Evaluating the presence of deregulated tumoral onco-microRNAs in serum-derived exosomes of gastric cancer patients as noninvasive diagnostic biomarkers.

Introduction: Exosomal microRNAs (miRNAs) are emerging diagnostic biomarkers for different types of cancers. We aim to detect gastric cancer (GC)-specific miRNAs in serum exosomes with diagnostic potential. Methods: A pair of 43 tumor and tumor-adjacent tissue biopsies obtained from GC patients, also 5 mL peripheral blood (following 12h fasting) were collected from the same patients and healthy controls (HCs). QIAGEN miRCURY LNA miRNA Focus PCR Panel applied to screen differentially expressed onco-miRNAs. The candidate miRNAs with the highest fold changes proceeded for validation by qRT-PCR in individuals. Results: We identified that exosomal miR-10a-5p, miR-19b-3p, miR-215-5p, and miR-18a-5p were significantly upregulated in GC patient's exosomes in contrast to HCs exosomes, Roc curve analysis indicated area under the ROC curve (AUC) of 0.801, 0.721, 0.780 and 0.736 respectively. The Roc curve analysis for the combined signature of four exosomal miRNAs indicated AUC of 0.813. Also, Spearman's correlation coefficients indicated that the miRNA expression is highly correlated between tumor and exosome. Conclusion: Herein, we specifically identified four miRNAs in serum exosomes of GC patients for a diagnostic purpose which are directly associated with tumoral miRNA expression profile.

Impact of RAS/RAF mutations on clinical and prognostic outcomes in metastatic colorectal cancer.

Introduction: Early-activated RAS/RAF mutation status is a key molecular finding in colorectal cancer (CRC), while these mutations have been proposed as predictive and prognostic biomarkers. The present study has been designed as a longitudinal study to evaluate and summarize the different genotypes of metastatic CRC (mCRC), and assessing any association with the disease prognosis and clinicopathological characteristics. This study was performed in two main referral hospitals of Tabriz University of Medical Sciences, over three years (2016-2018). Methods: Mutations were detected by Idylla tests of KRAS/NRAS/BRAF among a total of 173 mCRCs, using surgically-resected specimens or biopsied samples. To evaluate the factors associated with overall survival (OS) and prognosis, the Cox proportional hazards model was used in two steps to estimate the outcome measures (hazard ratio, or HR) with a 95% confidence interval (CI). Results: The nominal 1 to 5-year OS rates were 78%, 65%, 55%, 46%, and 42%, respectively. KRAS mutations in codon 12 was an independent significant prognostic factor, as the patients with codon 12 mutations had a significantly lower OS (P Log-rank=0.049) and a higher hazard of mortality (HR=2.30; 95% CI: 0.95-5.58; P =0.066). Also, the mCRC patients with liver metastasis (HR=2.49; 95% CI: 1.49-12.52; P =0.002) and tumors of the distal colon (HR=3.36; 95% CI: 1.07-10.49; P =0.037) had a significantly worse prognosis. Conclusion: KRAS mutation in codon 12 was an independent significant poor prognostic factor, and patients with liver metastasis had a significantly worse prognosis. Routinely performing specific oncogenic tests may help improve the patients' prognosis and life expectancy.

CpG Islands Methylation Analysis of CDH11, EphA5, and HS3ST2 Genes in Gastric Adenocarcinoma Patients.

PURPOSE: Gastric cancer is an aggressive disease which is the fourth prevalent malignancy in the world. Beside the genetic factors, epigenetic alterations such as promoter CpG island hyper methylation are involved in the emergence of gastric cancer. Herein, we investigated the methylation status of CDH11, EphA5, and HS3ST2 genes in patients with and without gastric adenocarcinoma for the first time. METHODS: In the study 40 paraffin-embedded tissue sections from gastric adenocarcinoma patients and 40 specimens from patients with functional dyspepsia were taken. DNA extraction was performed using a modified salting out method. Epizen DNA methylation kit was used to the bisulfite DNA conversion. The methylation status of CDH11, EphA5, and HS3ST2 genes were analyzed by methylation-specific PCR (MSP) technique. RESULTS: Among the 80 specimens, 71 DNA samples were achieved (34 gastric adenocarcinoma patients and 37 control patients). The results showed that CDH11, EphA5, and HS3ST2 genes are methylated in 28 (82.45%), 19 (55.88%), and 26 (76.47%) of 34 DNA samples from gastric adenocarcinoma patients, respectively, whereas, these genes are methylated in 7 (18.91%), 9 (24.32%) and 7 (18.91%) of 37 samples from noncancerous patients, respectively. Statistical analyses using a chi-squared test showed that there is a statistically significant difference in methylation level of CDH11, EphA5, and HS3ST2 genes between gastric cancer and uncancerous patients (p < 0.05). CONCLUSION: To the best of our knowledge, this is the first report on methylation of CDH11, EphA5, and HS3ST2 promoters' in gastric adenocarcinoma patients using MSP. Identification of novel cancer-related molecular mechanisms can be useful in detection of new treatment strategies.

Seroepidemiology and Risk Factors of Hepatitis B Virus Infection: A Population-Based Azar Cohort Study.

BACKGROUND: Hepatitis B is a major global health problem. It can cause chronic infections and put people at high risk of death from cirrhosis and hepatocellular carcinoma. The aim of this study was to report the epidemiological features of hepatitis B virus (HBV) infection and risk factors based on the data from Azar Cohort. METHODS: The population of this study comprised the people in the age range of 35-70 yr from Azar cohort, East Azerbaijan Province, Iran between 2015 and 2016. Based on cluster sampling, 4,949 people were selected and invited to complete the questionnaire and perform the tests. Blood samples were analyzed for serum HBV markers (HBsAg, HBsAb and HBcAb) by ELFA method. The data were analyzed using SPSS statistical software. RESULTS: The mean (SD) age of the participants was 49.15 ± 9.02 years. The frequency rates of HBsAg, HBsAb and HBcAb were estimated as 1.03%, 16.9% and 24.95%, respectively. There was statistically significant association between family history of hepatitis (P<0.001) and jaundice history (P<0.001) with the presence of HBsAg. There was also a positive correlation between marital status (P=0.002), history of hospitalization (P<0.001), smoking (P=0.001), dental procedures (P<0.001), foreign travels (P=0.005), occupation status (P=0.002) and the presence of HBcAb. CONCLUSION: The frequency of hepatitis B in Azar Cohort was 1.03% which is a lower rate compared with other reports from Iran. The association of the population studied and the increase of public awareness in this area can probably prevent this disease.

Is normal body mass index a good indicator of metabolic health in Azar cohort population?

Introduction: Metabolic syndrome (Mets) has become most important public health problem in the world. We examined the association between Mets and different cardiometabolic phenotype in Azar cohort population. Methods: In the present study, the data of 13099 subjects who participated in Azar cohort study were cross-sectionally analyzed. Mets was defined according to the National Cholesterol Education Program's Adult Treatment Panel III report (ATPIII) criteria. Participants were categorized into four cardiometabolic phenotypes including metabolically healthy Lean (MHL), metabolically unhealthy lean (MUHL), metabolically healthy Obese (MHO), metabolically unhealthy obese (MUHO) according to BMI cut-off point (25 kg/m2 ), and the presence of Mets. Results: Totally, the prevalence of Mets was 33.20% with the higher prevalence in women (40.1%). About 46.7% of participants were MHO and 1.6% of them were MHL. In both genders, MUHL had the highest prevalence of hyperglycemia, hypertrigliceridemia, hypo-HDL-cholestrolemia and Frahmingham 10-year CVD risk. In both MUHL and MUHO phenotypes, hypertriglyceridemia (OR: 31.97 [95% CI: 22.31, 45.81] and OR: 20.28 [95% CI: 17.32, 23.75]) and hypo-HDL cholestrolemia (OR:27.97 [95% CI: 17.35, 45.09] and OR:11.0 [95% CI: 9.62, 12.58]) are the strongest predictor of incidence of Mets. Also, the results of multinominal regression analyses indicated that in all cardiometabolic phenotypes, Framingham 10- year CVD risks had the lowest power for predicting of Mets incidence. Conclusion: Based on the results, in addition to obese individuals, multiple metabolic abnormalities were seen in normal weight individuals and these subjects are even at higher risk of developing Mets compared with metabolically obese individuals. So, it seems that decision on initiation of lifestyle interventions should not be only based on the BMI; rather metabolic status seems to be even more important.

Clinical predictors of colorectal polyps and carcinoma in a low prevalence region: results of a colonoscopy based study.

AIM: To estimate the prevalence of colorectal cancer (CRC) in patients with long lasting colonic symptoms undergoing total colonoscopy; and to establish clinical features predicting its occurrence. METHODS: This prospective study was carried out in Imam Hospital, Tabriz University of medical sciences, Iran. Continuous patients with long lasting lower gastrointestinal tract symptoms who had the criteria of a colonoscopy were included. The endoscopist visualized the caecum documented by a photo and/or a specimen from terminal ileum. RESULTS: Four hundred and eighty consecutive symptomatic patients [mean age (SD): 42.73 (16.21)] were included. The prevalence of colorectal neoplasia was 15.3% (34 subjects) and 37.7% (181 subjects) had a completely normal colon. Adenomatous polyps were detected in 56 (11.7%) patients, in 12.3% of men and 10.9% of women. The mean age of the patients with a polyp was significantly higher than the others (49.53 +/- 14.16 vs 41.85 +/- 16.26, P = 0.001). Most of the adenomatous polyps were left sided and tubular; only 22.5% of polyps were more than 10 mm. Cancer was detected in 16 (3.6%) of our study population, which was mostly right sided (57.2%). The mean age of patients with cancer was significantly higher than the others (60.25 +/- 8.26 vs 42.13 +/- 16.08, P < 0.005) and higher than patients with polyps [60.25 (8.26) vs 49.53 (1.91) (P < 0.0005)]. None of the symptoms (diarrhea, abdominal pain, rectal bleeding, constipation, altering diarrhea and constipation, history of cancer, known irritable bowel disease, history of polyp and fissure or family history of cancer) were predictors for cancer or polyps, but the age of the patient and unexplained anemia independently predicted cancer. CONCLUSION: Less advanced patterns and smaller sizes of adenomas in Iran is compatible with other data from Asia and the Middle East, but in contrast to western countries. Prevalence of colonic neoplasia in our community seems to be lower than that in western population. Colonic symptoms are not predictors for polyps or cancer but unexplained anemia and elder age can predict CRC.

Nrf2 overexpression is associated with P-glycoprotein upregulation in gastric cancer.

The efficacy of chemotherapeutic agents remains very poor in gastric cancer (GC) patients due to the development of multidrug resistance (MDR) phenotype. The nuclear factor erythroid 2-related factor 2 (Nrf2), is a pivotal transcriptional factor that regulates phase II detoxifying enzymes, antioxidants and efflux transporters including P-glycoprotein (P-gp). The aim of this study was to investigate the association of Nrf2 and P-gp and their correlations with clinicopathological criteria in GC patients.Nrf2 and MDR1/P-gp expressions in both mRNA and protein levels were examined by real-time PCR and immunohistochemical staining (IHC) respectively, in endoscopic biopsy samples from60 GC patients compared with those expressions in non-GC individuals. Our results from IHC examinations revealed that Nrf2 expression in GC patients (46.7%) is markedly higher than that in non-GC individuals (11.7%) (p<0.001, Mann-Whitney test) which was confirmed by real-time PCR in mRNA levels. Induction of P-gp as a drug efflux pump, was associated with Nrf2 overexpression in these samples (r=0.55, p<0.001). There was also a strong correlation between Nrf2 overexpression and tumor size, histological grade, lymph node and distant metastasis while P-gp upregulation was shown to be associated only with the histological grade and tumor size (Chi-square, all p<0.05). Our results suggest that therapeutic inhibition of Nrf2 expression can improve the efficacy of chemotherapeutic agents for GC patients by down regulation of P-gp expression.

A neonate with cleft palate and a fetal mass in the oral cavity: a rare case of an oral fetus-in-fetu.

Fetus-in-fetu is a rare congenital condition in which a malformed fetus-like structure is found in the body of its twin. We report a unique case of a male neonate with cleft palate and a fetus-like structure arising in his oral cavity. The neonate underwent emergent surgical removal of the mass immediately after delivery. Radiological and pathological studies of the resected mass provided supportive evidence for the case of an oral fetus-in-fetu. To our knowledge, there are few cases of oral fetus-in-fetu in the literature. Moreover, the presence of cleft palate in this neonate is of potential interest and clinical importance.

Liver mass due to penetration of a silent duodenal ulcer.

Liver penetration is a rare but serious complication of peptic ulcer disease. We report a 60-year-old man, without any serious risk factor for peptic ulcer, presented with mild abdominal discomfort, food-related vomiting and weight loss, and a mass in the left hepatic lobe, which was the result of a silent duodenal ulcer penetration. The diagnosis was based on histological examination of the endoscopic biopsies.

Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway.

Colorectal carcinomas develop according to particular genetic pathways, including the chromosomal instability (CIN+), microsatellite instability (MSI+) and MSI- CIN- routes. We have determined the genetic pathway in patients with MYH-associated polyposis (MAP), a syndrome of colorectal adenomas and cancer that results from defective base excision repair (BER). As in previous studies, MAP tumors showed a high frequency of G>T mutations in APC, in accordance with defective BER. We found that K-ras mutations were common in MAP tumors, all of the changes comprising conversion of the first guanine residue of codon 12 to thymidine (G12C, GGT>TGT). We found no BRAF mutations at the codon 599 hotspot or elsewhere in exon 14. Almost all of the MAP cancers were near-diploid (CIN-), and none was MSI+. A few p53 mutations were found, but these were not predominantly G>T changes. p53 overexpression was, however, frequent. No SMAD4 or TGFBIIR mutations were found. MAP tumors appear to follow a distinct genetic pathway, with some features of both the CIN and MSI pathways. BER deficiency is rarely accompanied by CIN or MSI. The spectrum of somatic mutations in MAP tumors reflects both selection and hypermutation to which certain guanine residues are particularly prone.

The Efficacy of Zinc Administration in the Treatment of Primary Dysmenorrhea.

OBJECTIVES: Dysmenorrhea is a common complaint in women. Primary dysmenorrhea is defined as painful menstruation in the absence of pelvic disease and is caused by uterine contractions caused by prostaglandins released from the endometrium. Conventional treatments include nonsteroidal anti-inflammatory drugs and oral contraceptives. We sought to evaluate the efficacy of zinc supplementation in the treatment of primary dysmenorrhea. . METHODS: Two-hundred participants with primary dysmenorrhea were randomized into one of two groups. The intervention group received zinc and mefenamic acid, and the control group received mefenamic acid and a placebo drug. After three months of treatment, changes in the incidence of dysmenorrhea and the degree of pain were measured in both groups. . RESULTS: The mean pain score before administration of zinc and mefenamic acid in the intervention group was 5.3±1.8 and after treatment was 1.2±1.9 (p < 0.001). In the control group, the mean pain score before administration of mefenamic acid and placebo was 5.8±2.1 and after treatment was 2.9±2.6 (p < 0.001). The difference in pain levels before and after treatment in the intervention group was 4.1±2.8, and in the control group was 2.9±1.7 (p > 0.050). We also found that 64% of case group and 33% of the control group did not experience dysmenorrhea after treatment (p < 0.001). . CONCLUSIONS: The use of a zinc supplement in combination with mefenamic acid was superior in reducing primary dysmenorrhea compared to mefenamic acid alone.

A case of concurrent several forms of thyroid cancer.

Simultaneous occurrence of papillary and follicular thyroid cancer, known as differentiated thyroid cancer, has been reported with various presentations, but presence of an anaplastic cancer, as an undifferentiated cancer, in addition to differentiated thyroid cancer is rarely reported. We here report a 40-year-old man with papillary thyroid cancer on his right thyroid lobe and metastasized to the right posterior triangle of the neck. Survey on the mass in the right posterior triangle revealed presence of simultaneous papillary, follicular, and anaplastic thyroid cancer. The patient underwent right thyroid lobectomy and he received adjuvant radiotherapy in combination with chemotherapy.

Lovastatin raises serum osteoprotegerin level in people with type 2 diabetic nephropathy.

OBJECTIVES: Osteoprotegerin (OPG), a glycoprotein, is a member of the tumor necrotizing factor alpha receptor super-family. By considering the possible role of OPG in cardiovascular disease (CVD), higher incidence of CVD in people with type 2 diabetic nephropathy (T2DN), and anti-atherosclerotic effects of statins, the present study aimed to investigate the effects of lovastatin on serum levels of OPG and soluble receptor activator of nuclear factor-κB ligand (sRANKL) in people with T2DN. DESIGN AND METHODS: Thirty patients completed the study course, out of 38 adult male patients with T2DN who were initially enrolled. Lovastatin, 20mg/d, was administered for 90 days. Afterwards, lovastatin was withdrawn for the next 30 days. Serum levels of OPG and sRANKL were measured using commercial ELISA kits at baseline, after 90 days of intervention, and after 30 days of withdrawal of lovastatin. RESULTS: Serum level of OPG was significantly increased (10.76 ± 16.44) and decreased (-7.38 ± 11.98) during 90 days of intervention and 30 days of withdrawal periods, respectively, while, sRANKL level was significantly decreased (-1192.08 ± 578.20) and increased (4418.67 ± 2124.66) during the same periods, respectively. CONCLUSIONS: Lovastatin therapy increased serum OPG level and decreased sRANKL level in people with T2DN. The withdrawal of lovastatin decreased serum OPG level, while sRANKL level was extensively increased.

Colorectal neoplasms in symptomatic patients without evidence of bleeding: a prospective study in an Iranian population.

BACKGROUND: Colorectal cancer (CRC) is a preventable disease with a high mortality and morbidity. Data on its prevalence are lacking in Iran, as well as for adenomatous polyps. This study was conducted to estimate prevalence of CRC in patients with long lasting colonic symptoms (except for known risk factors for cancer and those with rectal bleeding) who underwent total colonoscopy. METHODS: This prospective study was carried out in Imam Hospital, Tabriz University of Medical Sciences, Iran. The recruitment procedure involved 228 individuals aged more than 30 who visited a gastroenterologist because of lower gastrointestinal tract symptoms and had criteria for a colonoscopy. The endoscopist visualized the caecum in all, documented by a photo of caecum and/or specimen of the terminal ileum. The Chi square test and multiple logistic regression analysis were used to determine the significance of associations between different symptoms and colonoscopic findings. RESULTS: Thirty four subjects (14.9%) were found to have colorectal neoplasia and 112 (49.1%) had a completely normal colon. Adenomatous polyps were detected in 27 patients, which included 15.6% of men and 7.0% of women. Most of them were tubular (58.3%) and severe dysplasia was reported in only 3 cases (11.1%). Mean age of patients with a polyp (51.1+/-12.5 years) was not significantly different compared to others (p=0.381) nor mean duration of symptoms (21.1 months, p=0.435). Cancer was detected in 7 (3.1%) of our study population, the mean age of 65.7+/-6.0 years in this case being significantly elevated (p<0.0005). None of the symptoms were predictors of cancer or polyps. This result was the same by a multivariate analysis including age, gender and duration of the symptoms. CONCLUSION: The low prevalence of colorectal neoplasms as well as the less advanced pattern of adenomas in Iran are compatible with other data from Asia and the Middle East, contrasting with western countries.