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<h3>Review</h3> <div class='row'> <div class='small-10 medium-7 large-5 small-centered columns'> <ul class='tabs row' data-tab> <li class='tab-title small-6 centered active'> <a href='#articles'>241 Articles</a> </li> <li class='tab-title small-6 centered '> <a href='#posts'>0 Posts</a> </li> </ul> </div> </div> <div class='tabs-content'> <div class='content active' id='articles'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/2?content=articles&page=2">2</a></li> <li><a href="/tags/2?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/2?content=articles&page=24">24</a></li> <li><a href="/tags/2?content=articles&page=25">25</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/2?content=articles&page=2">Next →</a></li></ul></div> </div> </div> <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> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/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> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/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> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185102">Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185102">Carina Seah, … , Laura M. Huckins, Kristen J. Brennand</a> <a class='hide-for-small show-more' data-reveal-id='article45815-more' href='#'> <div class='article-authors'> Carina Seah, … , Laura M. Huckins, Kristen J. Brennand </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e185102. <a href="https://doi.org/10.1172/JCI185102">https://doi.org/10.1172/JCI185102</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185102">Text</a> | <a href="/articles/view/185102/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/JCI185102' 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/185102/figure/1' ref='group' title='Schematic of scientific rationale and methods to understanding gene × environment interactions in post-traumatic stress disorder. (A) Post-traumatic stress disorder (PTSD) is a heterogeneous disorder characterized by individualized patterns of risk requiring individualized interventions, despite convergence on a common phenotype. (B) PTSD is the result of both genetic and environmental risk factors as well as the impact of trauma. The neurobiology of each of these risk factors should be characterized independently and jointly in order to advance our understanding of PTSD pathophysiology. This includes understanding the biological impact of the underlying socioeconomic and home environment, delineating the long-term encoding of traumatic exposures on the brain, and identifying how genetic risk functionally affects brain neurobiology. The functional elucidation of genetic hits will require linking genetics to downstream-omics, such as transcriptomics and epigenetics, exploring genetic models of disorder risk, genetics-matched electronic health records, and clinical and imaging data.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185102/small/JCI185102.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45815-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185102">Implications of gene × environment interactions in post-traumatic stress disorder risk and treatment</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185102">Text</a></li> <li><a class="button tiny" href="/articles/view/185102/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Exposure to traumatic stress is common in the general population. Variation in the brain’s molecular encoding of stress potentially contributes to the heterogeneous clinical outcomes in response to traumatic experiences. For instance, only a minority of those exposed to trauma will develop post-traumatic stress disorder (PTSD). Risk for PTSD is at least partially heritable, with a growing number of genetic factors identified through GWAS. A major limitation of genetic studies is that they capture only the genetic component of risk, whereas PTSD by definition requires an environmental traumatic exposure. Furthermore, the extent, timing, and type of trauma affects susceptibility. Here, we discuss the molecular mechanisms of PTSD risk together with gene × environment interactions, with a focus on how either might inform genetic screening for individuals at high risk for disease, reveal biological mechanisms that might one day yield novel therapeutics, and impact best clinical practices even today. To close, we discuss the interaction of trauma with sex, gender, and race, with a focus on the implications for treatment. Altogether, we suggest that predicting, preventing, and treating PTSD will require integrating both genotypic and environmental information.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Carina Seah, Anne Elizabeth Sidamon-Eristoff, Laura M. Huckins, Kristen J. Brennand</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/187996">Bacteriophage therapy for multidrug-resistant infections: current technologies and therapeutic approaches</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/187996">Minyoung Kevin Kim, … , Paul L. Bollyky, Jessica C. Sacher</a> <a class='hide-for-small show-more' data-reveal-id='article45820-more' href='#'> <div class='article-authors'> Minyoung Kevin Kim, … , Paul L. Bollyky, Jessica C. Sacher </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e187996. <a href="https://doi.org/10.1172/JCI187996">https://doi.org/10.1172/JCI187996</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/187996">Text</a> | <a href="/articles/view/187996/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/JCI187996' 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/187996/figure/1' ref='group' title='Development and implementation of phage therapy. (A) A summary of the key steps in phage therapy development and clinical implementation. The process typically begins with phage identification and selection, including phage bank establishment (sourcing, storage, and characterization of phages), followed by susceptibility testing (using spot tests, plaque assays, efficiency of plating [EOP] assays, and growth kinetics studies). The manufacturing phase involves phage propagation (using selected bacterial strains in liquid- or solid-based systems) and rigorous purification with quality control measures (including endotoxin removal and standardized quality protocols). The therapeutic administration phase encompasses clinical applications (considering various administration routes and dosing strategies) and therapeutic monitoring (tracking treatment efficacy, patient response, and monitoring for potential resistance development and adverse events). Note that these steps are not universally applied in all phage therapies. (B) Phage therapy approaches can be personalized to individual patients (patient-specific phage preparation), fixed (preformulated), or administered as a hybrid of the two approaches. The hybrid model represents an intermediate approach combining elements of both personalized and fixed phage therapy strategies.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/187000/187996/small/JCI187996.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45820-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/187996">Bacteriophage therapy for multidrug-resistant infections: current technologies and therapeutic approaches</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/187996">Text</a></li> <li><a class="button tiny" href="/articles/view/187996/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Bacteriophage (phage) therapy has emerged as a promising solution to combat the growing crisis of multidrug-resistant (MDR) infections. There are several international centers actively engaged in implementation of phage therapy, and recent case series have reported encouraging success rates in patients receiving personalized, compassionate phage therapy for difficult-to-treat infections. Nonetheless, substantial hurdles remain in the way of more widespread adoption and more consistent success. This Review offers a comprehensive overview of current phage therapy technologies and therapeutic approaches. We first delineate the common steps in phage therapy development, from phage bank establishment to clinical administration, and examine the spectrum of therapeutic approaches, from personalized to fixed phage cocktails. Using the framework of a conventional drug development pipeline, we then identify critical knowledge gaps in areas such as cocktail design, formulation, pharmacology, and clinical trial design. We conclude that, while phage therapy holds promise, a structured drug development pipeline and sustained government support are crucial for widespread adoption of phage therapy for MDR infections.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Minyoung Kevin Kim, Gina A. Suh, Grace D. Cullen, Saumel Perez Rodriguez, Tejas Dharmaraj, Tony Hong Wei Chang, Zhiwei Li, Qingquan Chen, Sabrina I. Green, Rob Lavigne, Jean-Paul Pirnay, Paul L. Bollyky, Jessica C. Sacher</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186702">Basic science and translational implications of current knowledge on neuroendocrine tumors</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186702">Lynnette Fernandez-Cuesta, … , Thomas Walter, Matthieu Foll</a> <a class='hide-for-small show-more' data-reveal-id='article45822-more' href='#'> <div class='article-authors'> Lynnette Fernandez-Cuesta, … , Thomas Walter, Matthieu Foll </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e186702. <a href="https://doi.org/10.1172/JCI186702">https://doi.org/10.1172/JCI186702</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186702">Text</a> | <a href="/articles/view/186702/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/JCI186702' 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/186702/figure/1' ref='group' title='Epidemiology of NETs. (A) Anatomic sites where NETs originate. (B) Temporal trend of NET incidence in the United States from the Surveillance, Epidemiology, and End Results (SEER; https://seer.cancer.gov/) database (data from ref. 7, Supplemental Table 1). (C) Five-year survival rate of patients with NETs with distant metastases as a function of anatomic site (data from ref. 7, Supplemental Table 3).'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186702/small/JCI186702.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45822-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186702">Basic science and translational implications of current knowledge on neuroendocrine tumors</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186702">Text</a></li> <li><a class="button tiny" href="/articles/view/186702/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Neuroendocrine tumors (NETs) are a diverse group of malignancies that can occur in various organs, with a notable prevalence in the lungs and gastrointestinal tract, which are the focus of this Review. Although NETs are rare in individual organs, their incidence has increased over recent decades, highlighting the urgent need for current classification systems to evolve by incorporating recent advances in the understanding of NET biology. Several omics studies have revealed molecular subtypes, which, when integrated into existing classification frameworks, may provide more clinically relevant insights for patients with NETs. This Review examines recent progress in elucidating the biology of NETs, with a particular emphasis on the tumor microenvironment and cells of origin. The existence of different cells of origin, which may contribute to distinct molecular groups, along with profiles of immune infiltration — despite being generally low — could explain the emergence of more aggressive cases and the potential for metastatic progression. Given the molecular heterogeneity of NETs and the diversity of their microenvironments and different cells of origin, there is an urgent need to develop morphomolecular classification systems. Such systems would make it possible to better characterize tumor progression, identify new therapeutic targets, and, ultimately, guide the development of personalized therapies.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Lynnette Fernandez-Cuesta, Nicolas Alcala, Emilie Mathian, Jules Derks, Chrissie Thirlwell, Talya Dayton, Ilaria Marinoni, Aurel Perren, Thomas Walter, Matthieu Foll</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185218">T cells in cardiac health and disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185218">Pilar Martín, Francisco Sánchez-Madrid</a> <a class='hide-for-small show-more' data-reveal-id='article45696-more' href='#'> <div class='article-authors'> Pilar Martín, Francisco Sánchez-Madrid </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e185218. <a href="https://doi.org/10.1172/JCI185218">https://doi.org/10.1172/JCI185218</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185218">Text</a> | <a href="/articles/view/185218/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/JCI185218' 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/185218/figure/1' ref='group' title='The role of CD69 in various cardiovascular pathologies. (A) oxLDL binding to the CD69 receptor regulates NR4A expression in T cells, which has been shown to promote Treg differentiation. In mice, CD69 deficiency has been linked to altered NR4A1 expression, Treg–Th17 cell imbalance, and exacerbation of atherosclerosis. oxLDL/CD69 signaling also regulates PD-1 expression in CD4+ T cells, which is known to regulate vascular changes in the inflamed aorta. (B) The CD69 receptor’s interaction with oxLDL, Gal-1, and S100A8/S100A9 regulates the FOXP3/RORγt pathway to promote Treg differentiation. In models of myocarditis and dilated cardiomyopathy, CD69–/– hearts have altered Treg–Th17 cell immune cell infiltration and altered RORγt/Foxp3 signaling. (C) In models of myocardial ischemia, CD69 deficiency increases infarct size. CD69 is linked to activation of the aryl hydrocarbon receptor (AhR) and increased CD39 transcription, which promotes Treg control of γδ T cell activity.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185218/small/JCI185218.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45696-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185218">T cells in cardiac health and disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185218">Text</a></li> <li><a class="button tiny" href="/articles/view/185218/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. T lymphocytes are crucial components of the adaptive immune system that have emerged as key mediators in both cardiac health and the development and progression of CVD. This Review explores the diverse roles of T cell subsets, including Th1, Th17, γδ T cells, and Tregs, in myocardial inflammatory processes such as autoimmune myocarditis and myocardial infarction. We discuss the contribution of T cells to myocardial injury and remodeling, with emphasis on specific immune receptors, e.g., CD69, that have a critical role in regulating immune tolerance and maintaining the balance between T cell subsets in the heart. Additionally, we offer a perspective on recent advances in T cell–targeted therapies and their potential to modulate immune responses and improve clinical outcomes in patients with CVD and in heart transplant recipients. Understanding the intricate interplay between T cells and cardiovascular pathology is essential for developing novel immunotherapeutic strategies against CVD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Pilar Martín, Francisco Sánchez-Madrid</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185785">Recent clinical and mechanistic insights into vitiligo offer new treatment options for cell-specific autoimmunity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185785">Khaled Ezzedine, … , Todd F. Pearson, John E. Harris</a> <a class='hide-for-small show-more' data-reveal-id='article45701-more' href='#'> <div class='article-authors'> Khaled Ezzedine, … , Todd F. Pearson, John E. Harris </div> </a> <span class='article-published-at'> Published January 16, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/2">135(2)</a>:e185785. <a href="https://doi.org/10.1172/JCI185785">https://doi.org/10.1172/JCI185785</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185785">Text</a> | <a href="/articles/view/185785/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/JCI185785' 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/185785/figure/1' ref='group' title='Clinical presentations of vitiligo. (A and B) Individuals with nonsegmental vitiligo, displaying characteristic symmetrical lesions on the body. Note normal body hair pigmentation in A. (C and D) Segmental vitiligo, with asymmetric lesions limited by the midline. Note depigmented lesional hairs in C. (E) Mixed vitiligo, characterized by segmental lesions that stop at the midline on the left anterior trunk as well as symmetric nonsegmental lesions on the hands. Photos are shown with patient consent.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185785/small/JCI185785.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45701-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185785">Recent clinical and mechanistic insights into vitiligo offer new treatment options for cell-specific autoimmunity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185785">Text</a></li> <li><a class="button tiny" href="/articles/view/185785/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Vitiligo is an autoimmune disease that has been recognized, stigmatized, and treated for millennia. Recent translational research has revealed key mechanisms of disease, including cellular stress, innate immune activation, T cell–mediated elimination of melanocytes from the skin resulting in clinically apparent white spots, as well as stem cell regeneration that reverses established lesions. Many of these pathways have been targeted therapeutically, leading to the first FDA-approved medication to reverse the disease, with many more in clinical trials. Despite these impressive advances, many questions remain, which will be answered through integration of additional basic, translational, and clinical research studies. This vitiligo revolution has led to great excitement for individuals with vitiligo, those who know them, and the dermatologists who care for their patients. But just as importantly, these advances have great potential to shed light on autoimmune diseases that are more difficult to study, possibly leading to treatment advances that could not be achieved otherwise.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Khaled Ezzedine, Rim Tannous, Todd F. Pearson, John E. Harris</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183836">Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183836">James P. Bridges, … , David W.H. Riches, David A. Schwartz</a> <a class='hide-for-small show-more' data-reveal-id='article45647-more' href='#'> <div class='article-authors'> James P. Bridges, … , David W.H. Riches, David A. Schwartz </div> </a> <span class='article-published-at'> Published January 2, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/1">135(1)</a>:e183836. <a href="https://doi.org/10.1172/JCI183836">https://doi.org/10.1172/JCI183836</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183836">Text</a> | <a href="/articles/view/183836/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/JCI183836' 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/183836/figure/1' ref='group' title='Two-hit model of pulmonary fibrosis. We postulate that genetic and epigenetic etiologic drivers establish a vulnerable bronchiolar and alveolar epithelia (first hit) and that this results in homeostatic adaptation without the development of lung fibrosis. Persistent and progressive lung fibrosis can be triggered by a second hit (such as tobacco smoke, air pollution, inflammation, and/or aging) to the bronchiolar and alveolar epithelia, resulting in epithelial reprogramming, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), apoptosis, and ultimately leading to fibroblast accumulation and activation, fibrosis, and abnormal lung remodeling.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183836/small/JCI183836.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45647-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183836">Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183836">Text</a></li> <li><a class="button tiny" href="/articles/view/183836/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>James P. Bridges, Eszter K. Vladar, Jonathan S. Kurche, Andrei Krivoi, Ian T. Stancil, Evgenia Dobrinskikh, Yan Hu, Sarah K. Sasse, Joyce S. Lee, Rachel Z. Blumhagen, Ivana V. Yang, Anthony N. Gerber, Anna L. Peljto, Christopher M. Evans, Elizabeth F. Redente, David W.H. Riches, David A. Schwartz</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182317">A vaccine against cytomegalovirus: how close are we?</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182317">Sallie R. Permar, … , Mark R. Schleiss, Stanley A. Plotkin</a> <a class='hide-for-small show-more' data-reveal-id='article45651-more' href='#'> <div class='article-authors'> Sallie R. Permar, … , Mark R. Schleiss, Stanley A. Plotkin </div> </a> <span class='article-published-at'> Published January 2, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/1">135(1)</a>:e182317. <a href="https://doi.org/10.1172/JCI182317">https://doi.org/10.1172/JCI182317</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182317">Text</a> | <a href="/articles/view/182317/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/JCI182317' 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/182317/figure/1' ref='group' title='Schematic of the types of immunity, target population, and endpoints for efficacy of a CMV vaccine. Potential immune correlates of protection, the potential target populations, and possible endpoints to establish efficacy for CMV vaccine candidates are listed.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/182000/182317/small/JCI182317.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45651-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182317">A vaccine against cytomegalovirus: how close are we?</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182317">Text</a></li> <li><a class="button tiny" href="/articles/view/182317/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The pursuit of a vaccine against the human cytomegalovirus (HCMV) has been ongoing for more than 50 years. HCMV is the leading infectious cause of birth defects, including damage to the brain, and is a common cause of complications in organ transplantation. The complex biology of HCMV has made vaccine development difficult, but a recent meeting sponsored by the National Institute of Allergy and Infectious Diseases in September of 2023 brought together experts from academia, industry, and federal agencies to discuss progress in the field. The meeting reviewed the status of candidate HCMV vaccines under study and the challenges in clinical trial design in demonstrating efficacy against congenital CMV infection or the reduction of HCMV disease following solid organ transplantation or hematopoietic stem cell transplantation. Discussion in the meeting revealed that, with the numerous candidate vaccines that are under study, it is clear that a safe and effective HCMV vaccine is within reach. Meeting attendees achieved a consensus opinion that even a partially effective vaccine would have a major effect on the global health consequences of HCMV infection.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sallie R. Permar, Mark R. Schleiss, Stanley A. 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