International Scientist Exchange Program 2011
NCTR received 29 applications from regulatory research scientists representing 12 different countries for its International Scientist Exchange Program (ISEP). The ISEP program is funded by the Office of International Programs in support of the Agency’s regulatory capacity strengthening efforts and provides an opportunity for researchers from developing countries to conduct regulatory research projects at NCTR for up to six months. The research training experience is focused on learning concepts, skills, and techniques that are critical for scientists to build a regulatory infrastructure needed to be successful in the global context.
For additional information, please contact Margaret Miller, Ph.D., Associate Director for Regulatory Activities, FDA/NCTR.
Joint NCTR and CBER Workshop
Representatives from the Office of Biostatistics and Epidemiology (OBE) in the Center for Biologics Evaluation and Research (CBER), including the Director, Deputy Director, and Associate Director for Research, visited NCTR on January 19-20, 2011, to discuss NCTR’s ongoing research in systems biology and omics approaches, biomarker discovery, modeling, and bioinformatics technologies in relation to the regulatory demands of CBER. The discussions were focused on the intricacies of the scientific and regulatory issues in connection with biologics safety and the capabilities of NCTR bioinformatics to address these details.
Robert Sills, Ph.D., Chief, Cellular and Molecular Pathology Branch, National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), visited NCTR on January 19, 2011, to present an overview of pathology and molecular pathology at the NTP and NIEHS, learn about the breadth of regulatory science at NCTR, and discuss areas of collaboration between NCTR and NTP/NIEHS. Dr. Sills also outlined the integration of biomarkers, molecular biology, and imaging in the future development of pathology endpoints in order to understand the mechanism of action of carcinogenesis and non-neoplastic disease.
Martin Philbert, Ph.D., Dean, School of Public Health, University of Michigan, visited NCTR on January 20, 2011, to discuss the use of nanotechnology to explore mechanisms of toxicity, potential collaborations between NCTR and the University of Michigan, and the organization and implementation of the Nanotechnology Core Facility.
NTP Technical Report Review Meeting
The National Toxicology Program (NTP) held a public meeting on January 26, 2011, on the National Institute of Environmental Health Sciences (NIEHS) campus. NTP Technical Reports were reviewed by a panel of 11 peer-review scientists, who advised NTP on the conduct and conclusions of the studies. The conclusions were that the animal studies indicated:
- Kava kava (dietary supplement) extracts were carcinogenic in male and female mice, but not carcinogenic in rats following gavage administration
- Retinyl palmitate (in cosmetics and sunscreens), topically applied to hairless mice, had an enhancing effect above the control-vehicle effect on the photocarcinogenesis of simulated solar light
- Methyl trans-styryl ketone (in cosmetics) was not carcinogenic in mice or rats following dermal application
- Styrene-acrylonitrile trimer (in plastics) had no evidence of carcinogenesis in male and female rats following dietary exposure
- Alpha/beta thujone (terpene found in herbs and other plants) administration by gavage resulted in some evidence of carcinogenic activity only in male rats
Additionally, studies on Retinyl Palmitate that were conducted at FDA/NCTR were presented by an NCTR investigator. These studies are part of the interagency agreement between the FDA and the NIEHS/NTP that support the FDA risk-assessment process.
For additional information, please contact Paul Howard, Ph.D., Associate Director, Office of Scientific Coordination and FDA Liaison to NTP, FDA/NCTR.
Long-Lasting Effects of Pediatric Use of Ketamine Anesthesia
NCTR investigators have demonstrated that a single 24-hour exposure to ketamine anesthesia during a sensitive period of brain development results in long-lasting deficits in brain function in nonhuman primates and provides proof-of-concept that general anesthesia administered to pediatric patients during critical periods of brain development could result in subsequent functional deficits. Nonhuman primates were exposed to ketamine for 24 hours on day 5 or 6 after birth and were tested for aspects of learning, motivation, color discrimination, and short-term memory using the NCTR Operant Test Battery (OTB) beginning at 7 months of age. At 10 months of age, the ketamine-exposed animals were significantly outperformed by the control animals. These treated animals, exposed to a single 24-hour exposure to anesthesia, continue to manifest cognitive impairments at over 3.5 years of age. These studies were supported by the National Institute of Child Health and Human Development (NICHD), the Center for Drug Evaluation and Research (CDER), and NCTR. A manuscript describing the results of this study has recently been accepted for publication in the journal Neurotoxicology and Teratology.
Tobacco Products Workshop
Scientists from the Center for Tobacco Products (CTP) and the Center for Disease Control and Prevention (CDC) visited NCTR on February 8-9, 2011, to discuss the legislative issues concerning tobacco product regulation and the research priorities of CTP. The discussions focused on the need for research in the areas of addiction, biomarkers of effect, and toxicology related to tobacco products and how the research expertise and capabilities at NCTR could be utilized to address these needs.
Next-Generation Sequencing (NGS)
NCTR scientists wrote an invited review titled: “Next-generation sequencing and its applications in molecular diagnostics” to be published in the journal Expert Review of Molecular Diagnostics. Next-generation sequencing technologies offer a low-cost, high-throughput method for whole-genome sequencing to study human diseases and/or obtain whole-genome information on individual patients, a key requirement for personalized medicine. These benefits come with a number of challenges that must be addressed and that are discussed in the review, such as high error rates and immense volumes of short sequence reads.
Preprints are available from Leming Shi, Ph.D., Division of Systems Biology, FDA/NCTR.
On February 9-10, 2011, NCTR hosted two scientists from the Center for Veterinary Medicine (CVM) for on-site training on the isolation and culture of rodent primary hepatocytes. NCTR’s training programs are an important mechanism to facilitate the sharing of scientific knowledge, laboratory expertise, and technology to build and strengthen intra-agency collaborations within FDA's mission of improving public health.
Microbes and Oil Spills
The Director of NCTR's Division of Microbiology was a colloquium participant with other experts from the American Academy of Microbiology that published a report titled “FAQ: Microbes and Oil Spills.” The publication addresses questions raised following the Gulf oil spill, which sparked concern over the Gulf seafood supply, and provides science-based answers concerning the natural processes of oil degradation by microorganisms. The publication is posted on the American Academy of Microbiology website under Colloquia-Reports.
NCTR Strategic Planning
On February 23-24, 2011, NCTR administrators and Division Directors met to discuss and develop NCTR’s Strategic Plan for 2011-2015. The discussion focused on identification of Center goals and outcomes in support of the FDA mission.
Posting of NCTR Studies with Potential Regulatory Impact and Questions from Public
The draft technical reports for three studies with potential regulatory impact that were conducted at NCTR have been posted to the National Toxicology Program (NTP) website.
- Aloe barbadensis (Aloe vera) is a common herbal remedy for a variety of conditions. In a 2-year drinking water study, a non-decolorized whole leaf extract of Aloe vera was demonstrated to have clear carcinogenic activity in the colons of male and female rats, but not in mice.
- Acrylamide exposure occurs through food contamination (in baked and fried starchy foods), cigarettes, and occupational exposure. In a 2-year drinking water study, acrylamide was shown to have clear carcinogenic activity in both rats and mice.
- AIDS therapeutic agents are increasingly administered to HIV-positive pregnant women with little information on the long-term consequences to noninfected offspring. A transplacental exposure study was performed in mice with the antiretroviral drugs (AZT, 3TC, NVP and NFV) in various combinations. Carcinogenic activity was observed with numerous combinations, with the exception of the AZT, 3TC, and NFV combination that had no carcinogenic activity.
These reports will be evaluated by NTP in a public meeting April 5, 2011.
For more information, please contact Paul C. Howard, Ph.D., NCTR, FDA Liaison to the NTP, or visit the NTP website.
Combinatorial Therapy Approach to Pancreatic Cancer Treatment
NCTR scientists in collaboration with the Purdue University Cancer Center for Research have shown that the dietary agent, indole-3-carbinol (I3C) significantly increases the in vitro efficacy of gemcitabine, the gold standard treatment for pancreatic cancer. I3C—a compound in Brassica vegetables, such as cabbage and broccoli—lowers the LD50 of gemcitabine and also reactivates the tumor suppressor gene, p16INK4a, by reversing its epigenetic silencing that occurs early in cancer progression. These findings may provide a new strategy for treating pancreatic cancer, which has a poor prognosis, due in part to the lack of effective therapies.
Society for Toxicology (SOT) Annual Meeting
On March 6-10, 2011, at the 50th Anniversary Annual Meeting and ToxExpo™ of the Society for Toxicology held in Washington, D.C., scientists from NCTR gave seven platform presentations and presented posters on topics ranging from risk assessment to bioinformatics to nanotoxicology. NCTR's Director, William Slikker, Jr., Ph.D., co-chaired an SOT special issues session titled “What It Means to Be Global,” which focused on the global agenda for toxicology from the perspectives of industry, academia, government, and clinical research organizations. Weida Tong, Ph.D., Division of Systems Biology, was awarded the SOT Translational Impact Award and presented the Translational Impact Award Lecture titled: “Integration of Bioinformatics into Regulatory Decision Making.” SOT is the premier professional society for toxicologists from academia, industry, and government.
OECD Genotoxicity Test Guidelines
On March 1-4, 2011, two NCTR scientists represented FDA at the meeting of the Organisation for Economic Co-operation and Development (OECD), Expert Group on the Revision and Development of OECD Test Guidelines on Genotoxicity. Discussions focused on current and new guidelines, as well as projects that will lead to the development of new guidelines for the Comet Assay and for DNA adducts. Workgroups will be established to revise current in vitro and in vivo genotoxicity guidelines. Martha Moore, Ph.D., Director of NCTR's Division of Genetic and Molecular Toxicology will lead in drafting a new OECD guideline for the mouse lymphoma assay. The OECD is comprised of 34 member countries and is dedicated to global economic and social development.
The MicroArray Quality Control (MAQC-I) publication is highlighted in the fifteenth anniversary edition of the journal Nature Biotechnology as it revisits ten of the most important advances and most highly cited research articles of the past five years. The MAQC-I project was a large international consortium led by the FDA to provide quality-control guidelines and evaluate data-analysis methods for DNA microarray data. The MAQC project has since expanded to the evaluation of microarray-based predictive models (MAQC-II) and next-generation sequencing platforms (MAQC-III).
Similarities in S. Heidelberg Isolates from Human and Food/Animal Sources
NCTR scientists and colleagues from the Marshfield Clinic Research Foundation, Sam Houston State University and the Arkansas Department of Health have shown that Salmonella enterica serovar Heidelberg isolates from sick human patients are similar to isolates from food- and animal-related sources, with respect to genotypic profiles and resistance traits. S. Heidelberg tends to cause a disproportionately high number of invasive infections that require antimicrobial therapy. Historically, these infections have been linked to consumption of contaminated eggs. However, S. Heidelberg has increasingly been isolated from other food-related sources, such as retail meat, and little information has been available on the potential of these strains to infect humans. This study demonstrates the potential for multiple foods to serve as sources of S. Heidelberg infections. The results of this study were recently published in the Journal of Clinical Microbiology (March 2011).
Multi-Scale Toxicology Initiative — March 15, 2011
The Battelle Multi-Scale Toxciology Initiative (MSTI) and opportunities for collaborative projects were discussed at a recent meeting held at NCTR.
Representatives from Battelle, Oak Ridge National Laboratory, Brookhaven National Laboratory, Pacific Northwest National Laboratory, and Lawrence Livermore National Laboratory participated in the discussion.
The MSTI was formed to improve and hasten the safety assessments of new drug candidates through advanced toxicology science.
Hepatotoxicity Special Interest Group Meeting — March 23-24, 2011
Donna Mendrick, Ph.D., Director, Division of Systems Biology at NCTR made an innovative presentation to a gathering organized to facilitate discussions concerning recent clinical research in the field of drug-induced liver injury.
The event was held at FDA Headquarters in Silver Spring, Maryland, and co-sponsored by the FDA/Center for Drug Evaluation and Research (FDA/CDER), the American Association for the Study of Liver Disease (AASLD), and the Pharmaceutical Research and manufacturers of America (PhRMA).
Materials and slides of the meeting and Dr. Mendrick's presentation entitled: "Hepatotoxins: Wolves or Sheep?" will be available at http://www.aasld.org.