Faculty Bibliography

Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes, including premalignant and malignant skin tumors, total mortality, pregnancy outcomes, and children's cognitive development. In this paper, we provide descriptions of the study methods including study design, study population, data collection, response rates, and exposure and outcome assessments. We also present characteristics of the study participants including the distribution of exposure and the prevalence of skin lesion at baseline recruitment. A total of 11,746 married men and women between 18 and 75 years of age participated in the study at baseline (a response rate of 98%) and completed a full questionnaire interview that included a food frequency questionnaire, with a response rate of 98%. Among the 98% of the participants who completed the clinical evaluation, over 90% provided blood samples and spot urine samples. Higher educational status, male gender, and presence of premalignant skin lesions were associated with an increased likelihood of providing blood and urine samples. Older participants were less likely to donate a blood sample. About one-third of the participants consumed water from a well with As concentration in each of three groups: >100 mug/l, 25-100 mug/l, and <25 mug/l. Average urinary As concentrations were 140 and 136 mug/l for males and females, respectively. HEALS has several unique features, including a prospective study design, comprehensive assessments of both past and future changes in As exposure at the individual level, a large repository of biological samples, and a full dose range of As exposures in the study population. HEALS is a valuable resource for examining novel research questions on the health effects of As exposure.Journal of Exposure Analysis and Environmental Epidemiology advance online publication, 14 September 2005; doi:10.1038/sj.jea.7500449

We conducted a population-based prevalence survey in Araihazar, Bangladesh, to describe the distribution of arsenic exposure in a rural Bangladeshi population and to assess the population's awareness to this problem as well as to possible remediation options. Water samples from 5,967 contiguous tube wells in a defined geographic area were tested using laboratory-based methods. Additionally, for each well, the owner/caretaker (or a close relative) was interviewed regarding his or her awareness of the health consequences of As exposure. Arsenic exposure data and demographic characteristics for the 65,876 users of these wells were also collected from the 5,967 respondents. Among the 65,876 residents, more than half (54%) regularly consumed well water with an As concentration > or = 50 microg/L--above the acceptable government standard in Bangladesh. Respondents were 15-92 years of age, with an average age of 42 years, and 43% were male. Presence of awareness was significantly related to male sex, nonlabor head of household occupation, better housing, and having had the well tested for As concentration. Most respondents (92%) expressed a willingness to take steps to reduce their exposure, with switching to a safe well the most favored option (46.2%). Willingness to reduce exposure was positively related to awareness of the health risks of As. However, the association between awareness and switching to a safe well [odds ratio (OR) = 1.25; 95% confidence interval (CI), 1.01-1.54] was no stronger than the associations between awareness and using surface water (with or without treatments) (OR = 1.54; 95% CI, 1.22-1.95) or using an existing well after treatment or increasing the depth (OR = 1.34; 95% CI, 1.08-1.67). These findings suggest that health education programs may need to target individuals with lower socioeconomic status and that well switching should be encouraged with more appropriate health education. Increasing knowledge of the health consequences of As may be an important element in facilitating remediation

OBJECTIVE: We sought to determine whether supplementation of vitamin E (alpha-tocopherol), selenium (L-selenomethionine), or their combination improves arsenical skin lesions. METHODS: A 2 x 2 randomized, placebo-controlled, double-blind trial among 121 men and women chronically exposed to arsenic in drinking water was conducted in rural Bangladesh. Participants were randomized to one of four treatment arms: vitamin E, selenium, vitamin E and selenium (combination), or placebo and were treated for 6 months. RESULTS: At baseline, the average skin lesion scores were 2.23, 2.26, and 2.63 and at follow-up, the average skin lesion scores went down to 2.00, 2.06, and 2.47 in those receiving vitamin E, selenium, and the combination, respectively. CONCLUSIONS: Supplementation with vitamin E and selenium, either alone or in combination, slightly improved skin lesion status, although the improvement was not statistically significant

EphA4 signaling has recently been implicated in the regulation of synapse formation and plasticity. In this study, we show that ankyrin repeat-rich membrane spanning (ARMS; also known as a kinase D-interacting substrate of 220 kD), a substrate for ephrin and neurotrophin receptors, was expressed in developing muscle and was concentrated at the neuromuscular junction (NMJ). Using yeast two-hybrid screening, we identified a PDZ (PSD-95, Dlg, ZO-1) domain protein, alpha-syntrophin, as an ARMS-interacting protein in muscle. Overexpression of alpha-syntrophin induced ARMS clustering in a PDZ domain-dependent manner. Coexpression of ARMS enhanced EphA4 signaling, which was further augmented by the presence of alpha-syntrophin. Moreover, the ephrin-A1-induced tyrosine phosphorylation of EphA4 was reduced in C2C12 myotubes after the blockade of ARMS and alpha-syntrophin expression by RNA interference. Finally, alpha-syntrophin-null mice exhibited a disrupted localization of ARMS and EphA4 at the NMJ and a reduced expression of ARMS in muscle. Altogether, our findings suggest that ARMS may play an important role in regulating postsynaptic signal transduction through the syntrophin-mediated localization of receptor tyrosine kinases such as EphA4

BACKGROUND: Several case reports and series report an association between celiac disease and inflammatory bowel disease (IBD); however, there is no current data assessing this association. We therefore studied the occurrence of these conditions in a cohort of patients with celiac disease seen at a referral center. METHODS: A database of patients with celiac disease seen between 1981 and 2002 was analyzed. Only biopsy-proven adults were included. Patients who had endoscopic and pathologic evidence of IBD were identified, and their pathology was reviewed. Age- and sex-adjusted prevalence rate ratios were determined by comparing results with population-based prevalence data. RESULTS: Among 455 patients with celiac disease, IBD was identified in 10 (5 had ulcerative colitis and 5 had Crohn's disease). This represented an age- and sex-adjusted prevalence rate ratio for ulcerative colitis of 3.56 (95% confidence interval, 1.48-8.56) and for Crohn's disease of 8.49 (95% confidence interval, 3.53-20.42). CONCLUSION: Within our cohort of patients with celiac disease, IBD was significantly more common than in the general population

PURPOSE: TGFBR16A is a tumor susceptibility gene that increases breast, colon, and ovarian cancer risk. Fourteen percent of the general population carries TGFBR16A, and TGFBR16A homozygotes have a greater than 100% increased colon cancer risk compared with noncarriers. Low-penetrance genes such as TGFBR16A may account for a sizable proportion of familial colorectal cancer occurrences. To test this hypothesis, we determined whether TGFBR16A contributes to a proportion of mismatch repair (MMR) gene mutation-negative hereditary nonpolyposis colorectal cancer (HNPCC) patients. PATIENTS AND METHODS: A case-case study was performed of 208 index patients with HNPCC meeting the Amsterdam criteria. Patients were examined for mutations and genomic rearrangements in the MLH1, MSH2, and MSH6 genes and genotyped for TGFBR16A. Tumor microsatellite instability status was available for 95 patients. RESULTS: A total of 144 patients (69.2%) carried a deleterious mutation and were classified as positive for MMR gene mutation; 64 patients (30.8%) had no evidence of mutations and were classified as MMR negative. TGFBR16A allelic frequency was significantly higher among MMR-negative patients (0.195) than among MMR-positive patients (0.104; P = .011). The proportion of TGFBR16A homozygotes was nine-fold higher among MMR-negative (6.3%) than among MMR-positive patients (0.7%; P = .032). The highest TGFBR16A allelic frequency was found among MMR-negative patients with tumors exhibiting no microsatellite instability (0.211), and the lowest frequency was found among MMR-positive patients with tumors exhibiting microsatellite instability (0.121); the difference was not statistically significant (P = .17). CONCLUSION: TGFBR16A may be causally responsible for a proportion of HNPCC occurrences

Glutathione S-transferases (GSTs) are a family of isoenzymes that play an important role in protecting cells from cytotoxic and carcinogenic agents. GSTpi is encoded by the GSTP1 gene. GSTP1 null mice show an increased risk of skin tumorigenesis induced by carcinogens. GSTP1 is transcriptionally silenced by promoter hypermethylation in several human cancers including hepatocellular carcinoma (HCC). Methylation-specific PCR (MSP) was used to analyze the GSTP1 promoter hypermethylation status of 83 hepatocellular carcinoma tissues from Taiwan. Hypermethylation was detected in 38 of 83 (46%) tumors. GSTP1 expression by immunohistochemical staining of HCC tissue samples was significantly associated with methylation status. The relationship between methylation status and clinical parameters and tumor markers including environmental exposure to aflatoxin B1(AFB1) and polycyclic aromatic hydrocarbons (PAH), measured as DNA adducts, was also investigated. A statistically significant association was found between GSTP1 promoter hypermethylation and the level of AFB1-DNA adducts in tumor tissue (OR 2.81, 95% CI 1.03-7.70); a marginally significant association was found for adjacent non-tumor tissue (OR 2.57, 95% CI 0.97-6.80). There was no association between GSTP1 hypermethylation and PAH-DNA adducts in tumor or adjacent non-tumor tissues. These results suggest that epigenetic inactivation of GSTP1 plays an important role in the development of HCC and exposure to environmental carcinogens may be related to altered methylation of genes involved in hepatocarcinogenesis. The mechanism by which environmental exposures induce epigenetic changes in HCC needs further analysis

There is growing evidence that common variants of the transforming growth factor-beta (TGF-beta) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-beta signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-beta circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-beta signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-beta signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population

Secreted TGFbeta proteins of the Nodal family pattern the vertebrate body axes and induce mesoderm and endoderm . Nodal proteins can act as morphogens , but the mechanisms regulating their activity and signaling range are poorly understood. In particular, it has been unclear how inefficient processing or rapid turnover of the Nodal protein influences autocrine and paracrine signaling properties . Here, we evaluate the role of Nodal processing and stability in tissue culture and zebrafish embryos. Removal of the pro domain potentiates autocrine signaling but reduces Nodal stability and signaling range. Insertion of an N-glycosylation site present in several related TGFbeta proteins increases the stability of mature Nodal. The stabilized form of Nodal acts at a longer range than the wild-type form. These results suggest that increased proteolytic maturation of Nodal potentiates autocrine signaling, whereas increased Nodal stability extends paracrine signaling