tbuckley/cabot-search huggingface dataset:
Apoptosis-resistant megakaryocytes produce large and hyperreactive platelets in response to radiation injury
Authors: Chang-Hong Du, Yi-Ding Wu, Ke Yang, Wei-Nian Liao, Li Ran, Chao-Nan Liu, Shu-Zhen Zhang, Kuan Yu, Jun Chen, Yong Quan, Mo Chen, Ming-Qiang Shen, Hong Tang, Shi-Lei Chen, Song Wang, Jing-Hong Zhao, Tian-Min Cheng, Jun-Ping Wang
Journal: Military Medical Research (2023)

The essential roles of platelets in thrombosis have been well recognized. Unexpectedly, thrombosis is prevalent during thrombocytopenia induced by cytotoxicity of biological, physical and chemical origins, which could be suffered by military personnel and civilians during chemical, biological, radioactive, and nuclear events. Especially, thrombosis is considered a major cause of mortality from radiation injury-induced thrombocytopenia, while the underlying pathogenic mechanism remains elusive. A mouse model of radiation injury-induced thrombocytopenia was built by exposing mice to a sublethal dose of ionizing radiation (IR). The phenotypic and functional changes of platelets and megakaryocytes (MKs) were determined by a comprehensive set of in vitro and in vivo assays, including flow cytometry, flow chamber, histopathology, Western blotting, and chromatin immunoprecipitation, in combination with transcriptomic analysis. The molecular mechanism was investigated both in vitro and in vivo, and was consolidated using MK-specific knockout mice. The translational potential was evaluated using a human MK cell line and several pharmacological inhibitors. In contrast to primitive MKs, mature MKs (mMKs) are intrinsically programmed to be apoptosis-resistant through reprogramming the Bcl-xL-BAX/BAK axis. Interestingly, mMKs undergo minority mitochondrial outer membrane permeabilization (MOMP) post IR, resulting in the activation of the cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway via the release of mitochondrial DNA. The subsequent interferon-β (IFN-β) response in mMKs upregulates a GTPase guanylate-binding protein 2 (GBP2) to produce large and hyperreactive platelets that favor thrombosis. Further, we unmask that autophagy restrains minority MOMP in mMKs post IR. Our study identifies that megakaryocytic mitochondria-cGAS/STING-IFN-β-GBP2 axis serves as a fundamental checkpoint that instructs the size and function of platelets upon radiation injury and can be harnessed to treat platelet pathologies.
Lessons Learned from Immigrant Health Cohorts: A Review of the Evidence and Implications for Policy and Practice in Addressing Health Inequities among Asian Americans, Native Hawaiians, and Pacific Islanders
Authors: Alice Guan, AC S. Talingdan, Sora P. Tanjasiri, Alka M. Kanaya, Scarlett L. Gomez
Journal: Annual Review of Public Health (2023)

The health of Asian Americans, Native Hawaiians, and Pacific Islanders (AANHPI) is uniquely impacted by structural and social determinants of health (SSDH) shaped by immigration policies and colonization practices, patterns of settlement, and racism. These SSDH also create vast heterogeneity in disease risks across the AANHPI population, with some ethnic groups having high disease burden, often masked with aggregated data. Longitudinal cohort studies are an invaluable tool to identify risk factors of disease, and epidemiologic cohort studies among AANHPI populations have led to seminal discoveries of disease risk factors. This review summarizes the limited but growing literature, with a focus on SSDH factors, from seven longitudinal cohort studies with substantial AANHPI samples. We also discuss key information gaps and recommendations for the next generation of AANHPI cohorts, including oversampling AANHPI ethnic groups; measuring and innovating on measurements of SSDH; emphasizing the involvement of scholars from diverse disciplines; and, most critically, engaging community members to ensure relevancy for public health, policy, and clinical impact.
Enhanced bone regeneration via endochondral ossification using Exendin-4-modified mesenchymal stem cells
Authors: Zihao He, Hui Li, Yuanyuan Zhang, Shuang Gao, Kaini Liang, Yiqi Su, Du Wang, Zhen Yang, Yanan Du, Dan Xing, Jianhao Lin
Journal: Bioactive Materials (2023)

Nonunions and delayed unions pose significant challenges in orthopedic treatment, with current therapies often proving inadequate. Bone tissue engineering (BTE), particularly through endochondral ossification (ECO), emerges as a promising strategy for addressing critical bone defects. This study introduces mesenchymal stem cells overexpressing Exendin-4 (MSC-E4), designed to modulate bone remodeling via their autocrine and paracrine functions. We established a type I collagen (Col-I) sponge-based in vitro model that effectively recapitulates the ECO pathway. MSC-E4 demonstrated superior chondrogenic and hypertrophic differentiation and enhanced the ECO cell fate in single-cell sequencing analysis. Furthermore, MSC-E4 encapsulated in microscaffold, effectively facilitated bone regeneration in a rat calvarial defect model, underscoring its potential as a therapeutic agent for bone regeneration. Our findings advocate for MSC-E4 within a BTE framework as a novel and potent approach for treating significant bone defects, leveraging the intrinsic ECO process.
Neoadjuvant trebananib plus paclitaxel-based chemotherapy for stage II/III breast cancer in the adaptively randomized I-SPY2 trial — Efficacy and biomarker discovery
Authors: Kathy S. Albain, Christina Yau, Emanuel F. Petricoin, Denise M. Wolf, Julie E. Lang, A. Jo Chien, Tufia Haddad, Andres Forero-Torres, Anne M. Wallace, Henry Kaplan, Lajos Pusztai, David Euhus, Rita Nanda, Anthony D. Elias, Amy S. Clark, Constantine Godellas, Judy C. Boughey, Claudine Isaacs, Debu Tripathy, Janice Lu, Rachel L. Yung, Rosa I. Gallagher, Julia D. Wulfkuhle, Lamorna Brown-Swigart, Gregor Krings, Yunn Yi Chen, David A. Potter, Erica Stringer-Reasor, Sarah Blair, Smita M. Asare, Amy Wilson, Gillian L. Hirst, Ruby Singhrao, Meredith Buxton, Julia L. Clennell, Ashish Sanil, Scott Berry, Adam L. Asare, Jeffrey B. Matthews, Angela M. DeMichele, Nola M. Hylton, Michelle Melisko, Jane Perlmutter, Hope S. Rugo, W. Fraser Symmans, Laura J. van't Veer, Douglas Yee, Donald A. Berry, Laura J. Esserman
Journal: Clinical Cancer Research (2023)

Abstract Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority &amp;gt;90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.
The changing pattern of coronary artery bypass surgery.
Authors: Christakis Gt, Ivanov J, Weisel Rd, Birnbaum Pl, David Te, Salerno Ta
Journal: Circulation (1989)

Recent advances in interventional cardiology have altered the profile of patients referred for coronary artery bypass surgery. In recent years, the proportion of high-risk patients has increased dramatically. To evaluate the impact of the changing pattern of surgical patients, we prospectively followed up 7,334 patients who had coronary artery bypass surgery between 1982 and 1986. Multivariate analysis identified the following risk factors for operative mortality: urgency of surgery, left ventricular ejection fraction, age, female sex, previous bypass surgery, and left main coronary artery stenosis. Perioperative mortality has remained stable despite an increasing incidence of high-risk patients. However, perioperative morbidity has increased, due to the large number of high-risk patients. A multivariate analysis was performed by year to identify temporal trends in risk factors. Urgency of surgery, age, and previous bypass surgery have become more significant predictors of mortality with respect to time, whereas female sex, left ventricular ejection fraction, and left main coronary artery stenosis have become less significant determinants of mortality. Our results demonstrate the critical dependence of mortality and morbidity rates on the case mix, and further improvements in the results of coronary artery bypass surgery will require better strategies for the increasing number of high-risk patients.
Prognostic utility of Fibrosis-4 Index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study
Authors: Quentin M. Anstee, Tina L. Berentzen, Louise M. Nitze, Maximilian Jara, Anders B. Jensen, Mette S. Kjær, Kamal K. Mangla, Jens M. Tarp, Kamlesh Khunti
Journal: The Lancet Regional Health - Europe (2023)

The Fibrosis-4 Index (FIB-4) is used as a non-invasive tool for the presence of advanced liver fibrosis in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. However, evidence for an association between FIB-4 and risk of mortality and/or liver-related clinical outcomes is limited. The aim of this study was to investigate the association between FIB-4 and subsequent liver events, cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes examined in routine general practice.
Using Participatory Implementation Science to Advance Health Equity
Authors: Shoba Ramanadhan, Rosa Alemán, Cory D. Bradley, Jennifer L. Cruz, Nadia Safaeinili, Vanessa Simonds, Emma-Louise Aveling
Journal: Annual Review of Public Health (2023)

Participatory approaches to implementation science (IS) offer an inclusive, collaborative, and iterative perspective on implementing and sustaining evidence-based interventions (EBIs) to advance health equity. This review provides guidance on the principles and practice of participatory IS, which enables academic researchers, community members, implementers, and other actors to collaboratively integrate practice-, community-, and research-based evidence into public health and health care services. With a foundational focus on supporting academics in coproducing knowledge and action, participatory IS seeks to improve health, reduce inequity, and create transformational change. The three main sections of this review provide (
Guidelines for best practices in monitoring established coeliac disease in adult patients
Authors: Luca Elli, Daniel Leffler, Christophe Cellier, Benjamin Lebwohl, Carolina Ciacci, Michael Schumann, Knut E. A. Lundin, Stefania Chetcuti Zammit, Reena Sidhu, Leda Roncoroni, Julio C. Bai, Anne R. Lee, Melinda Dennis, Marie E. Robert, Kamran Rostami, Sherine Khater, Isabel Comino, Angel Cebolla, Federica Branchi, Elena F. Verdu, Juan Pablo Stefanolo, Randi Wolf, Sheba Bergman-Golden, Nick Trott, Luigia Scudeller, Fabiana Zingone, Lucia Scaramella, David S. Sanders
Journal: Nature Reviews Gastroenterology & Hepatology (2023)
Assessing the potential of GPT-4 to perpetuate racial and gender biases in health care: a model evaluation study
Authors: Travis Zack, Eric Lehman, Mirac Suzgun, Jorge A Rodriguez, Leo Anthony Celi, Judy Gichoya, Dan Jurafsky, Peter Szolovits, David W Bates, Raja-Elie E Abdulnour, Atul J Butte, Emily Alsentzer
Journal: The Lancet Digital Health (2023)

Large language models (LLMs) such as GPT-4 hold great promise as transformative tools in health care, ranging from automating administrative tasks to augmenting clinical decision making. However, these models also pose a danger of perpetuating biases and delivering incorrect medical diagnoses, which can have a direct, harmful impact on medical care. We aimed to assess whether GPT-4 encodes racial and gender biases that impact its use in health care.
Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation
Authors: Qianmin Ou, Xinhua Qiao, Zhengshi Li, Luhan Niu, Fangcao Lei, Ruifeng Cheng, Ting Xie, Ning Yang, Yao Liu, Ling Fu, Jing Yang, Xueli Mao, Xiaoxing Kou, Chang Chen, Songtao Shi
Journal: Cell Metabolism (2023)

Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H
A 4D Printed Adhesive, Thermo‐Contractile, and Degradable Hydrogel for Diabetic Wound Healing
Authors: Zhe Lu, Jingjing Cui, Fukang Liu, Chen Liang, Shiwei Feng, Yongding Sun, Weizi Gao, Yunlong Guo, Biao Zhang, Wei Huang
Journal: Advanced Healthcare Materials (2023)

Abstract Chronic wound healing remains a substantial clinical challenge. Current treatments are often either prohibitively expensive or insufficient in meeting the various requirements needed for effective diabetic wound healing. A 4D printing multifunctional hydrogel dressing is reported here, which aligns perfectly with wounds owning various complex shapes and depths, promoting both wound closure and tissue regeneration. The hydrogel is prepared via digital light process (DLP) 3D printing of the mixture containing N‐isopropylacrylamide (NIPAm), curcumin‐loaded Pluronic F127 micelles (Cur‐PF127), and poly(ethylene glycol) diacrylate‐dopamine (PEGDA575‐Do), a degradable crosslinker. The use of PEGDA575‐Do ensures tissue adhesion and degradability, and cur‐PF127 serves as an antibacterial agent. Moreover, the thermo‐responsive mainchains (i.e., polymerized NIPAm) enables the activation of wound contraction by body temperature. The features of the prepared hydrogel, including robust tissue adhesion, temperature‐responsive contraction, effective hemostasis, spectral antibacterial, biocompatibility, biodegradability, and inflammation regulation, contribute to accelerating diabetic wound healing in Methicillin‐resistant Staphylococcus aureus (MRSA)‐infected full‐thickness skin defect diabetic rat models and liver injury mouse models, highlighting the potential of this customizable, mechanobiological, and inflammation‐regulatory dressing to expedite wound healing in various clinical settings.
Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice
Authors: Pravin Yeapuri, Jatin Machhi, Yaman Lu, Mai Mohamed Abdelmoaty, Rana Kadry, Milankumar Patel, Shaurav Bhattarai, Eugene Lu, Krista L. Namminga, Katherine E. Olson, Emma G. Foster, R. Lee Mosley, Howard E. Gendelman
Journal: Molecular Neurodegeneration (2023)

Abstract Background Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCR A β ). The TCR Ab were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCR Aβ (TCR Aβ -Tregs) to reduce Aβ burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer’s disease. Methods TCR A β -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCR Ab identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCR Aβ -Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes. Results TCR Aβ -Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCR Aβ -Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18 F-fluorodeoxyglucose radiolabeled TCR Aβ -Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. Conclusions TCR Aβ -Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD. Graphical Abstract
De novo identification of expressed cancer somatic mutations from single-cell RNA sequencing data
Authors: Tianyun Zhang, Hanying Jia, Tairan Song, Lin Lv, Doga C Gulhan, Haishuai Wang, Wei Guo, Ruibin Xi, Hongshan Guo, Ning Shen
Journal: Genome Medicine (2023)

Abstract Identifying expressed somatic mutations from single-cell RNA sequencing data de novo is challenging but highly valuable. We propose RESA – Recurrently Expressed SNV Analysis, a computational framework to identify expressed somatic mutations from scRNA-seq data. RESA achieves an average precision of 0.77 on three in silico spike-in datasets. In extensive benchmarking against existing methods using 19 datasets, RESA consistently outperforms them. Furthermore, we applied RESA to analyze intratumor mutational heterogeneity in a melanoma drug resistance dataset. By enabling high precision detection of expressed somatic mutations, RESA substantially enhances the reliability of mutational analysis in scRNA-seq. RESA is available at https://github.com/ShenLab-Genomics/RESA .
Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation
Authors: Chi Kin Wong, Brent A. McLean, Laurie L. Baggio, Jacqueline A. Koehler, Rola Hammoud, Nikolaj Rittig, Julian M. Yabut, Randy J. Seeley, Theodore J. Brown, Daniel J. Drucker
Journal: Cell Metabolism (2023)
Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma
Authors: Yinghong Zhu, Xingxing Jian, Shuping Chen, Gang An, Duanfeng Jiang, Qin Yang, Jingyu Zhang, Jian Hu, Yi Qiu, Xiangling Feng, Jiaojiao Guo, Xun Chen, Zhengjiang Li, Ruiqi Zhou, Cong Hu, Nihan He, Fangming Shi, Siqing Huang, Hong Liu, Xin Li, Lu Xie, Yan Zhu, Lia Zhao, Yichuan Jiang, Jian Li, Jinuo Wang, Lugui Qiu, Xiang Chen, Wei Jia, Yanjuan He, Wen Zhou
Journal: Cell Metabolism (2023)

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.
Augmented reality versus standard tests to assess cognition and function in early Alzheimer’s disease
Authors: Marijn Muurling, Casper de Boer, Srinivasan Vairavan, Robbert L. Harms, Antonella Santuccione Chadha, Ioannis Tarnanas, Estefania Vilarino Luis, Dorota Religa, Martha Therese Gjestsen, Samantha Galluzzi, Marta Ibarria Sala, Ivan Koychev, Lucrezia Hausner, Mara Gkioka, Dag Aarsland, Pieter Jelle Visser, Anna-Katharine Brem
Journal: npj Digital Medicine (2023)

Abstract Augmented reality (AR) apps, in which the virtual and real world are combined, can recreate instrumental activities of daily living (IADL) and are therefore promising to measure cognition needed for IADL in early Alzheimer’s disease (AD) both in the clinic and in the home settings. The primary aim of this study was to distinguish and classify healthy controls (HC) from participants with AD pathology in an early AD stage using an AR app. The secondary aims were to test the association of the app with clinical cognitive and functional tests and investigate the feasibility of at-home testing using AR. We furthermore investigated the test-retest reliability and potential learning effects of the task. The digital score from the AR app could significantly distinguish HC from preclinical AD (preAD) and prodromal AD (proAD), and preAD from proAD, both with in-clinic and at-home tests. For the classification of the proAD group, the digital score (AUC clinic_visit = 0.84 [0.75–0.93], AUC at_home = 0.77 [0.61–0.93]) was as good as the cognitive score (AUC = 0.85 [0.78–0.93]), while for classifying the preAD group, the digital score (AUC clinic_visit = 0.66 [0.53–0.78], AUC at_home = 0.76 [0.61–0.91]) was superior to the cognitive score (AUC = 0.55 [0.42–0.68]). In-clinic and at-home tests moderately correlated (rho = 0.57, p &lt; 0.001). The digital score was associated with the clinical cognitive score (rho = 0.56, p &lt; 0.001). No learning effects were found. Here we report the AR app distinguishes HC from otherwise healthy Aβ-positive individuals, both in the outpatient setting and at home, which is currently not possible with standard cognitive tests.
Intrarectal injections of botulinum toxin versus placebo for the treatment of urge faecal incontinence in adults (FI-Toxin): a double-blind, multicentre, randomised, controlled phase 3 study
Authors: Anne-Marie Leroi, Michel Queralto, Frank Zerbib, Laurent Siproudhis, Véronique Vitton, Gérard Amarenco, Isabelle Etienney, Francois Mion, Valerie Bridoux, Julie Philip, Charlène Brochard, Henri Damon, Elie Lacroix, André Gillibert, Guillaume Gourcerol
Journal: The Lancet. Gastroenterology & hepatology (2023)