January-March 2014 Research Highlights
Gene Expression Signatures in Lung Adenocarcinoma
NCTR and National Taiwan University scientists have used a bioinformatic approach to identify a signature set of 16 predictive genes for lung adenocarcinoma (non-small cell lung cancer) from analysis of four biological databases. Additionally, the 16-gene signature correlated with the efficacy of an anti-cancer drug (ZD-6474) that targets the epidermal growth factor receptor. Thus, this signature panel may have potential as both a prognostic and predictive biomarker for lung adenocarcinoma with clinical applications. The results of this study are published in BMC Bioinformatics (2013, 14:371).
For additional information, please contact James J. Chen, Ph.D., Director, Biostatistics Branch, Division of Bioinformatics and Biostatistics, FDA/NCTR.
Genotoxicity of Doxorubicin in Rat
NCTR scientists showed that treatment of rats with doxorubicin induced a dose-dependent (1-3 mg/kg bw) increase in oxidative DNA damage in cardiac tissue and changes in the expression of DNA damage and repair genes. Doxorubicin is an anti-cancer drug most effective against pediatric lymphomas. However, it carries a risk of cardiotoxicity as a serious adverse effect which limits the life-time dose and its utility as a chemotherapeutic agent. This study suggests that the production of reactive oxygen species and the resulting persistent oxidative DNA damage may contribute to this cardiotoxicity. The research article describing this study was selected as the Editor’s Choice and is highlighted in the January 2014 issue of Environmental and Molecular Mutagenesis.
For additional information, please contact Mugimane Manjanatha, Ph.D., or Wei Ding, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
Final Reports On AIDS Therapeutics Toxicology Studies
The final reports for studies on the potential toxicity of 3’-azido-3’-deoxythymidine (AZT) and combinations of AZT, lamivudine, and nevirapine in genetically modified mice were published on the National Toxicology Program website. The studies showed that high doses of AZT given continuously or only during the perinatal and postnatal periods exhibited carcinogenic activity in a mouse model designed to detect genotoxic carcinogens. These studies were conducted at the FDA National Center for Toxicological Research under the auspices and funding of an Interagency Agreement between FDA/NCTR and NIEHS/NIH.
For additional information, please consult the final reports (GMM-14 and GMM-16) at the NTP website or contact Julian Leakey, Ph.D., Office of Scientific Coordination, FDA/NCTR.
NCTR Science Advisory Board Meeting
The annual NCTR Science Advisory Board (SAB) meeting was held January 29-30, 2014. Presentations to the Board included current NCTR research priorities and brief overviews from the six NCTR Division Directors; as well as an update on the Global Coalition for Regulatory Science Research and the Global Summits. The Microbiology Subcommittee Site Visit Report was presented to the Board and adopted. Chris Austin, Director, National Center for Advancing Translational Sciences (NCATS) introduced the second day discussions on national informatics needs. FDA’s Chief Health Informatics Officer and representatives from CDER, CDRH, CBER, CTP, CVM, and ORA made presentations on their Center priorities emphasizing the roles of bioinformatics; and the Arkansas Bioinformatics Consortium brought in discussions of their ongoing and future programs.
Age, Sex, and Tissue Differences in Gene Expression in the Rat
The Sequencing Quality Control Consortium, a large international effort led by NCTR scientists, generated a comprehensive gene expression atlas using next-generation sequencing technology. This technology catalogues variations in gene expression in 11 tissues at four developmental stages of male and female rats. The web-based, publicly-available Rat BodyMap database is expected to provide a comprehensive platform for biomedical research. The database is also expected to increase understanding of disease, drug efficacy, and toxicity in the rat model and ultimately improve the translation of preclinical findings to humans. This study was partially supported by the FDA Office of Women’s Health and is published in Nature Communications (2014, 5:3230).
For additional information, please contact James Fuscoe, Ph.D., Personalized Medicine Branch, Division of Systems Biology, FDA/NCTR, or Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.
Potential New Biomarkers of Drug-Induced Liver Injury (DILI)
NCTR scientists have published a review article in Toxicology Letters (2014, 225:401-406) that summarizes the issues surrounding the potential utility of blood and urine extracellular vesicle (EV)-based biomarkers for detection of drug hepatotoxicity. These circulating EVs are membrane-surrounded structures that contain molecules (mRNA, miRNA, and protein) that can be indicative of drug hepatotoxicity. Although recent evidence suggests these EV-based biomarkers may be more liver-specific and more informative about the offending drugs than are conventional biomarkers, a lack of standardized EV isolation methods and analytic approaches currently limits their regulatory and clinical utility.
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.
Toxicity Evaluation of Orally Administered BPA
NCTR scientists have published companion papers in Toxicological Sciences presenting data from:
- a 90-day, GLP-compliant toxicology study of orally administered BPA in rats (http://dx.doi.org/10.1093/toxsci/kfu022) and
- an evaluation of internal dosimetry for orally administered BPA throughout perinatal and adult life stages (http://dx.doi.org/10.1093/toxsci/kfu021)
The 90-day, Churchwell et al study provides new data for use to further refine physiologically based pharmacokinetic models used to extrapolate exposures in rodent tests to real world human exposures. The study is a component of the concurrently published subchronic range-finding study Delclos et al.
The second, Delclos et al study was used to determine doses and toxicological direction of the ongoing long-term (two-year) toxicological study currently under way at the FDA. The Delclos et al study results have been publicly available for some time. The results from the FDA’s long-term (two-year) study, which will include data generated by NIEHS-funded academic investigators, are expected to be release in early 2016.
For additional information, please contact Barry Delclos, Ph.D., or Daniel Doerge, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Pathogenesis and Host Adaptability of Salmonella
Scientists from NCTR, the University of Minnesota, and the University of Arkansas have published a review article in Microbiology and Molecular Biology Reviews that examines how Salmonella serotypes adapt to hosts and may cause human disease through consumption of contaminated poultry and eggs. The article addresses how the acquisition or loss of bacterial genes can potentially impact the range of hosts that Salmonella can infect. Additional factors that affect the ability of Salmonella to colonize a host species and cause disease include: the host’s immune system, specific pathogen responses, the host environment, and intestinal microbiota. An in-depth understanding of the mechanisms of Salmonella pathogenesis is essential for the development of better strategies for intervention and treatment in animals and humans.
For additional information, please contact Steven Foley, Ph.D., and Rajesh Nayak, Ph.D., Division of Microbiology, FDA/NCTR.
Disease Surveillance Using the FDA Adverse Event Reporting System
Scientists from NCTR and the Marshfield Clinic Research Foundation demonstrated the potential utility of the FDA Adverse Event Reporting System (FAERS) for identifying disease characteristics, in addition to its traditional applications in drug-safety monitoring. In this pilot study, data-mining approaches were used to identify 115 potential sex-biased diseases from FAERS (a public database that contains patient demographic information for more than 4 million adverse event cases reported between 1997-2011). Of these identified diseases, 53 have been reported in the literature, with 50 showing the sex-biased effect (94 percent concordance with FAERS). Finally, eight of these diseases were selected and further confirmed through analysis of patient electronic medical records. This approach could be further applied to other publically available disease surveillance databases and used to study other disease risk factors, such as age or ethnicity. The study was published online in Clinical Pharmacology & Therapeutics (2014).
For additional information, please contact Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.
Mechanisms of Ginkgo biloba Extract-Induced Genotoxicity
NCTR scientists have shown that Ginkgo biloba extract, as well as two of its constituents (quercetin and kaempferol) induce dose-dependent increases in the frequency of mutations and DNA double-strand breaks in in vitro genotoxicity assays. These results support a potential mutagenic mechanism of tumorigenesis. An observed increase in reactive oxygen species further suggests that an additional mechanism involving oxidative DNA damage may be at least partially responsible for the observed genotoxic effects. A National Toxicology Program carcinogenicity study showed that the same Ginkgo extract used in the current study was tumorigenic in rodents; however little was known about the mechanisms involved. Ginkgo biloba is commonly used as an herbal remedy and in dietary supplements. A manuscript detailing this study is now available online in Toxicological Sciences.
For additional information, please contact Haixia Lin, Ph.D., or Nan Mei, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.
Society for Toxicology Annual Meeting
On March 23-27, 2014, NCTR scientists gave platform presentations in continuing education courses and workshops, as well as poster presentations at the 53rd Annual Meeting and ToxExpo™ of the Society for Toxicology (SOT) in Phoenix, AZ. The presentations covered a wide range of topics including:
- miRNA biomarkers of toxicity
- imaging biomarkers
- pediatric anesthetics
- drug-induced liver injury
- results of studies with compounds of high FDA interest such as BPA, triclosan, furan, and melamine/cyanuric acid
Additionally, Dr. Annie Lumen received the “Best Postdoctoral Publication Award” for her paper on modeling effects of iodide and perchlorate exposure during human pregnancy (Toxicological Sciences, 2013, 133: 320-341). The SOT is the premier professional society for toxicologists from academia, industry, and government.
Society for Toxicology Awards
An NCTR research article titled “Ketamine-Induced Neuronal Damage and Altered N-Methyl-D-Aspartate Receptor Function in Rat Primary Forebrain Culture” was one of 2013’s top ten most cited articles in Toxicological Sciences. The in vitro study showed that ketamine, a common pediatric anesthetic, induces neuronal cell death through upregulation of the NMDA receptor; and L-carnitine is neuroprotective against ketamine’s adverse effects (Toxicological Sciences, 2013, 131: 548-557).
For additional information, contact Merle Paule, Ph.D., Director, Division of Neurotoxicology, FDA/NCTR.
Another NCTR research paper titled "Prediction and Ealuation of Route Dependent Dosimetry of BPA in Rats at Different Life Stages Using a Physiologically Based Pharmacokinetic Model" (Toxicol Appl Pharmacol, 270:45) was selected by a committee of the Risk Assessment Specialty Section as one of the Best Papers Published in 2013 Demonstrating Application of Risk Assessment.
A Postdoctoral Fellow in the Division of Biochemical Toxicology, received the SOT Carcinogenesis Specialty Section Postdoctoral Fellowship Award for the abstract entitled “Epigenetic alterations in the livers of Fisher 344 rats exposed to furan. The main focus of this study was to investigate the role of epigenetic alterations in the mechanisms of furan hepatotoxicity and carcinogenicity. The results of the study showed that exposure to furan causes dose-and time-dependent epigenetic aberrations that include alterations of DNA methylation status (global and gene-specific methylation), changes in the expression of chromatin modifying genes, and alterations in histone lysine methylation and acetylation patterns in the livers of male Fisher 344 rats. These findings significantly contribute to our understanding of the mechanisms of furan carcinogenesis and could be helpful for the future development of prevention strategies for early hepatic adverse effects associated with the furan exposure. This award recognizes the best abstract related to the field of carcinogenesis submitted by postdoctoral fellows.