Biology subjects

Benito, A.

Publications and source records attributed to Benito, A..

6 recordsLinked to original sources

bioRxiv2026

Association between Lifestyle Habits (Physical Exercise, Sleep, BMI, and Tobacco Consumption) and Academic Performance in Spanish University Students: A Cross-Sectional Study

Healthy lifestyle habits are a key pillar of physical, psychological, and social well-being, yet university years are often marked by declines in sleep quality, physical activity, and other health behaviors that may affect academic performance. This cross-sectional study examined these associations in 390 Spanish university students, assessed via an online and in-person questionnaire covering academic trajectory (grade point average, credits passed, curricular progression), sleep quality (PSQI), physical activity (IPAQ), tobacco use, Body Mass Index (BMI), and sociodemographic data. Bivariate associations were tested with chi-square, Pearson correlation, t-tests, and ANOVA, followed by generalized linear models for significant variables. Sports participation, but not IPAQ-measured physical activity, was significantly associated with academic progression, defined as advancing one grade level per year. Sleep indicators showed mixed, partly counterintuitive associations: poorer nocturnal sleep was linked to better progression, whereas better sleep quality predicted a higher percentage of credits completed. BMI was a modest positive predictor of credit completion, and underweight students performed significantly worse than overweight or obese peers. Tobacco use showed no significant associations. These findings suggest that sleep-related behaviors, sports participation, and, to a lesser extent, BMI, are relevant correlates of academic progress, supporting university health policies addressing sleep, physical activity, and nutrition.

animal behavior and cognition↗

bioRxiv2026

Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss

Metabolic adaptation is essential for cells experiencing chronic genomic stress, yet how such adaptations are organized at the nuclear level remains poorly understood. Loss of TP53 is associated with elevated genomic instability, DNA damage and altered metabolic requirements, creating context specific dependencies. Here, we identify a requirement for de novo purine biosynthesis in TP53-deficient cells, with a pronounced dependence on adenosine related metabolism. Perturbation of purine synthesis increases DNA damage and reduces nuclear ATP availability, particularly in TP53-deficient cells, and is accompanied by a rapid increase in histone methylation. This chromatin response is also induced by acute DNA damage and occurs with fast kinetics, indicating that histone methylation is an early, intrinsic feature of the nuclear stress response rather than a secondary epigenetic remodeling. Interfering with histone methylation is associated with reduced nuclear ATP levels and impaired DNA damage resolution, linking chromatin state to nuclear energy homeostasis. Genetic disruption of the purine biosynthesis enzyme PFAS selectively impairs the growth of TP53-deficient tumours in vivo, establishing the physiological relevance of this metabolic dependency. Together, these findings reveal nuclear adenosine metabolism as a compartmentalised adaptive response to genotoxic stress and highlight chromatin associated methylation as a key feature of nuclear metabolic regulation unmasked by TP53 loss.

cancer biology↗

bioRxiv2026

PCSK9 Exhibits Novel Nuclear Localization in LSEC and Its Targeting with Bioinspired Nanoparticles Reduces Colorectal Liver Metastasis

Background & AimsColorectal cancer liver metastasis is the leading cause of mortality in affected patients, with liver sinusoidal endothelial cells playing a pivotal role in metastatic niche formation. Proprotein convertase subtilisin/kexin type 9 has emerged as a regulator of tumor biology, but its function in the hepatic microenvironment remains poorly defined. This study aimed to characterize the role and subcellular localization of PCSK9 in liver sinusoidal endothelial cells and to evaluate the therapeutic potential of its endothelial-specific inhibition in colorectal liver metastasis. MethodsIn vitro studies were performed using human and murine liver sinusoidal endothelial cells stimulated with conditioned media from metastatic colorectal cancer cells and cancer stem cells. Subcellular localization was assessed by immunofluorescence, immunogold electron microscopy, and biochemical fractionation. Protein interactions were investigated using co-immunoprecipitation and proteomic analyses. For in vivo validation, a murine model of colorectal liver metastasis was generated by intrasplenic injection of tumor cells, followed by systemic administration of chondroitin sulfate-targeted nanoparticles delivering PCSK9 siRNA every 5 days for 18 days. ResultsPCSK9 was consistently expressed in liver sinusoidal endothelial cells and displayed a predominant nuclear localization, which increased upon tumor-induced activation. Proteomic integration identified multiple candidate interacting proteins involved in metabolic and tumor-related pathways. Targeted nanoparticle-mediated delivery achieved efficient PCSK9 silencing in vitro. In vivo, endothelial-specific PCSK9 inhibition significantly reduced liver metastatic tumor burden compared with control groups, whereas free siRNA showed no significant effect. ConclusionsPCSK9 exhibits a novel nuclear localization in liver sinusoidal endothelial cells and potentially interacts with proteins implicated in tumor mediated pathways. Selective inhibition of endothelial PCSK9 using targeted nanoparticles significantly reduces colorectal liver metastasis, highlighting a novel therapeutic strategy focused on the hepatic microenvironment. Impact and ImplicationsThis study provides mechanistic insight into how PCSK9 contributes to colorectal liver metastasis by identifying its novel nuclear localization and potential function in liver sinusoidal endothelial cells. These findings are important for researchers and clinicians seeking to understand microenvironment-driven metastasis and resistance to current therapies. The demonstration that endothelial-specific targeting of PCSK9 reduces metastatic burden suggests a new avenue for therapeutic development beyond systemic inhibition. Such strategies could be translated into precision nanomedicine approaches to improve outcomes in patients with metastatic colorectal cancer while minimizing off-target effects.

cancer biology↗

bioRxiv2025

Dual inhibition of the nonsense mediated mRNA decay enhances tumour immunogenicity, drives immunoediting, and potentiates checkpoint blockade

Immune checkpoint blockade has transformed cancer therapy, but current biomarkers such as tumour mutation burden often fail to reliably predict clinical benefit. One proposed reason for this discrepancy is the activity of nonsense-mediated mRNA decay (NMD), a cellular quality-control pathway that degrades mutant transcripts, potentially reducing the presentation of neoantigens that would otherwise stimulate anti-tumour immunity. To address this, we identified publicly available small-molecule inhibitors targeting the NMD factors SMG5 and SMG7 (NMDi), which we have prioritise as the NMD components most strongly associated with NMD efficiency across TCGA tumours, and evaluated their therapeutic potential in vivo. In a syngeneic, DNA repair deficient mouse model of lung adenocarcinoma, NMDi treatment alone substantially reduced tumour burden, and its combination with anti-PD-1 therapy led to additive benefit either treatment alone. These effects were immune-dependent and specifically required CD8{square} T cells. Transcriptomic and single-cell analyses revealed that NMDi reprograms the tumour immune microenvironment, enriching for clonally expanded, cytotoxic CD8{square} T cells and altering macrophage states toward those associated with tumour regression. Whole-genome sequencing of tumours revealed that NMDi also promotes immunoediting, leading to negative selection against immunogenic mutations and coding indels, with selective pressure comparable to or greater than that induced by anti-PD-1 treatment. Guided by these results, we generated a new protein language model trained on tumour mutations that can identify neopeptides with immunogenic properties, revealing that the NMDi tumour landscape provides a rich genomic and immunopeptidomic setting for exposing neoantigens that evade immunoediting. Together, these pre-clinical and integrative genomic-transcriptomic insights position NMD inhibition as a promising immunostimulatory strategy that can potentiate immune checkpoint blockade efficacy in tumours.

cancer biology↗

bioRxiv2024

RAS/PI3K pathway mutations sensitise epithelial ovarian cancer cells to a PARP/NAMPT inhibitor combination

The combination of PARP and NAMPT inhibitors (PARPi/NAMPTi) has been explored for the treatment of TNBC, Ewing Sarcoma and high grade serous carcinoma (HGSC). However, dose limiting toxicity has hampered NAMPTi in clinical trials. To maximise the therapeutic window, we set out to identify predictive genomic biomarkers. Bioinformatic analysis and screening of a panel of epithelial ovarian cancer (EOC) cell lines revealed that cells with RAS/PI3K pathway mutations were sensitive to the NAMPTi FK866. Activity of olaparib and FK866 was associated with a reduction in nicotinamide mononucleotide (NMN) and the PARP substrate nicotinamide adenine dinucleotide (NAD+), with coincident increases in ROS production, DNA damage and apoptosis induction. Caspase 3/7 activity was upregulated to a greater extent in RAS/PI3K mutant cell lines. Finally, the combination significantly reduced omental tumour weight and increased overall survival in mice injected with ID8 Trp53-/-;Pten-/- cells. This study highlights the potential of the PARPi/NAMPTi combination in RAS/PI3K pathway mutant EOC.

cancer biology↗

bioRxiv2020

Indisulam targets RNA splicing and metabolism to serve as a novel therapeutic strategy for high-risk neuroblastoma

Neuroblastoma is the most common solid tumour in childhood and prognosis remains poor for high-risk cases despite the use of multimodal treatment. Analysis of public drug sensitivity data showed neuroblastoma lines to be particularly sensitive to indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 for proteosomal degradation via DCAF15-E3-ubiquitin ligase. In neuroblastoma models, indisulam induced rapid loss of RBM39, accumulation of splicing errors and growth inhibition in a DCAF15- dependent manner. Integrative analysis of RNAseq and proteomics data highlighted a distinct disruption to cell cycle and metabolism. Metabolic profiling demonstrated metabolome perturbations and mitochondrial dysfunction resulting from indisulam. Complete tumour without relapse was observed in both xenografts and the Th-MYCN transgenic model of neuroblastoma after indisulam treatment, with RBM39 loss confirmed in vivo. Our data imply that dual targeting of metabolism and RNA splicing with anti-cancer sulphonamides such as indisulam is a promising therapeutic approach for high-risk neuroblastoma.

cancer biology↗