7 results on '"Eaton, David L."'
Search Results
2. Innovations in preclinical biology: ex vivo engineering of a human kidney tissue microperfusion system.
- Author
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Kelly, Edward J., Zhican Wang, Voellinger, Jenna L., Yeung, Cathy K., Shen, Danny D., Thummel, Kenneth E., Ying Zheng, Ligresti, Giovanni, Eaton, David L., Muczynski, Kimberly A., Duffield, Jeremy S., Neumann, Thomas, Tourovskaia, Anna, Fauver, Mark, Kramer, Greg, Asp, Elizabeth, and Himmelfarb, Jonathan
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KIDNEY diseases ,PUBLIC health ,MEDICAL innovations ,HEALTH of adults ,DRUG efficacy ,DRUG side effects - Abstract
Kidney disease is a public health problem that affects more than 20 million people in the US adult population, yet little is understood about the impact of kidney disease on drug disposition. Consequently there is a critical need to be able to model the human kidney and other organ systems, to improve our understanding of drug efficacy, safety, and toxicity, especially during drug development. The kidneys in general, and the proximal tubule specifically, play a central role in the elimination of xenobiotics. With recent advances in molecular investigation, considerable information has been gathered regarding the substrate profiles of the individual transporters expressed in the proximal tubule. However, we have little knowledge of how these transporters coupled with intracellular enzymes and influenced by metabolic pathways form an efficient secretory and reabsorptive mechanism in the renal tubule. Proximal tubular secretion and reabsorption of xenobiotics is critically dependent on interactions with peritubular capillaries and the interstitium. We plan to robustly model the human kidney tubule interstitium, utilizing an ex vivo three-dimensional modular microphysiological system with human kidney-derived cells. The microphysiological system should accurately reflect human physiology, be usable to predict renal handling of xenobiotics, and should assess mechanisms of kidney injury, and the biological response to injury, from endogenous and exogenous intoxicants. [ABSTRACT FROM AUTHOR]
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- 2013
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3. Characterization of Atrazine Biotransformation by Human and Murine Glutathione S-Transferases.
- Author
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Abel, Erika L., Opp, Shaun M., Verlinde, Christophe L. M. J., Bammler, Theo K., and Eaton, David L.
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ATRAZINE ,HERBICIDE research ,BIOTRANSFORMATION (Metabolism) ,BIOCHEMICAL substrates - Abstract
Atrazine is one of the most widely used herbicides in the United States and has been detected, occasionally, at low levels in drinking water sources. The biotransformation of atrazine in humans has not been fully characterized. Rodent studies suggest Phase I-dominated biotransformation with minor Phase II-mediated biotransformation by glutathione S-transferase(s) (GST). In human urine, mercapturates of atrazine are significant metabolites, yet the specific GST form(s) responsible for glutathione (GSH) conjugation have not been identified. Using recombinant alpha, mu, pi and theta class human GSTs, we demonstrated that only hGSTP1-1 displays significant activity toward atrazine (7.1 nmol/min/mg protein). We also confirmed that mouse GST Pi (π) protein is responsible for the GSH-dependent biotransformation of atrazine in mouse liver; recombinant mGSTP1-1 had a specific activity of 7.3-nmol/min/mg protein. Furthermore, cytosolic fractions from mouse and human liver conjugated atrazine with glutathione at rates of 282.3 and 3.0 pmol/min/mg, respectively. Docking studies of the atrazine-GST conjugate in the hGSTP1-1 substrate-binding site were used to elucidate a basis for the dramatic difference in activity between mouse GSTP1-1 and GSTP2-2 (7.14 versus 0.02 nmol/min/mg protein, respectively). The inactivity of mGSTP2-2 appears to be attributable to an indirect structural disruption of the G-site by Pro12. Possible effects of the hGSTP1 polymorphisms were investigated. No significant differences in catalytic-specific activity were noted among purified proteins corresponding to the four hGSTP1 variants: hGSTP1*A (most common form), hGSTP1*B (Ile105Val), hGSTP1*C (Ile105Val, Ala114Val), and hGSTP1*D (Ala114Val). Overall, this work supports a physiological role for GSTs in atrazine biotransformation and indicates a novel diagnostic substrate for human and mouse GSTP1-1 proteins. [ABSTRACT FROM AUTHOR]
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- 2004
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4. Meeting THE MERCURY Target.
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Tyson, David R., Farnsworth, Richard, Eaton, David L., and Paris, Henry G.
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MONOMOLECULAR films ,MERCURY ,WASTE management ,CHEMICAL processes ,ENVIRONMENTAL protection ,ENVIRONMENTAL engineering ,INDUSTRIAL research - Abstract
The article discusses the use of self-assembled monolayers on mesoporous supports (SAAMS) for treatment of liquid highly radioactive mercury wastes in the U.S. It examines the findings of a study on the residual liquid wastes which achieved success in reducing mercury below the EPA TCLP limit of 0.20 mg/l. It highlights the approval of a variance for the stabilization of the high levels of mercury using SAMMS absorbent. The use of mercury in many chemical processes and the challenges for remediation presented by legacy wastes are discoursed.
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- 2008
5. The NIEHS Superfund Research Program: 25 Years of Translational Research for Public Health.
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Landrigan PJ, Wright RO, Cordero JF, Eaton DL, Goldstein BD, Hennig B, Maier RM, Ozonoff DM, Smith MT, and Tukey RH
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- History, 20th Century, History, 21st Century, Humans, Translational Research, Biomedical, United States, Environmental Health history, Hazardous Waste analysis, Hazardous Waste Sites history, National Institute of Environmental Health Sciences (U.S.) history, Public Health history
- Abstract
Background: The Superfund Research Program (SRP) is an academically based, multidisciplinary, translational research program that for 25 years has sought scientific solutions to health and environmental problems associated with hazardous waste sites. SRP is coordinated by the National Institute of Environmental Health Sciences (NIEHS). It supports multi-project grants, undergraduate and postdoctoral training programs, individual research grants, and Small Business Innovation Research (SBIR) and Technology Transfer Research (STTR) grants., Results: SRP has had many successes: discovery of arsenic's toxicity to the developing human central nervous system; documentation of benzene toxicity to hematologic progenitor cells in human bone marrow; development of novel analytic techniques such as the luciferase expression assay and laser fragmentation fluorescence spectroscopy; demonstration that PCBs can cause developmental neurotoxicity at low levels and alter the genomic characteristics of sentinel animals; elucidation of the neurodevelopmental toxicity of organophosphate insecticides; documentation of links between antimicrobial agents and alterations in hormone response; discovery of biological mechanisms through which environmental chemicals may contribute to obesity, atherosclerosis, diabetes, and cancer; tracking the health and environmental effects of the attacks on the World Trade Center and Hurricane Katrina; and development of novel biological and engineering techniques to facilitate more efficient and lower-cost remediation of hazardous waste sites., Conclusion: SRP must continue to address the legacy of hazardous waste in the United States, respond to new issues caused by rapid advances in technology, and train the next generation of leaders in environmental health science while recognizing that most of the world's worst toxic hot spots are now located in low- and middle-income countries.
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- 2015
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6. FutureTox II: in vitro data and in silico models for predictive toxicology.
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Knudsen TB, Keller DA, Sander M, Carney EW, Doerrer NG, Eaton DL, Fitzpatrick SC, Hastings KL, Mendrick DL, Tice RR, Watkins PB, and Whelan M
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- Congresses as Topic, Predictive Value of Tests, Societies, Scientific, United States, Computer Simulation, In Vitro Techniques, Toxicology methods, Toxicology trends
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FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
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- 2015
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7. Genetic Susceptibility to Prostate Cancer: Prostate-specific Antigen and its Interaction with the Androgen Receptor (United States).
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Sieh W, Edwards KL, Fitzpatrick AL, Srinouanprachanh SL, Farin FM, Monks SA, Kronmal RA, and Eaton DL
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- Aged, Case-Control Studies, Cohort Studies, Genotype, Haplotypes, Humans, Male, Polymorphism, Genetic, Prostate-Specific Antigen blood, United States, Biomarkers, Tumor genetics, Genetic Predisposition to Disease genetics, Prostate-Specific Antigen genetics, Prostatic Neoplasms genetics, Receptors, Androgen genetics
- Abstract
Objective: To determine whether directly observed prostate-specific antigen (PSA) promoter diploid haplotype, either alone or in conjunction with androgen receptor (AR) genotype, is associated with prostate cancer risk., Methods: We conducted a case-control study nested within the US population-based Cardiovascular Health Study cohort. Incident prostate cancers were identified by linkage to cancer registry records for the years 1989-2000. We genotyped 193 cases and 391 controls for the PSA -252 G/A and -158 G/A SNPs and the AR CAG microsatellite, and developed methods to directly determine proximal PSA promoter haplotypes. Exact logistic regression was used to estimate odds ratios and significance levels., Results: No significant associations were observed between PSA diplotype and prostate cancer overall. Short (< 20) AR CAG repeat lengths were associated with modest increases in the risk of prostate cancer (OR, 1.46; 95% CI, 0.97-2.19; p = 0.071) that were significant for advanced disease (OR, 1.82; 95% CI, 1.02-3.26; p = 0.044). Men who possessed two copies of the PSA*2 (-252G/-158G) haplotype and short AR CAG repeat lengths had a 4-fold (95% CI, 1.05-20.75; exact p = 0.040) increased risk of prostate cancer, and a 7-fold (95% CI, 1.25-39.78; exact p = 0.026) increased risk of advanced disease., Conclusions: We found evidence that the PSA*2*2 diplotype in combination with short AR CAG alleles increases a man's risk of developing prostate cancer. These findings support an etiologic role in prostate cancer of genetic interactions between polymorphisms that increase AR transactivation strength and those that alter the regulatory regions of target genes such as PSA that are responsive to androgen stimulation.
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- 2006
- Full Text
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