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January-March 2013 Research Highlights
JANUARY 2013 NCTR RESEARCH HIGHLIGHTS
Omics Biomarkers for Tobacco-Related Harm
Scientists from NCTR and the Center for Tobacco Products (CTP) have published a review article in Biomarkers in Medicine that addresses the use of omics technologies to identify pulmonary biomarkers of harm related to tobacco exposure. Many respiratory diseases caused by tobacco use are chronic in nature; and thus, short-term predictive biomarkers could be valuable aids in the risk assessment of exposure to tobacco smoke and its constituents. This review presents the background, rationale, and strategy for using omics technologies (genomics, proteomics, and metabolomics) to develop new biomarkers that could be used by FDA in making regulatory decisions on tobacco products.
For additional information, please contact Donna Mendrick, Ph.D., Director, Division of Systems Biology, FDA/NCTR.
Assessing Drug-Induced Liver Injury (DILI)
Scientists from NCTR and Hannover Medical School analyzed 164 FDA-approved oral medications and have shown an association of high daily doses (≥ 100 mg/day) and lipophilicity (partition coefficient, logP ≥3) with significant risk for DILI; thus defining a “rule-of-two.” This principle was further applied and verified using an independent set of 179 oral medications, drug pairs with similar chemical structures and molecular targets but different DILI potential, and in clinical case studies with complex co-medication regimes. The “rule-of-two” is an appropriate means of estimating risk for DILI compared to dose alone and could help support regulatory applications. A manuscript detailing this study has been accepted for publication in Hepatology and is available at http://dx.doi.org/10.1002/hep.26208.
For additional information, please contact Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.
NCTR hosted Jonca Bull, Ph.D., Director, FDA Office of Minority Health on January 9, 2013. Dr. Bull described the need for new research addressing the emerging face of subgroups' health as a complex matrix including many factors: e.g., ethnicity, environment, personal behavior, and genetic background.
Next-Generation Sequencing in the Clinic
Next-generation sequencing (NGS) could have profound effects in clinical practice. Scientists from NCTR and China's Fudan University have published a review article in Cancer Letters that addresses the use of NGS in clinical applications. The review presents an overview of the strengths and limitations of the three major NGS platforms (Roche/454, Illumina/Solexa, and Life Technologies/SOLiD), applications of NGS technologies in clinical diagnostics and therapeutics, and the challenges of NGS data analysis. NGS technology has undergone rapid advancements in recent years, however, significant challenges associated with quality control and the processing, storage, and interpretation of NGS data still limit its integration into the clinic.
For additional information, please contact Leming Shi, Ph.D., Bioinformatics Branch, Division of Bioinformatics and Biostatistics, FDA/NCTR.
FEBRUARY 2013 NCTR RESEARCH HIGHLIGHTS
Scientists from NCTR and the University of Arkansas developed a novel, multilocus sequence typing method (MLST-seq) that combines a Polymerase Chain Reaction (PCR)-based target enrichment and next-generation sequencing technology for genotyping foodborne pathogens. In the study, 21 target genes for genotyping Salmonella strains were simultaneously amplified and used to demonstrate that MLST-seq — with an increased number of target genes — is an efficient way to improve discrimination among closely related Salmonella strains. Thus, MLST-seq provides an improvement in resolution and high-throughput capacity over current MLST approaches. This study was recently published in Molecular and Cellular Probes (2013, 27: 80-85; http://dx.doi.org/10.1016/j.mcp.2012.11.004).
For additional information, please contact Rajesh Nayak, Ph.D., or Steven Foley, Ph.D., Division of Microbiology, FDA/NCTR.
Scientists from NCTR and Korea's Chung-Ang University, Korea, have shown that a Microbacterium strain, isolated from a wastewater treatment plant, contains a glutamine synthetase enzyme involved in the detoxification of the antibacterial fluoroquinolone drug, norfloxacin. This enzyme plays a key role in the conversion of norfloxacin to the inactive N-acetylnorfloxacin. These results suggest that environmental bacteria that survive in the presence of low concentrations of fluoroquinolones in wastewater treatment plants may have the ability to enzymatically inactivate these drugs and contribute to drug resistance. This study was recently published in Applied and Environmental Microbiology (2013, 79:314-321; http://dx.doi.org/10.1128/AEM.02347-12).
For additional information, please contact John Sutherland, Ph.D., Division of Microbiology, FDA/NCTR.
Safe Medication Use During Pregnancy
An NCTR scientist served as an expert member at the Centers for Disease Control and Prevention’s (CDC) Treating for Two: Safe Medication Use in Pregnancy Initiative Meeting held in Atlanta, GA, on January 28-29, 2013. The meeting provided a forum to discuss a prototype for a formal review process to evaluate existing evidence for risks associated with the most commonly used medications during pregnancy. The goal is to develop a viable plan to initiate and sustain this review process with the ultimate goal of improving the health of pregnant women and their children.
For additional information, please contact Merle Paule, Ph.D., Director, Division of Neurotoxicology, FDA/NCTR.
Cigarette Smoke Condensate Induces Epigenetic Changes In Vitro
NCTR scientists demonstrated that treatment of a lung epithelial cell line with cigarette smoke condensates (CSCs) resulted in changes in gene expression and promoter methylation of a number of critical genes shown to be involved in lung cancer development (i.e., ECAD, MGMT, and RASSF1A). Furthermore, cells treated with CSCs for 28 days showed changes in morphology, invasion capacities, and global methylation status. These results suggest that epigenetic changes could serve as early biomarkers of harm due to cigarette smoke exposure. The results of this study have been published in an article in the International Journal of Toxicology .
For additional information, please contact George Hammons, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Cardiovascular Toxicity of Bitter Orange Extracts
Scientists from NCTR and the Center for Food Safety and Applied Nutrition (CFSAN) have shown that rats given daily doses (equivalent to or higher than the recommended daily dose for humans) of bitter orange extracts (Citrus aurantium) or purified synephrine (active compound of bitter orange) in combination with caffeine and exercise (3 sessions per week) had sustained elevations in systolic and diastolic blood pressure for eight hours after dosing. Bitter orange extract is commonly used in dietary supplements and herbal weight-loss products, but did not decrease food consumption or decrease body weight in the rats. A manuscript describing this study was recently accepted for publication in Cardiovascular Toxicology. Bitter orange was nominated by CFSAN, and the study was conducted at NCTR under an Interagency Agreement with the National Toxicology Program.
For additional information, please contact Deborah Hansen, Ph.D., Biomarkers and Alternative Models Branch, Division of Systems Biology, FDA/NCTR.
Bioimaging Pediatric Anesthetic-Induced Neurotoxicity
NCTR scientists have published a review article in the Journal of Applied Toxicologyon the application of small animal positron emission tomography (microPET) technology in imaging anesthetic-induced neuronal toxicity. The review discusses the power of microPET as a minimally-invasive technique that allows repeated studies of the same animal through time with the animal serving as its own control. Additionally, studies into anesthetic-induced neuronal toxicity in rodents and nonhuman primates are summarized, as well as the use of selected tracers to probe specific molecular interactions.
For additional information, please contact Xuan Zhang, MD, Ph.D., Staff Fellow, Division of Neurotoxicology, FDA/NCTR, or Merle Paule, Ph.D., Director, Division of Neurotoxicolgy, FDA/NCTR.
MARCH 2013 NCTR RESEARCH HIGHLIGHTS
Pharmacokinetics of BPA in Maternal and Fetal Nonhuman Primates
NCTR scientists used a nonhuman primate transplacental model to show that maternal, placenta, and fetal metabolism all serve to reduce the internal fetal exposures to the active form of bisphenol A (BPA) to less than half than that observed in the circulation of the mother, similar to a previous carefully controlled exposure in fetal rats. The current studies employed deuterium-labeled BPA that enabled accurate analysis of BPA and its metabolites in fetal blood and tissues without possible confounding by background contamination with BPA during sample collection, storage, or analysis. The results from BPA exposures in nonhuman primate and rodent models will be combined with available human data and new data from ongoing human studies in the NIEHS Clinical Research Unit into PBPK models to estimate perinatal exposures to BPA from food contact materials, medical devices, and other environmental sources (Toxicology and Applied Pharmacology, 2013, 267: 41-48).
For additional information, please contact Daniel Doerge, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.
Data Mining for Signal Detection of Adverse Event Safety Data
NCTR scientists, in collaboration with the Center for Drug Evaluation and Research (CDER), have developed a data mining process (algorithm) that allows the simultaneous characterization of the similarities and differences among drugs and adverse events in the FDA Adverse Events Reporting System (AERS) database. The algorithm identifies and describes associations between subsets of drugs and corresponding subsets of adverse events. These “biclusters” can then be investigated and applied to databases of other drugs and adverse event safety data to identify unrecognized adverse event associations with drugs, or highlight unusual anomalies. A safety data set consisting of 193 cardiovascular drugs with 8,543 adverse events was analyzed as an illustration. The results of this study have been published in the Journal of Biopharmaceutical Statistics (2013, 23:146-160).
For additional information, please contact James J. Chen, Ph.D., Biostatistics Branch Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.
Alternative Treatments for Staphylococcus aureus Infections
Scientists from NCTR and the University of Arkansas for Medical Sciences have identified and characterized hyaluronidases as potential virulence factors in diseases caused by Staphylococcus aureus. Extracellular hyaluronidases degrade hyaluronic acid in human tissue which may enable the spread of S. aureus and contribute to the infection process. However, SarA, (virulence gene regulator) mutants of S. aureus display increased hyaluronidase expression, but do not inhibit biofilm formation or promotion of bacterial dispersion from biofilms. Biofilms, which are a community of bacterial cells encased in an extracellular matrix of host molecules, are resistant to most if not all antimicrobials and can adhere to prosthetic devices, blood and urinary catheters, and heart valves. These results add to our understanding of staphylococcal biofilm-related infections and the search for alternatives to antibiotic treatment. The results of this study were recently published in Microbiology.
For additional information, please contact Mark E. Hart, Ph.D., Division of Microbiology, FDA/NCTR.
Heterogeneity of KRAS Genes in Colon and Lung Tumors Complicates Personalized Medicine Treatments
NCTR scientists have published a Special Report in Personalized Medicinesummarizing the evidence that undetected KRAS mutant subpopulations in tumors are subverting the efficacy of therapies targeting the epidermal growth factor receptor (EGFR). Although clinical studies have shown that the presence of KRAS mutations can predict failure of EGFR-targeted therapies, significant percentages of patients with wild-type KRAS tumors (no mutation detected) also fail to respond to these therapies. Frequently, colon and lung tumors contain KRAS mutant tumor subpopulations not detected by DNA sequencing and could account for the reduced efficacy. Since tumors frequently develop from more than one group of cells, novel preclinical models need to capture this complexity when evaluating and prioritizing combination therapies for subsequent clinical investigation.
For additional information, please contact Meagan Myers, Ph.D., or Barbara Parsons, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.