APRIL 2013 NCTR RESEARCH HIGHLIGHTS
Senator Boozman Visit
NCTR hosted a visit by U.S. Senator John Boozman and staffers on April 4, 2013. During the visit, Senator Boozman and his staff met with NCTR and Office of Regulatory Affairs (ORA)/Arkansas Regional Lab Senior Staff and were quite complimentary of the regulatory training outreach of NCTR scientific staff. The visit concluded with a tour of the NCTR Imaging Facility used to conduct studies in the identification of minimally-invasive biomarkers for pediatric anesthetics, and the NCTR/ORA Nanotechnology Core Facility used to characterize nanoscale materials for safety evaluations.
As quoted in the Pine Bluff Commercial, Senator Boozman said, "The United States is leading the way in nanotechnology and the cutting edge research being done by NCTR in that field is helping that to occur. This is an entity that is very important for the state of Arkansas and for the country as a whole," Boozman said, pointing out the unique and important research performed at NCTR. "What NCTR does nobody else can do."
MicroRNAs as Translational Biomarkers for Drug-Induced Liver Injury
NCTR scientists published a review article in Biomarkers in Medicine (2013, 7: 307-315), which discusses the potential advantages and challenges of using microRNAs (miRNAs) as new translational biomarkers of drug-induced liver injury (DILI). miRNAs are small single-stranded RNA molecules that can alter the expression of various genes. Although miRNAs appear to be more sensitive and organ-specific than conventional DILI biomarkers, their true value remains to be fully assessed due to a lack of standard quantification methods and confirmatory studies.
For additional information, please contact Qiang Shi, Ph.D., Innovative Safety and Technologies Branch, Division of Systems Biology, FDA/NCTR, or Donna Mendrick, Ph.D., Director, Division of Systems Biology, FDA/NCTR.
Preclinical Biomarkers of Idiosyncratic Drug-Induced Liver Injury
An NCTR scientist gave a presentation at the 2nd International Conference and Exhibition on Metabolomics and Systems Biology held in Northbrook, Illinois, on April 8-10, 2013. The talk focused on the use of metabolomics to evaluate preclinical biomarkers of hepatotoxicity; with special emphasis on common blood metabolite profiles between preclinical animals treated with drugs that cause observable liver injury and human patients with idiosyncratic drug-induced liver injury. The identification of common metabolite profiles could be useful in the development of improved clinical trial designs and improved detection of idiosyncratic DILI risk.
For additional information, please contact Richard Beger, Ph.D., Director, Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.
Physiologically Based Pharmacokinetic (PBPK) Modeling of BPA
NCTR scientists have developed a physiologically based pharmacokinetic (PBPK) model to predict the age-dependent pharmacokinetics of bisphenol A (BPA) and its metabolites in the young and adult rat. BPA is a ubiquitous environmental contaminant and present in many consumer products. Several published studies have raised concern for the potential toxicity at sensitive developmental stages in humans. However, in this current report, comparison of the predicted BPA dosimetry in rats, nonhuman primates, and humans suggest that the internal BPA exposures in the very young rats over-predict internal exposures expected in human infants for a given dose of BPA. Thus, dose adjustments are necessary when extrapolating from toxicity studies in neonatal rats to infant human children. A manuscript describing the results of this study was recently accepted for publication in Toxicology and Applied Pharmacology .
For additional information, please contact Jeffrey Fisher, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
NCTR scientists, in collaboration with FDA's Center for Food Safety and Applied Nutrition and the Illinois Institute of Technology, have shown that the thermal stability of ricin, a lethal protein toxin and potential bioterror agent, was enhanced in yogurt and yogurt-containing fruit drinks compared to other foods tested, such as milk, infant formulas, and fruit juices. The resistance to heat inactivation was further shown to be greater in moderately acidic conditions and to be potentiated by galactose, lactose, and exopolysaccharides commonly produced by yogurt microorganisms. These data demonstrate the importance of considering pH and the presence of stabilizing ligands for thermal inactivation of protein toxins in foods. The results of this study were recently accepted for publication in Food and Chemical Toxicology.
For additional information, please contact William Tolleson, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
MAY 2013 NCTR RESEARCH HIGHLIGHTS
KRAS Mutant Subpopulations and Implications for Cancer Therapeutics
NCTR scientists published an invited review in Discovery Medicine (2013, 15:259-267) that discusses the implications of KRAS mutant subpopulations in colon tumors on the efficacy of personalized cancer treatments. The authors summarize evidence that most colon tumors carry KRAS mutations; and few, if any, colon tumors are truly KRAS wild-type. The use of monotherapies that target KRAS wild-type tumor cells creates an opportunity for the outgrowth of KRAS mutant subpopulations, which can lead to acquired resistance to treatment and relapse. Thus, combination therapeutics that target KRAS mutant cells may provide a more effective treatment of advanced colorectal cancer.
For additional information, please contact Barbara Parsons, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR, or Meagan Myers, Ph.D., Staff Fellow, Division of Genetic and Molecular Toxicology, FDA/NCTR.
Hepatotoxicity of Usnic Acid-Containing Dietary Supplements
NCTR scientists’ studies suggest that compromised metabolism could explain an association in clinical cases of severe liver injury in certain individuals that consume usnic acid-containing dietary supplements. Experiments with liver cell cultures demonstrated that inhibition of cytochrome enzyme activity (CYP1A and CYP3A), known to metabolize usnic acid, increased toxic response. It is also known that usnic acid is mainly metabolized by cytochrome CYP1A and CYP3A with human liver microsomes. This indicates usnic acid hepatotoxicity may be more likely to occur in individuals deficient in CYP1A or CYP3A activity. A manuscript describing the results of this study was recently accepted for publication in Journal of Applied Toxicology.
For additional information, please contact Qiang Shi, Ph.D., Division of Systems Biology, FDA/NCTR.
JUNE 2013 NCTR RESEARCH HIGHLIGHTS
Meta-Analysis for Identification of Salmonella Serotypes by PFGE Patterns
NCTR scientists, in collaboration with the Center for Disease Control and Prevention, China Medical University, and Feng Chia University, developed an algorithm to predict Salmonella serotypes with 94-96% accuracy based on a constructed database of pulsed-field gel electrophoresis (PFGE) patterns. The meta-analysis study utilized the PulseNet database information of 45,923 Salmonella PFGE patterns that represent the 32 most frequent serotypes associated with outbreaks. This initiative shows that the presence of distinct, serotype-specific banding patterns may provide useful information to aid in the rapid detection and identification of pathogens, or serve as a reference for traditional serotype results. The full text of this study is published in PLoS ONE (2013; 8(3):e59224).
For additional information, please contact Wen Zou, Ph.D., or James Chen, Ph.D., Biostatistics Branch, Division of Bioinformatics and Biostatistics, FDA/NCTR.
Inhibitor Protects Mouse in a Parkinson’s Disease Model
NCTR scientists, in collaboration with the University of Texas Health Science Center and Sega University (Japan), have shown that a selective inhibitor (INNO-406) of c-Abl (a non-receptor tyrosine kinase) prevented the progression of dopaminergic neuronal damage in a toxin-induced mouse model of Parkinson’s disease (PD). In the current study, INNO-406 administered to mice for one week prior to the toxin (MPTP) prevented activation of c-Abl and phosphorylation of parkin, which is known to be involved in the disease process. Additionally, the inhibitor prevented the characteristic dopaminergic neuronal and terminal damage of PD; and preserved dopamine content which is necessary for normal excitatory function. These results suggest that this class of c-Abl inhibitors could be neuroprotective by slowing the progression of PD and may represent a target molecule for development of potential therapies for PD. The results of this study are published in PLOS ONE (2013, 8(5): C65129).
For additional information, please contact Syed Imam, Ph.D., Division of Neurotoxicology, FDA/NCTR.
A Review of Prediction Biomarkers for Personalized Medicine
Scientists from NCTR, the China Medical University, and Feng Chia University (Taiwan) have published a review article in Pharmacogenomics (2013, 14:969-980) that discusses the development of prediction models, based on prognostic and predictive genomic biomarkers, to classify patients into subgroups for treatment decisions. Pharmacogenomics aims to identify variability among individual patients/subpopulations to guide personalized medicine and predict whether an individual patient would benefit from or have an adverse response to a given drug treatment. Effective preclinical/clinical drug development will require the development of new and innovative approaches to identify biomarkers that can improve compound prioritization and provide information on mechanisms that identify patient subgroups.
For additional information, please contact James Chen, Ph.D., Director, Biostatistics Branch, Division of Bioinformatics and Biostatistics, FDA/NCTR.
NTP Board of Scientific Counselors
On June 25, 2013, the National Toxicology Program (NTP) held a meeting of the NTP Board of Scientific Counselors at the National Institute of Environmental Health Sciences (NIEHS). The meeting included discussions on the following issues, which have information posted on the NTP website:
- NTP Monograph on Developmental Effects and Pregnancy Outcomes Associated with Cancer Chemotherapy Use During Pregnancy
- NTP Report on Carcinogens Peer Review Monograph Report on the Carcinogenicity of 1-Bromopropane and separately Cumene
- Review of program on Systematic Review and Evidence Integration for Literature-Based Health Assessments
- Review of proposal to gather data on Shift Work at Night, Light at Night, and Circadian Disruption
The FDA, along with NIEHS and NIOSH, is a founding member of the NTP and participates in NTP meetings and activities at multiple levels.
For additional information, please contact Paul C. Howard, Ph.D., FDA Liaison to the NTP, Director, Office of Scientific Coordination, FDA/NCTR.