tbuckley/cabot-search huggingface dataset:
Age-Dependent RGS5 Loss in Pericytes Induces Cardiac Dysfunction and Fibrosis
Authors: Anita Tamiato, Lukas S. Tombor, Ariane Fischer, Marion Muhly-Reinholz, Leah Rebecca Vanicek, Büşra Nur Toğru, Jessica Neitz, Simone Franziska Glaser, Maximilian Merten, David Rodriguez Morales, Jeonghyeon Kwon, Stephan Klatt, Bianca Schumacher, Stefan Günther, Wesley T. Abplanalp, David John, Ingrid Fleming, Nina Wettschureck, Stefanie Dimmeler, Guillermo Luxán
Journal: Circulation Research (2024)

BACKGROUND: Pericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although aging is one of the main risk factors for cardiovascular disease, the consequences of aging on cardiac pericytes are unknown. METHODS: In this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of aging on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of RGS5 (regulator of G-protein signaling 5) loss of function and finally have performed pericytes-fibroblasts coculture studies to understand the effect of RGS5 deletion in pericytes on the neighboring fibroblasts. RESULTS: Aging reduced the pericyte area and capillary coverage in the murine heart. Single-nucleus RNA sequencing analysis further revealed that the expression of Rgs5 was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, induced fibrosis, and morphological changes in pericytes characterized by a profibrotic gene expression signature and the expression of different ECM (extracellular matrix) components and growth factors, for example, TGFB2 and PDGFB . Indeed, culturing fibroblasts with the supernatant of RGS5-deficient pericytes induced their activation as evidenced by the increased expression of αSMA (alpha smooth muscle actin) in a TGFβ (transforming growth factor beta)2-dependent mechanism. CONCLUSIONS: Our results have identified RGS5 as a crucial regulator of pericyte function during cardiac aging. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac aging.
Correction: Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis
Authors: Ming G. Chai, Quyen Tu, Menino O. Cotta, Michelle J. Bauer, Ross Balch, Charles Okafor, Tracy Comans, Peter Kruger, Jason Meyer, Kiran Shekar, Kara Brady, Cheryl Fourie, Natalie Sharp, Luminita Vlad, David Whiley, Jacobus P. J. Ungerer, Brett C. Mcwhinney, Andras Farkas, David L. Paterson, Julia E. Clark, Krispin Hajkowicz, Sainath Raman, Seweryn Bialasiewicz, Jeffrey Lipman, Brian M. Forde, Patrick N. A. Harris, Luregn J. Schlapbach, Lachlan Coin, Jason A. Roberts, Adam D. Irwin
Journal: Intensive Care Medicine (2024)
Involvement of the <scp>JAK</scp>‐<scp>STAT</scp> pathway in the molecular landscape of tyrosine kinase fusion‐negative hypereosinophilic syndromes: A nationwide <scp>CEREO</scp> study
Authors: Matthieu Groh, Laurène Fenwarth, Mathilde Labro, Augustin Boudry, Elise Fournier, Mathieu Wemeau, Alice Marceau‐Renaut, Rafael Daltro de Oliveira, Julie Abraham, Marly Barry, Philippe Blanche, Quentin Bodard, Thorsten Braun, Safia Chebrek, Matthieu Decamp, Cécile‐Audrey Durel, Edouard Forcade, Mathieu Gerfaud‐Valentin, Camille Golfier, Clément Gourguechon, Nathalie Grardel, Olivier Kosmider, Nihal Martis, Sarah Melboucy Belkhir, Fatiha Merabet, Adrien Michon, Stéphane Moreau, Cécile Morice, Antoine Néel, Franck E. Nicolini, Laurent Pascal, Florence Pasquier, Andrea Pieragostini, Catherine Roche‐Lestienne, Philippe Rousselot, Louis Terriou, Anne Thiebaut‐Bertrand, Jean‐François Viallard, Claude Preudhomme, Jean‐Emmanuel Kahn, Guillaume Lefevre, Nicolas Duployez
Journal: American Journal of Hematology (2024)

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HE
Lifileucel, an Autologous Tumor-infiltrating Lymphocyte Monotherapy, in Patients with Advanced Non-small Cell Lung Cancer Resistant to Immune Checkpoint Inhibitors
Authors: Adam J. Schoenfeld, Sylvia M. Lee, Bernard Doger de Spéville, Scott N. Gettinger, Simon Häfliger, Ammar Sukari, Sophie Papa, Juan F. Rodríguez-Moreno, Friedrich Graf Finckenstein, Rana Fiaz, Melissa Catlett, Guang Chen, Rongsu Qi, Emma L. Masteller, Viktoria Gontcharova, Kai He
Journal: Cancer Discovery (2024)

Abstract In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non–small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1–6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1–negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1−negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy. Significance: Autologous tumor-infiltrating lymphocyte therapy lifileucel was administered to 28 patients with heavily pretreated metastatic non–small cell lung cancer (mNSCLC). Responses were observed in patients with driver mutations, and various tumor mutational burdens and PD-L1 expression, potentially addressing an unmet medical need in patients with mNSCLC refractory to prior therapy. See related commentary by Lotze et al., p. 1366
Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation
Authors: Megan Mulholland, Marie A C Depuydt, Gabriel Jakobsson, Irena Ljungcrantz, Andrietta Grentzmann, Fong To, Eva Bengtsson, Elin Jaensson Gyllenbäck, Caitríona Grönberg, Sara Rattik, David Liberg, Alexandru Schiopu, Harry Björkbacka, Johan Kuiper, Ilze Bot, Bram Slütter, Daniel Engelbertsen
Journal: Cardiovascular Research (2024)

Abstract Aims The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis. Methods and results Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E–deficient (Apoe−/−) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade. Conclusion Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.
Quality of Large Language Model Responses to Radiation Oncology Patient Care Questions
Authors: Amulya Yalamanchili, Bishwambhar Sengupta, Joshua Song, Sara Lim, Tarita O. Thomas, Bharat B. Mittal, Mohamed E. Abazeed, P. Troy Teo
Journal: JAMA Network Open (2024)

Artificial intelligence (AI) large language models (LLMs) demonstrate potential in simulating human-like dialogue. Their efficacy in accurate patient-clinician communication within radiation oncology has yet to be explored.
Exploring Mechanisms of Lipid Nanoparticle‐Mucus Interactions in Healthy and Cystic Fibrosis Conditions
Authors: Belal Tafech, Mohammad‐Reza Rokhforouz, Jerry Leung, Molly MH Sung, Paulo JC Lin, Don D Sin, Daniel Lauster, Stephan Block, Bradley S. Quon, Ying Tam, Pieter Cullis, James J Feng, Sarah Hedtrich
Journal: Advanced Healthcare Materials (2024)

Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerge as versatile non-viral gene delivery systems that can help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics (BD) simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery.
Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity
Authors: Max C. Petersen, Gordon I. Smith, Hector H. Palacios, Sarah S. Farabi, Mihoko Yoshino, Jun Yoshino, Kevin Cho, Victor G. Davila-Roman, Mahalakshmi Shankaran, Ruteja A. Barve, Jinsheng Yu, Jennifer H. Stern, Bruce W. Patterson, Marc K. Hellerstein, Gerald I. Shulman, Gary J. Patti, Samuel Klein
Journal: Cell Metabolism (2024)

There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).
Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss
Authors: Dongxian Guan, Yuqin Men, Alexander Bartlett, Mario Andrés Salazar Hernández, Jie Xu, Xinchi Yi, Hu-song Li, Dong Kong, Ralph Mazitschek, Umut Ozcan
Journal: Cell Metabolism (2024)
Unlocking the power of postbiotics: A revolutionary approach to nutrition for humans and animals
Authors: Xinjie Zhao, Shuai Liu, Sumin Li, Wen Jiang, Jingjun Wang, Jianxin Xiao, Tianyu Chen, Jiaying Ma, Muhammad Zahoor Khan, Wei Wang, Mengmeng Li, Shengli Li, Zhijun Cao
Journal: Cell Metabolism (2024)

Postbiotics, which comprise inanimate microorganisms or their constituents, have recently gained significant attention for their potential health benefits. Extensive research on postbiotics has uncovered many beneficial effects on hosts, including antioxidant activity, immunomodulatory effects, gut microbiota modulation, and enhancement of epithelial barrier function. Although these features resemble those of probiotics, the stability and safety of postbiotics make them an appealing alternative. In this review, we provide a comprehensive summary of the latest research on postbiotics, emphasizing their positive impacts on both human and animal health. As our understanding of the influence of postbiotics on living organisms continues to grow, their application in clinical and nutritional settings, as well as animal husbandry, is expected to expand. Moreover, by substituting postbiotics for antibiotics, we can promote health and productivity while minimizing adverse effects. This alternative approach holds immense potential for improving health outcomes and revolutionizing the food and animal products industries.
Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine
Authors: Sophie Mouillet-Richard, Antoine Cazelles, Marine Sroussi, Claire Gallois, Julien Taieb, Pierre Laurent-Puig
Journal: Clinical Cancer Research (2024)

Abstract Over the past decade, our understanding of the diversity of colorectal cancer has expanded significantly, raising hopes of tailoring treatments more precisely for individual patients. A key achievement in this direction was the establishment of the consensus molecular classification, particularly identifying the challenging consensus molecular subtype (CMS) CMS4 associated with poor prognosis. Because of its aggressive nature, extensive research is dedicated to the CMS4 subgroup. Recent years have unveiled molecular and microenvironmental features at the tissue level specific to CMS4 colorectal cancer. This has paved the way for mechanistic studies and the development of preclinical models. Simultaneously, efforts have been made to easily identify patients with CMS4 colorectal cancer. Reassessing clinical trial results through the CMS classification lens has improved our understanding of the therapeutic challenges linked to this subtype. Exploration of the biology of CMS4 colorectal cancer is yielding potential biomarkers and novel treatment approaches. This overview aims to provide insights into the clinico-biological characteristics of the CMS4 subgroup, the molecular pathways driving this subtype, and available diagnostic options. We also emphasize the therapeutic challenges associated with this subtype, offering potential explanations. Finally, we summarize the current tailored treatments for CMS4 colorectal cancer emerging from fundamental and preclinical studies.
Gastrointestinal microbiota and metabolites possibly contribute to distinct pathogenicity of SARS-CoV-2 proto or its variants in rhesus monkeys
Authors: Hongyu Chen, Junbin Wang, Kaiyun Ding, Jingwen Xu, Yun Yang, Cong Tang, Yanan Zhou, Wenhai Yu, Haixuan Wang, Qing Huang, Bai Li, Dexuan Kuang, Daoju Wu, Zhiwu Luo, Jiahong Gao, Yuan Zhao, Jiansheng Liu, Xiaozhong Peng, Shuaiyao Lu, Hongqi Liu
Journal: Gut Microbes (2024)

Gastrointestinal (GI) infection is evidenced with involvement in COVID-19 pathogenesis caused by SARS-CoV-2. However, the correlation between GI microbiota and the distinct pathogenicity of SARS-CoV-2 Proto and its emerging variants remains unclear. In this study, we aimed to determine if GI microbiota impacted COVID-19 pathogenesis and if the effect varied between SARS-CoV-2 Proto and its variants. We performed an integrative analysis of histopathology, microbiomics, and transcriptomics on the GI tract fragments from rhesus monkeys infected with SARS-CoV-2 proto or its variants. Based on the degree of pathological damage and microbiota profile in the GI tract, five of SARS-CoV-2 strains were classified into two distinct clusters, namely, the clusters of Alpha, Beta and Delta (ABD), and Proto and Omicron (PO). Notably, the abundance of potentially pathogenic microorganisms increased in ABD but not in the PO-infected rhesus monkeys. Specifically, the high abundance of UCG-002, UCG-005, and Treponema in ABD virus-infected animals positively correlated with interleukin, integrins, and antiviral genes. Overall, this study revealed that infection-induced alteration of GI microbiota and metabolites could increase the systemic burdens of inflammation or pathological injury in infected animals, especially in those infected with ABD viruses. Distinct GI microbiota and metabolite profiles may be responsible for the differential pathological phenotypes of PO and ABD virus-infected animals. These findings improve our understanding the roles of the GI microbiota in SARS-CoV-2 infection and provide important information for the precise prevention, control, and treatment of COVID-19.
Author Correction: Systemic dysfunction and plasticity of the immune macroenvironment in cancer models
Authors: Breanna M. Allen, Kamir J. Hiam, Cassandra E. Burnett, Anthony Venida, Rachel DeBarge, Iliana Tenvooren, Diana M. Marquez, Nam Woo Cho, Yaron Carmi, Matthew H. Spitzer
Journal: Nature Medicine (2024)
Toward an internationally accepted standard for reading charts
Authors: Wolfgang Radner
Journal: Progress in Retinal and Eye Research (2024)

Patients who suffer from sight-threatening eye diseases share a desire to regain a comfortable reading ability. In light of the modern advances achieved in ophthalmic diagnosis and therapy, and because a significant lack of comparability between reading charts still exists, there is an increasing need for a worldwide standard in the form of a norm for diagnostic reading charts. Already, applied advancements such as digital print, which allow a calibration of the print sizes of reading charts in correctly progressing geometric proportions by using the actual height of a lower case "x" in millimeters (x-height), and psychophysically standardizing reading charts and their test items by applying modern statistical methods have significantly contributed to establishing a norm for reading charts. In 2020, a proposal of the British delegation was accepted by the International Organization for Standardization (ISO) group "Visual Optics and Optical Instruments," and a working group was established. Bearing in mind the efforts of the ISO with regard to an international norm, this review article is intended to (a) give an overview of the historical background and related normative approaches for diagnostic reading tests used in ophthalmology and optometry, (b) explain psychophysical and technical concerns, and (c) discuss the possibilities and limits of concepts that seem relevant to developing a modern standard for reading charts.
Risk of death in Klebsiella pneumoniae bloodstream infections is associated with specific phylogenetic lineages
Authors: Aasmund Fostervold, Niclas Raffelsberger, Marit A.K. Hetland, Ragna Bakksjø, Eva Bernhoff, Ørjan Samuelsen, Arnfinn Sundsfjord, Jan E. Afset, Christopher F. Berntsen, Roar Bævre-Jensen, Marit H. Ebbesen, Karianne W. Gammelsrud, Anja D. Guleng, Nina Handal, Aleksandra Jakovljev, Simreen K. Johal, Åshild Marvik, Ane Natvik, Rolf-Arne Sandnes, Ståle Tofteland, Jørgen V. Bjørnholt, Iren H. Löhr
Journal: Journal of Infection (2024)

BackgroundKlebsiella pneumoniae species complex (KpSC) bloodstream infections (BSIs) are associated with considerable morbidity and mortality, particularly in elderly and multimorbid patients. Multidrug resistant (MDR) strains have been associated with poorer outcome. However, the clinical impact of KpSC phylogenetic lineages on BSI outcome is unclear.MethodsIn an 18-month nationwide Norwegian prospective study of KpSC BSI episodes in adults, we used whole genome sequencing to describe the molecular epidemiology of KpSC, and multivariable Cox regression analysis including clinical data to determine adjusted hazard ratios (aHR) for death associated with specific genomic lineages.FindingsWe included 1078 BSI episodes and 1082 bacterial isolates from 1055 patients. The overall 30-day case-fatality rate (CFR) was 12.5%. Median patient age was 73.4, 61.7% of patients were male. Median Charlson comorbidity score was 3. Klebsiella pneumoniae sensu stricto (Kp) (79.3%, n=858/1082) and K. variicola (15.7%, n=170/1082) were the dominating phylogroups. Global MDR-associated Kp clonal groups (CGs) were prevalent (25.0%, n=270/1082) but 78.9% (n=213/270) were not MDR, and 53.7% (n=145/270) were community acquired. The major findings were increased risk for death within 30 days in monomicrobial BSIs caused by K. variicola (CFR 16.9%, n=21; aHR 1.86, CI 1.10-3.17, p=0.02), and global MDR-associated Kp CGs (CFR 17.0%, n=36; aHR 1.52, CI 0.98-2.38, p=0.06) compared to Kp CGs not associated with MDR (CFR 10.1%, n=46).ConclusionBacterial traits, beyond antimicrobial resistance, have a major impact on the clinical outcome of KpSC BSIs. The global spread of MDR-associated Kp CGs is driven by other mechanisms than antibiotic selection alone. Further insights into virulence determinants, and their association with phylogenetic lineages are needed to better understand the epidemiology of KpSC infection and clinical outcome.
Publisher Correction: Bacteria-mediated resistance of neutrophil extracellular traps to enzymatic degradation drives the formation of dental calculi
Authors: Mei-chen Wan, Kai Jiao, Yi-na Zhu, Qian-qian Wan, Yi-peng Zhang, Long-zhang Niu, Chen Lei, Jing-han Song, Wei-cheng Lu, Hua-jie Liu, Zhao-yang Ren, Franklin Tay, Li-na Niu
Journal: Nature Biomedical Engineering (2024)