Faculty Bibliography

Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in approximately 5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in approximately 30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A. Cistrome and chromatin analyses revealed that HNF4G is a pioneer factor that generates and maintains enhancer landscape at gastrointestinal-lineage genes, independent of androgen-receptor signaling. In HNF4G/HNF1A-double-negative prostate cancer, exogenous expression of HNF4G at physiologic levels recapitulates the gastrointestinal transcriptome, chromatin landscape, and leads to relative castration resistance.

Background: Consistent evidence at high levels of water arsenic (>/=100 microg/l), and growing evidence at low-moderate levels (<100 microg/l), support a link with cardiovascular disease (CVD). The shape of the dose-response across low-moderate and high levels of arsenic in drinking water is uncertain and critical for risk assessment. Methods: We conducted a systematic review of general population epidemiological studies of arsenic and incident clinical CVD (all CVD, coronary heart disease (CHD) and stroke) with three or more exposure categories. In a dose-response meta-analysis, we estimated the pooled association between log-transformed water arsenic (log-linear) and restricted cubic splines of log-transformed water arsenic (non-linear) and the relative risk of each CVD endpoint. Results: Twelve studies (pooled N = 408 945) conducted at high ( N = 7) and low-moderate ( N = 5) levels of water arsenic met inclusion criteria, and 11 studies were included in the meta-analysis. Compared with 10 microg/l, the estimated pooled relative risks [95% confidence interval (CI)] for 20 microg/l water arsenic, based on a log-linear model, were 1.09 (1.03, 1.14) ( N = 2) for CVD incidence, 1.07 (1.01, 1.14) ( N = 6) for CVD mortality, 1.11 (1.05, 1.17) ( N = 4) for CHD incidence, 1.16 (1.07, 1.26) ( N = 6) for CHD mortality, 1.08 (0.99, 1.17) ( N = 2) for stroke incidence and 1.06 (0.93, 1.20) ( N = 6) for stroke mortality. We found no evidence of non-linearity, although these tests had low statistical power. Conclusions: Although limited by the small number of studies, this analysis supports quantitatively including CVD in inorganic arsenic risk assessment, and strengthens the evidence for an association between arsenic and CVD across low-moderate to high levels.

Background: Arsenic exposure has been associated with an increased risk of cardiovascular disease (CVD). Growing evidence suggests that B vitamins facilitate arsenic metabolism and may protect against arsenic toxicity. However, to our knowledge, few studies have evaluated this in US populations.Objective: Our objective was to examine whether higher B vitamin intake is associated with enhanced arsenic metabolism and lower concentrations of preclinical markers of CVD among New Hampshire adults.Methods: We used weighted quantile sum (WQS) regression to evaluate the collective impact of 6 dietary B vitamins (thiamin, riboflavin, folate, niacin, and vitamins B-6 and B-12) on 1) the proportion of arsenic metabolites in urine and 2) 6 CVD-related markers [including urinary 15-F2t-isoprostane (15-F2t-IsoP)] among 418 participants (26-75 y of age) from the New Hampshire Health Study. Contributions of arsenic metabolites to B vitamin-CVD marker associations were also explored in structural equation models.Results: In WQS models, the weighted sum of B vitamin intakes from food sources was inversely associated with the proportion of monomethyl arsenic species in urine (uMMA) (beta: -1.03; 95% CI: -1.91, -0.15; P = 0.02). Thiamin and vitamins B-6 and B-12 contributed the most to this association, whereas riboflavin had a negligible effect. Higher overall B vitamin intake was also inversely associated with 15-F2t-IsoP (beta: -0.21; 95% CI: -0.32, -0.11; P < 0.01), with equal contributions from the 6 B vitamins, which was partially explained by differences in the proportion of uMMA (indirect effect beta: -0.01; 95% CI: -0.04, -0.00).Conclusions: Among New Hampshire adults, higher intakes of certain B vitamins (particularly thiamin and vitamins B-6 and B-12 from food sources) may reduce the proportion of uMMA, an intermediate of arsenic metabolism that has been associated with an increased risk of CVD. Higher overall B vitamin intake may also reduce urinary 15-F2t-IsoP, a marker of oxidative stress and potential risk factor for CVD, in part by reducing the proportion of uMMA.

BACKGROUND: The present study assessed the association between periodontal pathogen colonization and the potential risk of developing precancerous lesions of gastric cancer (PLGC) in a clinical setting. METHODS: The present study included 35 newly diagnosed patients with PLGC and 70 age-matched individuals without PLGC. A full-mouth intra-oral examination was performed to assess the periodontal conditions. Stimulated whole saliva and pooled plaque samples were collected to evaluate colonization by Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia and Actinobacillus actinomycetemcomitans and to characterize the oral microbial diversity in the saliva and dental plaque. RESULTS: Compared with the control group, the patients with PLGC experienced a higher prevalence of bleeding on probing (BOP; 31.5% vs. 22.4%, P < 0.05), higher levels of T. denticola (P < 0.01) and A. actinomycetemcomitans (P <0.01), and less bacterial diversity in their saliva (P < 0.01). The final multivariate logistic regression model comprising all key socio-demographic characteristics, oral health behavioral factors and periodontal assessments revealed that elevated colonization with periodontal pathogens, specifically T. forsythia, T. denticola, and A. actinomycetemcomitans, decreased bacterial diversity in the dental plaque, and not flossing teeth regularly were significant predictors of an increased risk of PLGC (P = 0.022). CONCLUSION: The findings of the present study provide new evidence suggesting that periodontal pathogen burdens and bacterial diversity in the oral cavity are important factors contributing to a potential increased risk of developing precancerous gastric lesions.

BACKGROUND: In Bangladesh, CVD accounts for the majority of non-communicable mortality. The purpose of this study was to determine the role of socioeconomic status (SES) on subclinical atherosclerosis measured as carotid intima-media thickness (IMT) in a rural Bangladesh population. METHODS: Carotid IMT was measured between 2010 and 2011 in 1022 participants (average age 46, 40% male) randomly selected from the Health Effects of Arsenic Longitudinal Study (HEALS), a population-based prospective cohort study based in rural Bangladesh. SES was measured as occupation type, land ownership, educational attainment, and television ownership. RESULTS: Half of the participants received formal education (53%) and under half owned land (48%) and a television (44%). Women were primarily homemakers (95%) and men worked as factory workers (24%), laborers (18%), or in business (55%). In univariate analysis, those owning greater than one acre of land (p=0.03), owning a television (p=0.02), or laborers and business owners compared to factory workers had higher levels of carotid IMT (p<0.01). In multivariate analysis after adjustment for confounders, only men employed in the business sector had elevated carotid IMT compared to factory workers. The association was strongest in older men (58.7mum, 95% CI 17.2-100.0, >/=50years old) compared to younger men (13.7mum, 95% CI -7.8-35.2, <50years old). CONCLUSION: Business sector employment was positively associated with subclinical atherosclerosis after adjustment for confounders. This finding is consistent with evidence from other developing nations suggesting that certain SES factors are independent predictors of CVD.

Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individual-level data from studies participating in the United States National Cancer Institute Cohort Consortium. This paper describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations.

Background: Pregnancy alters metabolic and hormonal profiles influencing the risk of cardiovascular disease. Yet, studies of association between parity and carotid atherosclerosis reported conflicting results and were mainly from Western women with limited number of births. Methods: Using intima-media thickness (IMT) as a surrogate marker for atherosclerosis, we investigated the association between parity and IMT among 721 female participants (mean age 37.5 years at baseline) randomly selected from the Health Effect of Arsenic Longitudinal Study (HEALS), a population-based cohort study in Bangladesh. We used multivariate linear regression to assess the association and to control for potential confounders including age, smoking, betel use, BMI, education, SBP,

INTRODUCTION: Accumulating evidence indicates that arsenic (As), a potent environmental toxicant, may increase cardiovascular disease risk and adversely affect endothelial function at high levels of exposure. Pregnancy is a vulnerable time for both mother and child; however, studies examining the association between prenatal As exposure and plasma biomarkers of inflammation and endothelial function in mothers and newborns are lacking. METHODS: We examined maternal urinary As levels at gestational weeks 24-28 and levels of inflammatory biomarkers in plasma from 563 pregnant women and 500 infants' cord blood. We assessed a multiplexed panel of circulating inflammatory and endothelial function markers, including tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein 1 (MCP1), intercellular adhesion molecule (ICAM1) and vascular cell adhesion molecule (VCAM1). RESULTS: Compared with the bottom tertile, the highest tertile of maternal urinary As during pregnancy was associated with a 145.2ng/ml (95% CI 4.1, 286.3; p=0.04) increase in cord blood ICAM1 and 557.3ng/ml (95% CI -56.4, 1171.1; p=0.09) increase in cord blood VCAM1. Among mothers, the highest tertile of maternal urinary As during pregnancy was related to a 141.8ng/ml (95% CI 26.1, 257.5; p=0.02) increase maternal plasma VCAM1 levels. Urinary As was unrelated to MCP1 or TNFalpha in maternal plasma and cord blood. In structural equation models, the association between maternal urinary As and infant VCAM was mediated by maternal levels of VCAM (betamediation: 0.024, 95% CI: 0.002, 0.050). CONCLUSION: Our observations indicate that As exposure during pregnancy may affect markers of vascular health and endothelial function in both pregnant women and children, and suggest further investigation of the potential impacts on cardiovascular health in these susceptible populations.

RATIONALE: Estimating the probability of finding N2 or N3 (prN2/3) malignant nodal disease on endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with non-small cell lung cancer (NSCLC) can facilitate the selection of subsequent management strategies. OBJECTIVES: To develop a clinical prediction model for estimating the prN2/3. METHODS: We used the AQuIRE (American College of Chest Physicians Quality Improvement Registry, Evaluation, and Education) registry to identify patients with NSCLC with clinical radiographic stage T1-3, N0-3, M0 disease that had EBUS-TBNA for staging. The dependent variable was the presence of N2 or N3 disease (vs. N0 or N1) as assessed by EBUS-TBNA. Univariate followed by multivariable logistic regression analysis was used to develop a parsimonious clinical prediction model to estimate prN2/3. External validation was performed using data from three other hospitals. MEASUREMENTS AND MAIN RESULTS: The model derivation cohort (n = 633) had a 25% prevalence of malignant N2 or N3 disease. Younger age, central location, adenocarcinoma histology, and higher positron emission tomography-computed tomography N stage were associated with a higher prN2/3. Area under the receiver operating characteristic curve was 0.85 (95% confidence interval, 0.82-0.89), model fit was acceptable (Hosmer-Lemeshow, P = 0.62; Brier score, 0.125). We externally validated the model in 722 patients. Area under the receiver operating characteristic curve was 0.88 (95% confidence interval, 0.85-0.90). Calibration using the general calibration model method resulted in acceptable goodness of fit (Hosmer-Lemeshow test, P = 0.54; Brier score, 0.132). CONCLUSIONS: Our prediction rule can be used to estimate prN2/3 in patients with NSCLC. The model has the potential to facilitate clinical decision making in the staging of NSCLC.