Articles publicats (Medicina Experimental)

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    Methodological Review of Classification Trees for Risk Stratification: An Application Example in the Obesity Paradox
    (MDPI, 2025-05-31) Trujillano Cabello, Javier; Servià Goixart, Lluís; Badia Castello, Mariona; Serrano Casasola, José Carlos Enrique; Bordeje Laguna, Mª Luisa; Lorencio Cardenas, Carol; Vaquerizo Alonso, Clara; Flordelis Lasierra, Jose Luis; Martínez de Lagran, Itziar; Portugal Rodríguez, Esther; López Delgado, Juan Carlos
    Background: Classification trees (CTs) are widely used machine learning algorithms with growing applications in clinical research, especially for risk stratification. Their ability to generate interpretable decision rules makes them attractive to healthcare professionals. This review provides an accessible yet rigorous overview of CT methodology for clinicians, highlighting their utility through a case study addressing the "obesity paradox" in critically ill patients. Methods: We describe key methodological aspects of CTs, including model development, pruning, validation, and classification types (simple, ensemble, and hybrid). Using data from the ENPIC (Evaluation of Practical Nutrition Practices in the Critical Care Patient) study, which assessed artificial nutrition in ICU (intensive care unit) patients, we applied various CT approaches CART (classification and regression trees), CHAID (chi-square automatic interaction detection), and XGBoost (extreme gradient boosting) and compared them with logistic regression. SHAP (SHapley Additive exPlanation) values were used to interpret ensemble models. Results: CTs allowed for identification of optimal cut-off points in continuous variables and revealed complex, non-linear interactions among predictors. Although the obesity paradox was not confirmed in the full cohort, CTs uncovered a specific subgroup in which obesity was associated with reduced mortality. The ensemble model (XGBoost) achieved the best predictive performance (highest area under the ROC curve), though at the expense of interpretability. Conclusions: CTs are valuable tools in clinical epidemiology, complementing traditional models by uncovering hidden patterns and enhancing risk stratification. While ensemble models offer superior predictive accuracy, their complexity necessitates interpretability techniques such as SHAP. CT-based approaches can guide personalized medicine but require cautious interpretation and external validation.
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    Open Access
    Non-enzymatic modification of aminophospholipids induces angiogenesis, inflammation, and insulin signaling dysregulation in human renal glomerular endothelial cells in vitro
    (Elsevier, 2025) Rodriguez Mortera, Reyna; Torres Cabestany, Pascual; Fernández Bernal, Anna; Berdún Hernández, Rebeca; Ramírez-Núñez, Omar; Martín Garí, Meritxell; Serrano Casasola, José Carlos Enrique; He, John C.; Prat Corominas, Joan; Pamplona Gras, Reinald; Uribarri, Jaime; Portero Otín, Manuel
    Aims/hypothesis Advanced glycation end-products (AGEs) formation in proteins are involved in healthy aging and a variety of diseases including Alzheimer's disease, atherosclerosis, and diabetic complications. However, the biological effects of the non-enzymatic modification of aminophospholipids (lipid-AGEs) at cellular level are poorly understood. This study aimed to investigate the effects of lipid-AGEs on angiogenesis, inflammation, insulin signaling, and mitochondrial function in human renal glomerular endothelial cells (HRGEC), exploring their potential role in the pathophysiology of diabetic nephropathy (DN). Methods HRGEC cells were exposed to non-enzymatically modified phosphatidylethanolamine (PE) by AGEs (lipid-AGEs), non-modified PE (nmPE) (aminophospholipid without modification), employed as a negative control, and lipopolysaccharides (LPS) as a positive control. Angiogenesis was assessed through vascular network formation metrics, including capillary area, junction density, and endpoints, under different extracellular matrices. Gene expression of inflammatory and angiogenic markers was quantified by RT-qPCR. Insulin signaling components, including IRS1 and AKT phosphorylation, were evaluated by immunoblotting. Mitochondrial function was assessed using high-resolution respirometry to determine ATP production rates from glycolysis and oxidative phosphorylation. Results Lipid-AGEs induced dose-, time-, and matrix-dependent angiogenesis, with effects comparable to LPS, particularly in Engelbreth-Holm-Swarm extracellular matrix (ECM) (capillary area increase: 25 %, p < 0.05). Lipid-AGEs significantly upregulated the expression of inflammatory genes IL8 and NFKB (p < 0.05), and the angiogenesis-related markers TGFB1 and ANGPT2 (p < 0.05). Insulin signaling was disrupted, as lipid-AGEs enhanced inhibitory phosphorylation of IRS1 (Ser-1101, 1.8-fold increase, p < 0.01) and modulated AKT (Ser-473) and p42/p44 ERK activation. At lower doses, lipid-AGEs reduced eNOS phosphorylation (p < 0.05) impairing insulin responsiveness. High-resolution respirometry revealed that lipid-AGEs reduced basal oxygen consumption rates (OCR) by 20 % (p < 0.05), with no significant changes in glycolytic ATP production. Conclusion Lipid-AGEs induce angiogenesis, inflammation, and insulin signaling disruption in HRGEC, contributing to endothelial dysfunction. These findings underscore the potential role of lipid-AGEs in age-related decline of renal function, as well as the pathogenic potential in DN highlighting their relevance as therapeutic targets for mitigating vascular and metabolic complications in diabetes.
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    Open Access
    Novel Cell Models to Study Myelin and Microglia Interactions
    (MDPI, 2025) Santacreu-Vilaseca, Marta; Moreno-Magallón, Judith; Juanes, Alba; Gil-Sánchez, Anna; González Mingot, Cristina; Torres Cabestany, Pascual; Brieva Ruiz, Luis
    Multiple sclerosis (MS) is characterized by demyelination and neuroinflammation, with oxidative stress playing a pivotal role in lesion pathology. This study aimed to investigate the differential cellular responses to myelin debris under varying oxidative states. Myelin oxidation was induced using a Cu–peroxide system, confirmed by elevated TBARS levels and autofluorescence. BV-2 microglia viability remained unaffected by myelin exposure. However, oxidized myelin significantly altered oxidative stress markers, autophagy, and iron metabolism, as evidenced by changes in Sod2, Tfr1, p62, and P-Erk/Erk ratios. Morphological analyses revealed time- and dose-dependent differences in myelin processing, with oxidized myelin leading to distinct phagosome dynamics. Complementary studies using induced microglia-like cells (iMG)—a primary cell culture—confirmed the feasibility of employing oxidized microglia to study microglia activity. The use of iMGs provides a model closer to patient physiology, offering the potential to evaluate individual cellular responses to oxidative damage. This approach could be instrumental in identifying personalized therapeutic strategies by assessing patient-specific microglial behavior in response to myelin debris. These findings highlight the impact of myelin oxidative status on microglial function, advancing the understanding of oxidative stress in MS and paving the way for personalized medicine applications in neuroinflammation.
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    Matrix mechano-sensing at the invasive front induces a cytoskeletal and tran-scriptional memory supporting metástasis
    (Nature, 2025) Maiques Carlos, Oscar; Sallan, Marta C.; Laddach, Roman; Pandya, Pahini; Varela, Adrian; Crosas-Molist, Eva; Barcelo, Jaume; Courbot, Olivia; Liu, Yanbo; Graziani, Vittoria; Arafat, Youssef; Sewell, Joanne; Rodríguez Hernández, Irene; Fanshawe, Bruce; Jung-Garcia, Yaiza; Imbert, Paul; Grasset, Eloise M.; Albrengues, Jean; Santacana Espasa, Maria; Macià Armengol, Anna; Tarragona Foradada, Jordi; Matias-Guiu, Xavier; Martí Laborda, Rosa Ma.; Tsoka, Sophia; Gaggioli, Cedric; Orgaz, Jose L.; Fruhwirth, Gilbert O.; Wallberg, Fredrik; Betteridge, Kai; Reyes-Aldasoro, Constantino Carlos; Haider, Syed; Braun, Andrejs; Karagiannis, Sophia N.; Elosegui-Artola, Alberto; Sanz Moreno, Victoria
    The extracellular matrix (ECM) controls tumour dissemination. We characterise ECM organization in human and mouse tumours, identifying three regions: tumour body, proximal invasive front and distal invasive front. Invasive areas show increased matrix density, fibre thickness, length, and alignment, with unique radial fibre orientation at the distal invasive front correlating with amoeboid invasive features. Using patient samples and murine models, we find that metastases recapitulate ECM features of the primary tumour. Ex vivo culture of murine cancer cells isolated from the different tumour regions reveals a spatial cytoskeletal and transcriptional memory. Several in vitro models recapitulate the in vivo ECM organisation showing that increased matrix induces 3D confinement supporting Rho-ROCK-Myosin II activity, while radial orientation enhances directional invasion. Spatial transcriptomics identifies a mechano-inflammatory program associated with worse prognosis across multiple tumour types. These findings provide mechanistic insights into how ECM organization shapes local invasion and distant metastasis.
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    Cognition and objective sleep quality in post-COVID-19 patients
    (Frontiers Media, 2025) Carnes Vendrell, Anna; Piñol Ripoll, Gerard; Targa, Adriano; Tahan, Nuria; Ariza, Mar; Cano, Neus; Segura, Bárbara; Junque, Carme; Béjar, Javier; Barrue, Cristian; Nautilus Project Collaborative Group; Garolera i Freixa, Maite
    In the current study, we aimed (i) to evaluate sleep quality via wrist actigraphy monitoring of nonhospitalized and hospitalized post-COVID-19 condition (PCC) participants; (ii) to correlate actigraphy measures with subjective measures of sleep quality, such as the Pittsburgh Sleep Quality Index (PSQI); and (iii) to investigate whether total sleep time or sleep efficiency could affect PCC cognitive performance. We included 49 individuals with PCC from the NAUTILUS Project (NCT05307549 and NCT05307575) who were monitored for 1 week via actigraphy and who were also assessed with a comprehensive neuropsychological battery and the PSQI. We found that there were significant differences between nonhospitalized PCCs and hospitalized PCCs in the number of awakenings. We also found a correlation between the total sleep time of both measures (actigraphy and PSQI), but we did not observe correlations between objective and subjective parameters of latency and sleep efficiency. Regarding cognition and actigraphy measures, there was a trend of statistical significance in the performance of immediate visual memory, attention span and social cognition according to sleep efficiency. In conclusion, results indicate that although the PSQI provides clinically relevant indicators of sleep, there are divergent results between self-reported and objective sleep measures (actigraphy). Furthermore, we found a tendency toward statistical significance in cognitive performance in PCC participants according to their sleep efficiency which could indicate that is more important for cognitive function of post-COVID-19 patients than total sleep time.