tbuckley/cabot-search huggingface dataset:
Recent progress in Stevens–Johnson syndrome/toxic epidermal necrolysis: diagnostic criteria, pathogenesis and treatment
Authors: Natsumi Hama, Shigeki Aoki, Chun-Bing Chen, Akito Hasegawa, Youichi Ogawa, Marc Vocanson, Hideo Asada, Chia-Yu Chu, Cheng-Che E Lan, Roni P Dodiuk-Gad, Toshiharu Fujiyama, Tyng-Shiuan Hsieh, Kousei Ito, Elina Jerschow, Yoshiko Mizukawa, Saeko Nakajima, Kazutoshi Nakamura, Jean-François Nicolas, Takashi K Satoh, Tatsuo Shiohara, Hayato Takahashi, Mikiko Tohyama, Takahiro Ueda, Katsuaki Ura, Hideaki Watanabe, Yukie Yamaguchi, Thierry M Nordmann, Wen-Hung Chung, Dean Naisbitt, Carlo Pincelli, Werner J Pichler, Lars E French, Elizabeth Phillips, Riichiro Abe
Journal: British Journal of Dermatology (2024)

Abstract Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent a severe spectrum of rare mucocutaneous reactions that are primarily drug-induced and characterized by significant morbidity and mortality. These conditions manifest in extensive skin detachment, distinguishing them from other generalized skin eruptions. The rarity and severity of SJS/TEN underscore the importance of accurate diagnostic criteria and effective treatments, which are currently lacking consensus. This review proposes new diagnostic criteria to improve specificity and global applicability. Recent advances in understanding the immunopathogenesis of SJS/TEN are explored, emphasizing the role of drug-specific T-cell responses and human leucocyte antigen polymorphisms in disease onset. The review also addresses current therapeutic approaches, including controversies surrounding the use of immunosuppressive agents and the emerging role of tumour necrosis factor-α inhibitors. Novel therapeutic strategies targeting specific pathogenic mechanisms, such as necroptosis and specific immune cell pathways, are discussed. Furthermore, the development of new drugs based on these insights, including targeted monoclonal antibodies and inhibitors, are examined. The review concludes by advocating for more robust and coordinated efforts across multidisciplinary medical fields to develop effective treatments and diagnostic tools for SJS/TEN, with the aim of improving patient outcomes and understanding the disease and its mechanisms.
Human genetics and epigenetics of alcohol use disorder
Authors: Hang Zhou, Joel Gelernter
Journal: Journal of Clinical Investigation (2024)

Alcohol use disorder (AUD) is a prominent contributor to global morbidity and mortality. Its complex etiology involves genetics, epigenetics, and environmental factors. We review progress in understanding the genetics and epigenetics of AUD, summarizing the key findings. Advancements in technology over the decades have elevated research from early candidate gene studies to present-day genome-wide scans, unveiling numerous genetic and epigenetic risk factors for AUD. The latest GWAS on more than one million participants identified more than 100 genetic variants, and the largest epigenome-wide association studies (EWAS) in blood and brain samples have revealed tissue-specific epigenetic changes. Downstream analyses revealed enriched pathways, genetic correlations with other traits, transcriptome-wide association in brain tissues, and drug-gene interactions for AUD. We also discuss limitations and future directions, including increasing the power of GWAS and EWAS studies as well as expanding the diversity of populations included in these analyses. Larger samples, novel technologies, and analytic approaches are essential; these include whole-genome sequencing, multiomics, single-cell sequencing, spatial transcriptomics, deep-learning prediction of variant function, and integrated methods for disease risk prediction.
Mouse sarcopenia model reveals sex- and age-specific differences in phenotypic and molecular characteristics
Authors: Haiming L Kerr, Kora Krumm, Barbara Anderson, Anthony Christiani, Lena Strait, Theresa Li, Brynn Irwin, Siyi Jiang, Artur Rybachok, Amanda Chen, Elizabeth Dacek, Lucas Caeiro, Gennifer E Merrihew, James W MacDonald, Theo K Bammler, Michael J MacCoss, Jose M Garcia
Journal: Journal of Clinical Investigation (2024)

Our study was to characterize sarcopenia in C57BL/6J mice using a clinically relevant definition to investigate the underlying molecular mechanisms. Aged male (23-32 months old) and female (27-28 months old) C57BL/6J mice were classified as non-, probable-, or sarcopenic based on assessments of grip strength, muscle mass, and treadmill running time, using 2 SDs below the mean of their young counterparts as cutoff points. A 9%-22% prevalence of sarcopenia was identified in 23-26 month-old male mice, with more severe age-related declines in muscle function than mass. Females aged 27-28 months showed fewer sarcopenic but more probable cases compared with the males. As sarcopenia progressed, a decrease in muscle contractility and a trend toward lower type IIB fiber size were observed in males. Mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in males, with pathways linked to mitochondrial metabolism positively correlated with muscle mass. No age- or sarcopenia-related changes were observed in mitochondrial biogenesis, OXPHOS complexes, AMPK signaling, mitophagy, or atrogenes in females. Our results highlight the different trajectories of age-related declines in muscle mass and function, providing insights into sex-dependent molecular changes associated with sarcopenia progression, which may inform the future development of novel therapeutic interventions.
Rare genetic variants provide a mechanistic basis for immune imbalance in IgG4-related disease
Authors: Dominic J. Ciavatta
Journal: Journal of Clinical Investigation (2024)

Autoimmune diseases are commonly associated with a polygenic inheritance pattern. In rare instances, causal monogenic variants have been identified. The study by Liu et al. in this issue of the JCI provides an example of monogenic variants occurring in patients with IgG4-related disease (IgG4-RD). The authors investigated a familial cluster of IgG4-RD that consisted of an affected father and two daughters; the mother was unaffected. Genome sequencing of this quad identified a variant in IKZF1 (encoding IKAROS) and another variant in UBR4 (encoding E3 ubiquitin ligase). Both variants were present in the father and both daughters but absent in the unaffected mother. Using multidimensional profiling of immune cells and functional experiments in primary cells, the authors determined a molecular pathway contributing to T cell activation in IgG4-RD. Importantly, the characterization of these variants provides insights into pathogenic mechanisms in IgG4-RD and, potentially, other autoimmune diseases.
Prognostication and Interventional Guidance Using Acceleration-Ejection Time Ratio in Undifferentiated Paradoxical Low-Flow Low-Gradient Aortic Stenosis
Authors: Adrian Chong, Jonathan Sen, Reza Reyaldeen, Sudhir Wahi, Quan Huynh, William Y S Wang, Thomas H Marwick
Journal: JACC. Cardiovascular imaging (2024)
An Automated Machine Learning–Based Quantitative Multiparametric Approach for Mitral Regurgitation Severity Grading
Authors: Anita Sadeghpour, Zhubo Jiang, Yoran M Hummel, Matthew Frost, Carolyn S P Lam, Sanjiv J Shah, Lars H Lund, Gregg W Stone, Madhav Swaminathan, Neil J Weissman, Federico M Asch
Journal: JACC. Cardiovascular imaging (2024)
Polygenic Risk Is Associated With Long-Term Coronary Plaque Progression and High-Risk Plaque
Authors: Nick S. Nurmohamed, Injeong Shim, Emilie L. Gaillard, Shirin Ibrahim, Michiel J. Bom, James P. Earls, James K. Min, R. Nils Planken, Andrew D. Choi, Pradeep Natarajan, Erik S.G. Stroes, Paul Knaapen, Laurens F. Reeskamp, Akl C. Fahed
Journal: JACC. Cardiovascular imaging (2024)

The longitudinal relation between coronary artery disease (CAD) polygenic risk score (PRS) and long-term plaque progression and high-risk plaque (HRP) features is unknown. The goal of this study was to investigate the impact of CAD PRS on long-term coronary plaque progression and HRP. Patients underwent CAD PRS measurement and prospective serial coronary computed tomography angiography (CTA) imaging. Coronary CTA scans were analyzed with a previously validated artificial intelligence–based algorithm (atherosclerosis imaging–quantitative computed tomography imaging). The relationship between CAD PRS and change in percent atheroma volume (PAV), percent noncalcified plaque progression, and HRP prevalence was investigated in linear mixed-effect models adjusted for baseline plaque volume and conventional risk factors. A total of 288 subjects (mean age 58 ± 7 years; 60% male) were included in this study with a median scan interval of 10.2 years. At baseline, patients with a high CAD PRS had a more than 5-fold higher PAV than those with a low CAD PRS (10.4% vs 1.9%; P < 0.001). Per 10 years of follow-up, a 1 SD increase in CAD PRS was associated with a 0.69% increase in PAV progression in the multivariable adjusted model. CAD PRS provided additional discriminatory benefit for above-median noncalcified plaque progression during follow-up when added to a model with conventional risk factors (AUC: 0.73 vs 0.69; P = 0.039). Patients with high CAD PRS had an OR of 2.85 (95% CI: 1.14-7.14; P = 0.026) and 6.16 (95% CI: 2.55-14.91; P < 0.001) for having HRP at baseline and follow-up compared with those with low CAD PRS. Polygenic risk is strongly associated with future long-term plaque progression and HRP in patients suspected of having CAD.
Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1
Authors: Callum Beach, David MacLean, Dominika Majorova, Stavros Melemenidis, Dhanya K. Nambiar, Ryan K. Kim, Gabriel N. Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily V.S. Hillson, Ashley K. McCulloch, Ross K. McMahon, Kathryn Pennel, Joanne Edwards, Sean M. O’Cathail, Campbell S. Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, Albert C. Koong, Trent M. Woodruff, Edward E. Graves, Tim Maughan, Simon J.A. Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J. Leedham, Amato J. Giaccia, Monica M. Olcina
Journal: Journal of Clinical Investigation (2024)
LOXL2-induced PEAR1 Ser891 phosphorylation suppresses CD44 degradation and promotes triple-negative breast cancer metastasis
Authors: Yingzhi Shen, Jie Yan, Lin Li, Huiyan Sun, Lin Zhang, Guoming Li, Xinxia Wang, Ruoyan Liu, Xuefeng Wu, Baosan Han, Xueqing Sun, Junling Liu, Xuemei Fan
Journal: Journal of Clinical Investigation (2024)

CD44 is associated with a high risk of metastasis, recurrence, and drug resistance in various cancers. Here we report that platelet endothelial aggregation receptor 1 (PEAR1) is a CD44 chaperone protein that protected CD44 from endocytosis-mediated degradation and enhances cleavage of the CD44 intracellular domain (CD44-ICD). Furthermore, we found that lysyl oxidase-like protein 2 (LOXL2), an endogenous ligand of PEAR1, bound to the PEAR1-EMI domain and facilitated the interaction between PEAR1 and CD44 by inducing PEAR1 Ser891 phosphorylation in a manner that was independent of its enzyme activity. Levels of PEAR1 protein and PEAR1 phosphorylation at Ser891 were increased in patients with triple-negative breast cancer (TNBC), were positively correlated with expression of LOXL2 and CD44, and were negatively correlated with overall survival. The level of PEAR1 Ser891 phosphorylation was identified as the best independent prognostic factor in TNBC patients. The prognostic efficacy of the combination of PEAR1 phosphorylation at Ser891 and CD44 expression was superior to that of PEAR1 phosphorylation at Ser891 alone. Blocking the interaction between LOXL2 and PEAR1 with monoclonal antibodies significantly inhibited TNBC metastasis, representing a promising therapeutic strategy for TNBC.
What makes the kidney so tolerant?
Authors: Paolo Molinari, Paolo Cravedi
Journal: Journal of Clinical Investigation (2024)

Various organ allografts differ in their propensity to be spontaneously accepted without any immunosuppressive treatment. Understanding the mechanisms behind these differences can aid in managing alloimmune responses in general. C57BL/6 mice naturally accept DBA/2J kidney allografts, forming tertiary lymphoid organs containing regulatory T cells (rTLOs), crucial for graft acceptance. In this issue of the JCI, Yokose and colleagues revealed that rTLOs promote conversion of cytotoxic alloreactive CD8+ T cells into exhausted/regulatory ones, through an IFN-γ-mediated mechanism. Their study provides insights into tolerance development that could help promote the acceptance of grafts at higher risk of rejection.
Stress and substance use disorders: risk, relapse, and treatment outcomes
Authors: Rajita Sinha
Journal: Journal of Clinical Investigation (2024)

Stress has long been associated with substance misuse and substance use disorders (SUDs). The past two decades have seen a surge in research aimed at understanding the underlying mechanisms driving this association. This Review introduces a multilevel "adaptive stress response" framework, encompassing a stress baseline, acute reaction, and recovery with return-to-homeostasis phase that occurs at varying response times and across domains of analysis. It also discusses evidence showing the disruption of this adaptive stress response in the context of chronic and repeated stressors, trauma, adverse social and drug-related environments, as well as with acute and chronic drug misuse and with drug withdrawal and abstinence sequelae. Subjective, cognitive, peripheral, and neurobiological disruptions in the adaptive stress response phases and their link to inflexible, maladaptive coping; increased craving; relapse risk; and maintenance of drug intake are also presented. Finally, the prevention and treatment implications of targeting this "stress pathophysiology of addiction" are discussed, along with specific aspects that may be targeted in intervention development to rescue stress-related alterations in drug motivation and to improve SUD treatment outcomes.
Definition and Validation of Prognostic Phenotypes in Moderate Aortic Stenosis
Authors: Jonathan Sen, Sudhir Wahi, William Vollbon, Marcus Prior, Alex G C de Sá, David B Ascher, Quan Huynh, Thomas H Marwick
Journal: JACC. Cardiovascular imaging (2024)

Adverse outcomes from moderate aortic stenosis (AS) may be caused by progression to severe AS or by the effects of comorbidities. In the absence of randomized trial evidence favoring aortic valve replacement (AVR) in patients with moderate AS, phenotyping patients according to risk may assist decision making.
Posttranslationally modified self-peptides promote hypertension in mouse models
Authors: Nathaniel Bloodworth, Wei Chen, Kuniko Hunter, David Patrick, Amy Palubinsky, Elizabeth Phillips, Daniel Roeth, Markus Kalkum, Simon Mallal, Sean Davies, Mingfang Ao, Rocco Moretti, Jens Meiler, David G. Harrison
Journal: Journal of Clinical Investigation (2024)

Posttranslational modifications can enhance immunogenicity of self-proteins. In several conditions, including hypertension, systemic lupus erythematosus, and heart failure, isolevuglandins (IsoLGs) are formed by lipid peroxidation and covalently bond with protein lysine residues. Here, we show that the murine class I major histocompatibility complex (MHC-I) variant H-2Db uniquely presents isoLG-modified peptides and developed a computational pipeline that identifies structural features for MHC-I accommodation of such peptides. We identified isoLG-adducted peptides from renal proteins, including sodium glucose transporter 2, cadherin 16, Kelch domain-containing protein 7A, and solute carrier family 23, that are recognized by CD8+ T cells in tissues of hypertensive mice, induce T cell proliferation in vitro, and prime hypertension after adoptive transfer. Finally, we find patterns of isoLG-adducted antigen restriction in class I human leukocyte antigens that are similar to those in murine analogs. Thus, we have used a combined computational and experimental approach to define likely antigenic peptides in hypertension.
Decoding the decline: unveiling drivers of sarcopenia
Authors: Allison M Owen, Christopher S Fry
Journal: Journal of Clinical Investigation (2024)

There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI, Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression.
CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target
Authors: Quy Le, Brandon Hadland, Jenny L. Smith, Amanda Leonti, Benjamin J. Huang, Rhonda Ries, Tiffany A. Hylkema, Sommer Castro, Thao T. Tang, Cyd N. McKay, LaKeisha Perkins, Laura Pardo, Jay Sarthy, Amy K. Beckman, Robin Williams, Rhonda Idemmili, Scott Furlan, Takashi Ishida, Lindsey Call, Shivani Srivastava, Anisha M. Loeb, Filippo Milano, Suzan Imren, Shelli M. Morris, Fiona Pakiam, Jim M. Olson, Michael R. Loken, Lisa Brodersen, Stanley R. Riddell, Katherine Tarlock, Irwin D. Bernstein, Keith R. Loeb, Soheil Meshinchi
Journal: Journal of Clinical Investigation (2024)
Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses
Authors: Jianli He, Yalan Chen, Huihua Ding, Jin-An Zhou, Zhengcao Xing, Xinyu Yang, Qiuju Fan, Yong Zuo, Tianshi Wang, Jinke Cheng
Journal: Journal of Clinical Investigation (2024)

T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development. The addition of cardiolipin or modulating VEGF-B signaling improved T cell mitochondrial fitness and survival. Autocrine VEGF-B signaling through GA-binding protein α (GABPα) induced sentrin/SUMO-specific protease 2 (SENP2) expression, which further de-SUMOylated PPARγ and enhanced phospholipid synthesis, leading to a cardiolipin increase in activated T cells. These data suggest that autocrine VEGF-B mediates a signal to coordinate lipid synthesis and mitochondrial fitness with T cell activation for survival and immune response. Moreover, autocrine VEGF-B signaling in T cells provides a therapeutic target against infection and tumors as well as an avenue for the treatment of autoimmune diseases.
Towards risk-based surveillance for hepatocellular carcinoma after HCV cure?
Authors: Adriaan J. van der Meer, Milan J. Sonneveld
Journal: Hepatology (2024)

Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands Manuscript type editorial Correspondence Adriaan J. van der Meer, Erasmus MC, Gastroenterology & Hepatology. Email: [email protected]
Efficacy and safety of bintrafusp alfa in two phase 1 expansion cohorts with advanced hepatocellular carcinoma
Authors: Ho Yeong Lim, Jeong Heo, Julio A. Peguero, Baek-Yeol Ryoo, Thomas Decaens, Fabrice Barlesi, Markus H. Moehler, Genevieve Jehl, S. Peter Eggleton, Marcis Bajars, James L. Gulley
Journal: Hepatology (2024)

Simultaneous inhibition of the TGF-β and programmed cell death 1 ligand 1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death 1 ligand 1, was evaluated in patients with advanced HCC.
It’s good to know what to BACE the specificity of your inhibitors on
Authors: Aoife Murray, Ana Muñiz-García, Ivan Alić, Dean Nižetić
Journal: Journal of Clinical Investigation (2024)

Production, aggregation, and clearance of the amyloid β peptide (Aβ) are important processes governing the initial pathogenesis of Alzheimer's disease (AD). Inhibition of β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) (one of two key proteases responsible for Aβ production) as an AD-therapeutic approach so far has failed to yield a successful drug. BACE1 and its homologue BACE2 are frequently inhibited by the same inhibitors. Several genetic and cerebral organoid modeling studies suggest that BACE2 has dose-dependent AD-suppressing activity, which makes its unwanted inhibition potentially counterproductive for AD treatment. The in vivo effects of an unwanted cross inhibition of BACE2 have so far been impossible to monitor because of the lack of an easily accessible pharmacodynamic marker specific for BACE2 cleavage. In this issue of the JCI, work led by Stefan F. Lichtenthaler identifies soluble VEGFR3 (sVEGFR3) as a pharmacodynamic plasma marker for BACE2 activity not shared with BACE1.
The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis
Authors: Marcel S Woo, Lukas C Bal, Ingo Winschel, Elias Manca, Mark Walkenhorst, Bachar Sevgili, Jana K Sonner, Giovanni Di Liberto, Christina Mayer, Lars Binkle-Ladisch, Nicola Rothammer, Lisa Unger, Lukas Raich, Alexandros Hadjilaou, Barbara Noli, Antonio L Manai, Vanessa Vieira, Nina Meurs, Ingrid Wagner, Ole Pless, Cristina Cocco, Samuel B Stephens, Markus Glatzel, Doron Merkler, Manuel A Friese
Journal: Journal of Clinical Investigation (2024)

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.