tbuckley/cabot-search huggingface dataset:
Age-specific induction of mutant p53 drives clonal hematopoiesis and acute myeloid leukemia in adult mice
Authors: Rasoul Pourebrahim, Rafael Heinz Montoya, Hiroki Akiyama, Lauren Ostermann, Shayuan Khazaei, Muharrem Muftuoglu, Natalia Baran, Ran Zhao, Tom Lesluyes, Bin Liu, Joseph D. Khoury, Mihai Gagea, Peter Van Loo, Michael Andreeff
Journal: Cell Reports Medicine (2024)

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.
Structural transitions enable interleukin-18 maturation and signaling
Authors: Ying Dong, Jeffrey P. Bonin, Pascal Devant, Zhuoyi Liang, Alexander I.M. Sever, Julian Mintseris, James M. Aramini, Gang Du, Stephen P. Gygi, Jonathan C. Kagan, Lewis E. Kay, Hao Wu
Journal: Immunity (2024)
Plasma versus Tissue Tumor Mutational Burden as Biomarkers of Durvalumab plus Tremelimumab Response in Patients with Metastatic Colorectal Cancer in the CO.26 Trial
Authors: Jonathan M. Loree, Emma Titmuss, James T. Topham, Hagen F. Kennecke, Harriet Feilotter, Shakeel Virk, Young S. Lee, Kimberly Banks, Katie Quinn, Aly Karsan, Daniel J. Renouf, Derek J. Jonker, Dongsheng Tu, Chris J. O’Callaghan, Eric X. Chen
Journal: Clinical Cancer Research (2024)

Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold.
Two-Thirds of Unhoused People Have Mental Health Disorders
Authors: Emily Harris
Journal: JAMA (2024)

Rebecca Barry, PhD; Jennifer Anderson, BSc; Lan Tran, BA, BKin; Anees Bahji, MD; Gina Dimitropoulos, PhD; S. Monty Ghosh, MD, MPH; Julia Kirkham, MD; Geoffrey Messier, PhD; Scott B. Patten, MD, PhD; Katherine Rittenbach, PhD; Dallas Seitz, MD, PhD
Patient research partner involvement in rheumatology research: a systematic literature review informing the 2023 updated EULAR recommendations for the involvement of patient research partners
Authors: Krystel Aouad, Maarten de Wit, Muriel Elhai, Diego Benavent, Heidi Bertheussen, Condruta Zabalan, Jette Primdahl, Paul Studenic, Laure Gossec
Journal: Annals of the Rheumatic Diseases (2024)

Patient research partners (PRPs) are people with a disease who collaborate in a research team as partners. The aim of this systematic literature review (SLR) was to assess barriers and facilitators to PRP involvement in rheumatology research. The SLR was conducted in PubMed/Medline for articles on PRP involvement in rheumatology research, published between 2017 and 2023; websites were also searched in rheumatology and other specialties. Data were extracted regarding the definition of PRPs, their role and added value, as well as barriers and facilitators to PRP involvement. The quality of the articles was assessed. Quantitative data were analysed descriptively, and principles of thematic content analysis was applied to qualitative data. Of 1016 publications, 53 articles were included; the majority of these studies were qualitative studies (26%), opinion articles (21%), meeting reports (17%) and mixed-methods studies (11%). Roles of PRPs ranged from research partners to patient advocates, advisors and patient reviewers. PRPs were reported/advised to be involved early in the project (32% of articles) and in all research phases (30%), from the conception stage to the implementation of research findings. The main barriers were challenges in communication and support for both PRPs and researchers. Facilitators of PRP involvement included more than one PRP per project, training of PRPs and researchers, a supportive environment for PRPs (including adequate communication, acknowledgement and compensation of PRPs) and the presence of a PRP coordinator. This SLR identified barriers and facilitators to PRP involvement, and was key to updating the European Alliance of Associations for Rheumatology recommendations for PRP-researcher collaboration based on scientific evidence.
The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease
Authors: Siyan Cao, Jose L. Fachi, Kaiming Ma, Alina Ulezko Antonova, Qianli Wang, Zhangying Cai, Randal J. Kaufman, Matthew A. Ciorba, Parakkal Deepak, Marco Colonna
Journal: Journal of Clinical Investigation (2024)

Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. Endoplasmic reticulum (ER) stress is linked to inflammatory bowel disease (IBD). Herein, we used cell culture, mouse models, and human specimens to examine if ER stress in ILC3s impacts IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24h-rhythmic expression pattern of the master ER stress response regulator, IRE1α/XBP1. Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial reactive oxygen species (mtROS). IRE1α/XBP1 was activated in ILC3s of mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in Crohn's disease patients before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with response to treatment. We demonstrate that a non-canonical mtROS-IRE1α/XBP1 pathway augments cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting response to anti-IL-23 therapies in IBD.
Generalized sleep decoding with basal ganglia signals in multiple movement disorders
Authors: Zixiao Yin, Huiling Yu, Tianshuo Yuan, Clay Smyth, Md Fahim Anjum, Guanyu Zhu, Ruoyu Ma, Yichen Xu, Qi An, Yifei Gan, Timon Merk, Guofan Qin, Hutao Xie, Ning Zhang, Chunxue Wang, Yin Jiang, Fangang Meng, Anchao Yang, Wolf-Julian Neumann, Philip Starr, Simon Little, Luming Li, Jianguo Zhang
Journal: npj Digital Medicine (2024)

Abstract Sleep disturbances profoundly affect the quality of life in individuals with neurological disorders. Closed-loop deep brain stimulation (DBS) holds promise for alleviating sleep symptoms, however, this technique necessitates automated sleep stage decoding from intracranial signals. We leveraged overnight data from 121 patients with movement disorders (Parkinson’s disease, Essential Tremor, Dystonia, Essential Tremor, Huntington’s disease, and Tourette’s syndrome) in whom synchronized polysomnograms and basal ganglia local field potentials were recorded, to develop a generalized, multi-class, sleep specific decoder – BGOOSE . This generalized model achieved 85% average accuracy across patients and across disease conditions, even in the presence of recordings from different basal ganglia targets. Furthermore, we also investigated the role of electrocorticography on decoding performances and proposed an optimal decoding map, which was shown to facilitate channel selection for optimal model performances. BGOOSE emerges as a powerful tool for generalized sleep decoding, offering exciting potentials for the precision stimulation delivery of DBS and better management of sleep disturbances in movement disorders.
The power of Para sport: the effect of performance-focused swimming training on motor function in adolescents with cerebral palsy and high support needs (GMFCS IV) – a single-case experimental design with 30-month follow-up
Authors: Iain Mayank Dutia, Mark Connick, Emma Beckman, Leanne Johnston, Paula Wilson, Angelo Macaro, Jennifer O'Sullivan, Sean Tweedy
Journal: British Journal of Sports Medicine (2024)

Objective This study aims to evaluate the effect of a performance-focused swimming programme on motor function in previously untrained adolescents with cerebral palsy and high support needs (CPHSN) and to determine whether the motor decline typical of adolescents with CPHSN occurred in these swimmers. Methods A Multiple-Baseline, Single-Case Experimental Design (MB-SCED) study comprising five phases and a 30-month follow-up was conducted. Participants were two males and one female, all aged 15 years, untrained and with CPHSN. The intervention was a 46-month swimming training programme, focused exclusively on improving performance. Outcomes were swim performance (velocity); training load (rating of perceived exertion min/week; swim distance/week) and Gross Motor Function Measure-66-Item Set (GMFM-66). MB-SCED data were analysed using interrupted time-series simulation analysis. Motor function over 46 months was modelled (generalised additive model) using GMFM-66 scores and compared with a model of predicted motor decline. Results Improvements in GMFM-66 scores in response to training were significant (p&lt;0.001), and two periods of training withdrawal each resulted in significant motor decline (p≤0.001). Participant motor function remained above baseline levels for the study duration, and, importantly, participants did not experience the motor decline typical of other adolescents with CPHSN. Weekly training volumes were also commensurate with WHO recommended physical activity levels. Conclusions Results suggest that adolescents with CPHSN who meet physical activity guidelines through participation in competitive swimming may prevent motor decline. However, this population is clinically complex, and in order to permit safe, effective participation in competitive sport, priority should be placed on the development of programmes delivered by skilled multiprofessional teams. Trial registration number ACTRN12616000326493.
Applications of Quantitative Microbial Risk Assessment to Respiratory Pathogens and Implications for Uptake in Policy: A State-of-the-Science Review
Authors: Lizhan Tang, William J. Rhoads, Antonia Eichelberg, Kerry A. Hamilton, Timothy R. Julian
Journal: Environmental Health Perspectives (2024)

BACKGROUND: Respiratory tract infections are major contributors to the global disease burden.Quantitative microbial risk assessment (QMRA) holds potential as a rapidly deployable framework to understand respiratory pathogen transmission and inform policy on infection control.OBJECTIVES: The goal of this paper was to evaluate, motivate, and inform further development of the use of QMRA as a rapid tool to understand the transmission of respiratory pathogens and improve the evidence base for infection control policies.METHODS: We conducted a literature review to identify peer-reviewed studies of complete QMRA frameworks on aerosol inhalation or contact transmission of respiratory pathogens.From each of the identified studies, we extracted and summarized information on the applied exposure model approaches, dose-response models, and parameter values, including risk characterization.Finally, we reviewed linkages between model outcomes and policy.RESULTS: We identified 93 studies conducted in 16 different countries with complete QMRA frameworks for diverse respiratory pathogens, including SARS-CoV-2, Legionella spp., Staphylococcus aureus, influenza, and Bacillus anthracis.Six distinct exposure models were identified across diverse and complex transmission pathways.In 57 studies, exposure model frameworks were informed by their ability to model the efficacy of potential interventions.Among interventions, masking, ventilation, social distancing, and other environmental source controls were commonly assessed.Pathogen concentration, aerosol concentration, and partitioning coefficient were influential exposure parameters as identified by sensitivity analysis.Most (84%, n = 78) studies presented policy-relevant content including a) determining disease burden to call for policy intervention, b) determining risk-based threshold values for regulations, c) informing intervention and control strategies, and d) making recommendations and suggestions for QMRA application in policy.CONCLUSIONS: We identified needs to further the development of QMRA frameworks for respiratory pathogens that prioritize appropriate aerosol exposure modeling approaches, consider trade-offs between model validity and complexity, and incorporate research that strengthens confidence in QMRA results.
When I use a word . . . The languages of medicines—generics and bioavailability
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

The term "generic" derives from an IndoEuropean linguistic root, GN, which implies both knowing and begetting, and comes down to us via the Latin noun genus, a class or type. Generic drug names are names like British Approved Names and International Nonproprietary Names, which are simpler than the full chemical names that drugs have. Furthermore, they dissociate the drug from its original manufacturer, which will have marketed it under a brand name. Thus, on expiry of a patent that a company has taken out on an innovative medicine, other companies are at liberty to market the compound using its generic name. However, when they do so they are required to demonstrate that the bioavailability, or systemic availability, of the drug, from whatever formulation they market, is identical, or at least closely similar, to that of the originator's comparable formulation. They typically do this in studies of healthy volunteers under standard conditions, but occasionally a patient may not be represented by the results of such studies, because of age, for example, or because the conditions under which they take the drug are different from those in the formal study. It may then happen that a patient switches from one product to another and finds that the resulting outcome of treatment changes. In that case it may be that the new product has a different availability in that individual than would have been expected. If that happens, be prepared to prescribe a different marketed formulation of the same drug. In a few cases of modified-release formulations, it is better to stick to the same branded formulation throughout the period of treatment.
Novel functions for Von Willebrand factor
Authors: Ferdows Atiq, James S. O’Donnell
Journal: Blood (2024)

For many years, it has been known that von Willebrand factor (VWF) interacts with factor VIII, collagen, and platelets. In addition, the key roles played by VWF in regulating normal hemostasis have been well defined. However, accumulating recent evidence has shown that VWF can interact with a diverse array of other novel ligands. To date, over 60 different binding partners have been described, with interactions mapped to specific VWF domains in some cases. Although the biological significance of these VWF-binding interactions has not been fully elucidated, recent studies have identified some of these novel ligands as regulators of various aspects of VWF biology, including biosynthesis, proteolysis, and clearance. Conversely, VWF binding has been shown to directly affect the functional properties for some of its ligands. In keeping with those observations, exciting new roles for VWF in regulating a series of nonhemostatic biological functions have also emerged. These include inflammation, wound healing, angiogenesis, and bone metabolism. Finally, recent evidence supports the hypothesis that the nonhemostatic functions of VWF directly contribute to pathogenic mechanisms in a variety of diverse diseases including sepsis, malaria, sickle cell disease, and liver disease. In this manuscript, we review the accumulating data regarding novel ligand interactions for VWF and critically assess how these interactions may affect cellular biology. In addition, we consider the evidence that nonhemostatic VWF functions may contribute to the pathogenesis of human diseases beyond thrombosis and bleeding.
Redefine ‘benign’: a misnomer in the context of patients with genetic skin tumour syndromes
Authors: Julie Robinson, Nour Kibbi, Neil Rajan
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript Redefine "benign": A misnomer in the context of patients with genetic skin tumour syndromes Get access Julie Robinson, Julie Robinson Patient Search for other works by this author on: Oxford Academic Google Scholar Nour Kibbi, Nour Kibbi Stanford University, Department of Dermatology, Palo Alto, CA, USA Search for other works by this author on: Oxford Academic Google Scholar Neil Rajan Neil Rajan Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UKTranslational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK Corresponding author: Neil Rajan, MBBS PhD, Email:neil.rajan@newcastle.ac.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae185, https://doi.org/10.1093/bjd/ljae185 Published: 10 May 2024 Article history Received: 16 April 2024 Accepted: 26 April 2024 Published: 10 May 2024
A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression
Authors: Michael P. Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Alisha Holtzhausen, Georgia M. Beasley, Balamayooran Theivanthiran, Brent A. Hanks
Journal: Science Immunology (2024)

Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8 + T cell activation and suppressed melanoma progression. CD63 + mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63 + mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.
Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF
Authors: Maximilian Trum, Johannes Riechel, Elisa Schollmeier, Simon Lebek, Philipp Hegner, Kathrin Reuthner, Silvia Heers, Karoline Keller, Michael Wester, Susanne Klatt, Nazha Hamdani, Zdenek Provaznik, Christof Schmid, Lars Maier, Michael Arzt, Stefan Wagner
Journal: Cardiovascular Research (2024)

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are frequently observed in HFpEF. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial anti-arrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. Methods and results Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green–2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs. HFpEF: 0.21 ± 0.02 vs. 0.38 ± 0.04 mmol/L/min (N = 7 vs. 18); P = 0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. Conclusion We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to anti-arrhythmic effects in patients with HFpEF.
Does IPSS-R down staging before transplantation improve the prognosis of patients with Myelodysplastic neoplasms?
Authors: Christof Scheid, Diderik-Jan Eikema, Michel van Gelder, Urpu Salmenniemi, Johan Maertens, Jakob Passweg, Didier Blaise, Jennifer L. Byrne, Nicolaus Kröger, Katja Sockel, Patrice Chevallier, Jean Henri Bourhis, Jan J. Cornelissen, Henrik Sengeloev, Jürgen Finke, John A. Snowden, Tobias Gedde-Dahl, Jérôme Cornillon, Urs Schanz, Amit Patel, Linda Koster, Liesbeth C. de Wreede, Patrick Hayden, Kavita Raj, Joanna Drozd-Sokolowska, Carmelo Gurnari, Francesco Onida, Donal P. McLornan, Marie Robin, Ibrahim Yakoub-Agha
Journal: Blood (2024)
Nucleobase adducts bind MR1 and stimulate MR1-restricted T cells
Authors: Alessandro Vacchini, Andrew Chancellor, Qinmei Yang, Rodrigo Colombo, Julian Spagnuolo, Giuliano Berloffa, Daniel Joss, Ove Øyås, Chiara Lecchi, Giulia De Simone, Aisha Beshirova, Vladimir Nosi, José Pedro Loureiro, Aurelia Morabito, Corinne De Gregorio, Michael Pfeffer, Verena Schaefer, Gennaro Prota, Alfred Zippelius, Jörg Stelling, Daniel Häussinger, Laura Brunelli, Peter Villalta, Marco Lepore, Enrico Davoli, Silvia Balbo, Lucia Mori, Gennaro De Libero
Journal: Science Immunology (2024)

MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I–related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.