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January-March 2010 Research Highlights
Personalized Medicine—Method Developed To Identify Gene Sets Controlling Phenotypes
National Center for Toxicological Research mathematical statisticians have developed a new multivariate analysis of variance (MANOVA) method to identify gene sets that are characteristic of healthy-cell and disease-cell phenotypes. Because phenotype expression is the result of complex interactions between multiple gene and environmental factors, gene sets were analyzed. Individual genes or environmental factors contributing to a phenotype are often not recognized. You also must deal with the commonly encountered statistical problem of these large data sets where the numbers of related genes are often higher than the number of samples that can be analyzed on a practical basis. The new set of algorithms in this MANOVA addresses these issues and will aid in determining risk factors for toxicology and disease. (Bioinformatics 25: 897-903, 2009)
For additional information, please contact Dr. James Chen, Division of Personalized Nutrition and Medicine, FDA/NCTR.
Nanotechnology and Healthcare
National Center for Toxicological Research (NCTR) scientists participated in an invitation-only conference, “Nanotechnology and Healthcare,” held at the Winthrop Rockefeller Institute, January 6-9, 2010. Eleven plenary speakers from universities, national laboratories, industries, and funding agencies from across the nation initiated discussions by sharing their perspectives on research needs and opportunities for the applications of nanotechnology (nanoscale-technology) to improve healthcare.
The conferees were selected to increase opportunity for the development of interdisciplinary teams that would accelerate exploration and development of nanotechnology applications in the healthcare sciences. Participants included biologists, chemists, physicists, engineers, toxicologists, materials scientists, and clinical-care provider/investigators. Each investigator provided a poster of their research interests in nanotechnology as the foundation for further discussions and collaboration.
For additional information, please contact Dr. Paul C. Howard, Associate Director for Scientific Coordination, FDA/NCTR.
Cosmetic Safety—Azo Dyes
National Center for Toxicological Research (NCTR) microbiologists have demonstrated that normal human-skin bacteria can readily convert azo dyes, some of which are used in women's cosmetics, to metabolites that are more readily absorbed through the skin and have the potential to be DNA-damaging (genotoxic) chemicals. It is likely that multiple bacterial enzymes (specifically azo reductases) can metabolize azo dyes to these compounds, and research is continuing to characterize the range of dyes metabolized by these enzymes. These combined investigations provide data to assist FDA on analysis of the safety and toxicity of the azo dyes used in women's cosmetic products. These initial studies have been funded by the Office of Women's Health (Journal of Medical Microbiology, 2010 Vol. 59:108-114).
For additional information, please contact Dr. Huizhong Chen or Dr. Carl E. Cerniglia, FDA/NCTR.
Nutrition Phenotype Database Workshop
On January 20-21, 2010, the National Center for Toxicological Research (NCTR) hosted a planning workshop, co-organized by the European Nutrigenomics Organization (NuGo). Forty scientists from U.S. government agencies including the Food and Drug Administration, U.S. Department of Agriculture, Centers for Disease Control, and National Institutes for Health attended the workshop to outline principles for creation and implementation of a publicly available Nutrition Phenotype Database (dbNP). The database will provide uniform formats for data capture, storage, annotation, and retrieval of data from emerging nutrition research in the omics sciences (i.e., genomics, transcriptomics, proteomics, metabolomics, biomarkers, functional assays) and from traditional food composition and frequency questionnaires.
The dbNP will be a global gateway platform for scientists to integrate and analyze data gathered from nutrition conducted around the world, increasing the power of scientists to evaluate the role of nutrition in health and disease.
Presenters at the two-day workshop, including American and European scientists from government agencies, academia, and small and medium enterprises, provided a survey of the existing resources and needs of their agencies and institutions that may form the components of this international database effort. The next general meeting of the group is planned for the fall of 2010.
For additional information, please contact Dr. Jim Kaput, Director, Division of Personalized Nutrition and Medicine, FDA/NCTR.
Personalized Medicine—Cancer Therapy
Scientists from the National Center for Toxicological Research (NCTR), the Ukraine, and Canada have collaborated to demonstrate that the levels of the iron storage protein, ferritin, are substantially elevated in aggressive breast-cancer cells (mesenchymal phenotype) compared to the levels in less aggressive breast-cancer cells (epithelial phenotype). Furthermore, decreasing ferritin levels in the aggressive cell type using microRNAs made the cells more sensitive to the chemotherapeutic agent, doxorubicin. Several reports have shown that ferritin may be a potential target in cancer and that reducing ferritin may substantially increase the efficiency of cancer therapy.
The results of this study demonstrating the increased doxorubicin sensitivity increases in cells as ferritin levels decrease and highlights the potential benefits of targeting ferritin in breast-cancer therapy.
For additional information, please contact Dr. Fred Beland, Director, Division of Biochemical Toxicology, FDA/NCTR.
Collaborative studies by the Food and Drug Administration's National Center for Toxicological Research and Center for Drug Evaluation and Research, and the National Cancer Institute's Nanotechnology Characterization Laboratory suggest that formulation of sunscreens with nano- and submicron-titanium dioxide does not result in internal exposures to the nano- and submicron-particles. Analysis of organs and skin from mini-pigs that were treated 4-times daily for one month with typical sunscreen formulations showed no evidence of titanium dioxide in any internal organ; only insignificant levels (0.000006-0.002% of the applied dose) were detected in the dermis (inner skin) depending on the particle type. Pig skin is regarded as the best structural mimic for human skin.
Read the full study results in the publication titled: "Lack of Significant Dermal Penetration of Titanium Dioxide (TiDO2) from Sunscreen Formulations Containing Nano- and Sub-Micron Size TiO2 Particles."
For additional information, please contact Paul Howard, Ph.D., Associate Director, Office of Scientific Coordination, FDA/NCTR or Nakissa Sadrieh, Ph.D., Associate Director for Research Policy Implementation, Office of Pharmaceutical Science, FDA/CDER.
Personalized Medicine—American Association for the Advancement of Science (AAAS) Meeting
Dr. Donna Mendrick, Director of the Division of Systems Toxicology at the National Center for Toxicological Research, chaired and co-organized a seminar titled “The Road to Personalized Medicine” for the 2010 Annual Meeting of AAAS on February 19, 2010. The Society of Toxicology (SOT) Science Program Committee had requested this seminar to continue discussions held at the 2009 SOT annual meeting. The Presentation topics included:
- Translating biomarkers from animals to humans (translational medicine)
- Using genetically defined mice to identify idiosyncratic drug reactions
- Using human genetic information to predict and prevent drug toxicity
Environment, Safety, and Health (ESH) Training Provided to NCTR Staff
The National Center for Toxicological Research Office of Regulatory Compliance and Risk Management (RCRM) provided ESH training to over 300 employees between November 2009 and February 2010. The course offerings have focused on office and lab safety and also included hazardous waste management, respiratory protection, CPR and First Aid, campus security, blood-borne pathogen protection, and emergency response procedures. The courses are presented as an ongoing training program by RCRM staff members in response to regulatory requirements. This training is provided as a method to improve the health, safety, and security of our employees and as a means of reducing the risk of significant adverse impact on our environment.
Personalized Nutrition and Medicine—Community-Based Participatory Research
Scientists from the Division of Personalized Nutrition and Medicine represented the National Center for Toxicological Research (NCTR) at the Arkansas Society of Public Health Information on March 2, 2010. They presented interim results from NCTR's collaboration with the USDA's Agricultural Research Service (ARS) Delta Obesity Prevention Research Program. FDA/NCTR and USDA/ARS have partnered with a Community Development Center in the Mississippi Delta region of Arkansas to conduct community-based participatory research that studies the effects of dietary intake and its influence on the development of obesity-associated diseases.
This ongoing collaboration analyzes dietary intake patterns and micronutrients levels in the blood samples of children and adults. The research also involves mapping genetic ancestry that may alter micronutrient requirements and their metabolism. The research strategy links genes involved in micronutrient metabolism, or regulation, to chromosomal loci involved in obesity and associated diseases (e.g., type 2 diabetes).
For additional information, please contact Anna Williams, Division of Microbiology, FDA/NCTR, or Jim Kaput, Ph.D., Director, Division of Biometry and Risk Assessment, FDA/NCTR.
Food Safety—Antibiotic Resistance in Farm-Raised Catfish
Using molecular techniques, scientists from the National Center for Toxicological Research (NCTR) and the Arkansas Regional Laboratory have characterized virulence genes in 81 strains of Aeromonas veronii isolated from farm-raised catfish. Several of the isolates contained gene sequences (integrons) that confer resistance to multiple antibiotics. Aeromonas spp. are known to cause foodborne illness, and these studies illustrate that farm-raised catfish can serve as reservoirs for multiple virulence and antibiotic resistance genes. Although adequate cooking should eliminate pathogenic bacteria, undercooking, or cross-contamination of utensils during the preparation of catfish, is a concern for spread of sickness and a possible spread of antibiotic resistance. (Food Microbiology, 2010).
For additional information, please contact Mohamed Nawaz, Ph.D., FDA/NCTR or Carl E. Cerniglia, Ph.D., Division of Microbiology, Director, FDA/NCTR.
Bioimaging of Neurotoxicity
Scientists from the National Center for Toxicological Research (NCTR), the University of Tennessee, and industry have jointly evaluated a new tracer reagent (18F-dansylhydrazone fluorobenzaldehyde) to monitor apoptosis (cell death) in the brains of rats using microPET (Positron Emission Tomography) technology. The reagent crosses the blood-brain barrier more readily than previous tracers and marks neurons undergoing cell death. Apoptosis occurs naturally, however, an increased rate of apoptosis can be an indicator of neurotoxicity. The identification of reagents for noninvasive imaging of cellular processes in the brains of living animals can shed light on the dynamic changes that occur in the central-nervous system during drug- or disease-induced brain injury.
International Anesthesia Research Society (IARS) 2010 Annual Meeting
NCTR Director, William Slikker, Jr., Ph.D., was a featured speaker at the IARS and the Safety of Key Inhaled and Intravenous Drugs in Pediatrics (SAFEKIDS) International Science Symposium held March 20, 2010. Dr. Slikker's presentation was titled, “Translational Models and Biomarkers To Assess Pediatric Anesthetics.” Learn more about the SAFEKIDS Initiative.
NCTR Zebrafish Facility Is Operational
NCTR has established a zebrafish facility to provide adult fish and/or embryos for high-throughput toxicity assessments. The zebrafish is a vertebrate and shares many developmental and genetic similarities with humans and is widely used in developmental and genetic research. Zebrafish-based assays are increasingly utilized by industry to screen for drug/toxicant effects.
For additional information, please contact William Slikker, Jr., Ph.D., Director, FDA/NCTR or Merle Paule, Ph.D., Division of Neurotoxicology, Director, FDA/NCTR.