Vitamin D deficiency causes inward hypertrophic remodeling and alters vascular reactivity of rat cerebral arterioles

BACKGROUND AND PURPOSE: Vitamin D deficiency (VDD) is a global health problem, which can lead to several pathophysiological consequences including cardiovascular diseases. Its impact on the cerebrovascular system is not well understood. The goal of the present work was to examine the effects of VDD on the morphological, biomechanical and functional properties of cerebral arterioles. METHODS: Four-week-old male Wistar rats (n = 11 per group) were either fed with vitamin D deficient diet or received conventional rat chow with per os vitamin D supplementation. Cardiovascular parameters and hormone levels (testosterone, androstenedione, progesterone and 25-hydroxyvitamin D) were measured during the study. After 8 weeks of treatment anterior cerebral artery segments were prepared and their morphological, biomechanical and functional properties were examined using pressure microangiometry. Resorcin-fuchsin and smooth muscle actin staining were used to detect elastic fiber density and smooth muscle cell counts in the vessel wall, respectively. Sections were immunostained for eNOS and COX-2 as well. RESULTS: VDD markedly increased the wall thickness, the wall-to-lumen ratio and the wall cross-sectional area of arterioles as well as the number of smooth muscle cells in the tunica media. As a consequence, tangential wall stress was significantly lower in the VDD group. In addition, VDD increased the myogenic as well as the uridine 5'-triphosphate-induced tone and impaired bradykinin-induced relaxation. Decreased eNOS and increased COX-2 expression were also observed in the endothelium of VDD animals. CONCLUSIONS: VDD causes inward hypertrophic remodeling due to vascular smooth muscle cell proliferation and enhances the vessel tone probably because of increased vasoconstrictor prostanoid levels in young adult rats. In addition, the decreased eNOS expression results in endothelial dysfunction. These morphological and functional alterations can potentially compromise the cerebral circulation and lead to cerebrovascular disorders in VDD

PVR (CD155) epigenetic status mediates immunotherapy response in multiple myeloma

The immune system is tightly regulated but plastic in humans. It has several lines of control, and its imbalance has severe consequences for our health. Epigenetics encompasses heritable biochemical changes of the chromatin that do not affect the DNA sequence [1]. Epigenetics is constituted of various levels of control, from structural changes (such as 3D chromatin arrangement) to small biochemical changes (such as DNA methylation) which affect gene expression1. In the context of immunity, epigenetics has been described to control important events for the system, such as cytotoxic cell activation or exhaustion [2]. Cytotoxic cell activation is critical for tumor clearance. To activate cytotoxicity, several interactions need to occur between the target cell and the immune cell. This group of interactions are commonly known as immune checkpoint (IC) events and determine the outcome of the synapse [3]. IC signals can be co-stimulatory or co-inhibitory, and depending on the amount of signals the immune cells receive, they will determine if the system activates or not. Several rounds of inhibitory signals may induce a senescent state or exhaustion phenotype on the cytotoxic cells [3]. One of these inhibitory markers is the poliovirus receptor (PVR, also known as CD155), which interacts mainly with the T cell immunoreceptor with Ig and ITIM domains (TIGIT) in cytotoxic cells [4]. Tumoral cells can use DNA methylation to regulate inhibition of co-stimulatory or overexpression of co-inhibitory markers [3]. Hematological malignancies present aberrant promoter methylation in several immune checkpoint genes and this dysregulation supports their tumorigenesis [5,6,7]. Multiple myeloma (MM) is a hematological malignancy characterized by the abnormal accumulation of plasma cells in the bone marrow. MM is notorious for its incurable nature and tendency for relapse, often becoming refractory to treatment [8]. This poses significant challenges, highlighting the urgent need for innovative therapies to enhance the prognosis of affected patients. This work aims to elucidate the epigenetic regulation in PVR, an immune checkpoint marker, and its relation to cytotoxic activation and immunotherapy sensitivity in the context of MM cells.We thank CERCA Programme / Generalitat de Catalunya for institutional support. The Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia has provided funding to ME (2017 SGR1080 and 2021 SGR01494). ME has also received funding from the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033/EDRF ‘A way to make Europe’ (RTI2018-094049-B-I00 and PID2021-125282OB-I00), Cellex Foundation (CEL007) and “la Caixa” Foundation (LCF/PR/HR22/00732). LMV is a fellow of the Spanish Ministry of Science and Innovation grant under FPI contract no. PRE2019-089958. AOC received funding from the resident grant Ajut Clínic-La Pedrera 2019, granted by Hospital Clínic de Barcelona. CFL has received funding by grants from Asociación Española Contra el Cancer (AECC) LABAE21971FERN, the Instituto de Salud Carlos III (ISCIII) and co-founded by the European Union (FIS PI22/00647 and ICI19/00025), and 2021SGR01292 (AGAUR; Generalitat de Catalunya). GF is recipient of Ayuda Investigador AECC 2023 (INVES234765FERR), Fundación Científica AECC. We thank Bristol Myer Squibb for providing BMS-986207 anti-TIGIT Neutralizing Antibody and Genomics Unit of Josep Carreras Leukaemia Research Institute for their help and the advice provided.Peer reviewe

Genetic Variations in the Regulator of G-Protein Signaling Genes Are Associated with Survival in Late-Stage Non-Small Cell Lung Cancer

The regulator of G-protein signaling (RGS) pathway plays an important role in signaling transduction, cellular activities, and carcinogenesis. We hypothesized that genetic variations in RGS gene family may be associated with the response of late-stage non-small cell lung cancer (NSCLC) patients to chemotherapy or chemoradiotherapy. We selected 95 tagging single nucleotide polymorphisms (SNPs) in 17 RGS genes and genotyped them in 598 late-stage NSCLC patients. Thirteen SNPs were significantly associated with overall survival. Among them, rs2749786 of RGS12 was most significant. Stratified analysis by chemotherapy or chemoradiation further identified SNPs that were associated with overall survival in subgroups. Rs2816312 of RGS1 and rs6689169 of RGS7 were most significant in chemotherapy group and chemoradiotherapy group, respectively. A significant cumulative effect was observed when these SNPs were combined. Survival tree analyses identified potential interactions between rs944343, rs2816312, and rs1122794 in affecting survival time in patients treated with chemotherapy, while the genotype of rs6429264 affected survival in chemoradiation-treated patients. To our knowledge, this is the first study to reveal the importance of RGS gene family in the survival of late-stage NSCLC patients

Description of the EuroTARGET cohort: A European collaborative project on TArgeted therapy in renal cell cancer-GEnetic- and tumor-related biomarkers for response and toxicity

Personalised Therapeutic

Gene expression profile related to oxaliplatin resistance in a panel of sensitive human colorectal cancer cell lines with acquired resistance to the drug

13143 Background: Platinum drugs resistance acquisition is a complex process based in the alteration of genes that belong to several pathways related to drug metabolism. To clarify the multifactoriality of these mechanisms, we analyzed gene expression profile in the four CCR cell lines HT29, LoVo, DLD1 and LS513, and their sublines HTOXAR, LOVOXAR, DLDOXAR y LSOXAR that we induced oxaliplatin resistance in our laboratory. The aim of this work consisted on comparing gene expression profile between resistant cells group (cluster R) and sensitive cells group (cluster S) to determine genes and pathways that could play a role in oxaliplatin resistance acquisition process. Methods: Resistance level determination by MTT assay. Gene expression profile analysis through microarray technology (Human 19K oligo): labeled with Genisphere 3DNA Array350 (Dye Swap), and data analysis using Imagene 4.1, ArrayNorm1.7.2 y Genesis 1.5.0 (ANOVA). Results: According to ANOVA analysis of cluster R versus cluster S, we obtained 32 genes that showed significant changes in expression. 15 of these genes were up regulated and 17 were down regulated. We emphasize genes that belong to pathways previously related to oxaliplatin metabolism (AKT1, TRIP and NLK), family of genes that does not expressed in the same chromosome (KIAA0232 and KIAA0256, SLC39A9 and SLC30A9), and family of genes that had previously related to carcinogenesis processes (KRT19, KRT18 and KRT8). Conclusions: It is possible to develop oxaliplatin resistant CCR cell lines. In our oxaliplatin acquired resistance model, 32 genes showed gene expression changes between groups. These genes belong to signal transduction pathways and cellular integrity mechanisms and they could be a future oxaliplatin resistance prediction profile in colorectal cancer patients. No significant financial relationships to disclose. </jats:p