tbuckley/cabot-search huggingface dataset:
Myosin inhibitor reverses hypertrophic cardiomyopathy in genotypically diverse pediatric iPSC-cardiomyocytes to mirror variant correction
Authors: Caroline Kinnear, Abdelrahman Said, Guoliang Meng, Yimu Zhao, Erika Y. Wang, Naimeh Rafatian, Neha Parmar, Wei Wei, Filio Billia, Craig A. Simmons, Milica Radisic, James Ellis, Seema Mital
Journal: Cell Reports Medicine (2024)

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.
The Ottawa Statement implementation guidance document for cluster randomized trials in the hemodialysis setting
Authors: Cory E. Goldstein, Monica Taljaard, Stuart G. Nicholls, Mary Beaucage, Jamie Brehaut, Charles L. Cook, Brenden B. Cote, Jonathan C. Craig, Stephanie N. Dixon, Jessica Du Toit, Catherine C.S. Du Val, Amit X. Garg, Jeremy M. Grimshaw, Shasikara Kalatharan, Scott Y.H. Kim, Austin Kinsella, Valerie Luyckx, Charles Weijer
Journal: Kidney International (2024)

Research teams are increasingly interested in using cluster randomized trial (CRT) designs to generate practice-guiding evidence for in-center maintenance hemodialysis. However, CRTs raise complex ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, published in 2012, provides 15 recommendations to address ethical issues arising within 7 domains: justifying the CRT design, research ethics committee review, identifying research participants, obtaining informed consent, gatekeepers, assessing benefits and harms, and protecting vulnerable participants. But applying the Ottawa Statement recommendations to CRTs in the hemodialysis setting is complicated by the unique features of the setting and population. Here, with the help of content experts and patient partners, we co-developed this implementation guidance document to provide research teams, research ethics committees, and other stakeholders with detailed guidance on how to apply the Ottawa Statement recommendations to CRTs in the hemodialysis setting, the result of a 4-year research project. Thus, our work demonstrates how the voices of patients, caregivers, and all stakeholders may be included in the development of research ethics guidance.
A pig kidney supporting human physiology
Authors: Stuart J. Knechtle, Joseph M. Ladowski, Jean Kwun
Journal: Kidney International (2024)

Because of the global shortage of donor kidneys, xenotransplantation emerges as a potential solution for individuals with kidney failure who face challenges in securing a suitable donor kidney. A study featured in this month's issue of Kidney International assesses the kidney physiology of a porcine kidney transplanted into a brain-dead human with kidney failure, demonstrating life-sustaining physiological function for 7 days. Together with preclinical nonhuman primate studies, decedent models provide complementary data for development of clinical kidney xenotransplantation.
Consensus Guidelines versus Evidence-Based Medicine in the Treatment of Corneal Abrasions
Authors: Roy S Chuck, Bennie H Jeng, Flora Lum
Journal: Ophthalmology (2024)

Corneal abrasions are the most common condition of patients seeking treatment at emergency departments in the United States and Europe and are thought to account for approximately 4% of all emergency department visits.1 Our emergency physician colleagues perform essential work assessing these patients and managing their care in a timely fashion, often without the need for ophthalmic consultation. Patients subsequently may seek treatment from ophthalmologists for follow-up with the medications and treatments prescribed by our colleagues.
WIP1 inhibition as a new therapeutic strategy for collapsing glomerulopathy
Authors: Shreeram Akilesh
Journal: Kidney International (2024)

Collapsing glomerulopathy (CG) is an aggressive variant of focal and segmental glomerulosclerosis. Understanding the diverse mechanisms that can drive CG promises to uncover new therapeutic strategies. In this issue, Duret et al. identify WIP1 phosphatase as a therapeutic target for CG. Using genetic ablation and pharmacologic inhibition, they show that blockade of WIP1 activity is protective in 2 different mouse models of CG. This study highlights the complex interplay of glomerular signaling pathways in CG and offers hope for targeted therapies.
Guidelines for releasing a variant effect predictor
Authors: Benjamin J Livesey, Mihaly Badonyi, Mafalda Dias, Jonathan Frazer, Sushant Kumar, Kresten Lindorff-Larsen, David M McCandlish, Rose Orenbuch, Courtney A Shearer, Lara Muffley, Julia Foreman, Andrew M Glazer, Ben Lehner, Debora S Marks, Frederick P Roth, Alan F Rubin, Lea M Starita, Joseph A Marsh
Journal: Genome biology (2025)

Abstract Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in the assessment and interpretation of human genetic variation, as well as in other applications like protein engineering. Many different VEPs have been released, and there is tremendous variability in their underlying algorithms, outputs, and the ways in which the methodologies and predictions are shared. This leads to considerable difficulties for users trying to navigate the selection and application of VEPs. Here, to address these issues, we provide guidelines and recommendations for the release of novel VEPs.
Response to Comment on Beato-Víbora et al. A Multicenter Prospective Evaluation of the Benefits of Two Advanced Hybrid Closed-Loop Systems in Glucose Control and Patient-Reported Outcomes in a Real-world Setting. Diabetes Care 2024;47:216–224
Authors: Pilar Isabel Beato-Víbora, Ana Chico, Jesus Moreno-Fernandez, Virginia Bellido-Castañeda, Lia Nattero-Chávez, María José Picón-César, María Asunción Martínez-Brocca, Marga Giménez-Álvarez, Eva Aguilera-Hurtado, Elisenda Climent-Biescas, Sharona Azriel-Mira, Ángel Rebollo-Román, Carmen Yoldi-Vergara, Marcos Pazos-Couselo, Nuria Alonso-Carril, Carmen Quirós
Journal: Diabetes Care (2024)
Multimodal Technologies for Closed‐Loop Neural Modulation and Sensing
Authors: Lizhu Li, Bozhen Zhang, Wenxin Zhao, David Sheng, Lan Yin, Xing Sheng, Dezhong Yao
Journal: Advanced Healthcare Materials (2024)

Existing methods for studying neural circuits and treating neurological disorders are typically based on physical and chemical cues to manipulate and record neural activities. These approaches often involve predefined, rigid, and unchangeable signal patterns, which cannot be adjusted in real time according to the patient's condition or neural activities. With the continuous development of neural interfaces, conducting in vivo research on adaptive and modifiable treatments for neurological diseases and neural circuits is now possible. In this review, current and potential integration of various modalities to achieve precise, closed-loop modulation, and sensing in neural systems are summarized. Advanced materials, devices, or systems that generate or detect electrical, magnetic, optical, acoustic, or chemical signals are highlighted and utilized to interact with neural cells, tissues, and networks for closed-loop interrogation. Further, the significance of developing closed-loop techniques for diagnostics and treatment of neurological disorders such as epilepsy, depression, rehabilitation of spinal cord injury patients, and exploration of brain neural circuit functionality is elaborated.
Letter to the Editor “Machine learning to develop a novel model for predicting new-onset postoperative atrial fibrillation after coronary artery bypass grafting”
Authors: Zhan Peng, Xiaozheng Zhou, Xiubin Yang, Kun Hua
Journal: International Journal of Surgery (2024)

Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Vessel Disease, Beijing 100029, China Zhan Peng and Xiaozheng Zhou contributed equally to this work. Published online ■ ■ *Corresponding author. Address: 2# Anzhen Road, Cao Yang District, Beijing, China, 100029. E-mail address: [email protected] (X. Yang). *Corresponding author. Address: 2# Anzhen Road, Cao Yang district, Beijing, China, 100029. E-mail address: [email protected] (K. Hua). This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-nc-sa/4.0/
Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis
Authors: Pablo Canales-Herrerias, Mathieu Uzzan, Akihiro Seki, Rafael S. Czepielewski, Bram Verstockt, Alexandra E. Livanos, Fiona Raso, Alexandra Dunn, Daniel Dai, Andrew Wang, Zainab Al-taie, Jerome Martin, Thomas Laurent, Huaibin M. Ko, Minami Tokuyama, Michael Tankelevich, Hadar Meringer, Francesca Cossarini, Divya Jha, Azra Krek, John D. Paulsen, Matthew D. Taylor, Mohammad Zuber Nakadar, Joshua Wong, Emma C. Erlich, Rachel L. Mintz, Emily J. Onufer, Beth A. Helmink, Keshav Sharma, Adam Rosenstein, Danielle Ganjian, Grace Chung, Travis Dawson, Julius Juarez, Vijay Yajnik, Andrea Cerutti, Jeremiah J. Faith, Mayte Suarez-Farinas, Carmen Argmann, Francesca Petralia, Gwendalyn J. Randolph, Alexandros D. Polydorides, Andrea Reboldi, Jean-Frederic Colombel, Saurabh Mehandru
Journal: Science Immunology (2024)

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4β7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (β7 + ) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4β7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of β7 + IgG + plasmablasts in circulation, as well as IgG + plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4β7-targeted therapies, with major implications for this therapeutic paradigm in UC.
GPR1 and CMKLR1 Control Lipid Metabolism to Support the Development of Clear Cell Renal Cell Carcinoma
Authors: Dazhi Wang, Iqbal Mahmud, Vijay S. Thakur, Sze Kiat Tan, Daniel G. Isom, David B. Lombard, Mark L. Gonzalgo, Oleksandr N. Kryvenko, Philip L. Lorenzi, Vanina T. Tcheuyap, James Brugarolas, Scott M. Welford
Journal: Cancer Research (2024)

Abstract Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G protein–coupled receptors of the protumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacologic suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis, and autophagy, thereby significantly impeding ccRCC growth in cell lines and patient-derived xenograft models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, both receptors enforced suppression of adipose triglyceride lipase, but each receptor also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of sterol regulatory element–binding protein 1c and the CD36 scavenger receptor. Treating patient-derived xenograft models with the CMKLR1-targeting small molecule 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) led to a dramatic reduction in tumor growth, lipid storage, and clear-cell morphology. Together, these findings provide mechanistic insights into lipid regulation in ccRCC and identify a targetable axis at the core of the histologic definition of this tumor that could be exploited therapeutically. Significance: Extracellular control of lipid accumulation via G protein receptor–mediated cell signaling is a metabolic vulnerability in clear cell renal cell carcinoma, which depends on lipid storage to avoid oxidative toxicity.
Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos
Authors: Sicong Ma, Roger Sandhoff, Xiu Luo, Fuwei Shang, Qiaozhen Shi, Zhaolong Li, Jingxia Wu, Yanan Ming, Frank Schwarz, Alaa Madi, Nina Weisshaar, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Xin Yan, Kerstin Mohr, Nora ten Bosch, Zhe Li, Gernot Poschet, Hans-Reimer Rodewald, Nina Papavasiliou, Xi Wang, Pu Gao, Guoliang Cui
Journal: Science Immunology (2024)

CD4 + regulatory T (T reg ) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences T reg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed T reg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible T reg cell differentiation in vitro in a PD-1–dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for T reg cell differentiation and limits antitumor immunity.
Alcohol-associated liver disease—Global epidemiology
Authors: Fredrik Åberg, Z. Gordon Jiang, Helena Cortez-Pinto, Ville Männistö
Journal: Hepatology (2024)

Alcohol-associated liver disease (ALD), as highlighted in this narrative review, is a major public health concern, increasingly impacting global disease burden and premature mortality. In 2019, ALD accounted for the loss of 11 million life-years worldwide. The rising number of deaths and disability-adjusted life-years attributed to ALD, particularly pronounced in the United States, are alarming. Projections suggest that the economic impact of ALD, as seen in the United States, could potentially double by 2040. ALD is increasingly prevalent among younger adults (20-45 y) and has become the leading cause of liver transplantation in both United States and Europe. During the COVID-19 pandemic, the existing trend was further amplified as high-risk drinking patterns coincided with a rise in hospital admissions for alcohol-associated hepatitis and increased ALD-related mortality. The prevalence of ALD is estimated at 3.5% in the general population, 26.0% among hazardous drinkers, and 55.1% among those with alcohol use disorders. Alarmingly, 5-year mortality rates for patients with ALD exceed 50%, with even higher rates in more advanced disease stages. Methodological challenges, such as underreporting, diagnostic difficulties, and variability in registry data quality, complicate the accurate assessment of the impact of ALD. Additionally, the contribution of alcohol to the progression of other liver diseases is often under acknowledged in health care registries, leading to a significant underestimation of its broader implications for liver health. Addressing the growing ALD concern requires robust public health initiatives, heightened awareness, refined diagnostic techniques, and comprehensive epidemiological studies. These measures are vital to tackle the increasing prevalence of ALD and mitigate its extensive impact on individuals and health care systems.
Clonal hematopoiesis of indeterminate potential and risk of hepatocellular carcinoma: New kids on the block
Authors: Yi-Te Lee, Hsian-Rong Tseng, Ju Dong Yang
Journal: Hepatology (2024)

1Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA 2California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA 3Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA 4Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA 5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA Abbreviations: ALD, alcohol-associated liver diseases; CHIP, clonal hematopoiesis of indeterminate potential; CI, confidence interval; HCC hepatocellular carcinoma; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver diseases; OR, odds ratio; PRS-5, polygenic risk score-5; VAF, variant allele frequency. Correspondence Ju Dong Yang, Medical Director, Liver Cancer Program Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center Health Sciences Associate Clinical Professor, University of California, Los Angeles 8700 Beverly Blvd, Los Angeles, CA – 90048. Email: [email protected]
Multiparametric MRI for characterization of the tumour microenvironment
Authors: Emily Hoffmann, Max Masthoff, Wolfgang G. Kunz, Max Seidensticker, Stefanie Bobe, Mirjam Gerwing, Wolfgang E. Berdel, Christoph Schliemann, Cornelius Faber, Moritz Wildgruber
Journal: Nature Reviews Clinical Oncology (2024)
Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett’s oesophagus patients
Authors: Qiuyang Zhang, Kerry B Dunbar, Robert D Odze, Agoston T Agoston, Xuan Wang, Tianhong Su, Anh D Nguyen, Xi Zhang, Stuart Jon Spechler, Rhonda F Souza
Journal: Gut (2024)

Introduction Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett�s cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett�s oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. Methods 15 BO patients had endoscopy with biopsies of Barrett�s metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&amp;b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1a was knocked down with siRNA or shRNA. Results At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1a, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1a activation, which decreased miR-200a&amp;b while increasing VEGF, ZEB1 and motility; HIF-1a knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1a, increased VEGF and decreased miR-200a&amp;b. Conclusions In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1a signalling in Barrett�s metaplasia. In Barrett�s cells, ABS trigger EMP via HIF-1a signalling. Thus, HIF-1a appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. Trial registration number NCT02579460 .
Trends in Incidence of Hospitalization for Hypoglycemia and Diabetic Ketoacidosis in Individuals With Type 1 or Type 2 Diabetes With and Without Severe Mental Illness in Denmark From 1996 to 2020: A Nationwide Study
Authors: Stine H. Scheuer, Gregers S. Andersen, Bendix Carstensen, Lars Diaz, Vanja Kosjerina, Nanna Lindekilde, Sarah H. Wild, Caroline A. Jackson, Frans Pouwer, Michael E. Benros, Marit E. Jørgensen
Journal: Diabetes Care (2024)

To examine trends in incidence of acute diabetes complications in individuals with type 1 or type 2 diabetes with and without severe mental illness (SMI) in Denmark by age and calendar year.