Instituto de Biomedicina de Sevilla

CHRONOS is a multicenter, retrospective, cohort study involving acute graft-versus-host disease (aGvHD) adult patients with gastrointestinal (GI) symptoms, steroid- and ruxolitinib refractory, who initiated third-line therapy between 30 May 2019 and 30 September 2024. Primary endpoints were all-organ overall response rate (ORR) and GI-specific ORR (GI-ORR) around 28 days after treatment initiation. Secondary endpoints included duration of response, real-world progression-free survival (rwPFS) of underlying malignancy, and overall survival (OS). Fifty-nine patients from 16 sites in Europe were included. On Day 28, ORR was 36% (95% CI: 24-49%), GI-ORR was 37% (95% CI: 25-51%); 29% (95% CI: 11-49%) of responders lost response within 30 days, and 52% (95% CI: 29-72%) within 90 days. Median rwPFS and median OS were both 86 days (95% CI: 54-128 days). Median OS was higher in responders than in non-responders (186 versus 45 days). Over the 12-month follow-up period, 41 patients died, mainly due to aGvHD progression (n = 25), and infectious complications (n = 9). Within 3 months, Grade ≥ 2 infectious events occurred in 51% of patients; Grade 3-4 thrombocytopenia and neutropenia in 64% and 32%, respectively. These findings demonstrate limited effectiveness of third-line therapy in this cohort of steroid- and ruxolitinib-refractory aGvHD patients with GI symptoms.

ABSTRACTMetabolic dysfunction‐Associated Steatotic Liver Disease (MASLD) is a growing clinical challenge, necessitating effective diagnostic strategies to identify advanced liver fibrosis while minimising unnecessary referrals of mild cases. Current clinical guidelines recommend care pathways utilising non‐invasive tests (NITs) to stratify patients, but the optimal diagnostic algorithm across care settings remains unclear. This state‐of‐the‐art review systematically examines studies describing clinical care pathways for detecting advanced fibrotic MASLD and stratifying patients at risk. A comprehensive literature search of MEDLINE, Embase, Cochrane Library, and Scopus, finalised in January 2026, identified nine relevant studies that met predefined criteria including structured care plans and applicability beyond diagnosis alone. Pathway populations included patients at risk for MASLD (type 2 diabetes (n = 4) or broad range cardiometabolic risk factors (n = 1)) or confirmed MASLD (n = 4). The most frequently employed NITs were FIB‐4 and vibration‐controlled transient elastography (VCTE). Numbers needed to screen (NNS) for hepatology referral and advanced fibrosis detection varied considerably across pathways and populations, reflecting heterogeneity in design and fibrosis assessment methods. All studies reported improved patient risk stratification; attendance rates declined at each pathway step. Findings suggest that NIT‐based clinical care pathways can effectively align patient management and optimise transmural care for MASLD. Nonetheless, heterogeneity in pathway design and fibrosis determination highlights the need for standardised protocols and validation in larger, at‐risk cohorts to strengthen evidence supporting widespread adoption. This review contributes to advancing MASLD management within evolving clinical frameworks.

Abstract Lung cancer remains the most common cause of cancer mortality worldwide. While the introduction of immune checkpoint inhibitors has changed the treatment landscape in non-small cell lung cancer, primary and acquired resistance continue to limits their long-term efficacy. The identification of reliable, minimally invasive biomarkers to guide immunotherapy response remains an urgent clinical need. In this study, we performed an in-depth proteomic profiling of plasma-derived small extracellular vesicles collected prior to treatment in 65 non-small cell lung cancer patients receiving pembrolizumab, aiming to uncover predictive molecular signatures. Mass spectrometry analysis initially detected over two thousand plasma extracellular vesicles proteins, including reported extracellular vesicle proteins, thereby validating our isolation and detection methodology. Among these, a four-proteins panel (MUC1, MUC5B, MUC5AC, and ANPEP) was associated with T cell dysfunction and an immunosuppressive tumor phenotype. This signature correlated with systemic inflammatory markers, particularly the platelet-to-lymphocyte ratio, and accurately predicted immunotherapy outcomes. Based on these findings, we stablished a plasma-derived score that strongly correlated with both progression-free and overall survival, providing a promising non-invasive tool for patient stratification and personalized immunotherapy.

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We identified a role of hypothalamic microglia in controlling the HPG axis through receptor activator of nuclear factor κβ (Rank) signaling. Whole-body and microglia Rank depletion led to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) neuron function. In addition, we identified rare gene variants of RANK in patients with HH. Transcriptional profiling upon Rank loss revealed defective microglia activation and morphological alterations in the median eminence, decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH neuronal responses to kisspeptin. Overall, our data uncover the microglia as regulator of GnRH neuronal function through Rank signaling, with potential implications for reproductive maturation and fertility.

Metabolomic studies in COPD reveal systemic metabolic perturbations, yet sex is often treated as a covariate rather than a biological driver. We aimed to identify plasma metabolites differentiating COPD from controls and to define sex-specific metabolic signatures in both groups. Methods: In this controlled observational study (BIOMEPOC cohort), untargeted plasma metabolomics was performed by LC-MS/MS. Differential abundance was tested across four contrasts (COPD vs. controls; men vs. women within controls; men vs. women within COPD; sex-by-disease interaction) with a false discovery rate (FDR) correction. Because smoking history differed between COPD and controls, a post hoc ever-smokers analysis was conducted. Results: COPD differed from controls in nine metabolites (all decreased): DL-stachydrine, 3-methyl-L-histidine, fructose, pipecolinic and nipecotic acids, 5-nitro-o-toluidine, conjugated linoleic acid, aminoadipate, and creatinine. This pattern is compatible with metabolic depletion, remodeling, and/or altered flux across multiple compartments rather than simple substrate deficiency, spanning muscle-related pools, amino acid handling, carbohydrate-associated metabolism, and exposome-linked inputs. In ever-smokers, results were directionally consistent, with five metabolites remaining nominally significant. Among controls, five metabolites were higher in men after FDR correction (PABA, cis-4-hydroxy-D-proline, N-acetylasparagine, deoxycarnitine, and creatinine), consistent with physiological sex dimorphism in energy pathways, connective-tissue remodeling, and diet/microbiome-related metabolism. Within COPD, six metabolites differed by sex after FDR correction, defining three axes: creatine energy buffering (men: higher GAA/creatinine, lower creatine), purine/urate handling (men: higher urate), and conjugated bile acids (men: higher GCDCA), implicating muscle bioenergetics, redox/inflammatory tone, and gut-liver crosstalk. Conclusions: Plasma metabolomics identifies a pattern compatible with systemic remodeling in COPD and sex-associated divergences in creatine, purine/urate, and bile-acid pathways, supporting a sex-influenced view of systemic COPD heterogeneity and highlighting targets for mechanistic validation.

Sub-Saharan Africa, a region marked by enormous social and health inequalities, has the largest population infected with HIV and Mycobacterium tuberculosis, which are considered the main risk factors for fungal infections. At the same time, sub-Saharan Africa is the region of the world with the highest rates of helminth infections, whose immunomodulatory effects impair the host's immune responses to other microorganisms, including HIV and M. tuberculosis. Through this indirect way, helminth immune modulation could be another syndemic factor influencing the development of fungal infections. However, some epidemiological peculiarities of five fungal diseases in sub-Saharan Africa, which we analyze in this paper, suggest that the influence of helminth immune modulation on the development of fungal infections there could also be direct. In light of the knowledge of all those interactions, any healthcare and epidemiological approach to Invasive Fungal Infections in sub-Saharan Africa should be carried out from a syndemic perspective that takes into account the ways in which social environments contribute to the clustering of infections, the pathways through which infecting microorganisms could interact biologically in each individual, influencing the development and evolution of the disease in course, and the ways in which those interactions complicate diagnosis, treatment, and control.