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1.  Association of Mutations in the Basal Core Promoter and Pre-core Regions of the Hepatitis B Viral Genome and Longitudinal Changes in HBV Level in HBeAg Negative Individuals: Results From a Cohort Study in Northern Iran 
Hepatitis Monthly  2015;15(2):e23875.
Although certain HBV mutations are known to affect the expression of Hepatitis e antigen, their association with HBV viral level or clinical outcomes is less clear.
We evaluated associations between different mutations in the Basal Core promoter (BCP) and Pre-core (PC) regions of HBV genome and subsequent changes in HBV viral DNA level over seven years in a population of untreated HBeAg negative chronic hepatitis B (CHB) participants in Northeast of Iran.
Materials and Methods:
Participants in the current study were drawn from the Golestan Hepatitis B Cohort Study (GHBCS), a cohort of approximately 2590 HBsAg positive subjects (living in Gonbad city) embedded in the Golestan Cohort Study (GCS). At baseline, HBsAg was measured in all participants and revealed 2590 HBsAg positive cases. We randomly selected 304 participants who their blood sample were taken at both baseline and seven years later in follow-up and had not been treated for HBV during this time. HBV viral load were assessed at baseline and at year 7. The BCP and PC regions of the HBV DNA, at baseline, were amplified via hemi-nested PCR and sequenced by cycle sequencing. At year 7, liver stiffness was assessed by fibroscan; also, other parameters of liver disease were assessed following standard clinical protocols. Associations were assessed via tabulation, chi-square, t-tests and logistic regression. P values < 0.05 were considered statistically significant and all tests were two-sided.
Among 304 HBsAg positive participants, 99 had detectable HBV DNA at study baseline. Of these, 61.6% had PC mutations (48.5% A1896 and 25.2% G1899). In contrast to other mutations, A1896 was associated with a higher proportion of detectable HBV DNA at year 7 (39.6%) compared to patients with the wild type (13.7%) (OR: 4.36, CI95% = 1.63-11.70; P Value = 0.002). Although participants with the A1896 mutation had higher year-7 HBV viral load than participants with G1896 (2.30 ± 1.66 IU/mL vs. 1.76 ± 1 IU/mL among patients with detectable HBV; P value = 0.052), no association was observed with either serum level ALT or liver stiffness. Interestingly, mutations in the basal core promoter (BCP) region had no significant effect on virus DNA detection.
In this population with chronic HBeAg negative hepatitis B, an association was observed between the G1896A mutation in the Pre-core region of HBV and subsequent level of HBV DNA seven years later, which indicated that mutations in this region of HBV genome may contribute to disease progression in these patients and play an important role in HBV natural course of disease.
PMCID: PMC4350247  PMID: 25788956
Hepatitis B, Chronic; Mutation; Genome, Viral
2.  Correlation Between Low Bone Density and Disease Activity in Patients with Ulcerative Colitis 
Different clinical and epidemiological studies using dual-energy X-ray absorptiometry have shown an increased prevalence of low bone mineral density in patients with inflammatory bowel diseases. The aim of this study was to assess the correlation between bone density and the disease activity in patients with ulcerative colitis.
In this cross-sectional study, 52 patients with ulcerative colitis (duration of the disease less than 5 years) were invited to our research center, Golestan province, northeast of Iran, during February 2012 up to August 2012. A demographic checklist and Simple Clinical Colitis Activity Index was completed for each patients and 5 cc of blood sample was taken after obtaining the informed consent. We used colorimetry method for measuring serum calcium, UV method for serum phosphorus and ELISA for serum vitamin D. Dual-energy X-ray absorptiometry was done to evaluate the bone density. Data analysis was done using SPSS software version 16. Normality of data was assessed using Kolmogorov– Smirnov test. T and ANOVA tests were used if data had normal distribution. Mann-Whitney U or Kruskal-Wallis tests were used for the remaining data. Correlation between qualitative variables was evaluated by Chi-square test.
The mean (±SD) age and disease activity of the patients were 37.72 (±12.18) years and 4.78 (±1.98), respectively. There were no correlation between disease activity and mean age. Low bone density was seen in 30.8%, 11.5%, and 15.4% in spine, femur neck, and hip, respectively. There was no relationship between Z-score of total hip, spine, and femur neck with disease activity, age, and duration of disease (p>0.05).
Our results showed an acceptable rate of low bone density in patients with ulcerative colitis without any correlation with the disease activity index.
PMCID: PMC4293797  PMID: 25628850
Ulcerative colitis; Z-score; Bone densitometry; Low bone density
3.  Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance 
In cancer cells, apoptosis is an important mechanism that influences the outcome of chemotherapy and the development of chemoresistance. To find the genes involved in chemoresistance and the development of gastric cancer, we used the suppression subtractive hybridization method to identify the genes that are overexpressed in gastric cancer tissues compared to normal gastric tissues.
In the suppression subtractive hybridization library we constructed, the most highly overexpressed genes were humanin isoforms. Humanin is a recently identified endogenous peptide that has anti-apoptotic activity and has been selected for further study due to its potential role in the chemoresistance of gastric cancer. Upregulation of humanin isoforms was also observed in clinical samples by using quantitative real-time PCR. Among the studied isoforms, humanin isoform 3, with an expression level of 4.166 ± 1.44 fold, was the most overexpressed isoform in GC.
The overexpression of humanin in gastric cancer suggests a role for chemoresistance and provides new insight into the biology of gastric cancer. We propose that humanin isoforms are novel targets for combating chemoresistance in gastric cancer.
PMCID: PMC3896685  PMID: 24401285
Apoptosis; Chemoresistance; Gastric cancer; Suppression subtractive hybridization; Humanin
4.  Overexpression of FOXO3, MYD88, and GAPDH Identified by Suppression Subtractive Hybridization in Esophageal Cancer Is Associated with Autophagy 
To find genes involved in tumorigenesis and the development of esophageal cancer, the suppression subtractive hybridization (SSH) method was used to identify genes that are overexpressed in esophageal cancer tissues compared to normal esophageal tissues. In our SSH library, the forkhead box O3 (FOXO3), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and myeloid differentiation primary response 88 (MYD88) genes were the most highly upregulated genes, and they were selected for further studies because of their potential role in the induction of autophagy. Upregulation of these genes was also observed in clinical samples using qRT-PCR. In addition, coexpression analysis of the autophagy-related genes Beclin1, ATG12, Gabarapl, PIK3C3, and LC3 demonstrated a significant correlation between the differentially overexpressed genes and autophagy. Autophagy is an important mechanism in tumorigenesis and the development of chemoresistance in cancer cells. The upregulation of FOXO3, GAPDH, and MYD88 variants in esophageal cancer suggests a role for autophagy and provides new insight into the biology of esophageal cancer. We propose that FOXO3, GAPDH, and MYD88 are novel targets for combating autophagy in esophageal cancer.
PMCID: PMC3910442  PMID: 24527027
5.  Predictors of Colorectal Cancer Survival in Golestan, Iran: A Population-based Study 
Epidemiology and Health  2013;35:e2013004.
We aimed to investigate factors associated with colorectal cancer survival in Golestan, Iran.
We used a population based cancer registry to recruit study subjects. All patients registered since 2004 were contacted and data were collected using structured questionnaires and trained interviewers. All the existing evidences to determine the stage of the cancer were also collected. The time from first diagnosis to death was compared in patients according to their stage of cancer using the Kaplan-Meir method. A Cox proportional hazard model was built to examine their survival experience by taking into account other covariates.
Out of a total of 345 subjects, 227 were traced. Median age of the subjects was 54 and more than 42% were under 50 years old. We found 132 deaths among these patients, 5 of which were non-colorectal related deaths. The median survival time for the entire cohort was 3.56 years. A borderline significant difference in survival experience was detected for ethnicity (log rank test, p=0.053). Using Cox proportional hazard modeling, only cancer stage remained significantly associated with time of death in the final model.
Colorectal cancer occurs at a younger age among people living in Golestan province. A very young age at presentation and what appears to be a high proportion of patients presenting with late stage in this area suggest this population might benefit substantially from early diagnoses by introducing age adapted screening programs.
PMCID: PMC3691365  PMID: 23807907
Colorectal cancer; Stage; Survival
6.  Goiter Frequency Is More Strongly Associated with Gastric Adenocarcinoma than Urine Iodine Level 
Journal of Gastric Cancer  2013;13(2):106-110.
We designed our study to evaluate the hypothesis that gastric cancer is correlated with iodine deficiency or thyroid dysfunction.
Materials and Methods
We investigated the total body iodine reserve, thyroid function status and autoimmune disorder in 40 recently diagnosed gastric adenocarcinoma cases versus 80 healthy controls. The participants came from a region with high gastric cancer rate but sufficient iodine supply due to salt iodination. The investigation included urine iodine level, thyroid gland clinical and ultrasonographic examination, and thyroid function tests.
Goiter was detected more frequently in the case group (P=0.001); such a finding, however, was not true for lower than normal urine iodine levels. The free T3 mean level was significantly lower in the case group compared to the control group (P=0.005).
The higher prevalence of goiter rather than low levels of urinary iodine in gastric adenocarcinoma cases suggests that goiter, perhaps due to protracted but currently adjusted iodine deficiency, is more likely to be associated with gastric adenocarcinoma compared to the existing iodine deficiency itself.
PMCID: PMC3705130  PMID: 23844325
Stomach neoplasms; Goiter; Iodine; Thyroid function tests; Autoimmune diseases
7.  Modifiable Risk of Breast Cancer in Northeast Iran: Hope for the Future. A Case-Control Study 
Breast Care  2011;6(6):453-456.
Breast cancer is the most common cancer in women. Its prevalence is increasing annually by 2%. The determination of modifiable risk factors has been the subject of various studies. The aim of this study was to determine risk factors of breast cancer in women in Golestan Province.
Patients and Methods
This case-control study was conducted among women with breast cancer recorded in the cancer registry system between 2004 and 2006 (n = 134), and their age-matched healthy neighbors (n = 133). Data were statistically analyzed.
Age at marriage, menarche and pregnancy, breast feeding, positive family history, marital status, and educational level were not significantly correlated with risk of breast cancer, but age at menopause (< 46.6 years) was significantly correlated (95% confidence interval 1.15–7.37; p = 0.021). Live births, still births, and infant deaths were not significantly different between the 2 groups. For other variables, such as smoking history, no odds ratio was calculated.
Results show that there is no significant correlation between variables and risk of breast cancer in our population, except for age at menopause. A large cohort study is recommended.
PMCID: PMC3290010  PMID: 22419899
Breast cancer; Risk factors; Golestan; Case-control study
8.  None-endoscopic Screening for Esophageal Squamous Cell Carcinoma- A Review 
Esophageal cancer (EC) is the eighth most common cancer and sixth most frequent cause of cancer mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common type of EC. ESCC develops by progression from premalignant lesions, which are called esophageal squamous dysplasia (ESD). Prevention is the most effective strategy for controlling this disease. Generally, two methods may be defined for ESCC prevention. The aim of the first preventive method is to prevent the initiation of ESD by avoiding the known risk factors, or primary prevention. Secondary prevention focuses on detection of the disease in its early curable stage, thus preventing its progression into advanced stages. Endoscopy with iodine staining and biopsy is the diagnostic choice for ESD. However it is invasive and expensive, and not accepted by asymptomatic ESD cases. Therefore, it is necessary to find a non-endoscopic screening method. Despite the large number of studies conducted worldwide, no approved method has been developed for ESCC screening. Regarding the multi-factorial nature of ESCC, it is proposed that the use of a combination of various criteria, such as cytological examination, risk factors, genetic alteration, and molecular markers may result in the development of a comprehensive and effective ESCC screening program.
PMCID: PMC4017690  PMID: 24829644
Esophageal squamous cell carcinoma; Screening; Non-endoscopic; Review
9.  The Role of IL-6 for Predicting Neonatal Sepsis: A Systematic Review and Meta-Analysis 
Iranian Journal of Pediatrics  2011;21(4):411-417.
Neonatal sepsis (NS) is a common and life-threatening disorder in infants. Previous studies showed that interleukin-6 (IL-6) may be a valid non-invasive and rapid method for diagnosis of NS. We conducted this review to assess the validity of IL-6 for predicting NS.
This was a systematic review with meta-analysis. Embase, Medline and Web of Science databases were searched between January 1990 and December 2009. The search terms used were “cytokine”, “neonate”, “sepsis” and “interleukin-6". We used standard methods recommended for meta analyses of diagnostic test evaluations. The analysis was based on a summary ROC (SROC) curve. Meta-regression analysis was used to assess the effects of some confounding factors on the results of meta-analysis. Potential presence of publication bias was tested using funnel plots and the Egger test.
Meta-analysis was performed on 13 publications including 353 infants with sepsis and 691 control infants. The pooled sensitivity and specificity of IL-6 was 0.79 and 0.84, respectively. The maximum joint sensitivity and specificity (i.e., the Q value) in SROC curve was 0.82 and the area under curve (AUC) was 0.89 (95% CI: 0.84-0.94). Meta-regression analysis showed that the diagnostic accuracy of IL-6 was not affected by confounding variables. The evaluation of publication bias showed that the Egger test was not significant (P=0.07).
IL-6 seems to be a valid marker for predicting NS. It may be considered for early diagnosis of sepsis in neonatal care units.
PMCID: PMC3446138  PMID: 23056824
Interlukin-6; Cytokines; Sepsis; Neonate; Meta-analysis
11.  Incidence of Childhood Cancers in Golestan Province of Iran 
Iranian Journal of Pediatrics  2010;20(3):335-342.
This paper presents the incidence rates of childhood cancers using the data obtained from Golestan population based cancer registry (GPCR) between 2004 and 2006.
GPCR registers only primary cancers based on standard protocols of the international association of cancer registries (IACR). We collect data on newly diagnosed (incident) cancer cases from all public and private diagnostic and therapeutic centers of the whole province. CanReg-4 software was used for data entry and analysis.
Totally 5076 cancer cases (all ages) were diagnosed in GPCR between 2004 and 2006. Of these, 139 (2.74 %) were children (aged 0–14 years) with mean (±SD) age of 8.06 (±4.48) years. The age standardized incidence rates for childhood cancer were 119.8 and 78.3 per 1000000 person-years in male and female children, respectively. Leukemia was the most common childhood cancer in Golestan province of Iran. Lymphomas and central nervous system tumors were the second and third ones, respectively.
The incidence rates of childhood cancers were relatively high in Golestan province of Iran. So, controlling of childhood cancers should be mentioned as an important issue in health policy making in this area.
PMCID: PMC3446043  PMID: 23056726
Childhood; Cancer; Population; Cancer registry; Iran

Results 1-11 (11)