Exposure to polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines and incidence of esophageal cancer.

BACKGROUND: Studying carcinogens in tobacco and nontobacco sources may be key to understanding the pathogenesis and geographic distribution of esophageal cancer. METHODS: The Golestan Cohort Study has been conducted since 2004 in a region with high rates of esophageal squamous cell carcinoma. For this nested study, the cases comprised of all incident cases by January 1, 2018; controls were matched to the case by age, sex, residence, time in cohort, and tobacco use. We measured urinary concentrations of 33 exposure biomarkers of nicotine, polycyclic aromatic hydrocarbons, volatile organic compounds, and tobacco-specific nitrosamines. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals for associations between the 90th vs the 10th percentiles of the biomarker concentrations and incident esophageal squamous cell carcinoma. RESULTS: Among individuals who did not currently use tobacco (148 cases and 163 controls), 2 acrolein metabolites, 2 acrylonitrile metabolites, 1 propylene oxide metabolite, and one 1,3-butadiene metabolite were significantly associated with incident esophageal squamous cell carcinoma (adjusted odds ratios between 1.8 and 4.3). Among tobacco users (57 cases and 63 controls), metabolites of 2 other volatile organic compounds (styrene and xylene) were associated with esophageal squamous cell carcinoma (OR = 6.2 and 9.0, respectively). In tobacco users, 2 tobacco-specific nitrosamines (NNN and N'-Nitrosoanatabine) were also associated with esophageal squamous cell carcinoma. Suggestive associations were seen with some polycyclic aromatic hydrocarbons (especially 2-hydroxynaphthalene) in nonusers of tobacco products and other tobacco-specific nitrosamines in tobacco users. CONCLUSION: These novel associations based on individual-level data and samples collected many years before cancer diagnosis, from a population without occupational exposure, have important public health implications.

Decoding the expression pattern of MUC3A in gastric adenocarcinoma: unveiling the key to successful immunotherapy.

AIMS: Despite the promise of immunotherapy for gastric adenocarcinoma, resistance is common, necessitating the validation of new targets. Based on our previous bioinformatics analysis, the MUC3A antigen emerged as a promising candidate for immunotherapy against gastric adenocarcinoma. However, a comprehensive understanding of its expression at protein level remains elusive, despite its crucial role in determining clinical response. We also sought to establish a connection between the expression pattern and relevant clinical variables of the disease, whenever feasible. METHODS: Immunohistochemistry was used to determine the percentage of MUC3A-positive tumor cells in primary (PT) and metastatic tumor (MT) sites of 190 gastric adenocarcinoma patients. We also evaluated the association between MUC3A expression and variables such as Lauren classification, history of neoadjuvant chemotherapy and/or radiotherapy, and overall patient survival. RESULTS: Median MUC3A expression was 50% in PT and 70% in MT sites, exhibiting a positive correlation. MT intestinal type showed significantly higher MUC3A expression compared to other types. Neoadjuvant therapy history did not affect MUC3A expression. Higher MUC3A expression correlated with improved survival. CONCLUSIONS: Based on our previous bioinformatics data and the consistently high expression of MUC3A on gastric tumor cells, we propose advancing experimental aspects of anti-MUC3A immunotherapy for gastric adenocarcinoma.

Comparing per-pass performance of 2 types of needles for EUS-guided fine-needle biopsy sampling of pancreatobiliary masses in a randomized trial.

BACKGROUND AND AIMS: EUS-guided fine-needle biopsy sampling (EUS-FNB) has largely replaced FNA for tissue diagnosis of pancreatobiliary mass lesions. However, the optimal number of passes required for the diagnosis of malignancy is not clear. We aimed to compare the per-pass performance of 2 types of fine-needle biopsy (FNB) needles for the detection of malignancy. METHODS: One hundred fourteen patients referred for EUS evaluation of solid pancreatobiliary mass lesions underwent randomization between biopsy sampling with a Franseen needle and a 3-prong tip needle with an asymmetric cutting surfaces. Four passes of EUS-FNB were taken from each mass lesion. Two pathologists blinded to needle type analyzed the specimens. The final diagnosis of malignancy was made based on FNB specimen pathology, surgery, or a follow-up of at least 6 months after EUS-FNB. The sensitivity of EUS-FNB to diagnose malignancy was compared between the 2 groups. The cumulative sensitivity of detection of malignancy by EUS-FNB was calculated after each pass in each arm. Other characteristics of the specimens including cellularity and blood contents were also compared between the 2 groups. In the primary analysis, lesions categorized as suspicious on EUS-FNB were considered nondiagnostic for malignancy. RESULTS: Ninety-eight patients (86%) had a final diagnosis of malignancy, and 16 patients (14%) had benign disease. Four passes of EUS-FNB with the Franseen needle detected malignancy in 44 of 47 patients (sensitivity, 93.6%; 95% confidence interval [CI], 82.5-98.7) and with the 3-prong asymmetric-tip needle in 50 of 51 patients (sensitivity, 98%; 95% CI, 89.6-99.9; P = .35). Two passes of EUS-FNB detected malignancy with a sensitivity of 91.5% (95% CI, 79.6-97.6) with the Franseen needle and 90.2% (95% CI, 78.6-96.7) with the 3-prong asymmetric-tip needle. The cumulative sensitivities at pass 3 were 93.6% (95% CI, 82.5-98.6) and 96.1% (95% CI, 86.5-99.5), respectively. Samples collected with the Franseen needle had significantly higher cellularity than samples collected with the 3-prong asymmetric-tip needle (P < .01). However, no difference as found between the 2 types of needles in term of specimen bloodiness. CONCLUSIONS: No significant differences were found in the diagnostic performance of the Franseen needle versus the 3-prong asymmetric-tip needle in patients with suspected pancreatobiliary cancer. However, the Franseen needle yielded higher cellularity of the specimen. Two passes of EUS-FNB are required to detect malignancy with at least 90% sensitivity with either type of needle. (Clinical trial registration number: NCT04975620.).

Efficacy of adoptively transferred allogeneic CIK cells on colorectal cancer: Augmentative antitumoral effects of GvHD.

OBJECTIVE: A preclinical study was designed to evaluate the effects of adoptively transferred cytokine-induced killer (CIK) cells on colorectal adenocarcinoma. METHODS: Forty NOG mice bearing HT-29 xenograft tumors were developed and equally divided into 2 groups of treatment and control. The mice in the treatment group received cumulatively 40-60 × 106 CIK cells in four divided doses. RESULTS: Median tumor doubling times for HT-29 xenograft tumors in the treatment and control groups were found to be 8.98 and 4.32 days; respectively. The treatment resulted in tumor growth delay (TGD) of 52.5 %. CIK cell-induced log cell kill (LCK) was found to be 0.67, which implies reduction of 78.6 % of neoplastic colorectal cells. Median length of survival in the treated mice was significantly longer than controls (57 (41-63) vs 41 (31-57) days, P < 0.001). Mice in the treatment group experienced graft-versus-host disease (GvHD) from median of day 13th after the cell therapy. LCK and TGD significantly increased after emergence of GvHD. After necropsy, tumors of the treatment group contained high levels of human-originated CD3+, CD4+ and CD8+ cells and showed significantly lower mitotic counts (P < 0.001) and residual tumor scores (P = 0.005) than the controls (entirely negative for the mentioned CD markers). Ninety percent of the treated mice were found to be responding. CONCLUSIONS: Adoptive transfer of allogeneic CIK cells may be an efficient antitumoral therapy for colorectal cancer. Allogeneic CIK cell-mediated GvHD may contribute to amplification of graft-versus-tumor effects of the cellular therapy.

Overexpression of Bromodomain and Extraterminal Domain is Associated with Progression, Metastasis and Unfavorable Outcomes: Highlighting Prognostic and Therapeutic Value of the BET Protein Family in Gastric Cancer.

BACKGROUND: As epigenetic readers, Bromodomain and extraterminal domain (BET) proteins have attracted immense interest in developing novel therapies targeting this family to inhibit cancer progression. Although the impact of BRD4 in the carcinogenesis of various tumors has been widely investigated, little is known about the potential roles of the BET family in gastric cancer. METHODS: In this cohort study, we have screened the expression profile of the BET protein family, including three members, BRD2, BRD3 and BRD4, in fresh gastric cancer (GC), adjacent non-tumor and normal gastric tissues, as well as the anti-cancer effects and molecular mechanisms of BET inhibition in GC cell lines. RESULTS: Among GC patients, BRD2, BRD3 and BRD4 showed overexpression, 48.07% (25/52), 61.5% (32/52) and 63.46% (33/52), respectively. The overexpression of BRD3 and BRD4 were remarkably associated with unfavorable outcomes (HR = 2.023, P = 0.038; HR = 3.874, P = 0.001, respectively). However, multivariate Cox regression analysis indicated that BRDs mRNA expression could not be used as an independent prognostic factor for GC patients after adjustment with other variables. I-BET151, a potent pan-inhibitor, suppressing the BET family, decreased cell growth, migration and invasion of GC cells. Interestingly, I-BET151 induced G1 cell cycle arrest through down-regulation of c-Myc and its target, CDK2/Cyclin D1 complex. CONCLUSIONS: Our data provide insights into the prognostic role of the BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.

Does Adding a Cardia Biopsy Improve Gastric Intestinal Metaplasia Detection Rate by the Sydney System Protocol?

BACKGROUND: The Sydney system offers a standard biopsy protocol for detection and follow-up of gastric preneoplastic lesions such as intestinal metaplasia (IM). The highest frequency of cardia-type gastric adenocarcinoma (GA) in Iran has been documented in the north-western part of the country. This study aims to investigate the effect of the addition of mucosal biopsies of gastric cardia to the standard Sydney protocol on the rate of detection of IM in the asymptomatic residents of this high-risk region for proximal gastric cancer. METHODS: A retrospective new analysis was performed on the previous data obtained in cross-sectional endoscopic screening in 2000 as well as a biopsy study of 508 asymptomatic volunteer residents in Meshkinshahr district, Ardabil province. The screening study was conducted in a group of residents aged 40 years and older who did not have any previous GI or hemodynamic problems. RESULTS: Intestinal metaplasia at the Sydney protocol sampling sites was detected in 107 samples belonging to 76 of the 508 (14.99%) volunteers. Twenty-one patients had IM at the cardia. Of these, five patients had IM-cardia (IM only at the cardia). Therefore, adding a cardia biopsy to the set of biopsies diagnosed five more IM cases which were not diagnosed on the standard Sydney protocol (P=0.062). CONCLUSION: The addition of a biopsy from the cardia to the Sydney protocol biopsy set does not seem to improve the frequency of detection of IM in the residents of this high-risk geographic area for proximal gastric carcinoma.

Meat consumption and risk of esophageal and gastric cancer in the Golestan Cohort Study, Iran.

Red meat and processed meat are associated with some gastrointestinal cancers. Our study aims to investigate the association of different meat types with esophageal and gastric cancer (EC, GC) in a high-risk population. The Golestan Cohort Study (GCS) is a population-based cohort of 50 045 individuals aged 40 to 75 from northeast Iran. Detailed data on different exposures were collected using validated questionnaires. We considered quintiles of meat consumption, using grams and density (g/1000 kcal/day). We calculated intake of red, processed, organ and white meat, as well as total red meat, including the first three. We used proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between meat types and cancer. During 12 years of follow-up, out of 49 585 participants (57.4% women), 369 developed EC (48.2% women) and 368 developed GC (27.5% women), including 309 esophageal squamous cell, 20 esophageal adenocarcinomas, 216 cardia and 95 non-cardia GC. No association was found for EC except for red meat among females (HR for one quintile increase 1.13, 95% CI = 1.00-1.27). The risk of GC increased for intake of total red meat (HR 1.08, 95% CI = 1.00-1.17) and red meat separately (HR 1.09, 95% CI = 1.00-1.18). The HR for red meat and non-cardia GC was 1.23 (95% CI = 1.02-1.48). No associations were observed for other types of meat. In conclusion, in this high-risk population red meat intake is associated with GC, but not EC, suggesting a substantial role of this modifiable factor in determining the burden of GC.

Abdominal Ultrasound Combined with Laboratory Tests as a Reliable, Easily Accessible and Cost-Effective Way of Assessing the Stages of Liver Fibrosis and Cirrhosis.

BACKGROUND: In the last two decades, the simple low-cost abdominal ultrasound (US) examination for the diagnosis of advanced fibrosis and cirrhosis was displaced by very expensive and not readily available modern imaging systems like magnetic resonance imaging (MRI), computed tomography (CT) scan and transient elastography. The aim of this study is to evaluate and emphasize the potential of US for diagnosis of advanced liver fibrosis and cirrhosis. METHODS: US, laboratory tests (blood counts, transaminases, aspartate platelet ratio index [APRI], international normalized ratio [INR], serum albumin and bilirubin) and liver biopsy were performed on 197 patients with chronic liver diseases. Development of liver fibrosis was categorized in six stages, with stages 1-3 considered as mild to moderate and stages 4-6 as advanced fibrosis. Sonographic parameters (interrupted liver surface line, nodularity of liver surface, biconvexity of liver edges, grade of liver angle, caudate lobe diameter, parenchyma echotexture and spleen size) were obtained. All variables were dichotomized into zero and one and compared with respect to the different stages of liver fibrosis. The sensitivity, specificity, and positive and negative predictive values of all variables as well as their summations scores through receiver operating characteristic (ROC) curve analysis were calculated for the correct histologic diagnosis. RESULTS: Totally, 39 cases had severe fibrosis and cirrhosis and 158 had mild to moderate fibrosis. The area under the curve by ROC curve analysis of sonographic variables (surface nodularity, angle of left lobe, echotexture of liver and spleen size) was 85%, that of laboratory data (APRI, serum albumin and INR combined) was 83.8%, that of APRI alone was 81.8% and all combined (sonography and lab data together) was 92.4% for the correct diagnosis. CONCLUSION: The simple US examination, alone or combined with lab data, is able to diagnose advanced fibrosis and cirrhosis with excellent accuracy, making the use of other modern imaging modalities unnecessary.

Interpatient variability in mesothelin expression necessitates its evaluation before gastric cancer immunotherapy.

Aims: Mesothelin (MSLN) was applied for the immunotherapy of ovarian cancer and mesothelioma with a minimum expression of 60% to obtain a clinical response. Here, the authors evaluated MSLN expression as a potential target of gastric adenocarcinoma immunotherapy. Materials & methods: The expression of MSLN was evaluated by immunohistochemistry and was reported in primary tumor (PT) and metastatic tumor (MT) sites. Results: The results showed that only 17.1% and 13.5% of the patients had 60% or more MSLN expression in PT and MT sites, respectively. The expression of MSLN in PTs and MTs was not influenced by Lauren classification, neoadjuvant therapy or tumor stage. Conclusions: Interpatient variability in MSLN expression necessitates its evaluation before MSLN-based gastric cancer immunotherapy.

Dietary acid load and mortality from all causes, CVD and cancer: results from the Golestan Cohort Study.

Given the limited studies and controversial results on association between dietary acid load and mortality from CVD and cancers, we aimed to investigate this association in a large population cohort study in Middle East, with a wide range of dietary acid load. The study was conducted on the platform of the Golestan Cohort Study (GCS), which enrolled 50 045 participants in 2004-2008. Dietary intake was assessed using a validated FFQ. Dietary potential renal acid load (PRAL) score was calculated from nutrient intake. Death and its causes were identified and confirmed by two or three physicians. Cox proportional hazards regression was used to estimate hazard ratio (HR) and 95 % CI for total and cause-specific mortalities. Then, the associations were modelled using restricted cubic splines. PRAL range was -57·36 to +53·81 mEq/d for men and -76·70 to +49·08 for women. During 555 142 person-years of follow-up, we documented 6830 deaths, including 3070 cardiovascular deaths, 1502 cancer deaths and 2258 deaths from other causes. For overall deaths, in final model after adjustment for confounders, participants in the first and fifth quintiles of PRAL had a higher risk of mortality compared with the second quintile of PRAL (HR: 1·08; 95 % CI1·01, 1·16 and HR: 1·07; 95 % CI 1·01, 1·15, respectively); Pfor trend < 0·05). Participants in the first and fifth quintiles of PRAL had a 12 % higher risk of CVD mortality compared with the Q2 of PRAL (HR: 1·12; 95 % CI 1·01-1·25 and HR: 1·12; 95 % CI 1·01, 1·26, respectively; Pfor trend < 0·05). We found that all-cause and CVD mortality rates were higher in the lowest and highest PRAL values, in an approximately U-shaped relation (P-values for the overall association and the non-linear association of energy-adjusted PRAL with total mortality were < 0·001 and < 0·001, and with CVD mortality were 0·008 and 0·003, respectively). Our results highlight unfavourable associations of high acidity and alkalinity of diet with the increased total and CVD mortality risk. It may be important to consider a balanced acid-base diet as a protective strategy to prevent pre-mature death, especially from CVD.

Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.

TP53 Targeted Deep Sequencing of Cell-Free DNA in Esophageal Squamous Cell Carcinoma Using Low-Quality Serum: Concordance with Tumor Mutation.

Circulating cell-free DNA (cfDNA) is emerging as a potential tumor biomarker. CfDNA-based biomarkers may be applicable in tumors without an available non-invasive screening method among at-risk populations. Esophageal squamous cell carcinoma (ESCC) and residents of the Asian cancer belt are examples of those malignancies and populations. Previous epidemiological studies using cfDNA have pointed to the need for high volumes of good quality plasma (i.e., >1 mL plasma with 0 or 1 cycles of freeze-thaw) rather than archival serum, which is often the main available source of cfDNA in retrospective studies. Here, we have investigated the concordance of TP53 mutations in tumor tissue and cfDNA extracted from archival serum left-over from 42 cases and 39 matched controls (age, gender, residence) in a high-risk area of Northern Iran (Golestan). Deep sequencing of TP53 coding regions was complemented with a specialized variant caller (Needlestack). Overall, 23% to 31% of mutations were concordantly detected in tumor and serum cfDNA (based on two false discovery rate thresholds). Concordance was positively correlated with high cfDNA concentration, smoking history (p-value = 0.02) and mutations with a high potential of neoantigen formation (OR; 95%CI = 1.9 (1.11-3.29)), suggesting that tumor DNA release in the bloodstream might reflect the effects of immune and inflammatory context on tumor cell turnover. We identified TP53 mutations in five controls, one of whom was subsequently diagnosed with ESCC. Overall, the results showed that cfDNA mutations can be reliably identified by deep sequencing of archival serum, with a rate of success comparable to plasma. Nonetheless, 70% non-identifiable mutations among cancer patients and 12% mutation detection in controls are the main challenges in applying cfDNA to detect tumor-related variants when blindly targeting whole coding regions of the TP53 gene in ESCC.

Long-term opiate use and risk of cardiovascular mortality: results from the Golestan Cohort Study.

AIMS: Tens of millions of people worldwide use opiates but little is known about their potential role in causing cardiovascular diseases. We aimed to study the association of long-term opiate use with cardiovascular mortality and whether this association is independent of the known risk factors. METHODS AND RESULTS: In the population-based Golestan Cohort Study-50 045 Iranian participants, 40-75 years, 58% women-we used Cox regression to estimate hazard ratios and 95% confidence intervals (HRs, 95% CIs) for the association of opiate use (at least once a week for a period of 6 months) with cardiovascular mortality, adjusting for potential confounders-i.e. age, sex, education, wealth, residential place, marital status, ethnicity, and tobacco and alcohol use. To show independent association, the models were further adjusted for hypertension, diabetes, waist and hip circumferences, physical activity, fruit/vegetable intake, aspirin and statin use, and history of cardiovascular diseases and cancers. In total, 8487 participants (72.2% men) were opiate users for a median (IQR) of 10 (4-20) years. During 548 940 person-years-median of 11.3 years, >99% success follow-up-3079 cardiovascular deaths occurred, with substantially higher rates in opiate users than non-users (1005 vs. 478 deaths/100 000 person-years). Opiate use was associated with increased cardiovascular mortality, with adjusted HR (95% CI) of 1.63 (1.49-1.79). Overall 10.9% of cardiovascular deaths were attributable to opiate use. The association was independent of the traditional cardiovascular risk factors. CONCLUSION: Long-term opiate use was associated with an increased cardiovascular mortality independent of the traditional risk factors. Further research, particularly on mechanisms of action, is recommended.

Intravesical electromotive administration of botulinum toxin type A in improving the bladder and bowel functions: Evidence for novel mechanism of action.

Objective: To examine the hypothesis that what is the concomitant mechanism of action botulinum toxin type A (BoNTA) administration by intravesical electromotive into the bladder resulting in bladder function improvement. We also tried to confirm the possibility of retrograde trans-axonal transportation of toxin.Design: Animal study.Setting: Ten male rabbits were divided into two groups.Participants: Group 1 (G1) (n = 5) (BoNTA/EMDA), and group 2 (G2) (n = 5) the control group.Interventions: Animals in G1received 10 IU/Kg of intravesical BoNTA through a specific catheter for electromotive drug administration (BoNTA/EMDA). About 0.1-0.15 ml of toxin was diluted in 1 ml of distilled water. The maximum frequency of the device for drug solution delivery was set at 4 mA for 15 min. In G2 as the control group, the same procedure was performed to deliver normal saline to the bladder.Outcome measures: Multiple biopsies were taken from bladder's contiguous structures one month postoperatively. The immunohistochemical (IHC) evaluation was performed with anti-clostridium botulinum toxoid type A mouse IgM monoclonal antibody.Results: In specimens of G1, BoNTA penetrated through muscular layers of the bladder wall and the staining was uniform in the urothelium, interstitium, and muscular layers. Positive IHC staining showed that BoNTA was traced in the upper and lower spinal cord in addition to pelvic nerve, sacral nerve plexus, intestine wall, and pelvic floor muscle. In G2, all the specimens were intact in IHC staining.Conclusions: The presence of BoNTA in lower and upper spinal cord suggests the possibility of retrograde trans-axonal transfer of toxin to lower and upper neural pathways which may result in simultaneous improvement in bladder and bowel functions.

Association Between Serological Responses to Two Zoonotic Ruminant Pathogens and Esophageal Squamous Cell Carcinoma.

Questionnaire data have linked contact with ruminants to the risk of esophageal squamous cell carcinoma (ESCC) in high-risk Asian populations. To better understand this observed association, we investigated exposure to two major zoonotic ruminant pathogens relative to ESCC risk. Using enzyme-linked immunosorbent assay, immunofluorescence assay, and Brucella microagglutination test assays, we measured immunoglobulin G anti-Coxiella burnetii and anti-Brucella spp. antibodies in patients with ESCC (n = 177) and population-based controls (n = 177) matched by age, gender, and residence area from the Golestan case-control study in Iran. We found a similarly high seroprevalence of C. burnetii in ESCC cases and controls (75% and 80%, respectively), and a similarly low seroprevalence of Brucella spp. (0% and 0.6%, respectively). While documenting a high exposure to one of two zoonotic ruminant infections, this exposure failed to explain the observed association of ruminant contact and ESCC risk in this high-risk population.

Joint effect of diabetes and opiate use on all-cause and cause-specific mortality: the Golestan cohort study.

BACKGROUND: Many diabetic individuals use prescription and non-prescription opioids and opiates. We aimed to investigate the joint effect of diabetes and opiate use on all-cause and cause-specific mortality. METHODS: Golestan Cohort study is a prospective population-based study in Iran. A total of 50 045 people-aged 40-75, 28 811 women, 8487 opiate users, 3548 diabetic patients-were followed during a median of 11.1 years, with over 99% success follow-up. Hazard ratio and 95% confidence intervals (HRs, 95% CIs), and preventable death attributable to each risk factor, were calculated. RESULTS: After 533 309 person-years, 7060 deaths occurred: 4178 (10.8%) of non-diabetic non-opiate users, 757 (25.3%) diabetic non-users, 1906 (24.0%) non-diabetic opiate users and 219 (39.8%) diabetic opiate users. Compared with non-diabetic non-users, HRs (95% CIs) for all-cause mortality were 2.17 (2.00-2.35) in diabetic non-opiate users, 1.63 (1.53-1.74) in non-diabetic opiate users and 2.76 (2.40-3.17) in diabetic opiate users. Among those who both had diabetes and used opiates, 63.8% (95% CI: 58.3%-68.5%) of all deaths were attributable to these risk factors, compared with 53.9% (95% CI: 50%-57.4%) in people who only had diabetes and 38.7% (95% CI: 34.6%-42.5%) in non-diabetic opiate users. Diabetes was more strongly associated with cardiovascular than cancer mortality. The risk of early mortality in known cases of diabetes did not depend on whether they started opiate use before or after their diagnosis. CONCLUSIONS: Using opiates is detrimental to the health of diabetic patients. Public awareness about the health effects of opiates, and improvement of diabetes care especially among individuals with or at risk of opiate use, are necessary.

Prognostic and Therapeutic Significance of Androgen Receptor in Patients with Gastric Cancer.

PURPOSE: The clinical studies carried out in the last few decades unequivocally introduced activated androgen receptor (AR) as a pathogenic feature of human malignancies which not only endows cancer cells with survival advantage, but also may be exploited for anticancer interventions. PATIENTS AND METHODS: In this study, we have investigated the expression profile of AR and EMT-related genes in fresh gastric cancer (GC), adjacent nontumor and normal gastric tissues, as well as the effect and molecular mechanisms of AR inhibition in GC cell lines. RESULTS: Amongst 60 GC patients, 66.7% overexpressed AR that was remarkably correlated with the overexpression of Snail, ß-catenin, Twist1, and STAT3. AR overexpression was also remarkably associated with unfavorable outcome (HR=3.478, P=0.001); however, multivariate Cox regression analysis indicated that it was not an independent prognostic factor (HR=2.089, P=0.056). This study has investigated simultaneous assessment of AR and EMT-related genes expression and indicated that concurrent overexpression of AR and Snail is an independent unfavorable factor for GC overall survival after adjustment with other variables (HR=2.382, P=0.021). Interestingly, the inhibition of AR signaling by potent AR antagonist enzalutamide suppressed cell growth, migration and invasion of GC cells via regulation of apoptosis-, cell cycle-, and EMT-related gene expressions. CONCLUSION: Our findings have clinical importance proposing AR as an important prognostic factor involved in GC progression and metastasis, and submit AR inhibition as an appealing therapeutic approach for GC patients, either as a single agent or in a combined-modal strategy.

Habitual dietary intake of flavonoids and all-cause and cause-specific mortality: Golestan cohort study.

BACKGROUND AND OBJECTIVES: Flavonoids are the most important group of polyphenols with well-known beneficial effects on health. However; the association of intake of total flavonoid or their subclasses with all-cause or cause-specific mortality is not fully understood. The present study aims to evaluate the association between intake of total flavonoid, flavonoid subclasses, and total and cause-specific mortality in a developing country. METHODS: A total number of 49,173 participants from the Golestan cohort study, who completed a validated food frequency questionnaire at recruitment, were followed from 2004 till 2018. Phenol-Explorer database was applied to estimate dietary intakes of total flavonoid and different flavonoid subclasses. Associations were examined using adjusted Cox proportional hazards models. RESULTS: During a mean follow-up of 10.63 years, 5104 deaths were reported. After adjusting for several potential confounders, the hazard ratios (HRs) of all-cause mortality for the highest versus the lowest quintile of dietary flavanones, flavones, isoflavonoids, and dihydrochalcones were 0.81 (95% confidence interval = 0.73-0.89), 0.83(0.76-0.92), 0.88(0.80-0.96) and 0.83(0.77-0.90), respectively. However, there was no association between total flavonoid intake or other flavonoid subclasses with all-cause mortality. In cause-specific mortality analyses, flavanones and flavones intakes were inversely associated with CVD mortality [HRs: 0.86(0.73-1.00) and 0.85(0.72-1.00)] and isoflavonoids and dihydrochalcones were the only flavonoid subclasses that showed a protective association against cancer mortality [HR: 0.82(0.68-0.98)]. CONCLUSION: The results of our study suggest that certain subclasses of flavonoids can reduce all-cause mortality and mortality rate from CVD and cancer.

Methylated DNA Markers of Esophageal Squamous Cancer and Dysplasia: An International Study.

BACKGROUND: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. METHODS: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. RESULTS: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). CONCLUSIONS: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. IMPACT: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.