tbuckley/cabot-search huggingface dataset:
Epithelial barrier theory in the context of nutrition and environmental exposure in athletes
Authors: Walter Kistler, Michael Villiger, Beat Villiger, Duygu Yazici, Yagiz Pat, Yasutaka Mitamura, Sena Ardicli, Stephen Skolnick, Raja Dhir, Mübeccel Akdis, Kari Nadeau, Ismail Ogulur, Cezmi A. Akdis
Journal: Allergy (2024)

Exposure to toxic substances, introduced into our daily lives during industrialization and modernization, can disrupt the epithelial barriers in the skin, respiratory, and gastrointestinal systems, leading to microbial dysbiosis and inflammation. Athletes and physically active individuals are at increased risk of exposure to agents that damage the epithelial barriers and microbiome, and their extreme physical exercise exerts stress on many organs, resulting in tissue damage and inflammation. Epithelial barrier-damaging substances include surfactants and enzymes in cleaning products, laundry and dishwasher detergents, chlorine in swimming pools, microplastics, air pollutants such as ozone, particulate matter, and diesel exhaust. Athletes' high-calorie diet often relies on processed foods that may contain food emulsifiers and other additives that may cause epithelial barrier dysfunction and microbial dysbiosis. The type of the material used in the sport equipment and clothing and their extensive exposure may increase the inflammatory effects. Excessive travel-related stress, sleep disturbances and different food and microbe exposure may represent additional factors. Here, we review the detrimental impact of toxic agents on epithelial barriers and microbiome; bring a new perspective on the factors affecting the health and performance of athletes and physically active individuals.
Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers
Authors: Thomas S Fulford, Caroline Soliman, Rebecca G Castle, Marc Rigau, Zheng Ruan, Olan Dolezal, Rebecca Seneviratna, Hamish G Brown, Eric Hanssen, Andrew Hammet, Shihan Li, Samuel J Redmond, Amy Chung, Michael A Gorman, Michael W Parker, Onisha Patel, Thomas S Peat, Janet Newman, Andreas Behren, Nicholas A Gherardin, Dale I Godfrey, Adam P Uldrich
Journal: Nature Immunology (2024)
Pyrazinamide Safety, Efficacy, and Dosing for Treating Drug-Susceptible Pulmonary Tuberculosis: A Phase 3, Randomized, Controlled Clinical Trial
Authors: Ava Y Xu, Gustavo E Velásquez, Nan Zhang, Vincent K Chang, Patrick PJ Phillips, Payam Nahid, Susan E. Dorman, Ekaterina V Kurbatova, William C. Whitworth, Erin Sizemore, Kia Bryant, Wendy Carr, Nicole E. Brown, Melissa L Engle, Nguyen Viet Nhung, Pheona Nsubuga, Andreas Diacon, Kelly E Dooley, Richard E. Chaisson, Susan Swindells, Radojka M. Savic
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation.
A Multifunctional Nanocomposite Hydrogel Delivery System Based on Dual‐Loaded Liposomes for Scarless Wound Healing
Authors: Danlei Xing, Guoqing Xia, Xudong Tang, Zhiwei Zhuang, Jie Shan, Xiao Fang, Le Qiu, Xiaojun Zha, Xu‐Lin Chen
Journal: Advanced Healthcare Materials (2024)

Abstract Increased inflammatory responses and oxidative stress at the wound site following skin trauma impair healing. Furthermore, skin scarring places fibroblasts under severe mechanical stress and aggravates pathological fibrosis. A novel liposomal composite hydrogel is engineered for wound microenvironment remodeling, incorporating dual‐loaded liposomes into gelatin methacrylate to create a nanocomposite hydrogel. Notably, tetrahydrocurcumin (THC) and hepatocyte growth factor (HGF) are encapsulated in the hydrophobic and hydrophilic layers of liposomes, respectively. The composite hydrogel maintains porous nanoarchitecture, demonstrating sustainable THC and HGF release and enhanced mechanical properties and biocompatibility. This system effectively promotes cell proliferation and angiogenesis and attenuates apoptosis. It decreases the expression of the inflammatory factors by inhibiting the high‐mobility group box /receptor for advanced glycation end product/NF‐κB (HMGB1/RAGE/NF‐κB)pathway and increases macrophage polarization from M1 to M2 in vitro, effectively controlling inflammatory responses. It exhibits remarkable antioxidant properties by scavenging excess reactive oxygen species and free radicals. Most importantly, it effectively prevents scar formation by restraining the transforming growth factor beta (TGF‐β)/Smads pathway that downregulates associated fibrotic factors. It demonstrates strong therapeutic effects against inflammation and fibrosis in a rat skin wound model with biosafety, advancing the development of innovative hydrogel‐based therapeutic delivery strategies for clinical scarless wound therapy.
Enhanced Tissue Regeneration Through Immunomodulatory Extracellular Vesicles Encapsulated in Diversified Silk‐Based Injectable Hydrogels
Authors: Liangyan Sun, Menglin Xiao, Ling Chen, Lingyue Ni, Xiaoxuan Chen, Lina Zhang, Jinrong Yao, Zhengzhong Shao, Bingjiao Zhao, Xin Chen, Yuehua Liu
Journal: Advanced Healthcare Materials (2024)

Abstract Mesenchymal stem cells (MSCs) immunologically trained using lipopolysaccharide (LPS) display enhanced immunomodulatory capabilities. Extracellular vesicles (EVs) derived from MSCs are widely used in regenerative medicine owing to their bioactive properties without the drawbacks of cell therapy. However, it remains unclear whether EVs derived from LPS‐stimulated (trained) MSCs (L‐EVs) inherit the enhanced reparative potential from their parent cells. Thus, this study first aims to explore the effect of immunological training on the bioactivity of L‐EVs. LPS‐trained bone marrow‐derived MSCs (BMSCs) secrete more EVs, and these EVs significantly promote M2 macrophage polarization. Subsequently, hydrogel systems based on thixotropic injectable silk fibroin are prepared for in vivo EV delivery. These hydrogels have controllable gelation time and exhibit outstanding reparative effects on rat skin wounds and alveolar bone defects. Finally, it is revealed that L‐EVs promote M2 macrophage polarization by inhibiting the nuclear translocation of PKM2. Overall, this study shows that the immunological training of BMSCs effectively improves the therapeutic effects of their EVs and provides a convenient and diversified EV delivery strategy using an injectable silk fibroin hydrogel. This strategy has broad clinical application prospects for tissue regeneration.
Cu‐Doping Layered Double Hydroxides Nanozyme Integrated with Nitric Oxide Donor for Enhanced Antioxidant Therapy in Retinopathy
Authors: Bai Xue, Yu Lu, Shuyu Wang, Tingting Wu, Lulu Wang, Qing Xiao, Wei Jiang, Xiyun Yan, Bing Jiang
Journal: Advanced Healthcare Materials (2024)

The prevalence of retinal neovascular diseases necessitates novel treatments beyond current therapies like laser surgery or anti-VEGF treatments, which often carry significant side effects. A novel therapeutic approach is introduced using copper-containing layered double hydroxides (Cu-LDH) nanozymes integrated with nitric oxide-releasing molecules (GSHNO), forming Cu-LDH@GSHNO aimed at combating oxidative stress within the retinal vascular system. Combination of synthetic chemistry and biological testing, Cu-LDH@GSHNO are synthesized, characterized, and assessed for curative effect in HUVECs and an oxygen-induced retinopathy (OIR) mouse model. The results indicate that Cu-LDH@GSHNO demonstrates SOD-CAT cascade catalytic ability, accompanied with GSH and nitric oxide-releasing capabilities, which significantly reduces oxidative cell damage and restores vascular function, presenting a dual-function strategy that enhances treatment efficacy and safety for retinal vascular diseases. The findings encourage further development and clinical exploration of nanozyme-based therapies, promising a new horizon in therapeutic approaches for managing retinal diseases driven by oxidative stress.
Rapid Synthesis of Functions‐Integrated Hydrogel as a Self‐Powered Wound Dressing for Real‐Time Drug Release and Health Monitoring
Authors: Haiyu Li, Hui Zhang, Yangrui Peng, Xinxin Liu, Jie Du, Jianhe Liao
Journal: Advanced Healthcare Materials (2024)

A bio-hydrogel is prepared via a low-cost and time-saving strategy and is studied as a self-powered wound dressing for precision medicine and health monitoring. Promoted by a dual self-catalytic pair composed of Fe
Licensed H5N1 vaccines generate cross-neutralizing antibodies against highly pathogenic H5N1 clade 2.3.4.4b influenza virus
Authors: Surender Khurana, Lisa R King, Jody Manischewitz, Olivia Posadas, Ashish K Mishra, Dongxiao Liu, John H Beigel, Rino Rappuoli, John S Tsang, Hana Golding
Journal: Nature Medicine (2024)
Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction
Authors: Chen Gao, Zhaojun Xiong, Yunxia Liu, Meng Wang, Menglong Wang, Tian Liu, Jianfang Liu, Shuxun Ren, Nancy Cao, Hai Yan, Daniel J. Drucker, Christoph Daniel Rau, Tomohiro Yokota, Jijun Huang, Yibin Wang
Journal: Circulation Research (2024)

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. METHOD: We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lep ob /J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. RESULTS: In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. CONCLUSIONS: These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.
PD1/PD-L1 blockade in clear cell renal cell carcinoma: mechanistic insights, clinical efficacy, and future perspectives
Authors: Zhaoyang Zhu, Yigang Jin, Jing Zhou, Fei Chen, Minjie Chen, Zhaofeng Gao, Lingyu Hu, Jinyan Xuan, Xiaoping Li, Zhengwei Song, Xiao Guo
Journal: Molecular Cancer (2024)

The advent of PD1/PD-L1 inhibitors has significantly transformed the therapeutic landscape for clear cell renal cell carcinoma (ccRCC). This review provides an in-depth analysis of the biological functions and regulatory mechanisms of PD1 and PD-L1 in ccRCC, emphasizing their role in tumor immune evasion. We comprehensively evaluate the clinical efficacy and safety profiles of PD1/PD-L1 inhibitors, such as Nivolumab and Pembrolizumab, through a critical examination of recent clinical trial data. Furthermore, we discuss the challenges posed by resistance mechanisms to these therapies and potential strategies to overcome them. We also explores the synergistic potential of combination therapies, integrating PD1/PD-L1 inhibitors with other immunotherapies, targeted therapies, and conventional modalities such as chemotherapy and radiotherapy. In addition, we examine emerging predictive biomarkers for response to PD1/PD-L1 blockade and biomarkers indicative of resistance, providing a foundation for personalized therapeutic approaches. Finally, we outline future research directions, highlighting the need for novel therapeutic strategies, deeper mechanistic insights, and the development of individualized treatment regimens. Our work summarizes the latest knowledge and progress in this field, aiming to provide a valuable reference for improving clinical efficacy and guiding future research on the application of PD1/PD-L1 inhibitors in ccRCC.
Clinical application of liquid biopsy in colorectal cancer: detection, prediction, and treatment monitoring
Authors: Xiang-Yuan Tao, Qian-Qian Li, Yong Zeng
Journal: Molecular Cancer (2024)

Colorectal cancer (CRC) is one of the most prevalent malignancies affecting the gastrointestinal tract and is ranked third among cancers with the highest incidence and second-highest mortality rate worldwide. CRC exhibits a slow progression providing a wide treatment window. The currently employed CRC screening methods have shown great potential to prevent CRC and reduce CRC-related morbidity and mortality. The diagnosis of CRC is achieved by colonoscopy and tissue biopsy, with studies showing that liquid biopsy is more effective in detecting and diagnosing early CRC patients. Increasing number of studies have shown that the tumor components shed into circulating blood can be detected in liquid form, and can be applied in the clinical management of CRC. Analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), or tumor-associated platelets (TEPs) in the blood can be used for early screening and diagnosis of CRC, aid tumor staging, treatment response monitoring, and prediction of CRC recurrence and metastasis in a minimally invasive manner. This chapter provides an updated review of CTCs, ctDNA, and TEPs as novel biomarkers for CRC, highlighting their strengths and limitations.
Dysferlin Enables Tubular Membrane Proliferation in Cardiac Hypertrophy
Authors: Nora Josefine Paulke, Carolin Fleischhacker, Justus B. Wegener, Gabriel C. Riedemann, Constantin Cretu, Mufassra Mushtaq, Nina Zaremba, Wiebke Möbius, Yannik Zühlke, Jasper Wedemeyer, Lorenz Liebmann, Anastasiia A. Gorshkova, Daniel Kownatzki-Danger, Eva Wagner, Tobias Kohl, Carolin Wichmann, Olaf Jahn, Henning Urlaub, Karl Toischer, Gerd Hasenfuß, Tobias Moser, Julia Preobraschenski, Christof Lenz, Eva A. Rog-Zielinska, Stephan E. Lehnart, Sören Brandenburg
Journal: Circulation Research (2024)

BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies but can result in heart failure if left untreated. Here, we hypothesized that the membrane fusion and repair protein dysferlin is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes and contributes to the proliferation of TAT endomembranes during pressure overload–induced cardiac hypertrophy. METHODS: Stimulated emission depletion and electron microscopy were used to localize dysferlin in mouse and human cardiomyocytes. Data-independent acquisition mass spectrometry revealed the cardiac dysferlin interactome and proteomic changes of the heart in dysferlin-knockout mice. After transverse aortic constriction, we compared the hypertrophic response of wild-type versus dysferlin-knockout hearts and studied TAT network remodeling mechanisms inside cardiomyocytes by live-cell membrane imaging. RESULTS: We localized dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum, a.k.a. junctional complexes for Ca 2+ -induced Ca 2+ release. Interactome analyses demonstrated a novel protein interaction of dysferlin with the membrane-tethering sarcoplasmic reticulum protein juncophilin-2, a putative interactor of L-type Ca 2+ channels and ryanodine receptor Ca 2+ release channels in junctional complexes. Although the dysferlin-knockout caused a mild progressive phenotype of dilated cardiomyopathy, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction, dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while dysferlin-knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging showed a profound reorganization of the TAT network in wild-type left-ventricular myocytes after transverse aortic constriction with robust proliferation of axial tubules, which critically depended on the increased expression of dysferlin within newly emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-sarcoplasmic reticulum junctional complexes for regulated excitation-contraction coupling and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure overload.
Topical treatment of tyrosine kinase 2 inhibitor through borneol-embedded hydrogel: Evaluation for preventive, therapeutic, and Recurrent management of psoriasis
Authors: Yuhsien Lai, Xuesong Wu, Zhuoyu Jiang, Yifei Fang, Xiuting Liu, Dan Hong, Yanyun Jiang, Guozhen Tan, Shiqi Tang, Siyao Lu, David Wei, Sam T Hwang, Kit S Lam, Liangchun Wang, Yanyu Huang, Zhenrui Shi
Journal: Bioactive Materials (2024)

Psoriasis, an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course, continues to be primarily managed through topical therapy. While oral administration of tyrosine kinase 2 inhibitors (TYK2i) stands as an effective approach for psoriasis treatment, the potential efficacy of topical application of TYK2i remains unexplored. Herein, the carbomer/alginic acid hydrogel is embedded with borneol (BO) as a new topical carrier of TYK2i for achieving enhanced transdermal permeation and anti-psoriasis efficacy. The hydrogel system,
Adaptive evolution of two distinct adaptive haplotypes of Neanderthal origin at the immunoglobulin heavy-chain locus in East Asian and European populations
Authors: Xixian Ma, Yan Lu, Shuhua Xu
Journal: Molecular Biology and Evolution (2024)

Abstract Immunoglobulins (Igs) have a crucial role in humoral immunity. Two recent studies have reported a high-frequency Neanderthal-introgressed haplotype throughout Eurasia and a high-frequency Neanderthal-introgressed haplotype specific to southern East Asia at the immunoglobulin heavy-chain (IGH) gene locus on chromosome 14q32.33. Surprisingly, we found the previously reported high-frequency Neanderthal-introgressed haplotype does not exist throughout Eurasia. Instead, our study identified two distinct high-frequency haplotypes of putative Neanderthal origin in East Asia and Europe, although they shared introgressed alleles. Notably, the alleles of putative Neanderthal origin reduced the expression of IGHG1 and increased the expression of IGHG2 and IGHG3 in various tissues. These putatively introgressed alleles also affected the production of IgG1 upon antigen stimulation and increased the risk of systemic lupus erythematosus. Additionally, the greatest genetic differentiation across the whole genome between southern and northern East Asians was observed for the East Asian haplotype of putative Neanderthal origin. The frequency decreased from southern to northern East Asia and correlated positively with the genome-wide proportion of southern East Asian ancestry, indicating that this putative positive selection likely occurred in the common ancestor of southern East Asian populations before the admixture with northern East Asian populations.
FBXL6 is a vulnerability in AML and unmasks proteolytic cleavage as a major experimental pitfall in myeloid cells
Authors: Anna Sperk, Antje Gabriel, Daniela Koch, Abirami Augsburger, Victoria Sanchez, David Brockelt, Rupert Öllinger, Thomas Engleitner, Piero Giansanti, Romina Ludwig, Priska Auf der Maur, Wencke Walter, Torsten Haferlach, Irmela Jeremias, Roland Rad, Barbara Steigenberger, Bernhard Kuster, Ruth Eichner, Florian Bassermann
Journal: Leukemia (2024)

Acute myeloid leukemia (AML) is a heterogeneous blood-borne malignancy with an overall 5-year survival rate of 25 percent [1].Despite substantial genetic characterization in the last decades, only a few targeted therapies, such as FLT3 inhibitors, have entered clinical practice.Treatment still largely relies on chemotherapy and hematopoietic stem cell transplantation in younger patients, and epigenetic therapies as azacytidine in combination with the Bcl-2 inhibitor venetoclax in elderly patients, with the first causing relatively high rates of therapy-associated morbidity and mortality, and the latter showing limited responses [2].Therefore, the identification of new actionable vulnerabilities, beyond genetics and epigenetics, is highly demanded.Approaches investigating aberrant mechanisms on protein level, such as disease-specific post-translational modifications (PTM), hold great promise to provide new therapeutic targets.Ubiquitylation marks the major PTM that regulates the abundance of proteins, thus orchestrating key processes as proliferation, survival, and differentiation [3,4].SCF (SKP1/CUL1/F-box) E3 ubiquitin ligases are characterized by modular complexes containing one of the 72 individual F-box proteins as substrate recruiting receptors, the F-box adapter SKP1, the scaffold protein CUL1, and the RING protein RBX1 [5].While most SCF complexes have not yet been linked to substrates or biological activities, individual members have been found to play key roles in different tumor entities [6,7].Recent reports have now provided first insights into the roles of SCF E3 ligases in AML.Next to identifying the F-box protein FBXL2 as a tumor suppressor [8], the NEDD8 inhibitor pevonedistat showed some additional benefit when combined with azacytidine in AML patients in clinical trials [9], and is undergoing further investigation in AML and further hematological malignancies.Notably, NEDD8 inhibitors prevent