti–PD-1 refractory head and neck cancers to immunotherapy rechallenge</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/181671">Tingting Qin, … , Maureen A. Sartor, Sara I. Pai</a> <a class='hide-for-small show-more' data-reveal-id='article45871-more' href='#'> <div class='article-authors'> Tingting Qin, … , Maureen A. Sartor, Sara I. Pai </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e181671. <a href="https://doi.org/10.1172/JCI181671">https://doi.org/10.1172/JCI181671</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/181671">Text</a> | <a href="/articles/view/181671/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI181671' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/181671/figure/1' ref='group' title='Clinical trial schema and multi-omics datasets included in the study. (A) Participants with locoregional or metastatic head and neck cancer that progressed on prior ICB were enrolled into the clinical trial (www.clinicaltrials.gov; NCT3019003). Participants were treated with escalating doses of a DNA methyltransferase inhibitor, 5-azacytidine (5-aza), and fixed doses of durvalumab (α-PD-L1) and tremelimumab (α-CTLA-4). The primary objective was determining the biologically effective dose (BED) of 5-aza. The secondary outcome was assessing the safety of the combination therapy. (B) Tissue specimens were collected (black arrows) prior to 5-aza treatment (green arrow) and after combination therapy with durvalumab and tremelimumab (purple arrows), which were given at the same time as the second dose of 5-aza (on-treatment).'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/181000/181671/small/JCI181671.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45871-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/181671">Epigenetic therapy sensitizes anti–PD-1 refractory head and neck cancers to immunotherapy rechallenge</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/181671">Text</a></li> <li><a class="button tiny" href="/articles/view/181671/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, the majority of patients are refractory.METHODS In a nonrandomized, open-label Phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5-azacytidine (5-aza) daily for either 5 or 10 days in combination with durvalumab and tremelimumab after progression on ICB. The primary objective was to assess the biologically effective dose of 5-aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety.RESULTS Thirty-eight percent (3 of 8) of participants with evaluable paired tissue samples had a greater-than 2-fold increase from baseline in IFN-γ signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA), 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%), and 58% (7 of 12) of treated participants demonstrated prolonged OS of greater than 12 months.CONCLUSION Our findings suggest that low-dose 5-aza can reprogram systemic host immune responses and the local TME to increase IFN-γ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon ICB rechallenge.TRIAL REGISTRATION ClinicalTrials.gov NCT03019003.FUNDING NIH/NCI P01 CA240239.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Tingting Qin, Austin K. Mattox, Jean S. Campbell, Jong Chul Park, Kee-Young Shin, Shiting Li, Peter M. Sadow, William C. Faquin, Goran Micevic, Andrew J. Daniels, Robert Haddad, Christopher S. Garris, Mikael J. Pittet, Thorsten R. Mempel, Anne ONeill, Maureen A. Sartor, Sara I. Pai</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/183745">Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183745">Deepa Seetharam, … , Defne Bayik, Ashish H. Shah</a> <a class='hide-for-small show-more' data-reveal-id='article45851-more' href='#'> <div class='article-authors'> Deepa Seetharam, … , Defne Bayik, Ashish H. Shah </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e183745. <a href="https://doi.org/10.1172/JCI183745">https://doi.org/10.1172/JCI183745</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183745">Text</a> | <a href="/articles/view/183745/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183745' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183745/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183745/small/JCI183745.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45851-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183745">Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183745">Text</a></li> <li><a class="button tiny" href="/articles/view/183745/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Viral mimicry refers to the activation of innate antiviral immune responses due to the induction of endogenous retroelements (REs). Viral mimicry augments antitumor immune responses and sensitizes solid tumors to immunotherapy. Here, we found that targeting what we believe to be a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression, and poor immune cell infiltration. Targeting ZNF638 decreased H3K9 trimethylation, increased REs, and activated intracellular dsRNA signaling cascades. Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in diverse GBM models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate IFN signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1, and perivascular CD8 cell infiltration, suggesting that dsRNA signaling may mediate response to immunotherapy. Finally, low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in patients with rGBM and patients with melanoma. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Deepa Seetharam, Jay Chandar, Christian K. Ramsoomair, Jelisah F. Desgraves, Alexandra Alvarado Medina, Anna Jane Hudson, Ava Amidei, Jesus R. Castro, Vaidya Govindarajan, Sarah Wang, Yong Zhang, Adam M. Sonabend, Mynor J. Mendez Valdez, Dragan Maric, Vasundara Govindarajan, Sarah R. Rivas, Victor M. Lu, Ritika Tiwari, Nima Sharifi, Emmanuel Thomas, Marcus Alexander, Catherine DeMarino, Kory Johnson, Macarena I. De La Fuente, Ruham Alshiekh Nasany, Teresa Maria Rosaria Noviello, Michael E. Ivan, Ricardo J. Komotar, Antonio Iavarone, Avindra Nath, John Heiss, Michele Ceccarelli, Katherine B. Chiappinelli, Maria E. Figueroa, Defne Bayik, Ashish H. Shah</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/184243">Transcription of hepatitis B surface antigen shifts from cccDNA to integrated HBV DNA during treatment</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/184243">Maraake Taddese, … , Chloe L. Thio, Ashwin Balagopal</a> <a class='hide-for-small show-more' data-reveal-id='article45846-more' href='#'> <div class='article-authors'> Maraake Taddese, … , Chloe L. Thio, Ashwin Balagopal </div> </a> <span class='article-published-at'> Published February 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e184243. <a href="https://doi.org/10.1172/JCI184243">https://doi.org/10.1172/JCI184243</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184243">Text</a> | <a href="/articles/view/184243/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184243' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/184243/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/184000/184243/small/JCI184243.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45846-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184243">Transcription of hepatitis B surface antigen shifts from cccDNA to integrated HBV DNA during treatment</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184243">Text</a></li> <li><a class="button tiny" href="/articles/view/184243/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The cornerstone of functional cure for chronic hepatitis B (CHB) is hepatitis B surface antigen (HBsAg) loss from blood. HBsAg is encoded by covalently closed circular DNA (cccDNA) and HBV DNA integrated into the host genome (iDNA). Nucleos(t)ide analogs (NUCs), the mainstay of CHB treatment, rarely lead to HBsAg loss, which we hypothesized was due to continued iDNA transcription despite decreased cccDNA transcription. To test this, we applied a multiplex droplet digital PCR that identifies the dominant source of HBsAg mRNAs to 3,436 single cells from paired liver biopsies obtained from 10 people with CHB and HIV receiving NUCs. With increased NUC duration, cells producing HBsAg mRNAs shifted their transcription from chiefly cccDNA to chiefly iDNA. This shift was due to both a reduction in the number of cccDNA-containing cells and diminished cccDNA-derived transcription per cell; furthermore, it correlated with reduced detection of proteins deriving from cccDNA but not iDNA. Despite this shift in the primary source of HBsAg, rare cells remained with detectable cccDNA-derived transcription, suggesting a source for maintaining the replication cycle. Functional cure must address both iDNA and residual cccDNA transcription. Further research is required to understand the significance of HBsAg when chiefly derived from iDNA.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Maraake Taddese, Tanner Grudda, Giulia Belluccini, Mark Anderson, Gavin Cloherty, Hyon S. Hwang, Monika Mani, Che-Min Lo, Naomi Esrig, Mark S. Sulkowski, Richard K. Sterling, Yang Zhang, Ruy M. Ribeiro, David L. Thomas, Chloe L. Thio, Ashwin Balagopal</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/184283">High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in high-grade serous ovarian cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/184283">Harun Ozturk, … , Sandra Orsulic, Mazhar Adli</a> <a class='hide-for-small show-more' data-reveal-id='article45858-more' href='#'> <div class='article-authors'> Harun Ozturk, … , Sandra Orsulic, Mazhar Adli </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e184283. <a href="https://doi.org/10.1172/JCI184283">https://doi.org/10.1172/JCI184283</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184283">Text</a> | <a href="/articles/view/184283/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184283' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/184283/figure/1' ref='group' title='PRMT5 is highly expressed in OC and associated with poor patient survival. (A) Box plots display mean PRMT5 mRNA expression across 32 different human cancer types. The green arrow indicates PRMT5 expression in OC, and the blue line indicates mean PMRT5 expression in OC tumors. (B) Density plots compare PRMT5 expression between ovary versus OSC (left) and fallopian tube (FT) versus OSC (right). OSC, ovarian serous cystadenocarcinoma. (C) The Kaplan-Meier curve shows progression-free survival between HGSOC patients with tumors expressing low or high levels of PRMT5. The P value was determined by the log-rank (Mantel-Cox) test. (D) Ranked correlation of genes with PRMT5 expression based on TCGA-HGSOC dataset. Red circles highlight genes whose expression showed a significant positive correlation with PRMT5 expression (n = 526, FDR >0.0001, Spearman correlation >0.5). (E) Dot plot illustrating the associated GO terms for the genes identified in D.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/184000/184283/small/JCI184283.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45858-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184283">High PRMT5 levels, maintained by KEAP1 inhibition, drive chemoresistance in high-grade serous ovarian cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184283">Text</a></li> <li><a class="button tiny" href="/articles/view/184283/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyltransferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). PRMT5 levels and its enzymatic activity are induced in a platinum-resistant (Pt-resistant) state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed unbiased CRISPR screening. We identified Kelch-like ECH-associated protein 1 (KEAP1) as a top-scoring negative regulator of PRMT5. Our mechanistic studies show that KEAP1 directly interacted with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. At the genomic level, ChIP studies showed that elevated PRMT5 directly interacted with the promoters of stress response genes and positively regulated their transcription. Combined PRMT5 inhibition with Pt resulted in synergistic cellular cytotoxicity in vitro and reduced tumor growth in vivo in Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Harun Ozturk, Fidan Seker-Polat, Neda Abbaszadeh, Yasemin Kingham, Sandra Orsulic, Mazhar Adli</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/184740">ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/184740">Aaron L. Slusher, … , Gerald I. Shulman, Sonia Caprio</a> <a class='hide-for-small show-more' data-reveal-id='article45853-more' href='#'> <div class='article-authors'> Aaron L. Slusher, … , Gerald I. Shulman, Sonia Caprio </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e184740. <a href="https://doi.org/10.1172/JCI184740">https://doi.org/10.1172/JCI184740</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/184740">Text</a> | <a href="/articles/view/184740/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI184740' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/184740/figure/1' ref='group' title='In response to the HEC, no differences in plasma glucose were observed between groups. (A) Plasma insulin concentrations were greater in participants with IR compared with those with IS throughout the HEC, whereas relative increases in plasma insulin concentrations (compared with time point 0) were similar in both groups (B and C). Peripheral insulin sensitivity (M; adjusted for plasma insulin concentrations) during the second step of the HEC was lower in participants with IR compared with those with IS (D). Insulin-induced suppression of plasma non esterified fatty acid (NEFA) concentrations tended to be lower in participants with IR compared with those with IS during the first step of the HEC and were suppressed similarly in both groups throughout the HEC (E and F). Glycerol turnover rates reached steady state during each step of the HEC in both participant groups, and glycerol turnover rates were lower in participants with IR compared with those with IS throughout step 1 of the HEC (G). Consistent with these findings, insulin-induced suppression of glycerol turnover during the first step of the HEC was lower in participants with IR compared with those with IS (H). Finally, AT-IR was elevated in participants with IR compared with those with IS at the initiation of HEC and remained elevated during the first step. Similarly, the level of suppression tended to be lower in participants with IR compared with those with IS before near complete suppression was observed in both participant groups (I and J). Differences in continuous data were determined by Student’s t test or Mann–Whitney U analysis, and the impact of time on plasma protein and indices of insulin resistance in response to HEC tests were examined by repeated measures ANOVA. P values less than 0.05 were considered significant. Data are presented as means ± SD or IQR (25%, 75%). *P > 0.05.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/184000/184740/small/JCI184740.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45853-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/184740">ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/184740">Text</a></li> <li><a class="button tiny" href="/articles/view/184740/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND This study examined the underlying cellular mechanisms associated with insulin resistance (IR) and metabolic disease risk within subcutaneous adipose tissue (SAT) in youth with obesity and IR compared with those without IR.METHODS Thirteen adolescents who were insulin sensitive (IS) and 17 adolescents with IR and obesity underwent a 3-hour oral glucose tolerance test and MRI to measure abdominal fat distribution and liver fat content. Lipolysis was determined by glycerol turnover ([2H5]-glycerol infusion) and adipose triglyceride lipase (ATGL) phosphorylation (Western blot) from SAT samples biopsied prior to and 30-minutes following insulin infusion during a hyperinsulinemic-euglycemic clamp (HEC).RESULTS Glycerol turnover suppression during the HEC (first step) was lower in participants with IR compared with those with IS. Prior to insulin infusion, activated ATGL (reflected by the p-ATGL (Ser406)-to-ATGL ratio) was greater in participants with IR compared with those with IS and suppressed in response to a 30-minute insulin exposure in participants with IS, but not in those with IR. Lastly, greater ATGL inactivation is associated with greater glycerol suppression and lower liver fat.CONCLUSIONS Insulin-mediated inhibition of adipose tissue lipolysis via ATGL is dysregulated among adolescents with IR compared with those with IS, thereby serving as a vital mechanism linking glucose and insulin dysregulation and ectopic lipid storage within the liver.FUNDING This work was supported by funding from the NIH (R01-HD028016-25A1, T32- DK-007058, R01-DK124272, RO1-DK119968, R01MD015974, RO1-DK113984, P3-DK045735, RO1-DK133143, and RC2-DK120534) and the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Aaron L. Slusher, Nicola Santoro, Alla Vash-Margita, Alfonso Galderisi, Pamela Hu, Fuyuze Tokoglu, Zhongyao Li, Elena Tarabra, Jordan Strober, Daniel F. Vatner, Gerald I. Shulman, Sonia Caprio</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/185149">KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185149">Fang Yu, … , Tongjun Gu, Zhijian Qian</a> <a class='hide-for-small show-more' data-reveal-id='article45850-more' href='#'> <div class='article-authors'> Fang Yu, … , Tongjun Gu, Zhijian Qian </div> </a> <span class='article-published-at'> Published February 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e185149. <a href="https://doi.org/10.1172/JCI185149">https://doi.org/10.1172/JCI185149</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185149">Text</a> | <a href="/articles/view/185149/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185149' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185149/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185149/small/JCI185149.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45850-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185149">KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185149">Text</a></li> <li><a class="button tiny" href="/articles/view/185149/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Constitutively active mutations of KRAS are prevalent in non–small cell lung cancer (NSCLC). However, the relationship between these mutations and resistance to platinum-based chemotherapy and the underlying mechanisms remain elusive. In this study, we demonstrate that KRAS mutants confer resistance to platinum in NSCLC. Mechanistically, KRAS mutants mediate platinum resistance in NSCLC cells by activating ERK/JNK signaling, which inhibits AlkB homolog 5 (ALKBH5) N6-methyladenosine (m6A) demethylase activity by regulating posttranslational modifications (PTMs) of ALKBH5. Consequently, the KRAS mutant leads to a global increase in m6A methylation of mRNAs, particularly damage-specific DNA-binding protein 2 (DDB2) and XPC, which are essential for nucleotide excision repair. This methylation stabilized the mRNA of these 2 genes, thus enhancing NSCLC cells’ capability to repair platinum-induced DNA damage and avoid apoptosis, thereby contributing to drug resistance. Furthermore, blocking KRAS-mutant–induced m6A methylation, either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by inhibiting methyltransferase-like 3 (METTL3) pharmacologically, significantly sensitizes KRAS-mutant NSCLC cells to platinum drugs in vitro and in vivo. Collectively, our study uncovers a mechanism that mediates KRAS-mutant–induced chemoresistance in NSCLC cells by activating DNA repair through the modulation of the ERK/JNK/ALKBH5 PTM-induced m6A modification in DNA damage repair–related genes.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Fang Yu, Shikan Zheng, Chunjie Yu, Sanhui Gao, Zuqi Shen, Rukiye Nar, Zhexin Liu, Shuang Huang, Lizi Wu, Tongjun Gu, Zhijian Qian</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/185217">Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185217">Jun Inamo, … , Deepak A. Rao, Fan Zhang</a> <a class='hide-for-small show-more' data-reveal-id='article45855-more' href='#'> <div class='article-authors'> Jun Inamo, … , Deepak A. Rao, Fan Zhang </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e185217. <a href="https://doi.org/10.1172/JCI185217">https://doi.org/10.1172/JCI185217</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185217">Text</a> | <a href="/articles/view/185217/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185217' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185217/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185217/small/JCI185217.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45855-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185217">Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185217">Text</a></li> <li><a class="button tiny" href="/articles/view/185217/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Rheumatoid arthritis (RA) is a systemic autoimmune disease currently with no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in at-risk populations prior to clinical onset is crucial to establishing effective prevention strategies. Here, we applied multimodal single-cell technologies (mass cytometry and CITE-Seq) to characterize the immunophenotypes in blood from at-risk individuals (ARIs) identified through the presence of serum antibodies against citrullinated protein antigens (ACPAs) and/or first-degree relative (FDR) status, as compared with patients with established RA and people in a healthy control group. We identified significant cell expansions in ARIs compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5lo naive B cell population was expanded in ACPA-positive FDRs. Further, we uncovered the molecular phenotype of the CCR2+CD4+ T cells, expressing high levels of Th17- and Th22-related signature transcripts including CCR6, IL23R, KLRB1, CD96, and IL22. Our integrated study provides a promising approach to identify targets to improve prevention strategy development for RA.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jun Inamo, Joshua Keegan, Alec Griffith, Tusharkanti Ghosh, Alice Horisberger, Kaitlyn Howard, John F. Pulford, Ekaterina Murzin, Brandon Hancock, Salina T. Dominguez, Miranda G. Gurra, Siddarth Gurajala, Anna Helena Jonsson, Jennifer A. Seifert, Marie L. Feser, Jill M. Norris, Ye Cao, William Apruzzese, S. Louis Bridges, Vivian P. Bykerk, Susan Goodman, Laura T. Donlin, Gary S. Firestein, Joan M. Bathon, Laura B. Hughes, Andrew Filer, Costantino Pitzalis, Jennifer H. Anolik, Larry Moreland, Nir Hacohen, Joel M. Guthridge, Judith A. James, Carla M. Cuda, Harris Perlman, Michael B. Brenner, Soumya Raychaudhuri, Jeffrey A. Sparks, The Accelerating Medicines Partnership RA/SLE Network, V. Michael Holers, Kevin D. Deane, James Lederer, Deepak A. Rao, Fan Zhang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/185278">Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185278">Shihui Shen, … , Lei Li, Huaiyu Yang</a> <a class='hide-for-small show-more' data-reveal-id='article45859-more' href='#'> <div class='article-authors'> Shihui Shen, … , Lei Li, Huaiyu Yang </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e185278. <a href="https://doi.org/10.1172/JCI185278">https://doi.org/10.1172/JCI185278</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185278">Text</a> | <a href="/articles/view/185278/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185278' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185278/figure/1' ref='group' title='REGγ is overexpressed in KRAS-mutant cancers and correlated with specific KRAS-mutant subtypes. (A) Heatmap showing markedly expressed proteins (P < 0.05) between HCT8-KRASWT and HCT8-KRASG13D groups (n = 3). (B) Volcano plot showing markedly expressed proteins (P < 0.05, fold change <0.8 or fold change >1.5) between HCT8-KRASWT and HCT8-KRASG13D groups (n = 3). (C) Violin plots depicting distribution of REGγ expression level in normal tissues (n = 741), KRAS-WT (wild-type) cancer tissues (n = 8,661), and KRAS-MUT (mutant) cancer tissues (n = 769). Datasets of pan-cancer were derived from TCGA. ***P < 0.001. (D) Representative IHC images of REGγ expression in KRAS-WT and KRAS-MUT colon cancer tissues. Bottom: A higher magnification of sections. Scale bars: 20 μm (top), 10 μm (bottom). (E) REGγ staining scores are shown. Each value represents mean ± SEM (n = 3). *P < 0.05, **P < 0.01, ****P < 0.0001. (F) Quantitative analysis of REGγ IHC staining for adjacent normal tissue (n = 20), KRAS-WT (n = 14), and KRAS-MUT (n = 10). IHC signals were classified as negative, weak, moderate, or strong. (G) Western blot images showing high REGγ expression in KRAS-MUT lung cancer tissues. Each lane represents a tissue sample from an individual patient. (H and I) REGγ mRNA (H) and protein (I) levels were upregulated with the overexpression of KRAS mutants. A panel of KRAS mutant plasmids (KRASG12C, KRASG12D, KRASG12S, KRASG12V, and KRASG13D) in was transfected into HCT8 cells for 48 hours. Each value represents mean ± SEM (n = 3). ****P < 0.0001; P values were measured by 1-way ANOVA with Tukey’s multiple-comparison test.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185278/small/JCI185278.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45859-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185278">Targeting ubiquitin-independent proteasome with small molecule increases susceptibility in pan-KRAS–mutant cancer models</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185278">Text</a></li> <li><a class="button tiny" href="/articles/view/185278/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Despite advances in the development of direct KRAS inhibitors, KRAS-mutant cancers continue to exhibit resistance to the currently available therapies. Here, we identified REGγ as a mutant KRAS–associated factor that enhanced REGγ transcription through the KRAS intermediate NRF2, suggesting that the REGγ-proteasome is a potential target for pan-KRAS inhibitor development. We elucidated a mechanism involving the KRAS/NRF2/REGγ regulatory axis, which links activated KRAS to the ATP- and ubiquitin-independent proteasome. We subsequently developed RLY01, a REGγ-proteasome inhibitor that effectively suppressed tumor growth in KRAS-mutant cancer models and lung cancer organoids. Notably, the combination of RLY01 and the KRASG12C inhibitor AMG510 exhibited enhanced antitumor efficacy in KRASG12C cancer cells. Collectively, our data support the hypothesis that KRAS mutations enhance the capacity of the REGγ-proteasome by increasing REGγ expression, highlighting the potential of ubiquitin-independent proteasome inhibition as a therapeutic approach for pan-KRAS–mutant cancers.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Shihui Shen, Qiansen Zhang, Yuhan Wang, Hui Chen, Shuangming Gong, Yun Liu, Conghao Gai, Hansen Chen, Enhao Zhu, Bo Yang, Lin Liu, Siyuan Cao, Mengting Zhao, Wenjie Ren, Mengjuan Li, Zhuoya Peng, Lu Zhang, Shaoying Zhang, Juwen Shen, Bianhong Zhang, Patrick K.H. Lee, Kun Li, Lei Li, Huaiyu Yang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/185340">Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185340">Yu-Sheng Yeh, … , Irfan J. Lodhi, Babak Razani</a> <a class='hide-for-small show-more' data-reveal-id='article45866-more' href='#'> <div class='article-authors'> Yu-Sheng Yeh, … , Irfan J. Lodhi, Babak Razani </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e185340. <a href="https://doi.org/10.1172/JCI185340">https://doi.org/10.1172/JCI185340</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185340">Text</a> | <a href="/articles/view/185340/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185340' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185340/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185340/small/JCI185340.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45866-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185340">Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185340">Text</a></li> <li><a class="button tiny" href="/articles/view/185340/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yu-Sheng Yeh, Trent D. Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J. Schopfer, Adam C. Straub, Jaehyung Cho, Irfan J. Lodhi, Babak Razani</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/185443">A conserved human CD4<sup>+</sup> T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185443">Yuki Sakai, … , Go Hirai, Sho Yamasaki</a> <a class='hide-for-small show-more' data-reveal-id='article45873-more' href='#'> <div class='article-authors'> Yuki Sakai, … , Go Hirai, Sho Yamasaki </div> </a> <span class='article-published-at'> Published December 24, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e185443. <a href="https://doi.org/10.1172/JCI185443">https://doi.org/10.1172/JCI185443</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185443">Text</a> | <a href="/articles/view/185443/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185443' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185443/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185443/small/JCI185443.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45873-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185443">A conserved human CD4<sup>+</sup> T cell subset recognizing the mycobacterial adjuvant trehalose monomycolate</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185443">Text</a></li> <li><a class="button tiny" href="/articles/view/185443/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Mycobacterium tuberculosis causes human tuberculosis (TB). As mycobacteria are protected by a thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors. Although a few mycobacterial lipid antigens activate unconventional T cells, the antigenicity of most adjuvantic lipids is unknown. Here, we identified that trehalose monomycolate (TMM), an abundant mycobacterial adjuvant, activated human T cells bearing a unique αβ T cell receptor (αβTCR). This recognition was restricted by CD1b, a monomorphic antigen-presenting molecule conserved in primates but not mice. Single-cell TCR-RNA-Seq using newly established CD1b-TMM tetramers revealed that TMM-specific T cells were present as CD4+ effector memory T cells in the periphery of uninfected donors but expressed IFN-γ, TNF, and anti-mycobacterial effectors upon TMM stimulation. TMM-specific T cells were detected in cord blood and PBMCs of donors without bacillus Calmette-Guérin vaccination but were expanded in patients with active TB. A cryo-electron microscopy study of CD1b-TMM-TCR complexes revealed unique antigen recognition by conserved features of TCRs, positively charged CDR3α, and long CDR3β regions. These results indicate that humans have a commonly shared and preformed CD4+ T cell subset recognizing a typical mycobacterial adjuvant as an antigen. Furthermore, the dual role of TMM justifies reconsideration of the mechanism of action of adjuvants.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yuki Sakai, Minori Asa, Mika Hirose, Wakana Kusuhara, Nagatoshi Fujiwara, Hiroto Tamashima, Takahiro Ikazaki, Shiori Oka, Kota Kuraba, Kentaro Tanaka, Takashi Yoshiyama, Masamichi Nagae, Yoshihiko Hoshino, Daisuke Motooka, Ildiko Van Rhijn, Xiuyuan Lu, Eri Ishikawa, D. Branch Moody, Takayuki Kato, Shinsuke Inuki, Go Hirai, Sho Yamasaki</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/186388">A whole-body imaging technique for tumor-specific diagnostics and screening of B7H3-targeted therapies</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186388">Lei Xia, … , Hua Zhu, Zhi Yang</a> <a class='hide-for-small show-more' data-reveal-id='article45872-more' href='#'> <div class='article-authors'> Lei Xia, … , Hua Zhu, Zhi Yang </div> </a> <span class='article-published-at'> Published January 23, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e186388. <a href="https://doi.org/10.1172/JCI186388">https://doi.org/10.1172/JCI186388</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186388">Text</a> | <a href="/articles/view/186388/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186388' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186388/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186388/small/JCI186388.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45872-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186388">A whole-body imaging technique for tumor-specific diagnostics and screening of B7H3-targeted therapies</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186388">Text</a></li> <li><a class="button tiny" href="/articles/view/186388/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND B7H3, also known as CD276, is notably overexpressed in various malignant tumor cells in humans, with extremely high expression rates. The development of a radiotracer that targets B7H3 may provide a universal tumor-specific imaging agent and allow the noninvasive assessment of the whole-body distribution of B7H3-expressing lesions.METHODS We enhanced and optimized the structure of an affibody (ABY) that targets B7H3 to create the radiolabeled radiotracer [68Ga]Ga-B7H3-BCH, and then, we conducted both foundational experiments and clinical translational studies.RESULTS [68Ga]Ga-B7H3-BCH exhibited high affinity (equilibrium dissociation constant [KD] = 4.5 nM), and it was taken up in large amounts by B7H3-transfected cells (A549CD276 and H1975CD276 cells); these phenomena were inhibited by unlabeled precursors. Moreover, PET imaging of multiple xenograft models revealed extensive [68Ga]Ga-B7H3-BCH uptake by tumors. In a clinical study including 20 patients with malignant tumors, the [68Ga]Ga-B7H3-BCH signal aggregated in both primary and metastatic lesions, surpassing fluorine-18 fluorodeoxyglucose (18F-FDG) in overall diagnostic efficacy for tumors (85.0% vs. 81.7%), including differentiated hepatocellular and metastatic gastric cancers. A strong correlation between B7H3 expression and [68Ga]Ga-B7H3-BCH uptake in tumors was observed, and B7H3 expression was detected with 84.38% sensitivity and 100% specificity when a maximum standardized uptake value (SUVmax) of 3.85 was set as the cutoff value. Additionally, B7H3-specific PET imaging is expected to predict B7H3 expression levels in tumor cells, intratumoral stroma, and peritumoral tissues.CONCLUSION In summary, [68Ga]Ga-B7H3-BCH has potential for the noninvasive identification of B7H3 expression in systemic lesions in patients with malignant tumors. This agent has prospects for improving pretreatment evaluation, predicting therapeutic responses, and monitoring resistance to therapy in patients with malignancies.TRIAL REGISTRATION ClinicalTrials.gov NCT06454955.FUNDING This research was financially supported by the Natural Science Foundation of Beijing Municipality (no. 7242266), the National Natural Science Foundation of China (no. 82202201), and the Young Elite Scientists Sponsorship Program by China Association for Science and Technology (CAST) (no. YESS20220230).</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Lei Xia, Yan Wu, Yanan Ren, Zhen Wang, Nina Zhou, Wenyuan Zhou, Lixin Zhou, Ling Jia, Chengxue He, Xiangxi Meng, Hua Zhu, Zhi Yang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/186889">Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186889">Maude A. Liegeois, … , Tillie-Louise Hackett, John V. Fahy</a> <a class='hide-for-small show-more' data-reveal-id='article45862-more' href='#'> <div class='article-authors'> Maude A. Liegeois, … , Tillie-Louise Hackett, John V. Fahy </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e186889. <a href="https://doi.org/10.1172/JCI186889">https://doi.org/10.1172/JCI186889</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186889">Text</a> | <a href="/articles/view/186889/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186889' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186889/figure/1' ref='group' title='Selection of lung tissues from patients with asthma, patients with COPD, and lung disease–free individuals acting as controls. The flow diagram shows how tissues were selected from the James Hogg Lung Biobank at the University of British Columbia. It further illustrates the screening of lung tissue sections for mucus-plugged and unplugged airways and the number of samples analyzed by histology, immunofluorescence, and imaging mass cytometry.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186889/small/JCI186889.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45862-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186889">Cellular and molecular features of asthma mucus plugs provide clues about their formation and persistence</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186889">Text</a></li> <li><a class="button tiny" href="/articles/view/186889/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Mucus plugs form in acute asthma and persist in chronic disease. Although eosinophils are implicated in mechanisms of mucus pathology, many mechanistic details about mucus plug formation and persistence in asthma are unknown.METHODS Using histology and spatial, single-cell proteomics, we characterized mucus-plugged airways from nontransplantable donor lungs of 14 patients with asthma (9 with fatal asthma and 5 with nonfatal asthma) and individuals acting as controls (10 with chronic obstructive pulmonary disease and 14 free of lung disease). Additionally, we used an airway epithelial cell–eosinophil (AEC-eosinophil) coculture model to explore how AEC mucus affects eosinophil degranulation.RESULTS Asthma mucus plugs were tethered to airways showing infiltration with innate lymphoid type 2 cells and hyperplasia of smooth muscle cells and MUC5AC-expressing goblet cells. Asthma mucus plugs were infiltrated with immune cells that were mostly dual positive for eosinophil peroxidase (EPX) and neutrophil elastase, suggesting that neutrophils internalize EPX from degranulating eosinophils. Indeed, eosinophils exposed to mucus from IL-13–activated AECs underwent CD11b- and glycan-dependent cytolytic degranulation. Dual-positive granulocytes varied in frequency in mucus plugs. Whereas paucigranulocytic plugs were MUC5AC rich, granulocytic plugs had a mix of MUC5AC, MUC5B, and extracellular DNA traps. Paucigranulocytic plugs occurred more frequently in (acute) fatal asthma and granulocytic plugs predominated in (chronic) nonfatal asthma.CONCLUSION Together, our data suggest that mucin-rich mucus plugs in fatal asthma form because of acute goblet cell degranulation in remodeled airways and that granulocytic mucus plugs in chronic asthma persist because of a sustaining niche characterized by epithelial cell–mucin-granulocyte cross-talk.FUNDING NIH grants HL080414, HL107202, and AI077439.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Maude A. Liegeois, Aileen Hsieh, May Al-Fouadi, Annabelle R. Charbit, Chen Xi Yang, Tillie-Louise Hackett, John V. Fahy</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='corrigendum'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel5' name='corrigendum'> <strong></strong> <span class='toggle-icon'></span> Corrigenda </a> <div class='content active' id='panel5'> <div class='row'> <div class='small-12 columns'> <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/191396">The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191396">Xiang Chen, … , Seon Hee Chang, Chen Dong</a> <a class='hide-for-small show-more' data-reveal-id='article45867-more' href='#'> <div class='article-authors'> Xiang Chen, … , Seon Hee Chang, Chen Dong </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e191396. <a href="https://doi.org/10.1172/JCI191396">https://doi.org/10.1172/JCI191396</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191396">Text</a> | <a href="/articles/view/191396/pdf">PDF</a> | <a href="/articles/view/147566">Amended Article</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191396' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45867-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191396">The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191396">Text</a></li> <li><a class="button tiny" href="/articles/view/191396/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>Xiang Chen, Jia Hu, Yunfei Wang, Younghee Lee, Xiaohong Zhao, Huiping Lu, Gengzhen Zhu, Hui Wang, Yu Jiang, Fan Liu, Yongzhen Chen, Byung-Seok Kim, Qinghua Zhou, Xindong Liu, Xiaohu Wang, Seon Hee Chang, Chen Dong</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <div class='row'> <div class='small-12 columns'> <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/192014">Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/192014">Chester J. Kao, … , Won Jin Ho, Mark Yarchoan</a> <a class='hide-for-small show-more' data-reveal-id='article45875-more' href='#'> <div class='article-authors'> Chester J. Kao, … , Won Jin Ho, Mark Yarchoan </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e192014. <a href="https://doi.org/10.1172/JCI192014">https://doi.org/10.1172/JCI192014</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/192014">Text</a> | <a href="/articles/view/192014/pdf">PDF</a> | <a href="/articles/view/176567">Amended Article</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI192014' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45875-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/192014">Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/192014">Text</a></li> <li><a class="button tiny" href="/articles/view/192014/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>Chester J. Kao, Soren Charmsaz, Stephanie L. Alden, Madelena Brancati, Howard L. Li, Aanika Balaji, Kabeer Munjal, Kathryn Howe, Sarah Mitchell, James Leatherman, Ervin Griffin, Mari Nakazawa, Hua-Ling Tsai, Ludmila Danilova, Chris Thoburn, Jennifer Gizzi, Nicole E. Gross, Alexei Hernandez, Erin M. Coyne, Sarah M. Shin, Jayalaxmi Suresh Babu, George W. Apostol, Jennifer Durham, Brian J. Christmas, Maximilian F. Konig, Evan J. Lipson, Jarushka Naidoo, Laura C. Cappelli, Aliyah Pabani, Yasser Ged, Marina Baretti, Julie Brahmer, Jean Hoffman-Censits, Tanguy Y. Seiwert, Rachel Garonce-Hediger, Aditi Guha, Sanjay Bansal, Laura Tang, Elizabeth M. Jaffee, G. 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