Faculty Bibliography

PURPOSE: Taurine (2-aminoethanesulfonic acid), a molecule obtained from diet, is involved in bile acid conjugation, blood pressure regulation, anti-oxidation and anti-inflammation. We performed the first prospective study of taurine and CHD risk. METHODS: We conducted a case-control study nested in the New York University Women's Health Study to evaluate the association between circulating taurine levels and risk of coronary heart disease (CHD). Taurine was measured in two yearly pre-diagnostic serum samples of 223 CHD cases and 223 matched controls and averaged for a more reliable measurement of long-term taurine levels. RESULTS: Mean serum taurine was positively related to age and dietary intake of poultry, niacin, vitamin B1, fiber and iron, and negatively related to dietary intake of saturated fat (all p values 250 mg/dL) (adjusted OR = 0.39 (0.19-0.83) for the third versus first tertile; p for trend = 0.02) but not among those with low total serum cholesterol (p for interaction = 0.01). The data suggest a possible inverse association of serum taurine with diabetes and hypertension risk. CONCLUSIONS: The findings suggest that high levels of taurine may be protective against CHD among individuals with high serum cholesterol levels.

The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the beta4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of beta4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective beta4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant beta4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that beta4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the beta4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.

We examined whether colonization of selected oral pathogens is associated with gastric precancerous lesions in a cross-sectional study. A total of 119 participants were included, of which 37 were cases of chronic atrophic gastritis, intestinal metaplasia, or dysplasia. An oral examination was performed to measure periodontal indices. Plaque and saliva samples were tested with real-time quantitative PCR for DNA levels of pathogens related to periodontal disease (Porphyromonas gingivalis, Tannerella forsythensis, Treponema denticola, Actinobacillus actinomycetemcomitans) and dental caries (Streptococcus mutans and S. sobrinus). There were no consistent associations between DNA levels of selected bacterial species and gastric precancerous lesions, although an elevated but non-significant odds ratio (OR) for gastric precancerous lesions was observed in relation to increasing colonization of A. actinomycetemcomitans (OR = 1.36 for one standard deviation increase, 95% Confidence Interval = 0.87-2.12), P. gingivalis (OR = 1.12, 0.67-1.88) and T. denticola (OR = 1.34, 0.83-2.12) measured in plaque. To assess the influence of specific long-term infection, stratified analyses by levels of periodontal indices were conducted. A. actinomycetemcomitans was significantly associated with gastric precancerous lesions (OR = 2.51, 1.13-5.56) among those with >/= median of percent tooth sites with PD>/=3 mm, compared with no association among those below the median (OR = 0.86, 0.43-1.72). A significantly stronger relationship was observed between the cumulative bacterial burden score of periodontal disease-related pathogens and gastric precancerous lesions among those with higher versus lower levels of periodontal disease indices (p-values for interactions: 0.03-0.06). Among individuals with periodontal disease, high levels of colonization of periodontal pathogens are associated with an increased risk of gastric precancerous lesions.

BACKGROUND: Limited data are available on smoking-related mortality in low-income countries, where both chronic disease burden and prevalence of smoking are increasing. METHODS: Using data on 20,033 individuals in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, we prospectively evaluated the association between tobacco smoking and all-cause, cancer, and cardiovascular disease mortality during approximately 7.6 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for deaths from all-cause, cancer, CVD, ischemic heart disease (IHD), and stroke, in relation to status, duration, and intensity of cigarette/bidi and hookah smoking. RESULTS: Among men, cigarette/bidi smoking was positively associated with all-cause (HR 1.40, 95% CI 1.06 1.86) and cancer mortality (HR 2.91, 1.24 6.80), and there was a dose-response relationship between increasing intensity of cigarette/bidi consumption and increasing mortality. An elevated risk of death from ischemic heart disease (HR 1.87, 1.08 3.24) was associated with current cigarette/bidi smoking. Among women, the corresponding HRs were 1.65 (95% CI 1.16 2.36) for all-cause mortality and 2.69 (95% CI 1.20 6.01) for ischemic heart disease mortality. Similar associations were observed for hookah smoking. There was a trend towards reduced risk for the mortality outcomes with older age at onset of cigarette/bidi smoking and increasing years since quitting cigarette/bibi smoking among men. We estimated that cigarette/bidi smoking accounted for about 25.0% of deaths in men and 7.6% in women. CONCLUSIONS: Tobacco smoking was responsible for substantial proportion of premature deaths in the Bangladeshi population, especially among men. Stringent measures of tobacco control and cessation are needed to reduce tobacco-related deaths in Bangladesh.

Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.