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Cambridge, MA, United States

Radloff K.A.,Columbia University | Radloff K.A.,Lamont Doherty Earth Observatory | Radloff K.A.,Gradient Corporation | Zheng Y.,Lamont Doherty Earth Observatory | And 14 more authors.
Nature Geoscience | Year: 2011

The consumption of shallow groundwater with elevated concentrations of arsenic is causing widespread disease in many parts of South and Southeast Asia. In the Bengal Basin, a growing reliance on groundwater sourced below 150-m depth - where arsenic concentrations tend to be lower - has reduced exposure. Groundwater flow simulations have suggested that these deep waters are at risk of contamination due to replenishment with high-arsenic groundwater from above, even when deep water pumping is restricted to domestic use. However, these simulations have neglected the influence of sediment adsorption on arsenic migration. Here, we inject arsenic-bearing groundwater into a deep aquifer zone in Bangladesh, and monitor the reduction in arsenic levels over time following stepwise withdrawal of the water. Arsenic concentrations in the injected water declined by 70% after 24 h in the deep aquifer zone, owing to adsorption on sediments; concentrations of a co-injected inert tracer remain unchanged. We incorporate the experimentally determined adsorption properties of sands in the deep aquifer zone into a groundwater flow and transport model covering the Bengal Basin. Simulations using present and future scenarios of water-use suggest that arsenic adsorption significantly retards transport, thereby extending the area over which deep groundwater can be used with low risk of arsenic contamination. Risks are considerably lower when deep water is pumped for domestic use alone. Some areas remain vulnerable to arsenic intrusion, however, and we suggest that these be prioritized for monitoring. © 2011 Macmillan Publishers Limited. All rights reserved. Source

Zanetti K.A.,U.S. National Cancer Institute | Zanetti K.A.,Epidemiology and Genomics Research Program | Haznadar M.,U.S. National Cancer Institute | Welsh J.A.,U.S. National Cancer Institute | And 10 more authors.
Cancer Research | Year: 2012

Because chronic intestinal inflammation is a risk factor for colorectal cancer, we hypothesized that genetic variants of inflammatory mediators, such as mannose-binding lectin 2 (MBL2), are associated with colon cancer susceptibility. Here, we report the association of 24 MBL2 single-nucleotide polymorphisms (SNP) and corresponding haplotypes with colon cancer risk in a case-control study. Four SNPs in the 3′-untranslated region (UTR) of the gene (rs10082466, rs2120132, rs2099902, and rs10450310) were associated with an increased risk of colon cancer in African Americans. ORs for homozygous variants versus wild-type ranged from 3.17 [95% confidence interval (CI), 1.57-6.40] to 4.51 (95% CI, 1.94-10.50), whereas the 3′-UTR region haplotype consisting of these four variants had an OR of 2.10 (95% CI, 1.42-3.12). The C allele of rs10082466 exhibited a binding affinity of miR-27a and this allele was associated with both lower MBL plasma levels and activity. We found that 50 secretor haplotypes known to correlate with moderate and low MBL serum levels exhibited associations with increased risk of colon cancer in African Americans, specifically as driven by two haplotypes, LYPA and LYQC, relative to the referent HYPA haplotype (LYPA: OR, 2.60; 95% CI, 1.33-5.08 and LYQC: OR, 2.28; 95% CI, 1.20-4.30). Similar associations were not observed in Caucasians. Together, our results support the hypothesis that genetic variations in MBL2 increase colon cancer susceptibility in African Americans. ©2012 AACR. Source

Chang C.M.,U.S. National Institutes of Health | Chia V.M.,U.S. National Institutes of Health | Gunter M.J.,Imperial College London | Zanetti K.A.,Epidemiology and Genomics Research Program | And 11 more authors.
Carcinogenesis | Year: 2013

Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (ORper T allele = 0.68, 95% CI: 0.57-0.83, P = 7.7 × 10-5, adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (ORper T allele = 0.41, 95% CI: 0.30-0.55, P = 2.4 × 10-9) than for adenoma (ORper T allele = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (ORper T allele = 0.5, 95% CI: 0.37-0.69 and ORper T allele = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammationrelated genes may be related to the risk of colorectal neoplasia. © The Author 2013. Published by Oxford University Press. All rights reserved. Source

Meek M.E.,University of Ottawa | Levy L.S.,Cranfield University | Beck B.D.,Gradient Corporation | Danzeisen R.,International Copper Association | And 3 more authors.
Journal of Toxicology and Environmental Health - Part A: Current Issues | Year: 2010

This article addresses the content of the workshop, including a panel discussion relevant to delineation of a path forward in relation to risk assessment of essential metals. The state of the art of risk assessment and associated issues for essential metals are outlined initially, followed by brief illustration by the case studies considered at the workshop (i.e., copper, zinc, and manganese). Approaches for the future testing strategies of essential metals are discussed in terms of options to increase efficiency and accuracy of assessments. Subsequently, recommendations for pragmatic next steps to advance progress and facilitate uptake by the regulatory risk assessment community are presented. Source

Glynn S.A.,U.S. National Cancer Institute | Glynn S.A.,U.S. National Institutes of Health | Prueitt R.L.,U.S. National Cancer Institute | Ridnour L.A.,U.S. National Institutes of Health | And 7 more authors.
BMC Cancer | Year: 2010

Background: Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation.Methods: Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival.Results: COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196.Conclusions: Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype. © 2010 Glynn et al; licensee BioMed Central Ltd. Source

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