tbuckley/cabot-search huggingface dataset:
Synovial 5‐Lipoxygenase–Derived Oxylipins Define a Lympho‐Myeloid–Enriched Synovium
Authors: Jessica D. Murillo‐Saich, Roxana Coras, Julio Ramirez, Estefania Quesada‐Masachs, Marta Sala‐Climent, Katharina Eschelbach, Christopher B. Mahony, Raquel Celis, Aaron Armando, Oswald Quehenberger, Adam P. Croft, Arthur Kavanaugh, Eric Chang, Juan D. Cañete, Abha Singh, Monica Guma
Journal: Arthritis & Rheumatology (2024)

Oxylipins are bioactive lipids derived from polyunsaturated fatty acids (PUFAs) that modulate inflammation and may remain overexpressed in refractory synovitis. In plasma, they could also be biomarkers of synovial pathology. The aim of this study is to determine if synovial oxylipins in inflamed joints correlate with plasma oxylipins and with synovial histologic patterns.
Antigen-independent, autonomous B cell receptor signaling drives activated B cell DLBCL
Authors: Janneke A. Eken, Marvyn T. Koning, Kristyna Kupcova, Julieta H. Sepúlveda Yáñez, Ruben A.L. de Groen, Edwin Quinten, Jurriaan Janssen, Cornelis A.M. van Bergen, Joost S.P. Vermaat, Arjen Cleven, Marcelo A. Navarrete, Bauke Ylstra, Daphne de Jong, Ondrej Havranek, Hassan Jumaa, Hendrik Veelken
Journal: The Journal of Experimental Medicine (2024)

Diffuse large B cell lymphoma of activated B cell type (ABC-DLBCL), a major cell-of-origin DLBCL subtype, is characterized by chronic active B cell receptor (BCR) signaling and NF-κB activation, which can be explained by activating mutations of the BCR signaling cascade in a minority of cases. We demonstrate that autonomous BCR signaling, akin to its essential pathogenetic role in chronic lymphocytic leukemia (CLL), can explain chronic active BCR signaling in ABC-DLBCL. 13 of 18 tested DLBCL-derived BCR, including 12 cases selected for expression of IgM, induced spontaneous calcium flux and increased phosphorylation of the BCR signaling cascade in murine triple knockout pre-B cells without antigenic stimulation or external BCR crosslinking. Autonomous BCR signaling was associated with IgM isotype, dependent on somatic BCR mutations and individual HCDR3 sequences, and largely restricted to non-GCB DLBCL. Autonomous BCR signaling represents a novel immunological oncogenic driver mechanism in DLBCL originating from individual BCR sequences and adds a new dimension to currently proposed genetics- and transcriptomics-based DLBCL classifications.
Quality and safety of artificial intelligence generated health information
Authors: Michael J Sorich, Bradley D Menz, Ashley M Hopkins
Journal: BMJ (2024)

Generative artificial intelligence (AI) is advancing rapidly and has the potential to greatly improve many aspects of society, including health. The risks of potentially harmful consequences, however, necessitate effective oversight and mitigation measures. This article highlights distinct forms of health related risks of generative AI, with corresponding options for mitigating risk.
Insights from a multicenter study on adult H3 K27M-mutated glioma: Surgical resection’s limited influence on overall survival, ATRX as molecular prognosticator
Authors: Alice Ryba, Zeynep Özdemir, Nitzan Nissimov, Lisa Hönikl, Nicolas Neidert, Martin Jakobs, Darius Kalasauskas, Aleksandrs Krigers, Claudius Thomé, Christian F Freyschlag, Florian Ringel, Andreas Unterberg, Philip Dao Trong, Jürgen Beck, Dieter Henrik Heiland, Bernhard Meyer, Peter Vajkoczy, Julia Onken, Walter Stummer, Eric Suero Molina, Jens Gempt, Manfred Westphal, Ulrich Schüller, Malte Mohme
Journal: Neuro-Oncology (2024)

Abstract Background H3 K27M-mutated gliomas were first described as a new grade 4 entity in the 2016 World Health Organization classification. Current studies have focused on its typical appearance in children and young adults, increasing the need to better understand the prognostic factors and impact of surgery on adults. Here, we report a multicentric study of this entity in adults. Methods We included molecularly confirmed H3 K27M-mutated glioma cases in patients ≥ 18 years diagnosed between 2016 and 2022. Clinical, radiological, and surgical features were analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. Results Among 70 patients with a mean age of 36.1 years, the median overall survival (OS) was 13.6 ± 14 months. Gross-total resection was achieved in 14.3% of patients, whereas 30% had a subtotal resection and 54.3% a biopsy. Tumors located in telencephalon/diencephalon/myelencephalon were associated with a poorer OS, while a location in the mesencephalon/metencephalon showed a significantly longer OS (8.7 vs. 25.0 months, P = .007). Preoperative Karnofsky-Performance Score (KPS) ≤ 80 showed a reduced OS (4.2 vs. 18 months, P = .02). Furthermore, ATRX loss, found in 25.7%, was independently associated with an increased OS (31 vs. 8.3 months, P = .0029). Notably, patients undergoing resection showed no survival benefit over biopsy (12 vs. 11 months, P = .4006). Conclusions The present study describes surgical features of H3 K27M-mutated glioma in adulthood in a large multicentric study. Our data reveal that ATRX status, location and KPS significantly impact OS in H3 K27M-mutated glioma. Importantly, our dataset indicates that resection does not offer a survival advantage over biopsy.
Adaptation in Unstable Environments and Global Gene Losses: Small but Stable Gene Networks by the May–Wigner Theory
Authors: Shaohua Xu, Shao Shao, Xiao Feng, Sen Li, Lingjie Zhang, Weihong Wu, Min Liu, Miles E Tracy, Cairong Zhong, Zixiao Guo, Chung-I Wu, Suhua Shi, Ziwen He
Journal: Molecular Biology and Evolution (2024)

Abstract Although gene loss is common in evolution, it remains unclear whether it is an adaptive process. In a survey of seven major mangrove clades that are woody plants in the intertidal zones of daily environmental perturbations, we noticed that they generally evolved reduced gene numbers. We then focused on the largest clade of Rhizophoreae and observed the continual gene set reduction in each of the eight species. A great majority of gene losses are concentrated on environmental interaction processes, presumably to cope with the constant fluctuations in the tidal environments. Genes of the general processes for woody plants are largely retained. In particular, fewer gene losses are found in physiological traits such as viviparous seeds, high salinity, and high tannin content. Given the broad and continual genome reductions, we propose the May–Wigner theory (MWT) of system stability as a possible mechanism. In MWT, the most effective solution for buffering continual perturbations is to reduce the size of the system (or to weaken the total genic interactions). Mangroves are unique as immovable inhabitants of the compound environments in the land–sea interface, where environmental gradients (such as salinity) fluctuate constantly, often drastically. Extending MWT to gene regulatory network (GRN), computer simulations and transcriptome analyses support the stabilizing effects of smaller gene sets in mangroves vis-à-vis inland plants. In summary, we show the adaptive significance of gene losses in mangrove plants, including the specific role of promoting phenotype innovation and a general role in stabilizing GRN in unstable environments as predicted by MWT.
Managing risk of liver fibrosis in patients with psoriasis being considered for methotrexate
Authors: Fiona Campbell, Philip Laws
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript Managing risk of liver fibrosis in psoriatic patients being considered for methotrexate Get access Fiona Campbell, Fiona Campbell University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK Search for other works by this author on: Oxford Academic Google Scholar Philip Laws Philip Laws University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK Correspondence: Philip Laws, Email:philip.laws2@nhs.net https://orcid.org/0000-0002-4628-0699 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae114, https://doi.org/10.1093/bjd/ljae114 Published: 20 March 2024 Article history Received: 12 March 2024 Accepted: 18 March 2024 Published: 20 March 2024
Beyond the skin: B cells in pemphigus vulgaris, tolerance and treatment
Authors: Anne-Lise Strandmoe, Jeroen Bremer, Gilles F H Diercks, Antoni Gostyński, Emanuele Ammatuna, Hendri H Pas, Marjan Wouthuyzen-Bakker, Gerwin A Huls, Peter Heeringa, Jon D Laman, Barbara Horváth
Journal: British Journal of Dermatology (2024)

Pemphigus vulgaris (PV) is a rare autoimmune bullous disease characterized by blistering of the skin and mucosa owing to the presence of autoantibodies against the desmosome proteins desmoglein 3 and occasionally in conjunction with desmoglein 1. Fundamental research into the pathogenesis of PV has revolutionized its treatment and outcome with rituximab, a B-cell-depleting therapy. The critical contribution of B cells to the pathogenesis of pemphigus is well accepted. However, the exact pathomechanism, mechanisms of onset, disease course and relapse remain unclear. In this narrative review, we provide an overview of the fundamental research progress that has unfolded over the past few centuries to give rise to current and emerging therapies. Furthermore, we summarize the multifaceted roles of B cells in PV, including their development, maturation and antibody activity. Finally, we explored how these various aspects of B-cell function contribute to disease pathogenesis and pave the way for innovative therapeutic interventions.
Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM
Authors: Matteo Bassetti, Daniele R. Giacobbe, Christina Agvald-Ohman, Murat Akova, Ana Alastruey-Izquierdo, Sevtap Arikan-Akdagli, Elie Azoulay, Stijn Blot, Oliver A. Cornely, Manuel Cuenca-Estrella, Dylan W. de Lange, Francesco G. De Rosa, Jan J. De Waele, George Dimopoulos, Jose Garnacho-Montero, Martin Hoenigl, Souha S. Kanj, Philipp Koehler, Bart J. Kullberg, Frédéric Lamoth, Cornelia Lass-Flörl, Johan Maertens, Ignacio Martin-Loeches, Patricia Muñoz, Garyphallia Poulakou, Jordi Rello, Maurizio Sanguinetti, Fabio S. Taccone, Jean-François Timsit, Antoni Torres, Jose A. Vazquez, Joost Wauters, Erika Asperges, Andrea Cortegiani, Cecilia Grecchi, Ilias Karaiskos, Clément Le Bihan, Toine Mercier, Klaus L. Mortensen, Maddalena Peghin, Chiara Rebuffi, Sofia Tejada, Antonio Vena, Valentina Zuccaro, Luigia Scudeller, Thierry Calandra, Claire Roger, Christian Eckmann, Jean-Pierre Gangneux, Esther Segal, Geoffrey Coombs, Andreas Voss
Journal: Intensive Care Medicine (2024)

The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs). After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method. Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.
Electrical impedance tomography-guided positive end-expiratory pressure titration in ARDS: a systematic review and meta-analysis
Authors: Nickjaree Songsangvorn, Yonghao Xu, Cong Lu, Ori Rotstein, Laurent Brochard, Arthur S. Slutsky, Karen E. A. Burns, Haibo Zhang
Journal: Intensive Care Medicine (2024)

Assessing efficacy of electrical impedance tomography (EIT) in optimizing positive end-expiratory pressure (PEEP) for acute respiratory distress syndrome (ARDS) patients to enhance respiratory system mechanics and prevent ventilator-induced lung injury (VILI), compared to traditional methods. We carried out a systematic review and meta-analysis, spanning literature from January 2012 to May 2023, sourced from Scopus, PubMed, MEDLINE (Ovid), Cochrane, and LILACS, evaluated EIT-guided PEEP strategies in ARDS versus conventional methods. Thirteen studies (3 randomized, 10 non-randomized) involving 623 ARDS patients were analyzed using random-effects models for primary outcomes (respiratory mechanics and mechanical power) and secondary outcomes (PaO2/FiO2 ratio, mortality, stays in intensive care unit (ICU), ventilator-free days). EIT-guided PEEP significantly improved lung compliance (n = 941 cases, mean difference (MD) = 4.33, 95% confidence interval (CI) [2.94, 5.71]), reduced mechanical power (n = 148, MD = − 1.99, 95% CI [− 3.51, − 0.47]), and lowered driving pressure (n = 903, MD = − 1.20, 95% CI [− 2.33, − 0.07]) compared to traditional methods. Sensitivity analysis showed consistent positive effect of EIT-guided PEEP on lung compliance in randomized clinical trials vs. non-randomized studies pooled (MD) = 2.43 (95% CI − 0.39 to 5.26), indicating a trend towards improvement. A reduction in mortality rate (259 patients, relative risk (RR) = 0.64, 95% CI [0.45, 0.91]) was associated with modest improvements in compliance and driving pressure in three studies. EIT facilitates real-time, individualized PEEP adjustments, improving respiratory system mechanics. Integration of EIT as a guiding tool in mechanical ventilation holds potential benefits in preventing ventilator-induced lung injury. Larger-scale studies are essential to validate and optimize EIT's clinical utility in ARDS management.
Surveillance for Coccidioidomycosis, Histoplasmosis, and Blastomycosis During the COVID-19 Pandemic — United States, 2019–2021
Authors: Samantha L. Williams, Dallas J. Smith, Kaitlin Benedict, Jamie R. Ahlers, Connie Austin, Rachael Birn, Angel M. Carter, Natalie N. Christophe, Katie Cibulskas, Paul R. Cieslak, Suzanne N. Gibbons-Burgener, Michael Gosciminski, Malia J. Ireland, Katelyn V. Lazenby, Tom Loftus, Kristy Lunquest, Abby A. Mathewson, Alyssa D. Nguyen, Hanna N. Oltean, BreAnne Osborn, Erin M. Petro, Danny J. Power, Rebecca R. Reik, Levi Schlosser, Judi Sedivy, Chad B. Smelser, Tom Chiller, Mitsuru Toda
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Coccidioidomycosis, histoplasmosis, and blastomycosis are lower respiratory tract fungal infections whose signs and symptoms can resemble those of other respiratory illnesses, including pneumonia caused by bacterial or viral etiologies; this overlap in clinical presentation might lead to missed or delayed diagnoses.The causative fungi live in the environment, often in soil or plant matter.To describe the epidemiologic characteristics of cases of coccidioidomycosis, histoplasmosis, and blastomycosis during the COVID-19 pandemic, CDC analyzed case surveillance data for 2019-2021.During this period, a total of 59,655 coccidioidomycosis cases, 3,595 histoplasmosis cases, and 719 blastomycosis cases were reported to CDC.In 2020, fewer cases of each disease occurred in spring compared with other seasons, and most cases occurred in fall; national seasonality is not typically observed, and cases were seasonally distributed more evenly in 2019 and 2021.Fewer cases coinciding with the start of the COVID-19 pandemic, along with an unusually high blastomycosis case fatality rate in 2021 (17% compared with more typical rates of 8%-10%), suggest that the pandemic might have affected patients' health care-seeking behavior, public health reporting practices, or clinical management of these diseases.Increased awareness and education are needed to encourage health care providers to consider fungal diseases and to identify pneumonia of fungal etiology.Standardized diagnostic guidance and informational resources for fungal testing could be incorporated into broader respiratory disease awareness and preparedness efforts to improve early diagnosis of coccidioidomycosis, histoplasmosis, and blastomycosis.
Tuberculosis Preventive Treatment Update — U.S. President’s Emergency Plan for AIDS Relief, 36 Countries, 2016–2023
Authors: Aderonke S. Ajiboye, Stephanie O’Connor, Jonathan P. Smith, Sevim Ahmedov, William L. Coggin, Macarthur Charles, Smita Ghosh, Paul Pierre, Neha Shah, Richard A. Teran, Patrick K. Moonan, Anand Date
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Tuberculosis (TB) is the leading cause of death among persons with HIV.In 2022, an estimated 167,000 TB-related deaths occurred globally among persons with HIV.TB preventive treatment (TPT) helps prevent TB disease and is recommended for persons at high risk for developing TB, including those with HIV.TPT, when taken with antiretroviral treatment (ART), can reduce TB-attributable deaths among persons with HIV.In 2018, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) program committed to offer one course of TPT to all eligible clients receiving ART.This analysis describes trends in TPT initiation and completion among PEPFAR-supported programs in 36 countries in Africa, Central and South America, and Asia during fiscal years (FYs) 2017-2023.Overall, TPT initiation rates peaked in FY19, a possible sign of programmatic saturation.TPT initiation among clients who had been on ART <6 months reached 59%, and overall completion rates up to 87% were reported.Approximately 13 million persons with HIV have completed TPT since FY17, but widespread adoption of shorter regimens, patient-centered approaches, and electronic medical record systems might be needed to ensure full TPT coverage.Through PEPFAR's partnership with national HIV programs, TPT has become the standard of care for persons with HIV.† https://www.cdc.gov/globalhivtb/who-we-are/success-stories/success-storypages/scaling-tpt-ethiopia.html§ https://www.who.int/publications/m/item/political-declaration-of-the-ungeneral-assembly-high-level-meeting-on-the-fight-against-tuberculosis¶ https://na.usembassy.gov/wp-content/uploads/sites/132/PEPFAR-COP18-Guidance_FINAL-1.
Cataloging the phylogenetic diversity of human bladder bacterial isolates
Authors: Jingjie Du, Mark Khemmani, Thomas Halverson, Adriana Ene, Roberto Limeira, Lana Tinawi, Baylie R. Hochstedler-Kramer, Melline Fontes Noronha, Catherine Putonti, Alan J. Wolfe
Journal: Genome biology (2024)

Although the human bladder is reported to harbor unique microbiota, our understanding of how these microbial communities interact with their human hosts is limited, mostly owing to the lack of isolates to test mechanistic hypotheses. Niche-specific bacterial collections and associated reference genome databases have been instrumental in expanding knowledge of the microbiota of other anatomical sites, such as the gut and oral cavity.
The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer
Authors: Junyi Ju, Hui Zhang, Moubin Lin, Zifeng Yan, Liwei An, Zhifa Cao, Dandan Geng, Jingwu Yue, Yang Tang, Luyang Tian, Fan Chen, Yi Han, Wenjia Wang, Shimin Zhao, Shi Jiao, Zhaocai Zhou
Journal: Journal of Clinical Investigation (2024)

Lactylation has been recently identified as a new type of posttranslational modification widely occurring on lysine residues of both histone and non-histone proteins. The acetyl transferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A is about 1,000 times lower than that of acetyl-CoA, raising the question whether p300 is a genuine lactyl-transferase. Here, we report the Alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyl-transferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway that has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for GC patients. Collectively, this work discovered AARS1 with lactyl-transferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation.
Excess glucocorticoids inhibit murine bone turnover via modulating the immunometabolism of the skeletal microenvironment
Authors: Xu Li, Tongzhou Liang, Bingyang Dai, Liang Chang, Yuan Zhang, Shiwen Hu, Jiaxin Guo, Shunxiang Xu, Lizhen Zheng, Hao Yao, Hong Lian, Yu Nie, Ye Li, Xuan He, Zhi Yao, Wenxue Tong, Xinluan Wang, Dick Ho Kiu Chow, Jiankun Xu, Ling Qin
Journal: Journal of Clinical Investigation (2024)

Elevated bone resorption and diminished bone formation have been recognized as the primary features of glucocorticoid-associated skeletal disorders. However, the direct effects of excess glucocorticoids on bone turnover remains unclear. Here, we explored the outcomes of exogenous glucocorticoid treatment on bone loss and delayed fracture healing in mice and found that reduced bone turnover was a dominant feature, resulting in a net loss of bone mass. The primary effect of glucocorticoids on osteogenic differentiation was not inhibitory; instead, they cooperated with macrophages to facilitate osteogenesis. Impaired local nutrient status, notably, obstructed fatty acid transportation, was a key factor contributing to glucocorticoid-induced impairment of bone turnover in vivo. Furthermore, fatty acid oxidation in macrophages fueled the ability of glucocorticoid-liganded receptors to enter the nucleus and then promoted the expression of Bmp2, a key cytokine that facilitates osteogenesis. Metabolic reprogramming by localized fatty acid delivery partly rescued glucocorticoid-induced pathology by restoring a healthier immune-metabolic milieu. These data provide insights into the multifactorial metabolic mechanisms by which glucocorticoids generate skeletal disorders, thus suggesting possible therapeutic avenues.
Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation
Authors: Won Chan Hwang, Kibeom Park, Silvia Park, Na Young Cheon, Ja Yil Lee, Taejoo Hwang, Semin Lee, Jong-Mi Lee, Min Kyung Ju, Joo Rak Lee, Yong-Rim Kwon, Woo-Lam Jo, Myungshin Kim, Yoo-Jin Kim, Hongtae Kim
Journal: Leukemia (2024)

Abstract DEAD box helicase 41 (DDX41) mutations are the most prevalent predisposition to familial myelodysplastic syndrome (MDS). However, the precise roles of these variants in the pathogenesis of MDS have yet to be elucidated. Here, we discovered a novel mechanism by which DDX41 contributes to R-loop-induced DNA damage responses (DDR) in cooperation with the m6A-METTL complex (MAC) and YTHDC1 using DDX41 knockout (KO) and DDX41 knock-in (KI, R525H, Y259C) cell lines as well as primary samples from MDS patients. Compared to wild type (WT), DDX41 KO and KI led to increased levels of m6A RNA methylated R-loop. Interestingly, we found that DDX41 regulates m6A/R-loop levels by interacting with MAC components. Further, DDX41 promoted the recruitment of YTHDC1 to R-loops by promoting the binding between METTL3 and YTHDC1, which was dysregulated in DDX41 -deficient cells, contributing to genomic instability. Collectively, we demonstrated that DDX41 plays a key role in the physiological control of R-loops in cooperation with MAC and YTHDC1. These findings provide novel insights into how defects in DDX41 influence MDS pathogenesis and suggest potential therapeutic targets for the treatment of MDS.