Epigenetic drug therapy in the treatment of colorectal cancer

Colorectal cancer (CRC) is one of the most common cancers with a high rate of morbidity and mortality worldwide. The incidence of CRC is similar in men and women but is distributed uniformly globally. It has been demonstrated that epigenetic alterations which may cause changes in the expression of microRNA, DNA methylation and histone acetylation that results in inheritable modifications in gene expression in colorectal epithelial cells, plays a crucial role in the development of CRC. Recently, targeting epigenetic modification has emerged as a potentially important treatment approach in CRC. The US Food and Drug Association has approved the use of some epigenetic drugs that may be able to inhibit or reverse these alterations and also enhance sensitivity to chemotherapeutic agents and radiotherapy in CRC. In this review we have summarized the recent pre-clinical and clinical trial studies investigating the therapeutic value of using epigenetic drugs as novel therapeutic approach in CRC treatment. Keywords: epigenetic, colorectal cancer, drug, DNA methylation, histone acetylatio

Anatomical distribution and demographic data of gastric cancer in Mashhad, Iran

Introduction: The global incidence of gastric cancer (GC) has been decreased dramatically in recent decades and characteristics of this cancer has been changed. Most of these changes can be resulted from changes in dietary and nutritional habits. This cancer is the most common cancer in north and northeast of Iran. In present report we will briefly summaries the gastric tumor location in a population from north east of Iran. Methods: We have evaluated the stomach tumors location according to patient’s gender and age. Among 212 Iranian patients who were lived in Mashhad, Iran, the cardia was the most common involved anatomic location. There wasn’t any significant relation between patient gender and tumor location as well as patient age and tumor location. Results: According to our results, the incidence of gastric cancer in patients who are aged between 60 to 69 years is decreasing in our population while the most common anatomic site of tumor remains the same. Conclusion: By knowing the most prevalent tumor site and related risk factors, more precise diagnostic and preventing programs can be established. Increasing global awareness about the risk factors of GC seems to be the main reason and efforts should be made to speed up this issue

Rigosertib potently protects against colitis-associated intestinal fibrosis and inflammation by regulating PI3K/AKT and NF-kappa B signaling pathways

Aims: Rigosertib (RGS) is a PI3K inhibitor that exerts protective effects against tumor progression and cancer-related inflammation. This study was aimed to explore the regulatory effects of RGS on proliferative, pro-fibrotic and inflammatory factors in DSS- induced colitis mice model. Materials and methods: The present study integrates systems and molecular biology approaches to investigate the therapeutic potency of RGS in an experimental model of colitis specifically examining its effects on the PI3K/AKT and NF-kappa B signaling pathways. Key findings: Analysis of time-resolved proteome profiling showed that PI3K-AKT inhibitors regulate expression of many proteins in all stages of inflammation, fibrogenesis and extracellular matrix remodeling. Consistent with our in-silico findings, RGS improved colitis disease activity as assessed by changes in body weight, degree of stool consistency, rectal bleeding and prolapse. RGS also reduced oxidative stress markers and colon histopathological score by decreasing inflammatory responses in colon tissues. Moreover, expression of pro-fibrotic and pro-inflammatory factors including Acta 2, Col 1a1, Col 1a2, IL-1 beta, TNF-alpha, INF-gamma, and MCP-1 were suppressed in the mice treated with RGS compared to the control group. The protective effects of RGS were mediated by inactivation of PI3K/AKT and NF-kB signaling pathways. Significance: This study clearly demonstrates the anti-proliferative, anti-inflammatory and anti-fibrotic effects of RGS in colitis that may have implications for the treatment of colitis and colitis-associated cancer.Peer reviewe

Depression and anxiety symptoms are associated with white blood cell count and red cell distribution width: a sex-stratified analysis in a population-based study

Background: Depression and anxiety are two important mood disorders that are frequently associated with chronic diseases such as cardiovascular diseases (CVDs). Hyper-inflammation is related to both CVDs and psychiatric conditions such as depression and anxiety. Therefore, inflammation may partially explain the relationship between depression and cardiovascular disease. Objective: The objective of this study was to investigate the association between symptoms of depression/anxiety disorders and serum hs-CRP and inflammation linked conditions in a large Iranian population. Methods: Symptoms of depression and anxiety disorders and serum hs-CRP levels were measured in 9,759 participants (40% males and 60% females) enrolled in MASHAD study. Symptoms of depression and anxiety were evaluated with Beck Depression and Anxiety Inventories. According to the scores of depression and anxiety, individuals were categorized into four groups of no or minimal, low, moderate and severe categories. Results: The median serum hs-CRP concentration increased with increasing severity of depression and anxiety disorders. Male participants with severe depression had significantly higher levels of hs-CRP (p <0.001); however, this relationship was less marked among women (p = 0.04). Subjects with severe anxiety also had significantly higher levels of hs-CRP (p <0.001). Moreover, women with severe depression and anxiety had higher BMI. There was also a positive association between current smoking habit and depression/anxiety disorders. Conclusion: Depression and anxiety disorders are associated with elevated levels of hs-CRP, particularly among men. There were also a significant positive association between depression/anxiety disorders and inflammation linked conditions such as smoking and obesity; however, in the case of obesity this association was only present in women

Association between obesity categories with cardiovascular disease and its related risk factors in the MASHAD cohort study population

Background Cardiovascular disease (CVD) is a significant cause of morbidity and mortality globally. Obesity is an important CVD risk factor and is increasing in prevalence. Methods In this study, 3829 men and 5720 women (35‐65 years) were enrolled as part of the MASHAD cohort study. Four categories were identified according to body mass index and waist circumference that was defined by the World Health Organization. Logistic regression analysis was used to determine the adjusted odds ratio (OR) for the occurrence of CVD, and Cox regression model was used to evaluate the association of obesity with CVD incidence. Results We found that the higher risk groups defined by categories of adiposity were significantly related to a higher prevalence of a high serum total cholesterol (TC), and triglycerides (TG), and lower high‐density lipoprotein cholesterol (HDL), and higher fasting blood glucose (FBG) in both genders and a higher low‐density lipoprotein cholesterol (LDL) in women (P < .001). Additionally, a high percentage of participants with dyslipidemia, high LDL, high TC, and low HDL and a high percentage of participants with metabolic syndrome, diabetes, hypertension, and a high serum TG were observed across obesity categories (P < .001). Moreover, women with the very high degrees of obesity had a greater risk of CVD (HR: 1.91, 95% CI: 1.06‐3.43, P = .03). Conclusion Obesity strongly predicts several CVD risk factors. Following 6 years of follow‐up, in individuals within increasing degrees of obesity, there was a corresponding significant increase in CVD events, rising to approximately a twofold higher risk of cardiovascular events in women compared with men

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway

Background: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action. Methods: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC). Results: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9. Conclusion: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.Peer reviewe

Relationship between platelet count and platelet width distribution and serum uric acid 1 concentrations in patients with untreated essential hypertension

Hematological parameters have emerged as independent determinants of high serum concentrations of uric-acid and predictive-factors in the evaluation of the total cardiovascular-risk in patients with essential-hypertensive. Here we have investigated the possible relationships between hematological-factors and serum uric-acid levels in hypertensive-patients recruited as part of Mashhad-Stroke and Heart-Atherosclerotic-Disorders cohort study. Two-thousand three-hundred and thirty four hypertensive individuals were recruited from this cohort and these were divided into two groups; those with either high or low serum uric acid concentrations. Demographic, biochemical and hematological characteristics of population were evaluated in all the subjects. Logistic-regression-analysis was performed to determine the association of hematological-parameters with hypertension. Of the 2334 hypertensive-subjects, 290 cases had low uric-acid, and 2044 had high serum uric acid concentrations. Compared with the low uric acid group, the patients with high serum uric acid, had higher values for several hematological parameters, whilst platelet counts (PLT) were lower. Multiple linear regression analysis showed that PLT and serum hs-CRP were correlated with serum uric acid level. Stepwise multiple logistic regression model confirmed that PDW and gender were independent determinant of a high serum uric acid. PDW and PLT appear to be independently associated with serum uric acid level in patients with hypertension

Evaluating The Association Between Serum Hsp27 Antibody and Hypertension in Patients without Underlying Cardiovascular Disease

Introduction: An association between heat shock protein 27 (Hsp27) antigen with cardiovascular risk factors has been shown previously. Furthermore, higher levels of serum anti-HSP27 antibodies are also related to higher cardiovascular morbidity and mortality. In the current study, we looked at the relationship between serum Hsp27 antibodies and hypertension, as an important cardiovascular risk factor, in individuals without evidence of cardiovascular disease (CVD).Methods: A sub-population of hypertensive patients (HTN+) without underlying CVD were recruited from the Mashhad stroke and atherosclerosis heart disease (MASHAD) study to assess the association between serum Hsp27 antibodies and hypertension; independent of other cardiovascular risk factors. A total of 1599 people were studied of whom 288 individuals had hypertension and 1311 were used as controls (HTN-).Results: Mean serum Hsp27 antibody titers were 0.20 (0.27) OD in the whole population sample and was not significantly different in the normotensive (HTN-) compared to HTN+ individuals with different degrees of hypertension.Conclusion: There were no significant associations between serum anti-Hsp27 concentrations and either the presence or severity of hypertension. Future studies are warranted to explore the association of anti-Hsp27 antibody and antigen levels and other cardiovascular risk factors