Recent publications

J Autoimmun. 2025 Mar 26;153:103398. doi: 10.1016/j.jaut.2025.103398. Online ahead of print.

ABSTRACT

BACKGROUND: Following the results of the MANDARA trial, this real-life study aimed at comparing the effectiveness and safety profile of mepolizumab versus benralizumab in a European EGPA cohort.

METHODS: We conducted a retrospective observational comparative study including EGPA patients, who received mepolizumab or benralizumab at the asthma dose. Patients were matched 1:1 by sex, age, BVAS and oral corticosteroid (OCS) dosage at the treatment initiation (T0). Complete response (CR) and partial response (PR), disease activity, OCS, pulmonary parameters, eosinophil count, relapses, and safety outcomes were also compared at 3, 6 and 12 months.

RESULTS: Patients treated with mepolizumab or benralizumab (n = 88 each) were matched: 57 % were females, median age was 54 years (IQR 45-60), median OCS dose 10 (7.5-12.5) and 10 (7-13) mg/day, median BVAS 4 (2-7) and 3 (2-8), respectively. 45.4 % of patients in the mepolizumab group and 51.1 % in the benralizumab group achieved CR or PR at T3, with CR steadily increasing during follow-up for both treatments. At T12, a higher CR rate was found in the benralizumab group (48.1 % vs 32.4 %, p = 0.005). No differences in BVAS, OCS, and respiratory parameters were observed between groups at the different timepoints. Throughout the follow-up, both treatments reduced eosinophil count, although a deeper reduction was found in the benralizumab group at all timepoints (p < 0.0001). Safety profile was comparable between patient groups.

CONCLUSION: Mepolizumab and benralizumab showed comparable overall effectiveness and safety in EGPA. However, benralizumab achieved a higher CR rate at T12, and a deeper peripheral eosinophil reduction.

PMID:40147217 | DOI:10.1016/j.jaut.2025.103398

Commun Biol. 2025 Mar 22;8(1):478. doi: 10.1038/s42003-025-07848-9.

ABSTRACT

GPR35 is an orphan G-protein coupled receptor that has been implicated in the development of cancer. GPR35 regulates the Na+/K+-ATPase's pump and signalling function. Here we show GPR35's critical role in ion flux that in turn controls cellular osmotic pressure and Na+-dependent transport in HepG2 and SW480 cells. GPR35 deficiency results in increased levels of intracellular Na+, osmotic stress and changes in osmolytes leading to increased cells size and decreased glutamine import in vitro and in vivo. The GPR35-T108M risk variant, which increases risk for primary sclerosing cholangitis and inflammatory bowel disease, leads to lower intracellular Na+ levels, and enhanced glutamine uptake. High salt diet (HSD) in wildtype mice resembles the intestinal epithelial phenotype of their Gpr35-/- littermates with decreased Goblet cell size and numbers. This indicates that GPR35's regulation of the Na+/K+-ATPase controls ion homeostasis, osmosis and Na+-dependent transporters.

PMID:40121360 | DOI:10.1038/s42003-025-07848-9

BMJ Open. 2025 Mar 21;15(3):e089447. doi: 10.1136/bmjopen-2024-089447.

ABSTRACT

OBJECTIVES: Patient information sheets (PISs) and informed consent forms (ICFs) are essential tools to communicate and document informed consent for clinical trial participation. These documents need to be easily understandable, especially when used to take informed consent from acutely unwell patients. Health literacy guidance recommends written information should be at a level between reading ages 9-11. We aimed to assess the readability and complexity of PISs/ICFs used for clinical trials of acute therapies during the COVID-19 pandemic.

DESIGN: Retrospective document analysis.

SETTING: PISs/ICFs used in trials involving pharmaceutical interventions recruiting hospitalised patients with COVID-19 during the first year of the pandemic were sourced from hospitals across the UK.

PRIMARY AND SECONDARY OUTCOME MEASURES: PISs/ICFs were assessed for length, approximate reading time and subsection content. Readability and language complexity were assessed using Flesch-Kincaid Grade Level (FKGL) (range 1-18; higher is more complex), Gunning-Fog (GFOG) (range 1-20; higher is more complex) and Flesch Reading Ease Score (FRES) (range 0-100; below 60 is 'difficult' for comprehension).

RESULTS: 13 documents were analysed with a median length of 5139 words (range 1559-7026), equating to a median reading time of 21.4 min (range 6.5-29.3 min) at 240 words per minute. Median FKGL was 9.8 (9.1-10.8), GFOG 11.8 (10.4-13) and FRES was 54.6 (47.0-58.3). All documents were classified as 'difficult' for comprehension and had a reading age of 14 years old or higher.

CONCLUSIONS: All PISs/ICFs analysed contained literary complexity beyond both recommendations and the reading level of many in the UK population. Researchers should seek to improve communications to improve trial volunteer comprehension and recruitment.

PMID:40118493 | DOI:10.1136/bmjopen-2024-089447

Nature. 2025 Mar 20. doi: 10.1038/s41586-025-08886-3. Online ahead of print.

NO ABSTRACT

PMID:40113895 | DOI:10.1038/s41586-025-08886-3

Nature. 2025 Mar 19. doi: 10.1038/s41586-025-08708-6. Online ahead of print.

ABSTRACT

The landscapes of somatic mutation in normal cells inform us about the processes of mutation and selection operative throughout life, providing insight into normal ageing and the earliest stages of cancer development1. Here, by whole-genome sequencing of 238 microdissections2 from 30 individuals, including 18 with gastric cancer, we elucidate the developmental trajectories of normal and malignant gastric epithelium. We find that gastric glands are units of monoclonal cell populations that accrue roughly 28 somatic single-nucleotide variants per year, predominantly attributable to endogenous mutational processes. In individuals with gastric cancer, metaplastic glands often show elevated mutation burdens due to acceleration of mutational processes linked to proliferation and oxidative damage. Unusually for normal cells, gastric epithelial cells often carry recurrent trisomies of specific chromosomes, which are highly enriched in a subset of individuals. Surveying 829 polyclonal gastric microbiopsies by targeted sequencing, we find somatic 'driver' mutations in a distinctive repertoire of known cancer genes, including ARID1A, ARID1B, ARID2, CTNNB1 and KDM6A. The prevalence of mutant clones increases with age to occupy roughly 8% of the gastric epithelial lining by age 60 years and is significantly increased by the presence of severe chronic inflammation. Our findings provide insights into intrinsic and extrinsic influences on somatic evolution in the gastric epithelium in healthy, precancerous and malignant states.

PMID:40108450 | DOI:10.1038/s41586-025-08708-6

PLoS Biol. 2025 Mar 19;23(3):e3003070. doi: 10.1371/journal.pbio.3003070. eCollection 2025 Mar.

ABSTRACT

Multiplexed imaging is a powerful approach in spatial biology, although it is complex, expensive and labor-intensive. Here, we present the IBEX Knowledge-Base, a central resource for reagents, protocols and more, to enhance knowledge sharing, optimization and innovation of spatial proteomics techniques.

PMID:40106489 | DOI:10.1371/journal.pbio.3003070

Lupus. 2025 Mar 19:9612033251326990. doi: 10.1177/09612033251326990. Online ahead of print.

ABSTRACT

ObjectiveTo evaluate the long-term efficacy and safety of different doses of BI 655064 versus placebo added to standard of care during maintenance treatment for lupus nephritis (LN).Methods1293.13 was an exploratory, phase II maintenance trial. Patients were eligible for entry if they had completed 1 year of randomised treatment with BI 655064 (120, 180 or 240 mg) or placebo in the 1293.10 trial, responded to treatment at Year 1 (complete renal response [CRR], partial renal response or urinary protein/creatinine ratio ≤1) and consented to continue treatment. The primary endpoint was the proportion of patients with CRR without renal flares at Year 2. Secondary endpoints included change from baseline in Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores and safety/tolerability.Results69/121 patients (57.0%) from the 1293.10 trial entered 1293.13. The adjusted proportion of patients with CRR decreased in all groups between Year 1 (BI 655064: 53.4%-72.7%; placebo: 71.4%) and Year 2 (BI 655064: 48.2%-59.5%; placebo: 57.5%). At Year 2, mean decreases in total SELENA-SLEDAI scores were greatest with BI 655064 240 mg (-10.6 points), followed by 120 mg (-8.9 points), 180 mg (-7.2 points) and placebo (-5.3 points). SELENA-SLEDAI non-renal scores decreased at Year 1 (BI 655064: -3.0 to -3.4; placebo: -1.8); this pattern remained with BI 655064 during Year 2 (-2.4 to -4.1), whereas placebo returned to near-baseline scores (-0.4). Over 2 years of treatment, almost all patients (97.1%) experienced ≥1 adverse event (AE). Compared with the other groups, higher rates of serious AEs (42.9% vs 23.1%-33.3%)-mainly driven by serious infections (23.8% vs 7.7%-14.3%)-and severe AEs (47.6% vs 13.3%-28.6%) were reported with BI 655064 240 mg.ConclusionsThis exploratory, phase II maintenance trial failed to demonstrate the benefits of BI 655064 on renal outcomes in the treatment of LN. However, some benefits in total and non-renal SELENA-SLEDAI scores were observed.

PMID:40104960 | DOI:10.1177/09612033251326990

Trends Cancer. 2025 Apr;11(4):274-275. doi: 10.1016/j.trecan.2025.03.003. Epub 2025 Mar 17.

ABSTRACT

Tertiary lymphoid structures (TLS) are associated with anticancer immunity, but the mechanisms underpinning their formation remain poorly understood. Amisaki et al. have recently shown that IL-33 mediates ILC2 gut-tumoral migration and promotes TLS formation in pancreatic ductal adenocarcinoma (PDAC) by inducing group 2 innate lymphoid cell (ILC2) Ltb expression. This study highlights new potential therapeutic avenues to enhance immunotherapy.

PMID:40102086 | DOI:10.1016/j.trecan.2025.03.003

mBio. 2025 Mar 14:e0032225. doi: 10.1128/mbio.00322-25. Online ahead of print.

ABSTRACT

Mycobacterium abscessus is one of the leading causes of pulmonary infections caused by non-tuberculous mycobacteria. The ability of M. abscessus to establish a chronic infection in the lung relies on a series of adaptive mutations impacting, in part, global regulators and cell envelope biosynthetic enzymes. One of the genes under strong evolutionary pressure during host adaptation is ubiA, which participates in the elaboration of the arabinan domains of two major cell envelope polysaccharides: arabinogalactan (AG) and lipoarabinomannan (LAM). We here show that patient-derived UbiA mutations not only cause alterations in the AG, LAM, and mycolic acid contents of M. abscessus but also tend to render the bacterium more prone to forming biofilms while evading uptake by innate immune cells and enhancing their pro-inflammatory properties. The fact that the effects of UbiA mutations on the physiology and pathogenicity of M. abscessus were impacted by the rough or smooth morphotype of the strain suggests that the timing of their selection relative to morphotype switching may be key to their ability to promote chronic persistence in the host.IMPORTANCEMultidrug-resistant pulmonary infections caused by Mycobacterium abscessus and subspecies are increasing in the U.S.A. and globally. Little is known of the mechanisms of pathogenicity of these microorganisms. We have identified single-nucleotide polymorphisms (SNPs) in a gene involved in the biosynthesis of two major cell envelope polysaccharides, arabinogalactan and lipoarabinomannan, in lung-adapted isolates from 13 patients. Introduction of these individual SNPs in a reference M. abscessus strain allowed us to study their impact on the physiology of the bacterium and its interactions with immune cells. The significance of our work is in identifying some of the mechanisms used by M. abscessus to colonize and persist in the human lung, which will facilitate the early detection of potentially more virulent clinical isolates and lead to new therapeutic strategies. Our findings may further have broader biomedical impacts, as the ubiA gene is conserved in other tuberculous and non-tuberculous mycobacterial pathogens.

PMID:40084888 | DOI:10.1128/mbio.00322-25

J Infect Dis. 2025 Mar 14:jiaf136. doi: 10.1093/infdis/jiaf136. Online ahead of print.

ABSTRACT

Plasmodium vivax vaccine discovery lags behind P. falciparum due to the absence of a reliable in vitro culture system. We developed a miniature 384-well assay for the evolutionarily related parasite species P. cynomolgi and P. knowlesi, deploying it for screening invasion inhibition efficacy of antibodies elicited against 8 P. vivax proteins. All 8 antibodies showed consistent inhibition across both P. knowlesi and P. cynomolgi species, correlating with inhibition in ex vivo P. vivax isolates. The use of simian malaria parasites and this assay represents a robust, high-throughput method for prioritizing P. vivax blood stage vaccine candidates.

PMID:40083318 | DOI:10.1093/infdis/jiaf136

Nat Methods. 2025 Mar 13. doi: 10.1038/s41592-024-02563-5. Online ahead of print.

ABSTRACT

The Human BioMolecular Atlas Program (HuBMAP) aims to construct a 3D Human Reference Atlas (HRA) of the healthy adult body. Experts from 20+ consortia collaborate to develop a Common Coordinate Framework (CCF), knowledge graphs and tools that describe the multiscale structure of the human body (from organs and tissues down to cells, genes and biomarkers) and to use the HRA to characterize changes that occur with aging, disease and other perturbations. HRA v.2.0 covers 4,499 unique anatomical structures, 1,195 cell types and 2,089 biomarkers (such as genes, proteins and lipids) from 33 ASCT+B tables and 65 3D Reference Objects linked to ontologies. New experimental data can be mapped into the HRA using (1) cell type annotation tools (for example, Azimuth), (2) validated antibody panels or (3) by registering tissue data spatially. This paper describes HRA user stories, terminology, data formats, ontology validation, unified analysis workflows, user interfaces, instructional materials, application programming interfaces, flexible hybrid cloud infrastructure and previews atlas usage applications.

PMID:40082611 | DOI:10.1038/s41592-024-02563-5

J Immunol. 2025 Mar 9:vkae039. doi: 10.1093/jimmun/vkae039. Online ahead of print.

ABSTRACT

Long-lasting immunological memory is a core feature of the adaptive immune system that allows an organism to have a potent recall response to foreign agents that have been previously encountered. Persistent humoral immunity is afforded by long-lived memory B cells and plasma cells, which can mature in germinal centers (GCs) in secondary lymphoid organs. The development of new GC-derived immunity diminishes with age, thereby impairing our immune system's response to both natural infections and vaccinations. This review will describe the current knowledge of how aging affects the cells and microenvironment of the GC. A greater understanding of how the GC changes with age, and how to circumvent these changes, will be critical for tailoring vaccines for older people. This area of research is critical given the twenty-first century will witness a doubling of the aging population and an increased frequency of pandemics.

PMID:40073096 | DOI:10.1093/jimmun/vkae039

Rheumatology (Oxford). 2025 Mar 1;64(Supplement_1):i15-i18. doi: 10.1093/rheumatology/keae663.

ABSTRACT

Drug development in ANCA-associated vasculitis has aimed to improve on the success of the B cell depleting monoclonal antibody rituximab and exploit better understanding of inflammatory pathways. More potent B cell depletion strategies are being tested as are B cell cytokine inhibitors. The involvement of the complement system in pathogenesis is more complicated than previously thought and extends beyond C5a dysregulation and its inhibition with avacopan, broader complement inhibitors and complement regulatory agonists are potential newer therapies. Other approaches have aimed to directly control neutrophil activation and to try to modulate tissue repair and fibrosis that occurs following vasculitis inflammation.

PMID:40071424 | DOI:10.1093/rheumatology/keae663

Nat Commun. 2025 Mar 10;16(1):1979. doi: 10.1038/s41467-025-56473-x.

ABSTRACT

The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 and donor lung tissue with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage. We identify changes in cellular composition across progressive damage, including waves of molecularly distinct macrophages and depletion of epithelial and endothelial populations. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early damage, and fibrosis-related collagens in late damage. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early steps of alveolar damage. These results provide a comprehensive, spatially resolved atlas of alveolar damage progression in COVID-19, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways in severe disease.

PMID:40064844 | DOI:10.1038/s41467-025-56473-x

PLoS Comput Biol. 2025 Mar 7;21(3):e1012859. doi: 10.1371/journal.pcbi.1012859. eCollection 2025 Mar.

ABSTRACT

Gene expression studies often use bulk RNA sequencing of mixed cell populations because single cell or sorted cell sequencing may be prohibitively expensive. However, mixed cell studies may miss expression patterns that are restricted to specific cell populations. Computational deconvolution can be used to estimate cell fractions from bulk expression data and infer average cell-type expression in a set of samples (e.g., cases or controls), but imputing sample-level cell-type expression is required for more detailed analyses, such as relating expression to quantitative traits, and is less commonly addressed. Here, we assessed the accuracy of imputing sample-level cell-type expression using a real dataset where mixed peripheral blood mononuclear cells (PBMC) and sorted (CD4, CD8, CD14, CD19) RNA sequencing data were generated from the same subjects (N=158), and pseudobulk datasets synthesised from eQTLgen single cell RNA-seq data. We compared three domain-specific methods, CIBERSORTx, bMIND and debCAM/swCAM, and two cross-domain machine learning methods, multiple response LASSO and ridge, that had not been used for this task before. We also assessed the methods according to their ability to recover differential gene expression (DGE) results. LASSO/ridge showed higher sensitivity but lower specificity for recovering DGE signals seen in observed data compared to deconvolution methods, although LASSO/ridge had higher area under curves than deconvolution methods. Machine learning methods have the potential to outperform domain-specific methods when suitable training data are available.

PMID:40053530 | DOI:10.1371/journal.pcbi.1012859

Nature. 2025 Mar 5. doi: 10.1038/s41586-025-08626-7. Online ahead of print.

ABSTRACT

Metastasis is the spread of cancer cells from primary tumours to distant organs and is the cause of 90% of cancer deaths globally1,2. Metastasizing cancer cells are uniquely vulnerable to immune attack, as they are initially deprived of the immunosuppressive microenvironment found within established tumours3. There is interest in therapeutically exploiting this immune vulnerability to prevent recurrence in patients with early cancer at risk of metastasis. Here we show that inhibitors of cyclooxygenase 1 (COX-1), including aspirin, enhance immunity to cancer metastasis by releasing T cells from suppression by platelet-derived thromboxane A2 (TXA2). TXA2 acts on T cells to trigger an immunosuppressive pathway that is dependent on the guanine exchange factor ARHGEF1, suppressing T cell receptor-driven kinase signalling, proliferation and effector functions. T cell-specific conditional deletion of Arhgef1 in mice increases T cell activation at the metastatic site, provoking immune-mediated rejection of lung and liver metastases. Consequently, restricting the availability of TXA2 using aspirin, selective COX-1 inhibitors or platelet-specific deletion of COX-1 reduces the rate of metastasis in a manner that is dependent on T cell-intrinsic expression of ARHGEF1 and signalling by TXA2 in vivo. These findings reveal a novel immunosuppressive pathway that limits T cell immunity to cancer metastasis, providing mechanistic insights into the anti-metastatic activity of aspirin and paving the way for more effective anti-metastatic immunotherapies.

PMID:40044852 | DOI:10.1038/s41586-025-08626-7

Rheumatol Adv Pract. 2025 Feb 22;9(1):rkaf020. doi: 10.1093/rap/rkaf020. eCollection 2025.

NO ABSTRACT

PMID:40040686 | PMC:PMC11879314 | DOI:10.1093/rap/rkaf020

Rheumatology (Oxford). 2025 Mar 3:keaf122. doi: 10.1093/rheumatology/keaf122. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the efficacy and safety of avacopan in patients aged ≥65 years with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in the phase 3 ADVOCATE trial of avacopan vs a prednisone taper, plus either rituximab or cyclophosphamide.

METHODS: In this descriptive, post hoc analysis, patients receiving avacopan or a prednisone taper were stratified by age. Key efficacy outcomes included the rate of remission at week 26 and sustained remission at week 52.

RESULTS: Of 160 patients aged ≥65, 109 were aged 65-74, and 51 were ≥75. Remission at week 26 was achieved in 71.7% vs 69.4% of patients aged 65-74 and 73.1% vs 72.0% aged ≥75 in the avacopan vs prednisone taper groups, respectively. Sustained remission at week 52 was observed in 65.0% vs 55.1% of patients aged 65-74 and 65.4% vs 56.0% aged ≥75. Relapse rates in the avacopan vs prednisone taper groups were 12.3% vs 18.8% and 3.8% vs 20.8% in the 65-74 and ≥75 subgroups, respectively. Improvements in eGFR and HRQoL were observed in both treatment groups. Use of avacopan compared with a prednisone taper was associated with a 61% and 49% reduction in mean glucocorticoid dose in the 65-74 and ≥75 subgroups, respectively, and lower glucocorticoid toxicity. The proportions of patients with adverse events were similar between treatment groups within each age subgroup.

CONCLUSION: These data support the efficacy and safety of an avacopan-based regimen to treat patients with GPA or MPA aged ≥65.

PMID:40037556 | DOI:10.1093/rheumatology/keaf122

Cell. 2025 Feb 27:S0092-8674(25)00145-X. doi: 10.1016/j.cell.2025.01.043. Online ahead of print.

ABSTRACT

Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.

PMID:40023152 | DOI:10.1016/j.cell.2025.01.043

Microbiome. 2025 Feb 28;13(1):61. doi: 10.1186/s40168-025-02050-9.

ABSTRACT

BACKGROUND: Promoting resistance to enteric pathogen infection is a core function of the gut microbiota; however, many of the specific host-commensal interactions that mediate this protection remain uncharacterised. To address this knowledge gap, we monocolonised germ-free mice with mouse-derived commensal microbes to screen for microbiota-induced resistance to Salmonella Typhimurium infection.

RESULTS: We identified Enterocloster clostridioformis as a protective species against S. Typhimurium infection. E. clostridioformis selectively upregulates resistin-like molecule β and cell cycle pathway expression at the level of caecal epithelial cells and increases T-regulatory cells in the underlying mucosal immune system, potentially contributing to reduced infection-induced pathology.

CONCLUSIONS: We highlight novel mechanisms of host-microbe interactions that can mediate microbiota-induced resistance to acute salmonellosis. In the backdrop of increasing antibiotic resistance, this study identifies novel potential avenues for further research into protective host responses against enteric infections and could lead to new therapeutic approaches. Video Abstract.

PMID:40022210 | DOI:10.1186/s40168-025-02050-9