Instituto Cajal

This study aimed to assess the frequency of MDM4 amplification in endometrial carcinomas and its association with clinicopathological features, particularly relapse risk in early-stage low-grade endometrioid endometrial carcinoma. We conducted a case-control study including 110 stage I to II low-grade endometrioid endometrial carcinomas (39 relapsing and 71 non-relapsing tumors) and an additional cohort of 82 high-grade endometrial carcinomas. An independent retrospective cohort of 194 early-stage low-grade endometrioid endometrial carcinomas was used to validate the results. MDM4 amplification was analyzed by fluorescent in situ hybridization. Gene expression of MDM4 and GADD45A was measured by quantitative real-time polymerase chain reaction. Immunohistochemistry assessed hormone receptor status, p53, and mismatch repair proteins. POLE and CTNNB1 mutations were evaluated by Sanger sequencing. MDM4 amplification was detected in 31 of 186 tumors (16.7%): 14 of 104 low-grade endometrioid endometrial carcinomas (13.5%) and 17 of 82 high-grade endometrial carcinomas (20.7%). Among low-grade endometrioid endometrial carcinomas, amplification was significantly more frequent in relapsing tumors (11/38, 28.9%) than in non-relapsing ones (3/66, 4.5%) (p <.01). Concordant MDM4 amplification status was observed between biopsies and hysterectomy samples. In some relapsing cases, amplification emerged during disease progression. Multi-variable Cox regression identified MDM4 amplification as an independent predictor of relapse, alongside lymphovascular space invasion, tumor necrosis, and myometrial invasion. In the independent cohort, MDM4 amplification was associated with progression-free survival. Our study suggested that MDM4 amplification is a potential predictor of the risk of recurrence in early-stage low-grade endometrioid endometrial carcinoma that can be easily evaluated in endometrial samples.

The continuous increase in atmospheric CO₂ concentration underscores the urgent need for scalable and energy-efficient carbon removal technologies. This study demonstrates, for the first time, the implementation of a tailored Direct Air Capture (DAC) concept integrated within large-scale microalgae raceway reactors, enabling direct CO₂ uptake from ambient air without external gas supply. A 600 m² reactor operated continuously with Scenedesmus sp. maintained stable productivity (12 g m⁻² day⁻¹) under extreme carbon limitation (TIC ≈ 20 mg L⁻¹, pH ≈ 10). Fine-bubble aeration in the sump achieved nearly complete CO₂ removal from air streams, while passive absorption across the raceway and paddlewheel sections provided almost all the carbon required for biomass growth. The overall CO₂ removal efficiency reached 95%, confirming the reactor’s operation as a functional bio-DAC system. The estimated energy demand for air bubbling (≈ 2.9 kWh kg⁻¹ CO₂) is comparable to or below that of current engineered DAC technologies. This approach establishes a low-cost, renewable-compatible, and scalable pathway for atmospheric CO₂ capture that couples negative-emission performance with biomass production, laying the groundwork for decentralized, carbon-negative biotechnological systems contributing to global greenhouse-gas mitigation. • Large-scale microalgae raceways directly capture CO₂ from ambient air. • Sump-based aeration achieves up to 95% CO₂ removal efficiency. • pH-driven carbonate balance governs atmospheric CO₂ absorption and fixation. • Bio-DAC integrates carbon capture with renewable biomass production. • Demonstrated low-energy (≈ 2.9 kWh kg⁻¹ CO₂) pathway for negative emissions.

Our understanding of memory and learning has been largely overshadowed by neurocentric studies, leaving non-neuronal cells out of the equation. The cellular substrate for memory is thought to lie within engrams - ensembles of neurons that activate during learning, whose reactivation leads to recall of the acquired memory. Astrocytes are now taking centre stage in the modulation of memory and other cognitive functions. Contrary to widespread assumptions, these glial cells activate as sparse groups, or ensembles, and reactivation of astrocyte ensembles recruited during learning produces recall. Recent advances using activity-dependent tools to interrogate the roles of astrocytes in memory support a paradigm shift: engrams not only are composed of neurons but also include astrocyte ensembles that activate during learning, forming what we call 'astroengrams'. Thus, the coordinated activity of neuronal and astrocytic engrams provides an integrated framework to orchestrate memory storage and recall.

Current antidepressants targeting neurotransmitters often fail to alleviate symptoms. Alternative hypotheses suggest inflammation may trigger an alternative route that converts tryptophan into kynurenine, reducing the bioavailability of tryptophan to synthesize serotonin while producing neuroactive metabolites such as quinolinic acid (QUINA, excitotoxic) and kynurenic acid (KYNA, neuroprotective). This study evaluates the effects on these systems of a specific strain of Ligilactobacillus salivarius (L. salivarius), identified in the Spanish Type Culture Collection as CECT 30632, in a preclinical model depression. Male Wistar rats (n = 32) were divided into control (CT) and chronic mild stress (CMS) groups, treated with either vehicle or L. salivarius CECT 30632 for four weeks, starting one week before CMS exposure. Behavioral assessments, including the splash test (ST) and open field test (OF), were conducted. Biochemical analyses of peripheral blood mononuclear cells (PBMCs), plasma, and frontal cortex (FC) samples assessed antioxidant markers phospho-nuclear factor (erythroid-derived 2)-like 2 (p-Nrf2) and glutathione peroxidase 1 (GPx1), as well as tryptophan metabolites. In the ST, L. salivarius CECT 30,632 reduced latency to groom, indicating improved anhedonia and self-care, while no changes were observed in the OF test. CMS reduced p-Nrf2 and GPx1 expression in PBMCs, which was restored by L. salivarius CECT 30,632. This bacterium also reduced the QUINA/KYNA ratio in plasma and FC, suggesting a lower excitotoxicity risk. Ligilactobacillus salivarius CECT 30632 improved behavioral outcomes, enhanced antioxidant defenses, and modulated tryptophan metabolism in a rat model of CMS. These findings support its potential as a probiotic intervention for depression.

Ocular syphilis in the Iberian Peninsula shows a wide clinical spectrum and frequent posterior segment involvement. Most patients achieved favourable serological and visual outcomes. These findings support the effectiveness of standard therapies and highlight the need for early diagnosis, especially in high-risk populations.

Comprehensive and systematic radiologic assessment is crucial in differentiating rheumatoid arthritis from other inflammatory arthropathies.

812 Background: Muscle-invasive bladder carcinoma (MIBC) is associated with high recurrence and mortality rates, and current neoadjuvant chemotherapy (NACT) regimens offer limited efficacy and considerable toxicity. These limitations underscore the need for reliable biomarkers to improve treatment management and patient outcomes. Metaproteomics profiling allows for the simultaneous characterisation of human and microbial proteins within tumors, offering a new perspective on patient-microbiota interactions in cancer. Our group has identified three microbiota-related metaproteomics clusters (Microbiota1-3) associated with response to NACT in MIBC. Our objective is to evaluate the prognostic relevance in terms of disease-free survival (DFS) of these microbiota-related metaproteomics clusters. Methods: Fifty-eight FFPE transurethral resection (TURBT) samples from patients diagnosed with MIBC were analyzed using data-independent acquisition (DIA) mass spectrometry. Protein identification was performed against a custom database including the human proteome and bacterial proteomes from bacteria genera identified by 16S rRNA gene sequencing in the same samples. After quality control, bacterial and human proteins were analyzed using Perseus software and probabilistic graphical models (PGMs) to identify functional relationships. Patients were classified into three metaproteomic clusters (Microbiota1-3) according to their tumor microbiota protein profiles by hierarchical clustering. Disease-free survival (DFS) was estimated by the Kaplan-Meier method and compared among clusters using the log-rank (Mantel-Cox) test. Results: Kaplan-Meier analysis revealed significant differences in DFS between the three defined metaproteomics subtypes (Microbiota1-3) (p=0.01). Patients classified as Microbiota3 had the most favorable DFS and a lower proportion of relapse events, with median DFS not reached during the follow-up period. This group was previously associated with a higher proportion of responders to NACT, consistent with the favorable DFS observed. In contrast, Microbiota2 was associated with earlier relapse and shorter DFS (median DFS: 23 months), in line with its higher proportion of non-responders to NACT. Conclusions: To our knowledge, this is the first metaproteomics study focused in biomarker discovery using FFPE samples from bladder carcinoma patients. Distinct MIBC metaproteomics profiles are associated with differential DFS following NACT. The identification of these three microbiota-related proteomics clusters highlights the potential prognostic relevance of the tumor-associated microbiota. These findings support metaproteomics as a promising approach for refining patient stratification and guiding future biomarker-driven strategies in bladder cancer.

The overall health impact of alcohol remains controversial. The Global Burden of Disease (GBD) study made headlines in 2018 by stating that zero alcohol was the safest option. However, its 2022 update introduced age-specific adaptations, asserting that moderate drinking may offer net benefits in some populations. The 2025 U.S. Surgeon General report also discouraged any alcohol intake because of associated cancer risks, but a simultaneous report by the National Academies emphasized tailoring recommendations to individual risks. Mendelian randomization (MR) studies found no health benefits and highlighted increased risks—even at low alcohol doses—challenging dozens of conventional epidemiologic findings in large observational cohorts, some of them of high methodological quality. Given these contradictions, there is a pressing need for large randomized controlled trials in drinkers promoting cessation versus moderation. While small trials have shown some metabolic and cardiovascular benefits of moderate red wine consumption, no large-scale randomized trial has yet assessed hard clinical outcomes comprehensively. Without such evidence, debates will persist. Current guidelines appropriately discourage alcohol in certain populations, but generalizations such as “no safe level of alcohol” might lack sufficient empirical support and perhaps they need a tailored and practical strategy in the context of precision medicine. A balanced, evidence-based approach—free from bias, independent of the industry and grounded in rigorous research—is essential for informed public health policy decisions.

ATP-binding cassette A1 (ABCA1) is a membrane-associated cholesterol efflux pumpthat iscrucial for high-density lipoprotein (HDL) biogenesis and cellular cholesterol homeostasis. Pathogenic variants in the ABCA1 gene cause Tangier disease (TD), a rare autosomal recessive disorder characterized by nearly absent HDL in plasma and cholesteryl ester accumulation in tissue macrophages. Clinical manifestations vary among patients withTD, including splenomegaly, thrombocytopenia, and cardiovascular disease (CVD), with no clear association with specific ABCA1 pathogenic variants. Thrombocytopenia is attributed to hypersplenism-mediated platelet clearance; however, there is controversy regarding platelet production and function in TD. To identify and functionallycharacterizethe suspected alteration in ABCA1,and to study platelet production and function in a Spanish family with HDL deficiency and thrombocytopenia. Lipid and apolipoprotein profile analyses, next-generation/Sanger sequencing, in vitro ABCA1 expression and cholesterol efflux assays, primary megakaryocyte differentiation cultures, and platelet functional studies were performed. We identified a novel variant, ABCA1:NM_005502.4c.3306del:p.(Ile1103Serfs*16), which results in a truncated protein with defective apolipoprotein AI-dependent cholesterol efflux. Mild to severe thrombocytopenia and splenomegaly were observed in homozygous carriers; however,there was no clinical history of CVD. Platelet degranulation was overtly normal, although a distinct aggregation profile was observed in ABCA1:p.(Ile1103Serfs*16) carriers. Impaired megakaryocyte differentiation associated with aberrant accumulation of neutral lipids in megakaryocytes was observed in primary cell cultures from homozygous carriers. The ABCA1:NM_005502.4c.3306del:p.(Ile1103Serfs*16) variant causes TD. Our findings suggest that thrombocytopenia in TD is not merely due to platelet clearancebut also a consequence of ineffective megakaryopoiesis due to ABCA1 dysfunction.