Evaluating synergistic effects of metformin and simvastatin on ovarian cancer cells.

BACKGROUND: Ovarian Cancer (OC) stands as the most lethal gynecological malignancy, presenting an urgent clinical challenge in the quest to improve response rates. One approach to address this challenge is through drug repurposing, exemplified by the investigation of metabolic-modulating drugs such as Metformin (MTF) and Simvastatin (SIM). This study aims to explore the molecular mechanisms contributing to the potential synergistic anti-cancer effects between MTF and SIM on ovarian cancer cells. METHODS: We assessed the effects of the combination on the proliferation and viability of two cell lines OVCAR-3 and SKOV-3. IC50 concentrations of MTF and SIM were determined using a proliferation assay, followed by subtoxic concentrations to explore the potential synergistic effects on the viability of both cell lines. Transcriptomic analysis was conducted on OVCAR-3 treated cells, and the findings were validated by assessing the expression levels of differentially expressed genes (DEGs) through real-time PCR in both cell lines SK-OV-3 and OVCAR-3. RESULTS: Cytotoxicity analysis guided the selection of treatment concentrations as such MTF 10 mM and SIM 5 µM. The combined treatment of MTF and SIM demonstrated a synergistic inhibition of proliferation and viability in both cell lines. In OVCAR-3, exclusive identification of 507 DEGs was seen in the combination arm. Upregulation of FOXO3, RhoA, and TNFα, along with downregulation of PIK3R1, SKP2, and ATP6V1D levels, was observed in OVCAR-3 treated cells. Real-time PCR validation confirmed the consistency of expression levels for the mentioned DEGs. CONCLUSION: Our data strongly supports the presence of synergy between MTF and SIM in OC cells. The combination's effect is associated with the dysregulation of genes in the key regulators AMPK and mTOR alongside other interconnected pathways.

Waterpipe and cigarette epigenome analysis reveals markers implicated in addiction and smoking type inference.

Waterpipe smoking is frequent in the Middle East and Africa with emerging prevalence worldwide. The epigenome acts as a molecular sensor to exposures and a crucial driver in several diseases. With the widespread use of waterpipe smoking, it is timely to investigate its epigenomic markers and their role in addiction, as a central player in disease prevention and therapeutic strategies. DNA methylome-wide profiling was performed on an exposure-rich population from the Middle East, constituting of 216 blood samples split equally between never, cigarette-only and waterpipe-only smokers. Waterpipe smokers showed predominantly distinct epigenetic markers from cigarette smokers, even though both smoking forms are tobacco-based. Moreover, each smoking form could be accurately (∼90 %) inferred from the DNA methylome using machine learning. Top markers showed dose-response relationship with extent of smoking and were validated using independent technologies and additional samples (total N = 284). Smoking markers were enriched in regulatory regions and several biological pathways, primarily addiction. The epigenetically altered genes were not associated with genetic etiology of tobacco use, and the methylation levels of addiction genes, in particular, were more likely to reverse after smoking cessation. In contrast, other epigenetic markers continued to feature smoking exposure after cessation, which may explain long-term health effects observed in former smokers. This study reports, for the first time, blood epigenome-wide markers of waterpipe smokers and reveals new markers of cigarette smoking, with implications in mechanisms of addiction and the capacity to discriminate between different smoking types. These markers may offer actionable targets to reverse the epigenetic memory of addiction and can guide future prevention strategies for tobacco smoking as the most preventable cause of illnesses worldwide.

Prognostic significance of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH-1) mutation in glioblastoma multiforme patients: A single-center experience in the Middle East region.

OBJECTIVES: To determine the prevalence and prognostic value of MGMT promoter methylation and IDH1 mutation in glioblastoma multiforme (GBM) patients from the Middle East. PATIENTS AND METHODS: Records of patients diagnosed between 2003 and 2015 were reviewed. MGMT promoter methylation was measured using methylation-specific polymerase chain reaction and IDH-1 mutation was reported. The primary endpoint was overall survival (OS). RESULTS: A total of 110 patients were included. The median age was 51 years and 71 patients (64.5%) were males. The median diameter of GBM was 4.6 cm and 29 patients (26.4%) had multifocal disease. Gross total resection was achieved in 38 patients (24.9%). All patients received adjuvant radiation therapy, and 96 patients (91.4%) received concomitant temozolomide. At a median follow up of 13.6 months, the median OS was 17.2 months, and the OS at 1 and 2 years were 71.6% and 34.8%, respectively. On multivariate analysis, age at diagnosis (HR 1.019; P = 0.044) and multifocality (HR 2.373; P = 0.001) were the only independent prognostic variables. MGMT promoter methylation was found in 28.2% of patients but did not significantly correlate with survival (HR 1.160; P = 0.635). IDH-1 mutation was found in 10% of patients was associated with a non-significant trend for survival improvement (HR 0.502; P = 0.151). CONCLUSION: Patients with GBM from the Middle East have adequate survival outcomes when given the optimal treatment. In our patient population, MGMT promoter methylation did not seem to correlate with outcomes, but patients with IDH1 mutation had numerically higher survival outcomes.

Implementation and obstacles of pharmacogenetics in clinical practice: An international survey.

AIMS: Eight years ago, a paper-based survey was administered during the World Pharma 2010 meeting, asking about the challenges of implementing pharmacogenetics (PGx) in clinical practice. The data collected at the time gave an idea about the progress of this implementation and what still needs to be done. Since then, although there have been major initiatives to push PGx forward, PGx clinical implementation may still be facing different challenges in different parts of the world. Our aim was therefore to distribute a follow-up international survey in electronic format to elucidate an overview on the current stage of implementation, acceptance and challenges of PGx in academic institutions around the world. METHODS: This is an online anonymous LimeSurvey-based study launched on 11 November 2018. Survey questions were adapted from the initially published manuscript in 2010. An extensive web search for worldwide scientists potentially involved in PGx research resulted in a total of 1973 names. Countries were grouped based on the Human Development Index. RESULTS: There were 204 respondents from 43 countries. Despite the wide availability of PGx tests, the consistently positive attitude towards their applications and advances in the field, progress of the clinical implementation of PGx still faces many challenges all around the globe. CONCLUSIONS: Clinical implementation of PGx started over a decade ago but there is a gap in progress around the globe and discrepancies between the challenges reported by different countries, despite some challenges being universal. Further studies on ways to overcome these challenges are warranted.

Worsening of the Cardiovascular Profile in a Developing Country: The Greater Beirut Area Cardiovascular Cohort.

BACKGROUND: Lebanon has no established governmental noncommunicable diseases surveillance and monitoring system to permit reporting on noncommunicable diseases rates. The last World Health Organization-supported surveillance report showed worrying trends in cardiovascular disease (CVD) risk factors. OBJECTIVES: A cardiovascular cohort was established to permit CVD outcomes studies in an urban sample in the Lebanese capital and the study in hand presents the baseline CVD risk factors of this cohort. METHODS: A cross-sectional study was carried out including 501 Lebanese adults (64.3% women) from the Greater Beirut area using random multistage probability sampling. Interviews, physical exams, and blood withdrawal were conducted to collect information on demographic and lifestyle factors, body mass index, blood pressure, fasting blood glucose, blood lipids, as well as history of coronary artery diseases, hypertension, diabetes mellitus type 2, dyslipidemia, and stroke. Means with SD for continuous variables and frequencies and percentages for categorical variables are reported. RESULTS: The prevalence CVD risk factors including obesity, smoking, diabetes mellitus type 2, hypertension, and dyslipidemia prevalence in the Greater Beirut area was higher than that reported for the general population. Important sex and age differences were also observed, whereby older participants and women had higher rates of obesity, diabetes mellitus type 2, and dyslipidemia and younger participants and men were engaged more in cigarette smoking and alcohol consumption. Interestingly, water pipe smoking was similarly prevalent among genders. CONCLUSIONS: The overall prevalence of CVD risk factors in this urban population is higher than reported in the 2010 World Health Organization Stepwise Approach to Surveillance report on the Lebanese population, indicating that the urban population in the capital carries a higher burden of CVD risk. In addition, sex and age difference rates of CVD risk factors highlight the need for tailored public health measures to tackle the sex- and age-based CVD risk factors.

Bisphenol A urinary level, its correlates, and association with cardiometabolic risks in Lebanese urban adults.

Bisphenol A (BPA) is an endocrine disruptor with multiple purported metabolic effects. This study aimed to measure BPA among Lebanese population, to identify its predictors, and to explore any link to metabolic disorders. A representative sample of 501 adults from Lebanon was recruited in a cross-sectional study. Urinary BPA was measured, and data were collected for anthropometric measurements, medical history, food intake, and laboratory markers of metabolic conditions. BPA data was divided into tertiles. A total of 89% of the subjects had detectable urinary BPA levels, with an overall mean of 3.67 ± 4.75 µg/L and a mean creatinine-adjusted BPA of 2.90 ± 4.79 µg/g. There was a significant positive association with female gender and older age for being in the highest BPA tertile. BPA level was linked to metabolic syndrome (MetS), obesity, type-2 diabetes (T2D), hypertension, and dyslipidemia. After adjustment, the trend remained for BPA in association with MetS and T2D. Though urinary BPA in the Lebanese population was higher in older women, the levels were similar to world-reported figures. Our results suggest a link with metabolic disorders but not at a significant level. These findings call for longitudinal and broader sample measurements.