April 2006

Legislators Visit NCTR

On February 13, Congressman Mike Ross (D-AR) hosted a meeting of the Arkansas delegation and key members of their staffs at NCTR with additional participation via video conferencing. The meeting was developed by the Alliance for Economic Development, an association for promoting business interests in Jefferson County and south Arkansas. The central topics for discussion were the broad range of research fields at NCTR and the role of translational research in the FDA regulatory process. The visitors also showed considerable interest in this federal laboratory’s interactions with, and impact on, local universities as well as its potential for attracting high technology businesses into the State of Arkansas.

Economic Development Leaders Visit NCTR

Economic development leaders for southeast Arkansas and the State of Arkansas toured NCTR facilities on January 31. The Arkansas economy has been built upon agriculture and manufacturing industries; these leaders are seeking to attract more technology-based business to diversify the economy. NCTR staff told them how industry was using emerging technologies to develop innovative and more effective health products and how NCTR was developing the same technologies to ensure more economical and effective means for agency scientists to evaluate the safety of these products. The Commander of the Pine Bluff Arsenal also extended a special invitation to visit its facilities. Besides the state-of-the-art chemical demilitarization facility, several other commercial interests have co-located to the Arsenal in support of the Department of Defense and Homeland Security. FDA’s Jefferson Laboratories and the neighboring Pine Bluff Arsenal are among the largest employers of southeast Arkansas.

FDA Translational Research-Building Bridges to Improve Public Health

Representatives of the Department of Pediatrics, University of Arkansas for Medical Sciences, and Arkansas Children’s Hospital met with NCTR scientists January 6 to discuss current and future translational research. This exchange, the second in a series of joint meetings, is part of NCTR’s translational research initiative to take research from the bench to the public health arena. The group toured NCTR facilities and discussed ongoing studies presented in 45 posters authored by participating scientists. Six posters focused on the response of humans and of an animal model to ketamine, a representative anesthetic agent that is undergoing extensive safety evaluation because of reported adverse effects on brain cells during early development. Several pharmacogenomic studies focused on human genetic polymorphisms of hepatic enzymes that determine individual response to drugs and other chemicals. Pharmacogenomic approaches to efficacy and toxicity are forming the framework and underpinnings for the practice of personalized medicine in the future. Several posters documented examples of the application of genomics, proteomics, and metabolomics to help solve human health problems.

Why Use Metabolomics?

Animals and humans show consistent metabolic changes in response to a toxic insult or as the result of disease at later stages. These changes are complex and ideal biomarkers (or early predictors) of potential response related to drug efficacy or toxicity have not been identified. Metabolomics provides a noninvasive method to identify metabolic patterns or biomarkers as early predictors of disease and toxicity.

Recent Publications

NCTR conducts research designed to protect the public’s health. Results from some of these research projects have recently been accepted for publication in nationally recognized scientific journals.

• Beger, R. and Schnackenberg, L., Metabolomic study of cisplatin-induced nephrotoxicity, Kidney International.
• Beger, R., Lehman-McKeeman, L.D. and Thomas, C.A., Standardization of reporting methods for metabolic analyses: a draft policy document from the Standard Metabolic Reporting Structures (SMRS) group, 2005, Nature Biotechnology.
• Beger, R., Computational models of biological activity using NMR spectra, Drug Discovery Today.
• Bowyer, J.F. and Schmued, L.C., Fluoro-ruby labeling prior to an amphetamine neurotoxic insult shows a definitive massive loss of dopaminergic terminals and axons in the caudate-putamen, Brain Research.
• Chen, H., Recent advances in azo dye degrading enzyme research, 2006, Current Protein & Peptide Science.
• Edmondson, R.D. and Jones, R.C., GINS maintains association of Cdc45 with MCM in replisome progression complexes at eukaryotic DNA replication forks, 2006, Nature Cell Biology.
• Elkins, C. and Mullis, L., Mammalian steroid hormones are substrates for the major RND- and MFS-type tripartite multiple drug efflux pumps of Escherichia coli, 2006, Journal of Bacteriology.
• Fang, H., Xie, Q., Perkins, R.G., and Tong, W., Gene expression profile exploration of a large dataset on chronic fatigue syndrome, Pharmacogenomics.
• Ferguson, S.A., Siitonen, P.H., Cisneros, F.J., Gough, B.J. and Young, J.F., Steady state pharmacokinetics of oral treatment with 13-cis-retinoic acid or all-trans-retinoic acid in male and female adult rats, Basic & Clinical Pharmacology & Toxicology.
• Guo, L., Differences in hepatotoxicity and gene expression profiles by anti-diabetic PPAR agonists on rat primary hepatocytes and human HepG2 cells, Molecular Diversity.
• Hsueh, H., Tsai, C. and Chen, J.J., Incorporating the number of true null hypotheses to improve power in multiple testing: Application to gene microarray data, Journal of Statistical Computation and Simulation.
• Jhoo, J., Freeman, J.P., Heinze, T.M., Deck, J.D., Schnackenberg, L., Beger, R., Dragull, K., Tang, C. and Ang, C.Y., In vitro cytotoxicity of non-polar constituents from different parts of kava plant (piper methysticum), 2006, Journal of Agricultural and Food Chemistry.
• Ju, Y.H., Fultz, J., Allred, K.F., Doerge, D.R. and Helferich, W.G., Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer (MCF-7) tumor implanted in ovariectomized athymic mice, 2006, Carcinogenesis.
• Kim, W., Ahn, H. and Moon, H., A dose-response trend test via closed-form solutions for constrained MLEs in survival/sacrifice experiments, 2006, Statistics in Medicine.
• Kodell, R.L., Replace the NOAEL and LOAEL with the BMDL01 and BMDL10, Environmental and Ecological Statistics.
• Moore, M. and Chen, T., Mutagenicity of bromate: Implications for cancer risk assessment, 2006, Toxicology.
• Parsons, B.L., Delongchamp, R.R., Beland, F.A. and Heflich, R.H., Levels of H-ras codon 61 CAA to AAA mutation: response to 4-ABP-treatment and Pms2-deficiency, DNA Repair.
• Schmitt, T.C., Biris, A.S. and Miller, D.W., Analysis of effluent gases during the CCVD growth of multi wall carbon nanotubes from acetylene, Carbon.
• Tsai, C., and Chen, J.J., Kernel estimation for adjusted p-values in multiple testing, Computational Statistics and Data Analysis.
• Tuo, J., Bojanowski, C., Ning, B., Shen, D., Chew, E., Kadlubar, F.F., Chan, C. and Lin, Z., Synergistic effects of a functional variation of ERCC-6 5'-flanking region and a complement factor H variation confers high risk to age-related macular degeneration, Proceedings of the National Academy of Sciences of the United States of America.
• Wang, C., Sadovova, N.V., Hotchkiss, C.E., Fu, X., Scallet, A.C., Patterson, T.A., Hanig, J.P., Paule, M.G. and Slikker, W., Blockade of N-methyl-D-aspartate (NMDA) receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture, Journal of Toxicological Sciences.
• Wilkes, J.G., Buzatu, D.A., Dragan, Y., Chiarelli, M.P., Holland, R.D., Beaudoin, M.A., Heinze, T.M., Nayak, R.R. and Shvartsburg, A., Improved cell typing by charge-state deconvolution of MALDI mass spectra, Rapid Communications in Mass Spectrometry.
• Xia, Q., Yin, J., Cherng, S., Wamer, W., Boudreau, M.D., Howard, P. and Fu, P.P., UVA photoirradiation of retinyl palmitate-formation of singlet oxygen and superoxide, and their role in induction of lipid peroxidation, Toxicology Letters.

On-Line Research Information

Regulatory Research Perspectives: Impact on Public Health, an on-line journal that provides a vehicle for FDA scientists to communicate important scientific information, and NCTR’s FY 2005-2006 Research Accomplishments and Plans are available from NCTR’s web site at http://www.fda.gov/nctr/science/science.htm.

Contact Information

The NCTR Quarter Page is published four times a year by the Office of Planning and Resource Management at the National Center for Toxicological Research. For more information about NCTR contact Dr. William Slikker, Acting NCTR Director, at William.Slikker@fda.hhs.gov or [870] 543-7517.