Departament de Medicina i Ciències de la Vida
Documents de recerca, en accés obert, com ara articles de revista, llibres, comunicacions, ponències o posters a jornades i congressos, etc., del Departament de Ciències Experimentals i de la Salut de la UPF.
URI permanent per a aquesta comunitat http://hdl.handle.net/10230/6237
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Item type: Item , Comprehensive immunophenotyping of gastric adenocarcinoma identifies an inflamed class of tumors amenable to immunotherapies(BMJ Publishing Group, 2025) Veas Rodriguez, Joel; Piñol, Miquel; Sorolla, Maria Alba; Parisi, Eva; Sorolla, Anabel; Santacana, Maria; Ruiz, Maria; Parra Farré, Genís; Bernabeu, Mario; Iglesias Coma, Mar; Aracil, Carles; Escartin, Alfredo; Vilardell, Felip; Matias-Guiu, Xavier; Salud, Antonieta; Montal, RobertBackground: Gastric adenocarcinoma (GAC) imposes a considerable global health burden. Molecular profiling of GAC from the tumor microenvironment perspective through a multi-omics approach is eagerly awaited in order to allow a more precise application of novel therapies in the near future. Methods: To better understand the tumor-immune interface of GAC, we identified an internal cohort of 82 patients that allowed an integrative molecular analysis including mutational profiling by whole-exome sequencing, RNA gene expression of 770 genes associated with immune response, and multiplex protein expression at spatial resolution of 34 immuno-oncology targets at different compartments (tumorous cells and immune cells). Molecular findings were validated in 595 GAC from the TCGA and ACRG external cohorts with available multiomics data. Prediction of response to immunotherapies of the discovered immunophenotypes was assessed in 1039 patients with cancer from external cohorts with available transcriptome data. Results: Unsupervised clustering by gene expression identified a subgroup of GAC that includes 52% of the tumors, the so-called Inflamed class, characterized by high tumor immunogenicity and cytotoxicity, particularly in the tumor center at protein level, with enrichment of PIK3CA and ARID1A mutations and increased presence of exhausted CD8+ T cells as well as co-inhibitory receptors such as PD1, CTLA4, LAG3, and TIGIT. The remaining 48% of tumors were called non-inflamed based on the observed exclusion of T cell infiltration, with an overexpression of VEGFA and higher presence of TP53 mutations, resulting in a worse clinical outcome. A 10-gene RNA signature was developed for the identification of tumors belonging to these classes, demonstrating in evaluated datasets comparable clinical utility in predicting response to current immunotherapies when tested against other published gene signatures. Conclusions: Comprehensive immunophenotyping of GAC identifies an inflamed class of tumors that complements previously proposed tumor-based molecular clusters. Such findings may provide the rationale for exploring novel immunotherapeutic approaches for biomarker-enriched populations in order to improve GAC patient's survival.Item type: Item , Rilzabrutinib in antihistamine-refractory chronic spontaneous urticaria: The RILECSU phase 2 randomized clinical trial(American Medical Association, 2025) Giménez Arnau, Anna Maria; Ferrucci, Silvia M.; Ben-Shoshan, Moshe; Mikol, Vincent; Lucats, Laurence; Sun, Iris; Mannent, Leda P.; Gereige, JessicaImportance: Chronic spontaneous urticaria (CSU) is a skin disease driven mainly by the activation of cutaneous mast cells through various mechanisms. Bruton tyrosine kinase (BTK), expressed in B cells and mast cells, plays a critical role in multiple immune-mediated disease processes. Objective: To determine the efficacy and risk profile of rilzabrutinib (SAR444671), an oral, reversible, covalent, next-generation BTK inhibitor, in treating patients with CSU. Design, setting, and participants: The Rilzabrutinib Efficacy and Safety in CSU (RILECSU) randomized clinical trial was a 52-week phase 2 study comprising a 12-week, double-blind, placebo-controlled, dose-ranging period, followed by a 40-week open-label extension. The trial was conducted from November 24, 2021, through April 23, 2024. Fifty-one centers enrolled and randomized participants across 12 countries in Asia, Europe, North America, and South America. The trial participants included adults aged 18 to 80 years with moderate to severe CSU (weekly Urticaria Activity Score [UAS7] of 16 or more; weekly Itch Severity Score [ISS7] of 8 or more) not adequately controlled with H1-antihistamine treatment. Interventions: Patients were randomized 1:1:1:1 to rilzabrutinib, 400 mg, once every evening (400 mg/d), twice per day (800 mg/d), 3 times per day (1200 mg/d), or matching placebo. Main outcomes: The primary end point was change from baseline at week 12 in ISS7 (for US and US reference countries) or UAS7 (for non-US reference countries). Results: A total of 160 omalizumab-naive and omalizumab-incomplete responders were randomized (mean [SD] age, 44.1 [13.4] years; 112 [70.0%] female). The primary analysis population included only the 143 omalizumab-naive patients. Significant reductions at week 12 were observed with rilzabrutinib, 1200 mg/d, vs placebo from baseline in ISS7 (least squares [LS] mean, -9.21 vs -5.77; difference, -3.44 [95% CI, -6.25 to -0.62]; P = .02) and UAS7 (LS mean, -16.89 vs -10.14; difference, -6.75 [95% CI, -12.23 to -1.26]; P = .02). In addition, improvements in weekly Hives Severity Score (HSS7) and weekly Angioedema Activity Score (AAS7) were observed. Improvements in ISS7, UAS7, HSS7, and AAS7 were observed as early as week 1. CSU-related biomarkers, including soluble Mas-related G protein-coupled receptor X2, immunoglobulin (Ig)-G antithyroid peroxidase, IgG anti-Fc-ε receptor 1, and interleukin-31, were reduced compared to placebo at week 12. Rilzabrutinib demonstrated a favorable risk-benefit profile; adverse events occurring at a higher frequency with rilzabrutinib vs placebo included diarrhea, nausea, and headache. Conclusions and relevance: The results of the RILECSU randomized clinical trial demonstrated efficacy and rapid onset of action of rilzabrutinib, 1200 mg/d, over 12 weeks, in addition to an acceptable adverse event profile. Together, these data support the use of rilzabrutinib in treating patients with moderate to severe CSU refractory to H1-antihistamines. Further research is needed to determine long-term efficacy and potential harms. Trial registration: ClinicalTrials.gov Identifier: NCT05107115.Item type: Item , Synbiotic intervention reverses alcohol drinking-induced cognitive deficits in adolescent male mice by modulating the microbiota-gut-brain axis(Taylor & Francis, 2025) Barrera Conde, Marta; Korchevaya, Elizaveta; Kossatz de Mello, Elk, 1977-; Veza, Emma; Pujadas, Mitona; Alechaga, Élida; Nebot Forcada, Pau; Pozo Mendoza, Óscar J., 1975-; Torre Fornell, Rafael de la; Pizarro Lozano, Ma. Nieves; Robledo, Patricia, 1958-Adolescence is characterized by an increased vulnerability to substance abuse, including alcohol consumption. We investigated the effects of a synbiotic intervention on disruptions of the microbiota-gut-brain axis induced by a drinking in the dark model of intermittent alcohol exposure in adolescent mice. We found that alcohol drinking induced specific shifts in gut microbiota, namely it increased Erysipelotrichaceae and reduced fecal butyric and isovaleric acids. In adulthood, other types of gut bacteria were affected such as Rhodospirillales uncultured family and Entrorhabdus uncultured bacterium. Social and nonsocial cognitive impairments were also observed, and disruptions in prefrontal cortex ß-hydroxybutyrate and glutamate metabolic profile in the hippocampus were apparent. Importantly, the synbiotic restored gut microbiota alterations and exerted beneficial effects on alcohol-induced behavioral impairments and brain metabolite changes. In correlational studies, we identified two potential functional networks, one relating gut microbiota (Actinobacteria and Lactobacillaceae)-isovaleric acid with prefrontal glutamate metabolism and sociability, and the other relating SCFAs (propionic, butyric, valeric and isovaleric acids) with ß-hydroxybutyrate in the hippocampus and reference memory. These results provide correlative data showing that synbiotic supplementation may restore delayed behavioral alterations induced by voluntary sub-binge alcohol drinking during adolescence through microbiota-gut-brain interactions, and might represent a potential therapeutic tool against long-term alcohol induced behavioral and molecular disturbances.Item type: Item , Prepandemic levels of cytokines and immunoglobulins and risk of SARS-CoV-2 infection and COVID-19 in the general population of Barcelona(Frontiers, 2025) Porta, Miquel; Pumarega Rodríguez, José Antonio; Aguilar, Ruth; Prieto-Merino, David; Campi, Laura; Rius, Cristina; Villar García, Judit; Vidal, Marta; Jiménez, Alfons; Peña, Antonio; Muñoz Pérez, Miguel Ángel; Trasande, Leonardo; Bolúmar, Francisco; Moncunill, Gemma; Gasull Panadès, Magda; Dobaño, CarlotaBackground: From a public health perspective it is remarkable that there are yet no longitudinal studies in the general population investigating the influence of the basal immune state, measured before the pandemic, on the risk of SARS-CoV-2 infection and COVID-19. Objective: To investigate the specific and combined effects of personal levels of cytokines and immunoglobulins-measured in individuals' blood 4 years before the pandemic-on the risk of SARS-CoV-2 infection and COVID-19 in a general population. Methods: We conducted a prospective cohort study in 240 individuals from the general population of Barcelona. Thirty cytokines and 31 immunoglobulins were quantified in prepandemic serum samples (collected in 2016-17) by high-throughput multiplex quantitative suspension array technology. Results: Higher concentrations in 2016-17 of IL-8 and TNF-α significantly decreased the risk of SARS-CoV-2 seropositivity in 2020-21, whereas higher concentrations of MIP-1α were a risk factor for seropositivity. Most cytokines in mixtures with IL-8, MIP-1α, TNF-α or G-CSF were associated with SARS-CoV-2 seropositivity (all OR ≥2.0 or OR≤0.4 and p < 0.05). The five individual isotype-antigen pairs more clearly associated with seropositivity were: protectively, IgG to CMV pp150, IgG to CMV pp65, and IgG to N OC43; and, increasing risk of seropositivity, IgM to CMV pp65 and IgM to EBV EA-D. The four cytokines most consistently associated with the risk of COVID-19 were also G-CSF, IL-8, TNF-α, and MIP-1α. The four isotype-antigen pairs more strongly associated with risk of COVID-19 (all protective) were IgA to CMV pp65 and N 229E, and IgG to EBV EAD and VCAp18. Conclusion: The unique longitudinal design of this study, with measurements before and during the pandemic in a general population, provides novel knowledge on the protective and detrimental effects of specific individual cytokines and immunoglobulins, and their mixtures, on the risk of SARS-CoV-2 seropositivity and COVID-19. If confirmed, findings would be significantly relevant for medicine and public health.Item type: Item , Tuberculosis household contact tracing in children: axes of inequality, Barcelona 2003-2022(Frontiers, 2025) Prieto-García, Raquel; Millet, Joan-Pau; Soriano-Arandes, Antoni; Espiau, María; Broto, Claudia; Ronda, Mar; López, Núria; Noguera Julian, Antoni; Masdeu, Eva; Domingo Jimenez, Cristina; Ros Samsó, Miriam; Marcos Arroita, Maria Isabel; Ospina Valencia, Jesús Edison; García Rebollo, Carmen; Simon Viván, Pere; Rius Gibert, CristinaChildren under 15 years of age living in the household of a tuberculosis case constitute a very vulnerable group to tuberculosis infection (TBI). The objective of this study was to determine the prevalence of TBI and the risk factors associated with presenting TBI in this group, considering sex, age, and migratory status as axes of inequality. A population-based, analytical, cross-sectional observational study was carried out in the city of Barcelona in the period 2003-2022. The study population was household contacts under 15 years of age with index cases of pulmonary TB reported to the Barcelona Public Health Agency in the period 2003-2022. The analyses were performed using Generalized Estimating Equations (GEE) to predict the risk of TBI among these cohabiting contacts and were stratified considering the inequality axes of sex and migratory status. A total of 1084 contacts under 15 years of age were studied from 693 cases of tuberculosis. TBI prevalence among contacts was 24.5%. The factors associated with the presence of TBI in the contacts were having a smear positive in the index case, being older than 5 years in the contacts ([5,10], [10-15]) and the case and the contact being migrants; smear positive when the index case was native women and being from a municipal district with a lower incidence of tuberculosis when the index case was native women and the men. The results of the study confirm the importance of carrying out contact tracing and follow-up of household children, especially if the index case is smear positive. Contact tracing should be carried out as soon as possible to assess the prescription of primary chemoprophylaxis and TBI treatment to avoid rapid TB progression in children.