tbuckley/cabot-search huggingface dataset:
Uncovering two neutrophil-committed progenitors that immediately precede promyelocytes during human neutropoiesis
Authors: Ilaria Signoretto, Federica Calzetti, Giulia Finotti, Silvia Lonardi, Camillo Balanzin, Francisco Bianchetto-Aguilera, Sara Gasperini, Elisa Gardiman, Monica Castellucci, Anna Russignan, Massimiliano Bonifacio, Antonio Sica, William Vermi, Cristina Tecchio, Patrizia Scapini, Nicola Tamassia, Marco A. Cassatella
Journal: Cellular and Molecular Immunology (2025)

Abstract Technological advances have greatly improved our knowledge of myelopoiesis, for example, with the discovery of granulocyte‒monocyte‒dendritic cell (DC) progenitors (GMDPs), monocyte‒DC progenitors (MDPs), common DC progenitors (CDPs) and common monocyte progenitors (cMoPs) on the basis of flow cytometry approaches. Concomitantly, some progress has been made in characterizing the very early phases of human neutropoiesis with the description of novel CD66b + progenitors, including eNePs, PMs w/o eNePs, ProNeus, and PreNeus. More recently, we identified four SSC lo Lin - CD66b - CD45 dim CD34 + /CD34 dim/- CD64 dim CD115 - cells as the earliest precursors specifically committed to the neutrophil lineage present in human bone marrow (BM), which we called neutrophil-committed progenitors (NCPs, from NCP1s to NCP4s). In this study, we report the isolation and characterization of two new SSC hi CD66b - CD64 dim CD115 - NCPs that, by phenotypic, transcriptomic, maturation and immunohistochemistry properties, as well as by flow cytometric side-scattered light (SSC), stand after NCP4s but precede promyelocytes during the neutropoiesis cascade. Similar to SSC lo CD45RA + NCP2s/NCP3s and SSC lo CD45RA - NCP1s/NCP4s, these cells exhibit phenotypic differences in CD45RA expression levels and, therefore, were named SSC hi CD45RA + NCP5s and SSC hi CD45RA - NCP6s. Moreover, NCP5s were more immature than NCP6s, as determined by cell differentiation and proliferative potential, as well as by transcriptomic and phenotypical features. Finally, by examining whether NCPs and all other CD66b + neutrophil precursors are altered in representative hematological malignancies, we found that, in patients with chronic-phase chronic myeloid leukemia (CP-CML), but not with systemic mastocytosis (SM), there is an increased frequency of BM NCP4s, NCP6s, and all downstream CD45RA-negative neutrophil progenitors, suggesting their expansion in CML pathogenesis. Taken together, our data advance our knowledge of human neutropoiesis.
The AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes epidermal and immune homeostasis in atopic dermatitis-like skin inflammation
Authors: Zeyu Chen, Morgan Dragan, Peng Sun, Daniel Haensel, Remy Vu, Lian Cui, Peiyao Zhu, Nan Yang, Yuling Shi, Xing Dai
Journal: Cellular and Molecular Immunology (2025)

Abstract The skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonists have been approved by the FDA for psoriasis treatment and are in clinical trials for the treatment of atopic dermatitis (AD), but the underlying mechanism of action remains poorly defined. Here, we report that OVOL1/Ovol1 is a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 influences AhR-mediated regulation of keratinocyte gene expression and that OVOL1/Ovol1 ablation in keratinocytes impairs the barrier-promoting function of AhR, exacerbating AD-like inflammation. Mechanistically, we have identified Ovol1’s direct downstream targets genome-wide and provided in vivo evidence supporting the role of Id1 as a functional target in barrier maintenance, disease suppression, and neutrophil accumulation. Furthermore, our findings reveal that an IL-1/dermal γδT cell axis exacerbates type 2 and 3 immune responses downstream of barrier perturbation in Ovol1 -deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 functions in human AD skin. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis in the context of skin inflammation, identifying new therapeutic targets.
Discovery of a novel polymyxin adjuvant against multidrug-resistant Gram-negative bacteria through oxidative stress modulation
Authors: Taotao Lu, Hongguang Han, Chaohui Wu, Qian Li, Hongyan Hu, Wenwen Liu, Donglei Shi, Feifei Chen, Lefu Lan, Jian Li, Shihao Song, Baoli Li
Journal: Acta Pharmaceutica Sinica B (2025)

Antibiotic adjuvants offer a promising strategy for restoring antibiotic sensitivity, expanding antibacterial spectra, and reducing required dosages. Previously, compound 15 was identified as a potential adjuvant for Polymyxin B (PB) against multidrug-resistant (MDR) Pseudomonas aeruginosa DK2; however, its clinical utility was hindered by high cytotoxicity, uncertain in vivo efficacy, and an unclear synergetic mechanism. To address these challenges, we synthesized and evaluated a series of novel benzamide derivatives, with A22 emerging as a particularly promising candidate. A22 demonstrated potent synergistic activity to PB, minimal cytotoxicity, improved water solubility, and broad-spectrum synergism of polymyxins against various clinically isolated MDR Gram-negative strains. In vivo studies using Caenorhabditis elegans and mouse models further confirmed the efficacy of A22. Moreover, A22 effectively suppressed the development of PB resistance in Pseudomonas aeruginosa DK2. Mechanistic investigations revealed that A22 enhances polymyxins activity by inducing reactive oxygen species production, reducing ATP levels, increasing NOX activity, and inhibiting biofilm formation, leading to bacterial death. These findings position A22 as a highly promising candidate for the development of polymyxin adjuvants, offering a robust approach to combating MDR Gram-negative bacterial infections.
Bridging gap in the treatment of Alzheimer’s disease via postbiotics: Current practices and future prospects
Authors: Bushra Bashir, Monica Gulati, Sukriti Vishwas, Gaurav Gupta, Muralikrishnan Dhanasekaran, Keshav Raj Paudel, Dinesh Kumar Chellappan, Krishnan Anand, Poonam Negi, Pankaj Kumar Singh, Amarjitsing Rajput, Kamal Dua, Sachin Kumar Singh
Journal: Ageing Research Reviews (2025)
Modulating the PD-1-FABP5 Axis in ILC2s to Regulate Adipose Tissue Metabolism in Obesity
Authors: Jongho Ham, Jaemoon Koh, Jungeun Kim, Joo-Youn Cho, TaeSoo Kim, Doo Hyun Chung, Yong-Soo Bae, Hye Young Kim
Journal: Molecular Therapy (2025)
The public health co-benefits of strategies consistent with net-zero emissions: a systematic review
Authors: Léo Moutet, Paquito Bernard, Rosemary Green, James Milner, Andy Haines, Rémy Slama, Laura Temime, Kévin Jean
Journal: The Lancet Planetary Health (2025)

Moving towards net-zero emission societies is projected to provide human health co-benefits. However, the magnitude of these co-benefits is poorly documented and might be context specific. Synthesising the evidence on these co-benefits could enhance the engagement of decision makers and populations in climate mitigation actions. We performed database searches of PubMed, Web of Science, and Scopus for studies published between database inception and Jan 1, 2024, identifying 3976 papers. Of these, 58 quantitative studies met our inclusion criteria and were included in this systematic review. These 58 papers explored 125 net-zero emission scenarios and considered various pathways by which climate policies can affect human health. Pathways addressing air quality, physical activity, and dietary changes found substantial health co-benefits, with a median mortality reduction of 1·5%. National or sub-national studies showed that net-zero policies would yield substantial local air quality benefits, independently of the actions taken in neighbouring countries. However, these co-benefits varied with explored emission sector, decarbonisation levers, modelling approach, and location. Studies that included a cost-benefit analysis estimated that monetised benefits outweighed the costs of implementing climate policies. This systematic review highlights the need for a standardised framework to assess and compare health impacts of climate mitigation actions across sectors and confirms that achieving net-zero goals supports far-reaching public health policies. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
Combination Therapies in Locally Advanced and Metastatic Hormone-sensitive Prostate Cancer
Authors: Arun A Azad, Louise Kostos, Neeraj Agarwal, Gerhardt Attard, Ian D Davis, Tanya Dorff, Silke Gillessen, Chris Parker, Matthew R Smith, Christopher J Sweeney, Bertrand Tombal, Karim Fizazi
Journal: European Urology (2025)

The treatment landscape for advanced prostate cancer has evolved significantly over the past decade. The introduction of docetaxel, androgen receptor pathway inhibitors (ARPIs), poly(ADP-ribose) polymerase inhibitors, and targeted radionuclides has redefined the treatment paradigm, with a focus now on early treatment intensification through combination therapies. This narrative collaborative review summarises the current evidence of combination therapies in locally advanced and metastatic hormone-sensitive prostate cancer (mHSPC). We conducted a literature search up to November 2024. Search terms included "metastatic hormone-sensitive prostate cancer", "metastatic castration-sensitive prostate cancer", "locally advanced prostate cancer", "combination", "intensification", and "de-escalation". Articles were selected by the authors based on their scientific merit, clinical impact, and relevance to provide a summary of the evidence surrounding combination therapy in locally advanced prostate cancer and mHSPC. A doublet approach with an androgen deprivation therapy (ADT) backbone and an ARPI is now considered the standard treatment for mHSPC, with a triplet regimen incorporating docetaxel considered in select subgroups. Similar efforts to improve survival in the high-risk localised and locally advanced disease setting have led to several trials evaluating the benefit of combination therapy in addition to standard-of-care surgery or radiotherapy with ADT. Continued improvements in survival have turned the focus to optimising patient selection for treatment intensification and, in some cases, de-escalation, with the goal of reducing unnecessary overtreatment and minimising harm from long-term treatment toxicity. This is particularly important with the integration of prostate-specific membrane antigen positron emission tomography, which has led to the earlier detection of metastatic disease. In select subgroups, early treatment intensification with combination therapy leads to improved survival, though it can be associated with long-term toxicity.
Deep learning–based clustering for endotyping and post-arthroplasty response classification using knee osteoarthritis multiomic data
Authors: Jason S Rockel, Divya Sharma, Osvaldo Espin-Garcia, Katrina Hueniken, Amit Sandhu, Chiara Pastrello, Kala Sundararajan, Pratibha Potla, Noah Fine, Starlee S Lively, Kim Perry, Nizar N Mahomed, Khalid Syed, Igor Jurisica, Anthony V Perruccio, Y Raja Rampersaud, Rajiv Gandhi, Mohit Kapoor
Journal: Annals of the Rheumatic Diseases (2025)

Primary knee osteoarthritis (KOA) is a heterogeneous disease with clinical and molecular contributors. Biofluids contain microRNAs and metabolites that can be measured by omic technologies. Multimodal deep learning is adept at uncovering complex relationships within multidomain data. We developed a novel multimodal deep learning framework for clustering of multiomic data from 3 subject-matched biofluids to identify distinct KOA endotypes and classify 1-year post-total knee arthroplasty (TKA) pain/function responses. In 414 patients with KOA, subject-matched plasma, synovial fluid, and urine were analysed using microRNA sequencing or metabolomics. Integrating 4 high-dimensional datasets comprising metabolites from plasma and microRNAs from plasma, synovial fluid, or urine, a multimodal deep learning variational autoencoder architecture with K-means clustering was employed. Features influencing cluster assignment were identified and pathway analyses conducted. An integrative machine learning framework combining 4 molecular domains and a clinical domain was then used to classify Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain/function responses after TKA within each cluster. Multimodal deep learning-based clustering of subjects across 4 domains yielded 3 distinct patient clusters. Feature signatures comprising microRNAs and metabolites across biofluids included 30, 16, and 24 features associated with clusters 1 to 3, respectively. Pathway analyses revealed distinct pathways associated with each cluster. Integration of 4 multiomic domains along with clinical data improved response classification performance, surpassing individual domain classifications alone. We developed a multimodal deep learning-based clustering model capable of integrating complex multifluid, multiomic data to assist in uncovering biologically distinct patient endotypes and enhance outcome classifications to TKA surgery, which may aid in future precision medicine approaches.
1995-2025: thirty years of ASAS and its contribution to the understanding of spondyloarthritis
Authors: Désirée van der Heijde, Victoria Navarro-Compán, Robert Landewé, Joachim Sieper, Floris van Gaalen, Lianne S Gensler, Pedro M Machado, Helena Marzo-Ortega, Denis Poddubnyy, Mikhail Protopopov, Sofia Ramiro, Alexandre Sepriano, Xenofon Baraliakos
Journal: Annals of the Rheumatic Diseases (2025)

To describe the role of the Assessment of SpondyloArthritis interntational Society (ASAS) over the past 30 years in the understanding of the field of spondyloarthritis. A narrative review of the achievements. A summary of the role of ASAS in defining nomenclature, definition of and criteria for SpA, outcome assessments, recommendations, and education. ASAS played an important role in shaping the field of SpA.
Broad Immunomodulatory Effects of the Dipeptidyl-peptidase-1 Inhibitor Brensocatib in Bronchiectasis: Data from the Phase 2, Double-Blind, Place-controlled WILLOW Trial
Authors: Emma D Johnson, Merete B. Long, Lidia Perea, Vivian H Shih, Carlos Fernandez, Ariel Teper, David Cipolla, Eve McIntosh, Rachel Galloway, Zsofia Eke, Morven Shuttleworth, Rebecca Hull, Arietta Spinou, Anthony De Soyza, Felix C Ringshausen, Pieter Goeminne, Natalie Lorent, Charles Haworth, Michael R Loebinger, Francesco Blasi, Michal Shteinberg, Stefano Aliberti, Eva Polverino, Oriol Sibila, Amelia Shoemark, Kevin Mange, Jeffrey T. J. Huang, Jamie Stobo, James D. Chalmers
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

In the WILLOW trial, the Dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease (NSP) activity and prolonged time to first exacerbation in patients with bronchiectasis. We hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade. The WILLOW trial was a phase 2 randomized trial of brensocatib (10mg and 25mg) versus placebo. Sputum was collected at baseline, week 4, week 24 (end of treatment) and week 28 (4 weeks post-treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured by ELISA, mucin-5AC (MUC5AC) by liquid chromatography mass spectrometry, myeloperoxidase by immunoassay and 45 inflammatory cytokines by Olink® Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the EMBARC-BRIDGE bronchiectasis cohort. Of 82 patients randomized to 10mg brensocatib, 87 to 25mg brensocatib, and 87 to placebo, 71, 71 and 73 with sputum available for at least two time points were included. SLPI and α-defensin-3 increased significantly with brensocatib compared to placebo at both week 4 and week 24. MUC5AC reduced in response to treatment. Sub-analysis showed this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. 15 cytokines and chemokines increased significantly compared to placebo at week 4 or 28. CXCL10, CCL8, CCL7, CCL3 and IL-6 increased at both doses at both timepoints. In the EMBARC-BRIDGE cohort neutrophil elastase correlated inversely with SLPI, CCL13, IL7, CCL11, CXCL10, CCL8, CCL7, all markers increased by brensocatib. Brensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www. gov, ID: NCT03218917.
Current Smoker: A Clinical COPD Phenotype Affecting Disease Progression and Response to Therapy
Authors: Bartolome R. Celli, Stephanie A. Christenson, Klaus F. Rabe, MeiLan K. Han, Maarten van den Berge, Gerard J. Criner, Xavier Soler, Michel Djandji, Amr Radwan, Paul J Rowe, Yamo Deniz, Juby A. Jacob-Nara
Journal: American Journal of Respiratory and Critical Care Medicine (2025)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition of the lungs, characterized by chronic respiratory symptoms, primarily dyspnea, cough, and sputum production, due to airway and/or alveoli abnormalities that cause persistent, and often progressive, airflow obstruction. Although the underlying mechanisms responsible for COPD remain poorly understood, over the last several decades, clinical phenotypes and endotypes have been suggested. These include frequent exacerbator and eosinophilic groups that guide tailored therapies for patients with that clinical expression. In the developed world, smoking is the main known cause of COPD, responsible for ~80% of cases. Active smokers have more severe disease, with more rapid lung function decline and impaired quality of life, than former smokers. Unfortunately, smoking is still highly prevalent. Rates range between 3% and 37% globally, with factors including sex, age, race, education level, and geography influencing the rate of addiction. Importantly, several studies have shown that smoking detrimentally affects treatment efficacy of COPD medications; this is particularly true of inhaled corticosteroids and macrolides. In this review, we discuss the effects of smoking on the pathophysiology of COPD and the clinical impact of smoke exposure in patients with COPD.
Effect of vitamin A on adult lung function: a triangulation of evidence approach
Authors: Róisín Mongey, Diana A van der Plaat, Seif O Shaheen, Laura Portas, James Potts, Matthew David Hind, Cosetta Minelli
Journal: Thorax (2025)

Background Vitamin A, an essential micronutrient obtained through the diet, plays a crucial role in lung development and contributes to lung regeneration. We aimed to investigate its effect on adult lung function using triangulation of evidence from both observational and genetic data. Methods Using data on 150 000 individuals from UK Biobank and correcting for measurement error (generalised structural equation modelling), we first investigated the association of dietary vitamin A intake (total vitamin A, carotene and retinol) with lung function (forced vital capacity (FVC), forced expiratory volume in 1 s (FEV 1 )/FVC)). We then assessed the causality of these associations using Mendelian randomisation (MR), and we investigated the effects on adult lung function of 39 genes related to vitamin A, and their interaction with vitamin A intake. Findings Our observational analysis suggests a positive association between carotene intake and FVC only (13.3 mL per 100 µg/day; p=2.9×10 −9 ), with stronger associations in smokers, but no association of retinol intake with FVC or FEV 1 /FVC. The MR similarly shows a beneficial effect of serum beta-carotene on FVC only, with no effect of serum retinol on FVC nor FEV 1 /FVC. Nine of the vitamin A-related genes were associated with adult lung function, six of which have not been previously identified in genome-wide studies and three ( NCOA2, RDH10, RXRB ) in any type of genetic study of lung function. Five genes showed possible gene-vitamin A intake interactions. Interpretation Our triangulation study provides convincing evidence for a causal effect of vitamin A, carotene in particular, on adult lung function, suggesting a beneficial effect of a carotene-rich diet on adult lung health.
Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis
Authors: Haijing Xie, Kaiwen Zhang, Haimeng Yin, Siyu Zhang, Si Pan, Rui Wu, Yumo Han, Yi Xu, Weihong Jiang, Bo You
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Immunosuppression significantly contributes to treatment failure in nasopharyngeal carcinoma (NPC). Messenger RNA (mRNA) modifications such as methylation and acetylation play crucial roles in immunosuppression. However, N4-acetylcytidine (ac4C), the only acetylation modification event has rarely been studied in NPC. Methods First, clinical tissue samples and nude mouse models were used to explore the expression of N-acetyltransferase 10 (NAT10) in NPC and its influence on it. Second, The Cancer Genome Atlas immune database and transgenic mouse peripheral blood immune cell panel were used to verify the immune cells mainly affected by NAT10. Then, NAT10 ac4C acetylation modification and expression of significantly upregulated transcription factors were explored by acetylated RNA immunoprecipitation sequence binding to RNA sequencing. Then, the downstream regulatory genes of CCAAT enhancer binding protein γ (CEBPG), dead box helicase 5 (DDX5) and helicase-like transcription factors (HLTF) were analyzed by luciferase report and chromatin Immunoprecipitation. Finally, the effect of inhibition of NAT10 on anti-programmed cell death protein 1 (PD-1) treatment sensitivity was verified by animal models. Results In this study, we aimed to explore the role of NAT10, the enzyme responsible for ac4C modification, in NPC progression and patient prognosis. Elevated NAT10 promoted NPC progression and correlated with poor prognosis in patients with NPC. NAT10-mediated ac4C modification of CEBPG , DDX5 , and HLTF mRNA improved their stability and translation efficiency, with the NAT10/ac4C/DDX5 axis upregulating high mobility group box 1 (HMGB1) and inhibiting CD4+ and CD8+ T cells. Inhibition of NAT10 increased the sensitivity to PD-1 therapy. Additionally, HLTF was found to transcriptionally regulate NAT10, indicating the formation of an HLTF-NAT10 positive feedback loop. Conclusions Our study elucidates the mechanism by which the NAT10/DDX5/HMGB1 axis promotes the immunosuppression of NPC by promoting T-cell dysfunction. In addition, NAT10 knockdown can enhance anti-PD-1 treatment sensitivity as a combination therapy for NPC.