Multiple genetic alterations are well recognized as contributing to pancreatic carcinogenesis, although the finding of recurrent copy number changes indicates additional targets remain to be found. The objective of this study was to identify novel targets of genetic alteration that contribute to pancreatic cancer development or progression. We used Representational Oligonucleotide Microarray Analysis (ROMA) to identify copy number changes in pancreatic cancer xenografts, and validated these findings using FISH, quantitative PCR, Western blotting and immunohistochemical labeling. With this approach, we identified a 0.36-Mb amplification at 18q11.2 containing two known genes, GATA-6 and cTAGE1. Using a cutoff value of 3.0 fold compared to haploid controls, copy number gain or amplification was confirmed in 4 of 42 (9.5%) pancreatic carcinomas analyzed. Combined genetic and transcriptional analyses showed consistent overexpression of GATA-6 in all carcinomas with 18q11.2 gain, as well as in the majority of pancreatic cancers examined (17 of 30 cancers, 56.7%) that did not have gain of this region. By contrast, overexpression of cTAGE1 was rare in these same cancers suggesting GATA-6 is the true target of this copy number increase. GATA-6 mRNA overexpression corresponded to robust nuclear protein expression in cancer cell lines and resected tissues consistent with its role as a transcription factor. Intense nuclear labeling was significantly increased in PanIN-3 lesions and infiltrating carcinomas compared to normal duct epithelium (p < 0.000001 and p < 0.003, respectively). Forced overexpression of GATA6 in MiaPaca2 cells resulted in increased proliferation and growth in soft-agar. Gain and overexpression of the developmentrelated transcription factor GATA-6 may play an important and hitherto unrecognized role in pancreatic carcinogenesis.

EphA2 is a transmembrane receptor tyrosine kinase that functions in the regulation of cell growth, survival, angiogenesis, and migration and EphA2 targeting has been proposed as a novel therapeutic strategy for neoplasms that overexpress this protein. EphA2 overexpression has been correlated with increased invasive and metastatic ability in pancreatic cancer cell lines. However, the patterns of EphA2 expression in human pancreatic cancers and associated metastases is unknown, as are the genetics of EphA2 in this tumor type. We collected clinicopathologic data and paraffin-embedded materials from 98 patients with primary and/or metastatic pancreatic cancer and performed immunohistochemical labeling for EphA2 protein. EphA2 protein immunolabeling was found in 207 of 219 samples (95%). The expression was predominantly cytoplasmic, although predominant membranous staining was observed in a minority of cases. When evaluated specifically for labeling intensity, primary and metastatic carcinomas were more strongly positive compared to benign ducts and PanIN lesions (P < 0.00001 and P < 0.01, respectively) and poorly differentiated carcinomas were more strongly positive for EphA2 than well and moderately differentiated tumors (P < 0.005). When primary carcinomas without metastatic disease were specifically compared to carcinomas with associated metastatic disease, the advanced carcinomas showed relatively less strong positive labeling for EphA2 (P < 0.008). Moreover, decreased EphA2 labeling was more commonly found in liver (P < 0.002), lung (P < 0.004) or peritoneal metastases (P < 0.01) as compared to distant lymph node metastases (P < 0.01). Genetic sequencing of the tyrosine kinase domain of EPHA2 in 22 samples of xenograft enriched pancreatic cancer did not reveal any inactivating mutations. However, EPHA2 amplification was found in 1 of 33 pancreatic cancers corresponding to a lymph node metastasis, indicating EPHA2 genomic amplification may underlie EphA2 overexpression in a minority of patients. Our data confirms that EphA2 is overexpressed in pancreatic cancer, but suggests a relative loss of EphA2 in co-existent pancreatic cancer metastases as well as a role for EPHA2 in organ specific metastasis.

Objective To investigate associations of a oxidative balance score (OBS) with blood levels of total cholesterol, low-density lipoprotein-(LDL)-cholesterol, high-density lipoprotein-(HDL) cholesterol and triglycerides, and biomarkers of inflammation (serum C-reactive protein [CRP], albumin and venous total white blood cell [WBC] counts) among 19,825 participants in a nationwide study. Methods Using cross-sectional data 14 dietary and lifestyle components were incorporated into the OBS and the resulting score (range 3–26) was then divided into five equal intervals. Multivariable-adjusted odds ratios (ORs) for abnormal biomarker levels and 95% confidence intervals (CIs) were calculated using logistic regression models. Results The ORs (95% CIs) comparing those in the highest relative to those in the lowest OBS equal interval categories were 0.50 (0.38–0.66) for CRP, 0.50 (0.36–0.71) for the total WBC count, and 0.75 (0.58–0.98) for LDL-cholesterol; all three p-values for trend were <0.001. The OBS-HDL-cholesterol association was statistically significantly inverse among females, but not among males. The OBS was not associated with serum albumin or triglycerides. Conclusion Our findings suggest that an OBS may be associated with some, but not all, circulating lipids/lipoproteins and biomarkers of inflammation.

Purpose Oxidative stress is defined as an imbalance between pro-oxidants and antioxidants. Previous research found that a single comprehensive oxidative balance score (OBS) that includes individual pro-and anti-oxidant exposures may be associated with various conditions (including prostate cancer) in the absence of associations with the individual factors. We investigated an OBS-incident prostate cancer association among 43,325 men in the Cancer Prevention Study II Nutrition Cohort. Methods From 1999–2007, 3386 incident cases were identified. Twenty different components, used in two ways (unweighted or weighted based on literature reviews), were incorporated into the OBS, and the resulting scores were then expressed as three types of variables (continuous, quartiles, or six equal intervals). Multivariable-adjusted rate ratios were calculated using Cox proportional hazards models. Results We hypothesized that the OBS would be inversely associated with prostate cancer risk; however, the rate ratios (95% confidence intervals) comparing the highest with the lowest OBS categories ranged from 1.17 (1.04–1.32) to 1.39 (0.90–2.15) for all cases, 1.14 (0.87–1.50) to 1.59 (0.57–4.40) for aggressive disease (American Joint Committee on Cancer stage III/IV or Gleason score 8–10), and 0.91 (0.62–1.35) to 1.02 (1.02–1.04) for nonaggressive disease. Conclusions Our findings are not consistent with the hypothesis that oxidative balance–related exposures collectively affect risk for prostate cancer.

Context Oxidative balance score (OBS) is a composite measure of multiple pro- and antioxidant exposures. Objective To investigate associations of OBS with F2-isoprostanes (FIP), mitochondrial DNA copy number (mtDNA), and fluorescent oxidative products (FOP), and assess inter-relationships among the biomarkers. Methods In a cross-sectional study, associations of a thirteen-component OBS with biomarker levels were assessed using multivariable regression models. Results Association of OBS with FIP, but not with FOP, was in the hypothesized direction. The results for mtDNA were unstable and analysis-dependent. The three biomarkers were not inter-correlated. Conclusions Different biomarkers of oxidative stress may reflect different biological processes.

Hypertension is a risk factor for several vascular diseases. Evidence suggests that oxidative stress (OS) plays a significant role in its pathophysiology. Human studies have shown inconsistent results, varying based on the OS biomarker and study population. In a racially diverse population, examine the association between: (1) blood pressure or hypertension and four markers of OS and (2) blood pressure or hypertension and oxidative balance score (OBS). Using data (n = 317) from the cross-sectional study on race, stress, and hypertension, an OBS was constructed from various measures of pro-oxidant and antioxidant exposures. OS was assessed by four biomarkers: fluorescence oxidative products, F2-isoprostanes, mitochondrial DNA copy number, and gamma tocopherol. Multivariate linear and logistic regression analyses were used to estimate the associations of interest. None of the adjusted associations between hypertension and OS markers was statistically significant. OBS was inversely associated with hypertension after adjusting for study covariates. Persons with higher OBS have lower odds of having hypertension; however, the evidence on the relationship between OS markers and blood pressure remains unconvincing.

Our study shows that differential infection risk may explain nSES disparities in sepsis incidence, as higher nSES is associated with lower infection hospitalization rates, but there is no association with sepsis among those hospitalized. Mediation analysis showed that nSES may influence infection hospitalization risk at least partially through physical weakness, individual income, and comorbid diabetes.

While a mean age at menopause of 51 years has been reported in the United States (U.S.), some U.S. women experience menopause before age 45, possibly increasing risk of cardiovascular mortality; however, the role in all-cause and cerebrovascular-related mortality is unclear. The purpose of this study was to investigate the association between age at menopause and all-cause and cause-specific mortality by race, hormone replacement therapy (HRT) use, and smoking status. REasons for Geographic and Racial Differences in Stroke (REGARDS) is a population-based study of 30,239 participants aged ≥45 years enrolled between 2003 and 2007 of whom 14,361 were postmenopausal women. Age at menopause was defined as <45 (early) or ≥45. All-cause and cause-specific mortality were ascertained through 2013. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between age at menopause and mortality, adjusting for baseline measures. Of 11,287 eligible women (6403 white; 4884 black), mean menopause age was 45.2 (SD 7.9) with 1524 deaths over 7.1 years. Significant interactions were detected between early age at menopause (39%) and HRT use in association with all-cause mortality ( p < 0.01), mortality from coronary heart disease ( p = 0.06), and mortality from all other causes ( p = 0.04). An association between early age at menopause and all-cause mortality was observed among ever-HRT users (HR = 1.31, 95% CI: 1.10–1.56), but not never-HRT users (HR = 1.01, 95% CI: 0.85–1.20). There were no differences in associations examined by race or smoking status. Increased all-cause mortality risk was observed for ever-HRT users with menopause before age 45.