Rogelio González-Sarmiento

Alcohol use disorder (AUD) is influenced by genetic factors that affect key neurobiological systems, including dopaminergic and GABAergic pathways, which regulate neurobehavioral functions and are modulated by brain-derived neurotrophic factor (BDNF). Variations in these genes contribute to individual vulnerability to AUD. In this study, we investigated single-nucleotide polymorphisms (SNPs) and haplotypic associations in GABRA1, GABRA2, and GABRA6, along with the dopaminergic pathway genes DRD2/ANKK1 and BDNF, in a Spanish cohort. Peripheral blood-derived genomic DNA was genotyped, and haplotype analyses were conducted. Individual SNPs in GABRA1, GABRA2, BDNF, and DRD2/ANKK1 showed no significant associations with AUD. In GABRA6, the rs3219151 T allele was more frequent in AUD patients than in controls (57.9% vs. 49.3%; p = 0.03), while the C allele appeared to show a potential protective association. In addition, the GAC haplotype of GABRA6 (rs2197414, rs1992647, rs3219151) was less frequent in AUD than in controls (0.071 vs. 0.122) and showed a protective association (OR = 0.58; 95% CI = 0.34–0.99; p = 0.045). Our findings provide exploratory evidence suggesting that specific genetic variants and haplotypes may contribute to AUD susceptibility and support the relevance of multigenic and haplotypic approaches for exploring the neurobiological mechanisms underlying AUD.

Inherited mutations in BRCA1 are among the primary causes of hereditary breast and ovarian cancer (HBOC). Genetic testing has identified numerous pathogenic and benign mutations in BRCA1, but also thousands of variants of uncertain significance (VUS) with unclear functional consequences. Accurate cancer risk prediction for carriers of these VUS requires functional assays to assess their pathogenicity. In this study, we analyzed 16 BRCA1 VUS detected at the Hereditary Cancer Genetic Counseling Laboratory in Salamanca, Spain, with the goal of providing additional data to guide their reclassification. Since homologous recombination (HR) is the primary tumor-suppressive function of BRCA1, we employed two complementary HR repair assays to evaluate HR efficiency. The first, an already established assay, uses a HeLa-DR cell line harboring an HR reporter cassette and involves silencing endogenous BRCA1 followed by complementation with the VUS under study. The second, developed in this work, is also based in complementation assays that restore the green fluorescence protein (GFP) gene, and employs a breast cancer cell line with a similar HR reporter system (HCC1937-HR) that lacks BRCA1 expression, allowing direct complementation. Both assays consistently identified five VUS (p.V11G, p.H888Y, p.G1201S, p.Q1395R, and p.F1734L) as pathogenic due to significantly reduced HR efficiency, whereas the remaining 11 VUS were benign in terms of HR function. Notably, two pathogenic variants (p.H888Y, p.G1201S) were located outside the known functional domains of BRCA1. The five HR-deficient variants were further evaluated for their sensitivity to ionizing radiation, which confirmed the deleterious impact on DNA repair for variants p.V11G, p.H888Y, p.G1201S and p.F1734L. Sensitivity to the PARP inhibitor olaparib revealed hypersensitivity only in cells expressing p.V11G and p.F1734L, suggesting variant-specific mechanistic effects with potential therapeutic relevance. In conclusion, recombination-based functional assays complemented with sensitivity assays are effective tools for assessing the pathogenicity of BRCA1 VUS and can provide valuable information to support clinical decision-making. We propose that these assays can be completed within a timeframe compatible with clinical needs, offering critical insights for genetic counseling and personalized treatment strategies.

Purpose: The global incidence and mortality of early‐age onset colorectal cancer (EOCRC, or CRC diagnosed under 50 years) has increased in recent decades. High‐risk surveillance and personalised oncological treatment may improve patients' outcomes. This study aims to characterise real‐world somatic and germline molecular profiles in European EOCRC patients. Patients and Methods: Consecutive patients across the UK, Spain, Germany and Italy from the GEOCODE and SECOC consortia were identified using electronic patient records. Clinicopathological, somatic and germline testing data were collected on EOCRC patients. Tests included mismatch repair (MMR), somatic next generation sequencing (NGS) and germline multi‐gene panels. Results: Eight hundred ninety‐three EOCRC patients were identified from 23 European centres (45.7% female, median age 42, range 14–49), predominantly in the distal colorectum: 205/893 (22.9%) patients with right‐sided tumours, 302/893 (33.8%) left‐sided tumours, 288/893 (32.2%) rectal tumours and 97/893 (10.8%) unknown. On somatic analysis, 735/893 (82.3%) of patients had pMMR tumours and 148/893 (16.5%) dMMR. Although 534/893 (59.7%) did not receive NGS somatic testing, somatic variants were detected in 233/359 (64.9%) of those tested. Germline variants were detected in 133/210 (63.3%) patients tested. Lynch syndrome was diagnosed in 93/210 (44.2%), of whom 17/93 (18.2%) presented with pMMR tumours. Systematic recording of family history in these real‐world data was variable. In all patients with family history recorded, 153/484 (31.4%) patients reported a relative with CRC. Conclusions: Our results support universal and paired somatic and germline multi‐gene panels for all EOCRC patients, regardless of MMR status or family history. Systematic molecular testing approaches are necessary to address disparities in people with EOCRC. Larger unselected cohort studies would support validation of testing prediction models and estimates of clinically relevant variant actionability.

Introducción: Los profesionales sanitarios cuidan la salud de las personas. Para mantener su capacidad de trabajo necesitan tener buena salud, entornos de trabajo seguros y un equilibrio entre sus recursos personales y las demandas físicas y mentales. El objetivo de la revisión fue conocer más sobre los efectos de la promoción de la salud y las medidas preventivas en el trabajo sobre la capacidad laboral de estos trabajadores. Método: Se buscaron estudios observacionales y experimentales publicados desde 2014 hasta 2024 en PubMed, Scopus, Web of Science, Cochrane Library y Google Scholar, para identificar, en trabajadores del ámbito sanitario, intervenciones de promoción de la salud o prevención realizadas en el lugar de trabajo. La medida de resultado fue el índice de capacidad para el trabajo. Dos revisores seleccionaron los estudios y analizaron su calidad y fiabilidad tras una lectura crítica. Además, evaluaron el riesgo de sesgo y la calidad de la evidencia. Resultados: Se seleccionaron 19 estudios (10 ensayos aleatorizados, 6 cuasiexperimentales y 3 observacionales), de calidad media-baja y riesgo de sesgo incierto-alto. Se observó una mejora significativa en la capacidad de trabajo en 12 estudios (63 %), que analizaban programas de entrenamiento físico, dotación de recursos frente a las exigencias mentales, asesoramiento en hábitos saludables y mejoras ergonómicas. La calidad de la evidencia fue moderada. Discusión: Estas intervenciones pueden mejorar la capacidad laboral del personal sanitario. Se requieren estudios de mayor calidad y seguimientos más largos. Los hallazgos pueden ayudar a profesionales de salud ocupacional y gestores sanitarios en la decisión de implementar programas efectivos de promoción de la salud y prevención para los empleados.

SQSTM1/p62 has an essential role in autophagy, a catabolic pathway that is vital for maintaining cell homeostasis. p62 alterations have been observed in multiple pathological conditions, including neurodegenerative diseases and bone metabolism alterations. The p.R321C p62 protein mutation has been described in patients with amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Paget’s disease of bone. In vitro studies associated the p62-321C variant with a blockade of autophagy and with the activation of the NF-kB pathway. We aimed to provide a deeper understating of the pathophysiological consequences of the p.R321C p62 mutation using a humanized mouse model. Micro-computed tomography, immunohistochemistry, and western blot analysis studied the functional consequences of the p. R321C p62 mutation. Statistical analyses were performed using SPSS software. The results showed that the p62-321C mice developed seizures after tactile–vestibular stimulation, probably associated with a blockage of the autophagy and NF-kB activation. Changes in expression of cFos and p62 were found in the amygdala, hypothalamic nuclei, and hippocampi nuclei. In addition, numerous degenerating motor neurons were observed in the spinal cord of the p62-321C mice. We report that the blockage of the autophagy, caused by p.R321C p62 mutation, is associated with abnormalities in the central nervous system, mainly seizures after tactile–vestibular stimulation and degeneration of the motor neurons of the spinal cord but not with bone abnormalities in a humanized mouse model.

Background: Telomere length (TL) is a marker of cellular health and aging. Physical exercise has been associated with longer telomeres and, therefore, healthier aging. However, results supporting such effects vary across studies. Our aim was to synthesize existing evidence on the effect of different modalities and durations of physical exercise on TL. Objective: The aim of this study was to explore the needs and expectations of individuals with physical disabilities and their interventionists for the use of a virtual reality physical activity platform in a community organization. Methods: We performed an umbrella review and meta-analysis. Data sources included PubMed, Embase, Web of Science, Cochrane Library, and Scopus. We selected systematic reviews and meta-analyses of randomized and nonrandomized controlled clinical trials evaluating the effect of physical exercise on TL. Results: Our literature search retrieved 12 eligible systematic reviews, 5 of which included meta-analyses. We identified 22 distinct primary studies to estimate the overall effect size of physical exercise on TL. The overall effect size was 0.28 (95% CI 0.118-0.439), with a heterogeneity test value Q of 43.08 (P=.003) and I² coefficient of 51%. The number of weeks of intervention explained part of this heterogeneity (Q_B=8.25; P=.004), with higher effect sizes found in studies with an intervention of less than 30 weeks. Exercise modality explained additional heterogeneity within this subgroup (Q_B=10.28, P=.02). The effect sizes were small for aerobic exercise and endurance training, and moderate for high-intensity interval training. Conclusions: Our umbrella review and meta-analysis detected a small-moderate positive effect of physical exercise on TL, which seems to be influenced by the duration and type of physical exercise. High quality studies looking into the impact of standardized, evidence-based physical exercise programs on TL are still warranted.