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Background: The mode of action of Bacillus Calmette-Guérin (BCG) in the treatment of patients with non-muscle invasive bladder cancer (NMIBC) is incompletely understood, but recent studies support an association between BCG-induced trained immunity in circulating monocytes and disease-free survival., Objective: We compared epigenetic profiles in monocytes from NMIBC patients with early disease recurrence with those from recurrence-free patients., Methods: We conducted chromatin immunoprecipitation and DNA sequencing (ChIP-seq) on monocytes from seven patients treated with BCG (four with early recurrences and three recurrence-free after one year) to determine genome-wide distribution and abundance of histone 3 lysine 4 trimethylation (H3K4me3) prior to and after five weeks of induction therapy., Results: Genome-wide H3K4me3 profiles before or after BCG induction distinguished patients with early recurrences from those remaining recurrence-free. Furthermore, H3K4me3 levels at genes involved in specific pathways were increased in the recurrence-free group. Independent quantification showed increased H3K4me3 levels in elements of the Wnt and AMPK signaling pathways in the recurrence-free group before BCG initiation, while elements of the MAPK showed increased levels after five weeks of induction in the same group. Validation of these genes on an independent cohort of four additional patients that remained recurrence-free after one year and three with early recurrences revealed consistent increases in H3K4me3 levels associated with MAPK pathway genes after five weeks of BCG treatment in the recurrence-free group., Conclusions: Recurrence-free survival following BCG immunotherapy for NMIBC is associated with the accumulation of H3K4me3 at specific gene loci, and could lead to identification of prognostic biomarkers., Competing Interests: JFP, MT, AG, AA, CCTH, KT, DRS and CG have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)

The present work is aimed at finding variants associated with Type 1 and Type 2 diabetes mellitus (DM) that reside in functionally validated miRNAs binding sites and that can have a functional role in determining diabetes and related pathologies. Using bioinformatics analyses we obtained a database of validated polymorphic miRNA binding sites which has been intersected with genes related to DM or to variants associated and/or in linkage disequilibrium (LD) with it and is reported in genome-wide association studies (GWAS). The workflow we followed allowed us to find variants associated with DM that also reside in functional miRNA binding sites. These data have been demonstrated to have a functional role by impairing the functions of genes implicated in biological processes linked to DM. In conclusion, our work emphasized the importance of SNPs located in miRNA binding sites. The results discussed in this work may constitute the basis of further works aimed at finding functional candidates and variants affecting protein structure and function, transcription factor binding sites, and non-coding epigenetic variants, contributing to widen the knowledge about the pathogenesis of this important disease.

Objectives: Chemoresistance remains the main causes of treatment failure and mortality in cancer patients. There is an urgent need to investigate novel approaches to improve current therapeutic modalities and increase cancer patients' survival. Induction of drug efflux due to overexpression of P-glycoproteins is considered as an important leading cause of multidrug resistance. In this study, we investigated the role of combination treatments of docetaxel and vinblastine in overcoming P-glycoprotein mediated inhibition of apoptosis and induction of cell proliferation in human non-small cell lung carcinoma cells., Materials and Methods: Cell proliferation and apoptosis were assessed using MTT assay and DAPI staining, respectively. P-glycoprotein expression was evaluated in gene and protein levels by Real-time RT-PCR and Western blot analysis, respectively., Results: Combination treatment of the cells with docetaxel and vinblastine decreased the IC50 values for docetaxel from (30±3.1) to (15±2.6) nM and for vinblastine from (30±5.9) to (5±5.6) nM (P≤0.05). P-glycoprotein mRNA expression level showed a significant up-regulation in the cells incubated with each drug alone (P≤0.001). Incubation of the cells with combined concentrations of both agents neutralized P-glycoprotein overexpression (P≤0.05). Adding verapamil, a P-glycoprotein inhibitor caused a further increase in the percentage of apoptotic cells when the cells were treated with both agents., Conclusion: Our results suggest that combination therapy along with P-glycoprotein inhibition can be considered as a novel approach to improve the efficacy of chemotherapeutics in cancer patients with high P-glycoprotein expression.

Objectives: Degradation of sphingosine 1-phosphate (S1P), as a bioactive lipid, or deregulation of its production involves in tumor progression, metastasis and chemoresistance. Since the tumor progression effects of S1P and its mechanism in chronic lymphoblastic leukemia and non-small cell lung cancer is not fully understood, we investigated the role and one of the mechanisms of S1P in tumor progression of SKW3 and H1299 cells., Materials and Methods: The effects of S1P on proliferation, invasion and migration was studied using MTT assay, soft-agar colony forming assay and trans-well migration assay, respectively. In order to find out the mechanisms of S1P action, the role of S1P on expression of Survivin gene was assessed by real-time RT-PCR., Results: Our results demonstrated that although invasion was shown only in H1299 cells, low concentration of S1P, especially at 1 μM, mediated proliferation and migration in both cell lines. In addition, these effects of S1P in tumor progression are S1P receptor-dependent, and Survivin plays a key role in S1P tumorigenesis., Conclusion: Our results confirmed the involvement of S1P and its receptors in tumor progression of SKW3 and H1299. We also investigated another mechanism of S1P involved in cell survival, tumor progression, and Survivin signaling. In conclusion, data demonstrated the importance of this molecule as a target for designing new anticancer drugs such as anti-S1P monoclonal antibody for inhibiting major downstream signaling, which plays significant role in tumorigenesis.

Introduction: Developing novel strategies to increase the efficacy of chemotherapy is an urgent need. We investigated the impact of combination therapy with docetaxel, or vinblastine with tamoxifen in inhibition of proliferation and induction of apoptosis in MDA-MB-231 and H1299 cells., Materials and Methods: Cell proliferation was assessed by MTT assay and the percentage of apoptotic cells was measured using DAPI staining., Statistical Analysis: Statistical analysis was performed by one-way ANOVA using SPSS software., Results: Vinblastine or docetaxel induced higher percentage of apoptosis in MDA-MB-231 cells than H1299 cells (P < 0.05). Tamoxifen exhibited the highest percentage of cell death in H1299 cells (P < 0.05). Treatment of both cell lines with combination of docetaxel and vinblastine or tamoxifen showed enhanced apoptotic and anti-proliferative effects (P < 0.05)., Conclusion: Combination therapy of breast and lung cancer cell lines using docetaxel or vinblastine with tamoxifen synergistically increases the anti-proliferative affect of single agents.

Nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as a transcription factor that controls mechanisms of cellular defense response by regulation of three classes of genes, including endogenous antioxidants, phase II detoxifying enzymes and transporters. Previous studies have revealed roles of Nrf2 in resistance to chemotherapeutic agents and high level expression of Nrf2 has been found in many types of cancer. At physiological concentrations, luteolin as a flavonoid compound can inhibit Nrf2 and sensitize cancer cells to chemotherapeutic agents. We reported luteolin loaded in phytosomes as an advanced nanoparticle carrier sensitized MDA-MB 231 cells to doxorubicin. In this study, we prepared nano phytosomes of luteolin to enhance the bioavailability of luteolin and improve passive targeting in breast cancer cells. Our results showed that co- treatment of cells with nano particles containing luteolin and doxorubicin resulted in the highest percentage cell death in MDA-MB 231 cells (p<0.05). Furthermore, luteolin-loaded nanoparticles reduced Nrf2 gene expression at the mRNA level in cells to a greater extent than luteolin alone (p<0.05). Similarly, expression of downstream genes for Nrf2 including Ho1 and MDR1 were reduced significantly (p<0.05). Inhibition of Nrf-2 expression caused a marked increase in cancer cell death (p<0.05). Taken together, these results suggest that phytosome technology can improve the efficacy of chemotherapy by overcoming resistance and enhancing permeability of cancer cells to chemical agents and may thus be considered as a potential delivery system to improve therapeutic protocols for cancer patients.

Sphingosine-1 phosphate (S1P) is a bioactive lipid that mediates diverse cellular responses. Signaling of S1P is carried out by a family of G-protein coupled receptors (GPCRs), which show differential expression patterns depending on tissue and cell types. Activation of S1P receptors induces signaling pathway, which can subsequently lead to physiological process. Intercellular S1P concentration is regulated and determined by several enzymes including S1P lyase, S1P kinase and S1P phosphatase. Numerous studies showed the role of S1P in malignant behavior of cancer cells including breast, lung, colon, and leukemia cell lines. In the past decade, extensive research activities have focused on elucidating S1P signaling pathway, its receptors, enzymes involved in S1P metabolism, and its performance in cancer biology. In this review, we will explain the function of S1P in tumor progression that demonstrated in past research articles and we will express its importance as a target for designing futuristic anticancer drug.