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Journal articleYoung RJ, Kirkham A, Savage J, et al., 2025,
Selumetinib in Combination with Anti Retroviral Therapy in HIV-associated Kaposi sarcoma (SCART): an open-label, multicentre, phase I/II trial
, BMC Cancer, Vol: 25Background: Kaposi sarcoma (KS) is the commonest HIV-associated malignancy. It is caused by co-infection with Kaposi sarcoma herpesvirus (KSHV), which upregulates the MAPK pathway. The aim of the SCART trial was to identify a safe dose for the MEK inhibitor selumetinib in combination with antiretroviral therapy (ART) and to establish evidence of the combination’s efficacy. Methods: SCART was a prospective, single arm, open-label, multi-centre, phase I/II trial, recruiting from four UK centres. Eligible patients were HIV positive, established on an ART regimen ≥ 3 months, had HIV viral load ≤ 200/ml, and had histologically confirmed KS with progressive disease. Phase I primary outcomes were occurrence of dose limiting toxicity (DLT) to determine the maximum tolerated dose/recommended phase II dose (RP2D), and pharmacokinetic assessments of selumetinib and N-desmethyl metabolite. Phase II primary outcome was occurrence of objective response (OR) as defined by AIDS Clinical Trials Group (ACTG) criteria. Results: Between 15-Jun-2012 and 25-Sep-2018, 19 patients were recruited; three did not start treatment and were not included in the final analysis. Ten eligible patients were treated in phase I and an additional six in phase II. There was one DLT at the 75 mg bd dose, which was deemed to be the RP2D. Of those patients receiving the RP2D (six within phase I, six within phase II), one achieved a partial response (OR 8.3%, 90% confidence interval: 0.4, 33.9). Further to the DLT, two serious adverse reactions, one unrelated serious adverse event (AE), and six non-serious grade 3 AEs were reported, together with 360 AEs graded 1 or 2. No detrimental impact on ART drug levels or HIV viral load were observed, with improvements in CD4 count and evidence of response in Angiopoietin-2 demonstrated. Conclusions: SCART was closed early due to slow recruitment, partly due to the rarity of KS because of improvements in HIV care, but also due to patients’ conce
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Journal articleHerzog MK-M, Peters A, Shayya N, et al., 2025,
Comparing Campylobacter jejuni to three other enteric pathogens in OligoMM12 mice reveals pathogen-specific host and microbiota responses.
, Gut Microbes, Vol: 17Campylobacter jejuni, non-typhoidal Salmonella spp., Listeria monocytogenes and enteropathogenic/enterohemorrhagic Escherichia coli (EPEC/EHEC) are leading causes of food-borne illness worldwide. Citrobacter rodentium has been used to model EPEC and EHEC infection in mice. The gut microbiome is well-known to affect gut colonization and host responses to many food-borne pathogens. Recent progress has established gnotobiotic mice as valuable models to study how microbiota affect the enteric infections by S. Typhimurium, C. rodentium and L. monocytogenes. However, for C. jejuni, we are still lacking a suitable gnotobiotic mouse model. Moreover, the limited comparability of data across laboratories is often negatively affected by variations between different research facilities or murine microbiotas. In this study, we applied the standardized gnotobiotic OligoMM12 microbiota mouse model and compared the infections in the same facility. We provide evidence of robust colonization and significant pathological changes in OligoMM12 mice following infection with these pathogens. Moreover, we offer insights into pathogen-specific host responses and metabolite signatures, highlighting the advantages of a standardized mouse model for direct comparisons of factors influencing the pathogenesis of major food-borne pathogens. Notably, we reveal for the first time that C. jejuni stably colonizes OligoMM12 mice, triggering inflammation. Additionally, our comparative approach successfully identifies pathogen-specific responses, including the detection of genes uniquely associated with C. jejuni infection in humans. These findings underscore the potential of the OligoMM12 model as a versatile tool for advancing our understanding of food-borne pathogen interactions.
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Journal articleYang J, Qureshi M, Kolli R, et al., 2025,
The haemagglutinin gene of bovine-origin H5N1 influenza viruses currently retains receptor-binding and pH-fusion characteristics of avian host phenotype.
, Emerg Microbes Infect, Vol: 14Clade 2.3.4.4b H5N1 high pathogenicity avian influenza virus (HPAIV) has caused a panzootic affecting all continents except Australia, expanding its host range to several mammalian species. In March 2024, H5N1 HPAIV was first detected in dairy cattle and goats in the United States. Over 891 dairy farms across 16 states have tested positive until 25 December 2024, with zoonotic infections reported among dairy workers. This raises concerns about the virus undergoing evolutionary changes in cattle that could enhance its zoonotic potential. The Influenza glycoprotein haemagglutinin (HA) facilitates entry into host cells through receptor binding and pH-induced fusion with cellular membranes. Adaptive changes in HA modulate virus-host cell interactions. This study compared the HA genes of cattle and goat H5N1 viruses with the dominant avian-origin clade 2.3.4.4b H5N1 in the United Kingdom, focusing on receptor binding, pH fusion, and thermostability. All the tested H5N1 viruses showed binding exclusively to avian-like receptors, with a pH fusion of 5.9, outside the pH range associated with efficient human airborne transmissibility (pH 5.0-5.5). We further investigated the impact of emerging HA substitutions seen in the ongoing cattle outbreaks, but saw little phenotypic difference, with continued exclusive binding to avian-like receptor analogues and pHs of fusion above 5.8. This suggests that the HA genes from the cattle and goat outbreaks do not pose an enhanced threat compared to circulating avian viruses. However, given the rapid evolution of H5 viruses, continuous monitoring and updated risk assessments remain essential to understanding virus zoonotic and pandemic risks.
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Journal articleGruevska A, Leslie J, Perpinán E, et al., 2025,
Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver
, Metabolism, Vol: 168, ISSN: 0026-0495Background and aimsSteatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development.MethodsWe analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs).ResultsBulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected >40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs.ConclusionsOur spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.
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Journal articleMills E, Silva M, Delli V, et al., 2025,
Intranasal kisspeptin administration rapidly stimulates gonadotropin release in humans
, EBioMedicine, Vol: 115, ISSN: 2352-3964BackgroundKisspeptin administration by intravenous or subcutaneous routes activates hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is being developed to treat reproductive disorders. However, these invasive routes markedly limit patient acceptability and clinical use. Recent rodent data has identified a large GnRH population within the olfactory system communicating directly with hypothalamic GnRH neurons. Intranasal kisspeptin administration may be able to capitalise on this novel pathway and thus offer a potential non-invasive approach to stimulate reproductive hormones. Herein, we examine intranasal kisspeptin using human, pharmaceutical, and rodent studies.MethodsReproductive hormone profiles were measured after intranasal kisspeptin administration in healthy volunteers and patients with reproductive disorders as part of a randomised, double-blinded, crossover, placebo-controlled clinical study. Pharmaceutical testing evaluated the chemical stability and nasal kisspeptin delivery, and rodent studies provided mechanistic insight.FindingsIntranasal kisspeptin-54 rapidly stimulates gonadotropin release in healthy men and women, and in patients with a common reproductive disorder (hypothalamic amenorrhoea), without any side effects or adverse events encountered. Specifically, intranasal kisspeptin (at 12.8 nmol/kg) induced clinically-significant mean maximal increases above baseline in serum luteinising hormone in all study groups: 4.4 ± 0.6 IU/L (mean difference = 3.1 IU/L [95% CI, 1.2–4.9], P = 0.002 vs. placebo) in healthy men; 1.4 ± 0.3 IU/L (mean difference = 1.0 IU/L [95% CI, 0.4–1.7], P = 0.004 vs. placebo) in healthy women; 4.4 ± 0.2 IU/L (mean difference = 4.3 IU/L [95% CI, 2.7–6.0], P < 0.001 vs. placebo) in patients with hypothalamic amenorrhoea. Kisspeptin-54 was delivered effectively via nasal spray and was stable for up to 60 days at 4 °C. Mirroring the human effects, intranasal kisspeptin-5
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Journal articleRomán-Trufero M, Kleijn IT, Blighe K, et al., 2025,
An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation.
, Life Sci Alliance, Vol: 8The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.
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Journal articleAltmann DM, Rasmussen AL, 2025,
How to respond when biomedical science and global health is under existential threat.
, Nat Rev Immunol -
Journal articleGuillaume SM, Foster WS, San Martín Molina I, et al., 2025,
Lung B cells in ectopic germinal centers undergo affinity maturation
, Proceedings of the National Academy of Sciences, Vol: 122, ISSN: 0027-8424The lungs are constantly exposed to the external environment and a myriad of antigenic challenges within the air. Chronic exposure to allergens and other airborne antigens can result in the formation of lymphocyte aggregates in the lung, which can harbor ectopic germinal centers (GCs). After allergen exposure, GCs that form in the lung are much smaller and less densely packed with B cells than lymph node GCs. Despite this, ectopic lung GCs support somatic hypermutation and affinity-based maturation as in lymph node GCs, and export memory B cells (MBCs) directly into the lung tissue. This demonstrates that the lung can locally diversify B cell responses and supports the generation of tissue MBC populations in situ.
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Journal articleMechelli R, Umeton R, Bellucci G, et al., 2025,
A disease-specific convergence of host and Epstein–Barr virus genetics in multiple sclerosis
, Proceedings of the National Academy of Sciences, Vol: 122, ISSN: 0027-8424Recent sero-epidemiological studies have strengthened the hypothesis that Epstein–Barr virus (EBV) may be a causal factor in multiple sclerosis (MS). Given the complexity of the EBV–host interaction, various mechanisms may be responsible for the disease pathogenesis. Furthermore, it remains unclear whether this is a disease-specific process. Here, we showed that genes encoding EBV interactors are enriched in loci associated with MS but not with other diseases and in prioritized therapeutic targets. Analyses of MS blood and brain transcriptomes confirmed a dysregulation of MS-associated EBV interactors affecting the CD40 pathway. Such interactors were strongly enriched in binding sites for the EBV nuclear antigen 2 (EBNA2) viral transcriptional regulator, often in colocalization with CCCTC binding factor (CTCF) and RNA Polymerase II Subunit A (POLR2A). EBNA2 was expressed in the MS brain. The 1.2 EBNA2 allele downregulated the expression of the CD40 MS-associated gene analogously to the CD40 MS-risk variant. Finally, we showed that the 1.2 EBNA2 allele associates with the risk of MS. This study delineates how host and viral genetic variability converge in MS-specific pathogenetic mechanisms.
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Journal articleMaher TM, 2025,
Predicting Failure: Can Blood Biomarkers Identify Likely Treatment Non-Responders in IPF?
, Respirology
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