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  1. Science & Research (NCTR)

2018-NCTR Research Highlights

2018 NCTR Research Highlights and Accomplishments

2018-NCTR Research Highlights

 


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October-December 2018

  • Microbiome Research at NCTR — Tobacco, Arsenic, and more…
    • NCTR Represented at the Health and Environmental Sciences Institute’s (HESI) “The Gut Microbiome Workshop”
    • NCTR Represented at Ninth International Conference on Antimicrobial Agents in Veterinary Medicine (AAVM)
    • NCTR represented at the 2nd NIH-FDA Joint Agency Microbiome Meeting
    • Smokeless Tobacco Impacts Oral Microbiota
    • Impact of a Single or a Short Term Repeated Exposure of Arsenic on Intestinal Microbiome and Immune Status
  • Bioinformatics Research at NCTR
    • Division of Bioinformatics and Biostatistics (DBB) Newest Branch — R2R (review-to-research and return) Branch
    • NCTR’s Contribution to Maintaining American Leadership in Artificial Intelligence (AI)
    • Androgen Receptor (AR) Structural Changes Due to Antagonist Binding
    • Massive Analysis Quality Control Society

July-September 2018

  • Biomarkers, BEST Resource, and more
    • BEST (Biomarkers, EndpointS, and other Tools) Resource
    • Biomarkers and Diagnostic Tests: Qualification, Approval, and Role in Clinical Practice
    • Immune-Response Proteins as Biomarkers of Doxorubicin (DOX)-Induced Cardiotoxicity in Breast-Cancer Patients
    • Contrast-Enhanced Imaging Used To Measure a Potential Biomarker of Drug-Induced Liver Injury (DILI)
    • Altered MicroRNAs Identified in Serum of a Mouse Model of Parkinson’s Disease
  • Antimicrobial-Resistance Research
    • Impact of Tetracycline on the Human Intestinal Microbiome and Antimicrobial Resistance
    • Variable Changes in the Bacterial Community After Tetracycline Exposure
    • Plasmids from Salmonella Can Contribute to their Antimicrobial Resistance and Potential Virulence
    • Importance of Plasmids as Vehicles for the Spread of Antimicrobial Resistance and Bacterial Toxins Among Bacterial Pathogens
  • Cancer Research at NCTR... Latest News
    • Lung Tumor Model Improves Understanding of Cancer-Drug Resistance
    • Comparative Toxicity of 34 FDA-Approved Cancer Drugs
    • Targeted Therapy for Triple-Negative Breast Cancer (TNBC)
    • NCTR’s Role in the American Association of Cancer Research (AACR) Annual Meeting

May-June 2018

  • Read the latest NCTR Research Highlights – June 28, 2018
    • First Report on the CLARITY-BPA Study
    • NCTR Scientists to Present at HESI Gut Microbiome Workshop
    • FDA and Other Federal Agencies Release Strategic Plan for Microbiome Research
    • Genome-Wide Mutation Detection
    • Microbial Contamination Found in Tattoo and Permanent Makeup (PMU) Inks
  • NCTR... Focused on Food Safety
    • NCTR Collaboration with the Food Safety Commission of Japan
    • SAVE THE DATE: 8th Annual 2018 Global Summit for Regulatory Science (GSRS18)
    • Spread of Plasmids That Can Transfer Antimicrobial Resistance (AMR)
    • Key Animal Model of Arsenic Toxicity
    • RAPID-B: A Selective Real-Time Detector of Pathogenic Bacteria
  • Neuroscience News at NCTR
    • Model of Traumatic Brain Injury (TBI) to the Blood-Brain Barrier (BBB)
    • Award-Winning Publication on the Effects of Chemotherapeutics in an Animal Model
    • Fluidic Biomarkers of Neurotoxicity
    • Alzheimer's Disease – FDA Research on Ethnicity and Gender Differences
    • Multi-Electrode Array (MEA) Analysis for Neurotoxicity
  • NCTR... Improving Understanding of Liver Toxicity
    • Role of Cytochromes in Dronedarone-Induced Liver Toxicity
    • Therapeutic Bile Acids and the Risks for Liver Toxicity
    • Monograph Published on Drug-Induced Liver Toxicity
    • Early and Sensitive Biomarkers of Liver Toxicity Discovered

Microbiome Research at NCTR — Tobacco, Arsenic, and more…

NCTR Represented at the Health and Environmental Sciences Institute’s (HESI) “The Gut Microbiome Workshop”

Donna Mendrick, Ph.D., NCTR Associate Director of Regulatory Activities served as co-chair and gave the opening presentation to a HESI meeting titled: “The Gut Microbiome: Markers of Human Health, Drug Efficacy, and Xenobiotic Toxicity” that was held June 25-26, 2018, in Alexandria, Virginia. Drs. Carl Cerniglia, Steve Foley, and Sangeeta Khare from NCTR’s Division of Microbiology were members of the workshop’s planning committee and Drs. Foley and Khare led discussion groups. Dr. Cerniglia presented on the topic “Challenges in Determining Sensitive Biomarkers of Dysbiosis When Assessing the Impact of Antimicrobial Drug Residues in Food on the Human Intestinal Microbiome.”

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NCTR Represented at Ninth International Conference on Antimicrobial Agents in Veterinary Medicine (AAVM)

Carl Cerniglia, Ph.D., Director, Division of Microbiology, was an invited speaker at the Ninth International Conference on Antimicrobial Agents in Veterinary Medicine (AAVM) held in Rome, Italy, October 16‐19, 2018. The title of his presentation was “The Effects of Residue Levels of Tetracycline on the Intestinal Microbiome.” Dr. Cerniglia also was the co-chair of the session on Antimicrobial Resistance. Visit www.aavm2018.com for more information.

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NCTR represented at the 2nd NIH-FDA Joint Agency Microbiome Meeting

The 2nd NIH-FDA joint conference on Intramural Microbiome Research was held on June 15, 2018, at the Center for Food Safety and Applied Nutrition, Food and Drug Administration. NCTR’s Sangeeta Khare, Ph.D., Division of Microbiology served as co-chair for the meeting. From the Division of Microbiology, Drs. Sangeeta Khare, Kuppan Gokulan, Jinshan Jin, and Mohamed Lahiani presented their research during the meeting on the following topics:

  • Developmental exposure to arsenite: Effects on intestinal microbiome and mechanism of immunotoxicity. — Dr. Sangeeta Khare

  • Effect of aloin on intestinal bacterial community structure and the production of short-chain fatty acids. — Kuppan Gokulan

  • Evaluation of the effects of smokeless tobacco on oral microbiota in a Syrian Golden hamster cheek pouch carcinogenesis model. — Jinshan Jin

  • The Impact of pristine graphene on rat intestinal microbiota using in-vitro and ex-vivo models. — Mohamed Lahiani

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Smokeless Tobacco Impacts Oral Microbiota
Scientists from NCTR, in collaboration with FDA’s Center for Tobacco Products, have assessed the research need to evaluate the impact of smokeless tobacco on the oral microbiota by using a hamster-cheek pouch carcinogenesis model. The use of smokeless tobacco products (STP) can cause direct and indirect adverse health consequences to humans. Exposure of STP to microbiota in the oral cavity has the potential to disrupt the microbial population with influence on periodontal disease and other systemic health-related problems. Analysis results from oral-cavity samples indicated that exposure to STP has a dose-dependent effect on the diversity of oral bacterial community.

After four weeks of exposure to low-dose (2.5 mg) levels of STP, the bacterial diversity significantly decreased, while exposure to high-dose (250 mg) levels increased the diversity. Metagenomic sequencing analysis (relating to the diversification) revealed that administering 250 mg of STP increased the relative abundance of Streptococcus, Lactobacillus, Veilonella, Eubacterium, Actinomyces, Aggregatibacter, and Staphylococcus species.  This suggests that exposure to STP disrupts the ecological balance of the oral microbiota, changing bacterial diversity and composition abundance of oral microbiota. The information from this investigation will extend FDA’s knowledge about the toxicity of smokeless tobacco, which could aid in the risk assessment of smokeless tobacco. A manuscript describing this study is available online in Anaerobe.

For more information, contact Huizhong Chen, Ph.D., Division of Microbiology, or Carl Cerniglia, Ph.D., Director, Division of Microbiology.

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Impact of a Single or a Short Term Repeated Exposure of Arsenic on Intestinal Microbiome and Immune Status

NCTR scientists, as part of a study funded by the National Toxicology Program, assessed the impact of single or repeated doses of arsenic exposure on mice intestinal-microbial population diversity and gut-associated immune mediators during early-development, as well as at adulthood. Dose- and time-dependent responses in bacterial recovery, microbial composition, and immune status were observed in adult mice after a single oral dose of arsenic. The results in adult mice showed:

  • a transient decrease in the recovery of intestinal bacteria,

  • an increase in the bacterial population with arsenic resistance or detoxification mechanisms,

  • evidence for host metabolism of arsenic into less-reactive trivalent methylated species,

  • a decreased abundance of bacterial species that are involved in the conversion of protein to butyrate — a short chain fatty acid metabolite — that is an alternative energy source in the intestine,

  • the intestinal mucosal immune cytokine profile reflected a mechanism of protection from arsenic toxicity.

Furthermore, arsenic exposure during early development resulted in the development of distinct bacterial populations. Overall, this study addressed some of the knowledge gaps concerning the effects of arsenic exposure 1) during early development and 2) when an adult mouse is exposed to arsenic-only both acutely and chronically for only a short period. A manuscript describing the study is available online at mBio

For more information, contact Sangeeta Khare, Ph.D., Division of Microbiology, FDA/NCTR.

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Bioinformatics Research at NCTR

Division of Bioinformatics and Biostatistics (DBB) Newest Branch — R2R (review-to-research and return) Branch
NCTR’s newest research branch in DBB is called R2R (review-to research and return). The R2R branch focuses on “knowledge uptake” of the division research products for regulatory application and “data liberation” of regulatory data from the FDA product centers to facilitate regulatory science research, and thus promotes NCTR's interactions with the product centers. The four branches of DBB are: 1) bioinformatics, 2) biostatistics, 3) scientific computing, and 4) R2R.

The division director, Weida Tong, Ph.D. stated, “with the R2R program, the division’s capabilities continue to evolve to be more diverse, robust, and capable of meeting future requirements of the FDA.” Find more information about the Division of Bioinformatics and Biostatistics.

NCTR’s Contribution to Maintaining American Leadership in Artificial Intelligence (AI)
AI is a broad concept of training machines to think and behave like humans, which encompasses many methodologies. For example, machine learning is one of the major statistical approaches to realize AI with which the Division of Bioinformatics and Biostatistics (DBB) has developed many applications. Deep learning is one of the machine- learning approach that drives a broad application of AI in biomedical science. DBB has several projects in collaboration with other centers to 1) apply deep learning and 2) address regulatory needs. For example, the division is developing an AI-based screening and prioritizing approach for FDA’s Office of Regulatory Affairs (ORA) to use on regulated products entering the US. Another ORA collaboration — with their Arkansas Lab — involves filth detection focused on imaging analysis with deep learning. Currently, DBB is developing deep-learning methodologies to handle the large amount of FDA text documents, such as FDA-approved drug labeling documents and data from the FDA Adverse Events Reporting System.

For more information, contact Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.

Androgen Receptor (AR) Structural Changes Due to Antagonist Binding
Scientists from NCTR and Immuneering Corporation have identified the structural changes of the androgen receptor (AR) caused by antiandrogens (chemicals that inhibit male hormones) using simulations. The identified structural changes could facilitate AR targeting-drug discovery. Scientists need a three-dimensional (3D) structure of the wild-type AR bound with an androgen antagonist to understand the mechanism of antiandrogenic activity. However, this type of 3D wild-type AR is not available in protein data banks. By combining molecular docking and molecular dynamics simulations, the 3D structure of wild-type AR bound with the antagonist bicalutamide was studied. This finding revealed that the activation function 2 (AF2) site is key to understanding the impact of antagonist binding on subsequent co-regulator binding. The results and more information can be found in Frontiers in Pharmacology.

For more information, contact Huixiao Hong, Ph.D., Division of Bioinformatics and Biostatistics, FDA/NCTR.

Massive Analysis Quality Control Society
The inaugural meeting of the Little Rock Chapter of the Massive Analysis Quality Control Society — organized by NCTR — was held September 7-8, 2018, in Little Rock, Arkansas. The participants were from FDA, the National Institutes of Health, biotechnology companies, and academia, with roughly 40 participants onsite and 10 online. Participants examined the progress of the FDA-led Sequencing Quality Control Project/Phase 2 (SEQC-2) in comprehensively assessing next-generation sequencing oncology-panel technologies. The SEQC-2 project aims to develop a set of validated genomic reference materials. SEQC-2 participants are conducting a cross-lab evaluation for eight Pan-Cancer panels. The panels examine the similarities and differences among the genomic and cellular alterations found across diverse tumor types. They are also examining four liquid biopsy-focused panels that can detect rare mutations of circulating tumor DNA. NCTR’s Director, William Slikker, Jr., Ph.D., gave opening remarks followed by regulatory perspectives from Dr. Jai Pandey of FDA’s Center for Devices and Radiological Health. After discussing the significant progress made by the SEQC-2 project, the participants developed a plan to advance the project.

For more information, contact Joshua Xu, Ph.D., Division of Bioinformatics and Biostatistics, FDA/NCTR.

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Biomarkers, BEST Resource, and more

BEST (Biomarkers, EndpointS, and other Tools) Resource
Scientists from NIH and FDA have assembled an online collection of definitions for terms related to biomarkers and their use called BEST (Biomarkers, EndpointS, and other Tools). The BEST Resource meets one of the goals set out in the 21st Century Cures Act, passed in December 2016 to develop a glossary of definitions related to biomarkers. The first question to be answered… “What is a biomarker?”

Blood pressure, serum cholesterol, and serum glucose are all 'biomarkers.' However, new technologies have resulted in an explosion of biomarker discovery. These new biomarkers generate confusion as to their potential uses and the validity of those uses. To reach agreement that a given biomarker was acceptable for a given use, scientists had to agree on the definitions of the types of biomarker and the types of use.

As an example, the BEST Resource defines a 'biomarker' as a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. This resource contains definitions for over 50 terms and concepts important for biomarker research and is designed to be regularly updated as new terms and concepts are introduced. View the BEST Resource.

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Biomarkers and Diagnostic Tests: Qualification, Approval, and Role in Clinical Practice
NCTR scientists summarized very recent developments in the FDA's biomarker qualification program and contrasted biomarker qualification with companion diagnostic evaluation. While the term 'biomarker' is relatively new, (and has been defined concisely in the BEST Resource), the concept is millennia old. However, with the introduction of new technologies to discover potential biomarkers comes the need to assess their utility. This is particularly true for the use of biomarkers to support regulatory decisions in medical-product development. FDA has developed processes for the qualification of biomarkers and other medical-product development tools, underscored by recent legislation (i.e., the 21st Century Cures Act). This effort contrasts biomarker qualification with companion diagnostic evaluation and will be highly informative for researchers considering taking a biomarker discovery farther along the road to validation. A manuscript describing the study is available online at Experimental Biology and Medicine.

For more information, contact William Mattes, Ph.D., Director, Division of Systems Biology, FDA/NCTR.

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Immune-Response Proteins as Biomarkers of Doxorubicin (DOX)-Induced Cardiotoxicity in Breast-Cancer Patients
In this pilot study, NCTR scientists identified proteins with significantly changed plasma levels in a group of breast-cancer patients who were treated with DOX-based chemotherapy and who later showed signs of cardiotoxicity. These proteins were associated with immune response and were identified before DOX treatment and/or at early doses of treatment; thus, they could be potential predictive biomarkers of cardiotoxicity. Although DOX has long proven to be useful in cancer treatment, it is known for its potential to induce cumulative dose-dependent cardiotoxicity. While it is critical to detect potential cardiotoxicity early—before onset of symptomatic cardiac dysfunction or heart failure—there are currently no biomarkers that can identify patients at risk of cardiotoxicity prior to or during the initial doses of chemotherapy.

In this study, plasma samples were collected before and after the first and second cycles of DOX-based chemotherapy from 27 breast-cancer patients. These samples were analyzed for the level of 83 proteins involved in immune responses or cardiovascular disease and several proteins were identified that may serve as biomarkers predicting poor heart function in DOX-treated patients. A manuscript describing the study is available online at Experimental Biology and Medicine.   

For more information, contact Li-Rong Yu, Ph.D., Division of Systems Biology, FDA/NCTR.

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Contrast-Enhanced Imaging Used To Measure a Potential Biomarker of Drug-Induced Liver Injury (DILI)

NCTR scientists—as part of a study in collaboration with multiple pharmaceutical and academic laboratories—explored the use of gadoxetate (a gadolinium-based MRI-contrast agent) dynamic contrast-enhanced MRI to measure liver bile function, with promising results. The liver bile function was measured because in some cases, DILI is a result of the drug's effect on the liver's production of bile. The antibiotic, rifampicin, was used as a test drug in a rat study where both the uptake and excretion of gadoxetate were inhibited by the clinical dose of the antibiotic. The result and size of the effect was consistent across all participating laboratories. Therefore, this preliminary study suggests promise for liver bile function as a potential biomarker for DILI and may warrant further studies to determine its broader utility. A manuscript describing the study is available online at PLoS One.

For more information, contact Serguei Liachenko, Ph.D., Division of Neurotoxicology, FDA/NCTR.

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Altered MicroRNAs Identified in Serum of a Mouse Model of Parkinson’s Disease    
In a study using a mouse model of Parkinson’s disease (PD), NCTR scientists identified four microRNAs that showed decreased expression in the blood compared to normal mice. This mouse model is like human PD—one of the deadlier neurodegenerative diseases of the elderly—because it shows a loss of dopamine brain cells and dopamine fibers. The presence of these microRNAs can now be further validated in large populations of PD patients to further evaluate their potential as biomarkers for PD. Because in PD-affected individuals, the motor symptoms do not typically appear until at least 70% of the neurons in the midbrain are either lost or damaged, it is important to search for new methods that aid in the early diagnosis of PD. Most PD cases are caused by a gene mutation; however, some toxicants such as MPTP— a contaminant found in street drugs—or high doses of pesticides can also cause PD in humans. MicroRNAs have emerged as potential biomarkers to help diagnose a variety of diseases, and NCTR is pursuing studies of microRNAs as biomarkers of PD. More information about this study can be found in Neuroscience Letters.

For more information, please contact Sumit Sarkar, Ph.D., Division of Neurotoxicology, FDA/NCTR.

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Antimicrobial-Resistance Research

Impact of Tetracycline on the Human Intestinal Microbiome and Antimicrobial Resistance
Scientists from NCTR and CVM have shown—using in vitro batch cultures of bacteria-laden fecal slurries derived from humans—that tetracycline, an antibiotic, at low-residue concentrations following acute and chronic exposure could affect the human intestinal-microbiome composition and the antimicrobial-resistance gene profile. There are two microbiological endpoints that are measured based on national regulatory guidelines: 1) microbial composition changes that could cause colonization barrier disruption and 2) selection/emergence of resistance after antibiotic exposure. The use of antibiotics in food-producing animals may result in residues of these drugs in meat, milk, and eggs. Dietary exposure to antimicrobial agents in food may lower the gastrointestinal-colonization barrier to allow the emergence of resistant bacteria in the human intestinal microbiome.

Changes in the bacterial community after tetracycline exposure were variable due to inter-individual differences in the intestinal microbiome composition. Among the 23 tetracycline-resistance genes screened, four genes were common in both tetracycline-dosed and non-dosed fecal samples. A slight increase in antibiotic-resistance genes appeared to be related to the tetracycline treatment. Despite the inherent variability of the intestinal microbiota among and within individuals, this pilot study—using high-throughput sequencing, quantitative PCR, and bioinformatic analysis—has contributed to the knowledge base. It has helped assess the safety of veterinary antimicrobial-drug residues in food, their impact on the human intestinal microbiome, and the potential for antimicrobial resistance. A manuscript describing the study is available online at Anaerobe.

For more information, contact Carl Cerniglia, Ph.D., Director, Division of Microbiology or Youngbeom Ahn, Ph.D., Division of Microbiology, FDA/NCTR.

Plasmids from Salmonella Can Contribute to their Antimicrobial Resistance and Potential Virulence
Scientists from NCTR, the University of Arkansas at Fayetteville, and the University of Arkansas at Pine Bluff found that many plasmids carry genes for bacterial toxins that may give bacterial strains (that carry the plasmids) a competitive advantage in shared environments. Antimicrobial resistance and virulence properties in Salmonella can be encoded on plasmids—non-chromosomal DNA elements that replicate independently of the bacterial chromosome—that can carry and spread antimicrobial resistance and pathogenicity-associated genes in bacteria. In this study, scientists evaluated 92 Salmonella enterica strains (known to carry a class of plasmids termed "incompatibility group I1 plasmids") for their susceptibility to nine different antimicrobial agents and ability to produce bacterial colicin toxins. Approximately 90 percent of the strains were resistant to at least one antimicrobial, and more than 50 percent were resistant to five or more antimicrobials. Over half of the strains also produced colicin toxins that inhibited the growth of another bacterial strain.

These research findings confirmed the importance of plasmids as vehicles for the spread of antimicrobial resistance and bacterial toxins among bacterial pathogens and help the research community better understand this public-health challenge that has limited the effectiveness of antimicrobials to prevent and treat infections. A manuscript describing the study can be found in Foodborne Pathogens and Diseases.

For more information, contact Steven Foley, Ph.D., Deputy Director, Division of Microbiology, FDA/NCTR.

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Cancer Research at NCTR... Latest News 

Lung Tumor Model Improves Understanding of Cancer-Drug Resistance
NCTR scientists detected the outgrowth and enrichment of mutant tumor cells clinically associated with the development of drug resistance. They cultured primary lung tumor organoids—tiny, self-organized three-dimensional tissue cultures—in the presence of varying concentrations of erlotinib (Tarceva®), a drug used to treat lung cancer. Using this novel model and a sensitive method for mutation detection (ACB-PCR) they detected increases in mutant tumor cells after culture. Better patient outcomes are being achieved using personalized cancer treatments, by selecting therapies based on tumor genetics. Unfortunately, resistance to the therapy occurs frequently and limits drug efficacy. Because this lung tumor-organoid model reproduces the cellular and mutational diversity of human lung adenocarcinomas, it has the potential to identify treatment strategies and drug combinations that reduce or eliminate drug resistance.

For more information, please contact Barbara L. Parsons, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR. 

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Comparative Toxicity of 34 FDA-Approved Cancer Drugs 
Scientists from FDA’s National Center for Toxicological Research and Center for Drug Evaluation and Research demonstrated that direct hepatocyte toxicity may contribute to the mechanism of kinase inhibitor (KI)-induced liver damage. KIs are a relatively new type of drug that has played an increasingly important role in the treatment of cancer and inflammation. The scientists examined the toxicity of 34 FDA-approved KIs in cultured rat- and human-liver cells (hepatocytes). The hepatocytes were treated with KIs at ten concentrations that reflect maximum therapeutic clinical blood levels (Cmax). The results of the study indicate that direct hepatocyte toxicity may contribute to the mechanism of KI-induced liver damage because some of the tested KIs caused significant toxicity in human hepatocytes at concentrations equal to Cmax. The data from this study helps FDA develop a better understanding of why some KIs result in liver damage. Furthermore, the results suggest that in vitro models may be useful in predicting clinical liver toxicity. A manuscript describing the study is available in Toxicology Letters.  

For more information, please contact Dr. Qiang Shi, Ph.D., Division of Systems Biology, FDA/NCTR.   

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Targeted Therapy for Triple-Negative Breast Cancer (TNBC)
NCTR scientists have shown that vorinostat—an FDA-approved histone deacetylase (HDAC) inhibitor—re-expresses estrogen and progesterone receptors, making cancer cells sensitive to targeted drugs like tamoxifen. This finding is important for treating TNBC, a highly aggressive type of breast cancer that currently lacks targeted therapies because of its lack of receptors. The five TNBC subtypes—each with a different molecular profile—are known to respond differently to cancer therapies, but HDAC inhibitors are emerging as a possible new therapy. At the 2018 American Association of Cancer Research Annual Meeting, Beverly Lyn-Cook. Ph.D., presented NCTR research showing that vorinostat controls critical microRNAs (epigenetic targets for drug development) that play important roles in cell proliferation, drug resistance, cell invasion, and metastasis. Cell lines from both African Americans and European American women were used in the research study, which was funded by FDA’s Office of Women’s Health. The data from this study contributes to meeting the unmet need for targeted therapies for TNBC. 

For more information, please contact Beverly Lyn-Cook, Ph.D., Division of Biochemical Toxicology, FDA/NCTR. 

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NCTR’s Role in the American Association of Cancer Research (AACR) Annual Meeting
NCTR’s Beverly Lyn-Cook, Ph.D., played a key role in the 2018 AACR Annual Meeting held April 12-14, 2018, in Chicago, Illinois. AACR is the leading forum for cutting-edge basic, translational, and clinical cancer discoveries and it is during the annual meeting that the research agenda for the cancer community is set. This year’s meeting—with the theme “Driving Innovative Cancer Science to Patient Care”—was the largest in AACR’s history with more than 22,500 participants from around the world. Dr. Lyn-Cook was engaged in the following 2018 AACR Annual Meeting activities. 

  • Co-chaired a pre-conference Distinguished Lectureship titled “From Bench to Community: Driving Innovative Cancer Research to Patient Care and Health Equity” in honor of Minority Cancer Health week. The lectureship was sponsored by the AACR Minorities in Cancer Research Council, of which Dr. Lyn-Cook is a member.
  • Moderated the Thirteenth Annual Undergraduate Student Caucus, sponsored by the AACR Science Education and Career Advancement Committee, of which Dr. Lyn-Cook is also a member.
  • Served as lead judge of the poster competition where over 100 undergraduates from across the country competed. 

For more information including meeting summaries and the recorded Webcasts, visit the AACR website.

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Read the latest NCTR Research Highlights – June 28, 2018

First Report on the CLARITY-BPA Study
A “Draft NTP Research Report on the CLARITY-BPA Core Study: A Perinatal and Chronic Extended-Dose-Range Study of Bisphenol A in Rats” was publicly released by the National Toxicology Program (NTP) in February 2018, and was reviewed by a panel of experts in April 2018. The NCTR-conducted two-year study was part of an NTP-led effort known as CLARITY-BPA — short for Consortium Linking Academic and Regulatory Insights on BPA Toxicity. As stated in NTP’s Update Newsletter, “National Institute of Environmental Health Sciences (NIEHS) and FDA convened CLARITY-BPA to study the full range of potential health effects from exposure to BPA in rats and to provide data that could be used for regulatory decisions. CLARITY-BPA united standard research practices used by regulators, called federal guideline studies, with innovative research conducted at universities through grants from NIEHS.” CLARITY-BPA includes two components:

  • core chronic rat study — conducted at FDA/NCTR
  • grantee studies — conducted by the academic researchers using biological samples provided by FDA/NCTR and that originated from the same core study. 

The consortium involved 14 NIEHS-funded academic grantees and scientists from:

  • NIEHS/NTP
  • NIEHS/Division of Extramural Research and Training
  • FDA/NCTR
  • FDA/Center for Food Safety and Applied Nutrition.

The final Core Study Research Report is expected in August 2018. Follow the progress of CLARITY-BPA. For more information, contact Barry Delclos, Ph.D. or Luísa Camacho, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.

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NCTR Scientists to Present at HESI Gut Microbiome Workshop 
This June 25-26, 2018 in Alexandria, Virginia scientists from NCTR will participate in the Health and Environmental Sciences Institute’s (HESI) Gut Microbiome Workshop — Dr. Donna Mendrick is co-chair and will be the introductory speaker, Dr. Carl Cerniglia is an invited speaker, and Drs. Steve Foley and Sangeeta Khare will serve as discussion leaders. The HESI website states “This workshop will review the science and initiate discussions on multiple topics, including a) identification of biomarkers of toxicity for alterations in gut microbial function, b) if changes in the microbiome can affect efficacy of medicines, and c) if exposure to xenobiotics can eventually result in a disease state through changes in the microbiome. Conclusions from this workshop will help determine the location of data gaps so researchers can start answering these questions.”

For more information about the workshop visit http://hesiglobal.org/event/the-gut-microbiome-workshop/.

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FDA and Other Federal Agencies Release Strategic Plan for Microbiome Research
Carl Cerniglia, Ph.D., Director of NCTR’s Division of Microbiology, represented FDA on the Microbiome Interagency Working Group comprised of 23 U.S. government agencies. This working group was charged with developing a five-year Interagency Strategic Plan for Microbiome Research. The strategic plan outlines the objectives, structure, and principles for coordinated research in the important field of microbiome research. The plan’s executive summary states, “Microbiome science aims to advance understanding of microbial communities (microbiomes) for applications in areas such as health care, food production, and environmental restoration to benefit individuals, communities, and the planet.”

You can find more information on the National Science Foundation web site.

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Genome-Wide Mutation Detection
Scientists from NCTR demonstrated that genome sequencing—using InterClonal Genetic Variation (ICGV)—can directly measure gene mutations. One of the advantages of ICGV is that it can identify mutations genome-wide by comparing next-generation sequencing data from single-cell clones from the same organism. To provide a proof-of-principle for this assay, E. coli and rats were exposed to standard mutagens. In the bacterial studies, dose- and treatment time-dependent increases in mutation frequency were detected using ICGV. In fact, using ICGV, scientists could identify a ∼20-fold increase in mutations in the T-cell clones cultured from mutagen-treated rats.

Conventional mutation assays estimate the frequency of mutations by screening for the activation or inactivation of reporter genes. These reporter genes enable scientists to measure mutation frequency, but these assays can only detect mutations in narrow areas of the genome and their use is often restricted to certain models. ICGV demonstrates that genetic differences of single-cell clones can be used for genome-wide mutation detection in a variety of species and without the need for reporter genes. This work by scientists at NCTR was recently awarded the FDA Commissioner’s Special Citation. An article describing these findings is now available in Mutation Research/Genetic Toxicology and Environmental Mutagenesis.

For more information, please contact Javier R. Revollo, Ph.D., Division of Genetic and Molecular Toxicology, FDA/NCTR.

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Microbial Contamination Found in Tattoo and Permanent Makeup (PMU) Inks
Scientists from FDA’s NCTR and Center for Food Safety and Nutrition surveyed unopened, sealed bottles of tattoo and PMU inks sold in the United States for microbial contamination and found evidence that contamination of tattoo and PMU inks is more common than previously thought. The results of this study highlight the importance of monitoring these products for potentially pathogenic microorganisms. Among the 85 tattoo and PMU inks purchased from 13 companies, 42 inks (49%) were contaminated mostly with bacteria, but fungi were also detected. However, levels of microbiological contamination varied, and 83 bacterial strains belonging to 20 genera and 49 species were identified, including possibly clinically relevant pathogenic strains — Pseudomonas aeruginosa, Dermacoccus barathri, and Roseomonas mucosa. Tattoo and PMU ink-related microbial infections have recently increased and are now considered to be an emerging safety concern for public health. A manuscript describing the study is available in the Journal of Applied Microbiology.
For more information, please contact Carl Cerniglia, Ph.D., Director, Division of Microbiology, FDA/NCTR or Seong-Jae Kim, Ph.D., Division of Microbiology, FDA/NCTR.

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NCTR...Focused on Food Safety

NCTR Collaboration with the Food Safety Commission of Japan
On March 20, 2018, two Research Collaboration Agreements (RCA) were signed between FDA/NCTR and the Food Safety Commission of Japan (FSCJ) to work on two separate joint research projects. Today’s consumer products are increasingly globalized, impacting public health worldwide and posing new challenges for regulatory authorities. In the first project, Weida Tong, Ph.D., NCTR Division Director, Bioinformatics and Biostatistics, will be collaborating with FSCJ on a project to develop knowledge base tools that can help international risk-assessment agencies who work on chemical toxicological prediction. Scientists from both organizations will test and verify the applicability of NCTR-developed predictive models for hepatotoxicity, carcinogenicity, and endocrine disruption on food-related products provided by Japan. FSCJ is currently developing a toxicity database and its feedback on the applicability and usability of FDA’s knowledge base tools serves a proof-of-concept for developing a mutually beneficial mechanism and leveraging the resource and knowledge between government agencies in the global context. These tests and the lessons learned will provide information to improve international usability of the tools and further the development of tools and adoption of technologies needed by regulatory authorities throughout the world.

In the second project, Daniel Doerge, Ph.D., NCTR Division of Biochemical Toxicology will be collaborating with FSCJ to provide the most appropriate suite of tools for use in risk assessment of contaminants in food (e.g. acrylamide, furan, bisphenol A, and arsenic species). The scientists will combine pharmacokinetic studies and physiologically based pharmacokinetic modeling with dietary intake assessments and benchmark dose analysis for dietary contaminants. This interactive project will provide a platform for application of basic research and testing combined with computational analysis to evaluate toxicological findings in the context of human internal exposures from dietary intake estimates in countries around the world. Both FDA and FSCJ hope to establish a set of best practices to minimize the uncertainty of regulatory decisions that often combine high-dose animal toxicity studies with limited human data. 

SAVE THE DATE: 8th Annual 2018 Global Summit for Regulatory Science (GSRS18)
Theme:
   Risk/Benefit of Dietary Supplements and Herbal Medicine in the Era of Data Science
Location:  Beijing, China
Date:  September 26-27, 2018
Deadline to submit abstract applications – July 31, 2018
There is no registration fee; however, registration is required to attend the conference.
For recurring updates, abstract guidelines, agenda, and more visit www.fda.gov/globalsummit.

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Spread of Plasmids That Can Transfer Antimicrobial Resistance (AMR)
NCTR scientists have demonstrated that when certain Salmonella strains were exposed to different concentrations of specific antibiotics, there was an increase in the rate of resistance transfer by plasmids. In collaboration with FDA’s Center for Veterinary Medicine (CVM), NCTR scientists used techniques to better understand the diversity of organisms and studied the presence of plasmids ─ independent DNA molecules commonly found in cells ─ that can contribute to AMR and enhanced disease-causing ability. NCTR and CVM continue their efforts in this vastly understudied area of research ─ comparing the impact of antimicrobial exposure on the spread of plasmids that can transfer AMR and the potential for increased pathogenicity to a cell. This study continues in 2018 and manuscripts describing this research can be found at Genome Announcements and BMC Genomics.

For additional information, please contact Steven L. Foley, Ph.D., Division of Microbiology, FDA/NCTR.

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Key Animal Model of Arsenic Toxicity
Results from an NCTR study provide links between administered dose, metabolism, and internal exposures from a key animal model of arsenic toxicity. Metabolic methylation of inorganic arsenic decreases acute toxicity; however, tissue binding of arsenic metabolites is evidence for simultaneous formation of toxic species. Pregnant and fetal CD-1 mice represent a key animal model for arsenic carcinogenesis since adult-only exposures have minimal effects. The study evaluated inorganic arsenic and its metabolites in blood and tissues from maternal and fetal CD-1 mice after repeated administration of arsenic through drinking water. Because arsenic is widely distributed in the earth's soil and water, and human diseases are linked with arsenic exposures similar to dietary-intake estimates it is important for FDA to better understand the cancer risks from human exposure to environmental arsenic. A manuscript describing the study can be found in Food and Chemical Toxicology

For additional information, please contact Daniel R. Doerge, Ph.D., Division of Biochemical Toxicology, FDA/NCTR.

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RAPID-B: A Selective Real-Time Detector of Pathogenic Bacteria
Scientists from NCTR’s Division of Systems Biology demonstrated RAPID-B —a field portable, ultrasensitive, and selective real-time flow cytometric detector of pathogenic bacteria in food, such as E. coli O157, Salmonella, and Listeria monocytogenes at a national government conference. The scientists demonstrated this portability by transporting the instrument by car to the 2018 U.S. Department of Agriculture (USDA) Food Safety Inspection Service and Agriculture Research Service Annual Conference in Shepherdstown, West Virginia. As part of the conference, the NCTR scientists demonstrated RAPID-B and described detection of the different bacterial pathogens as well as “mad cow” prions. Several USDA administrators and lead scientists requested personal demonstrations. Collaborations between NCTR and USDA are planned in this area with USDA having identified portable, real-time detection of Listeria and Salmonella in food as a department priority.

For additional information, please contact Jon Wilkes, Ph.D. or Dan Buzatu, Ph.D.,  Division of Systems Biology, FDA/NCTR.

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Neuroscience News at NCTR

Model of Traumatic Brain Injury (TBI) to the Blood-Brain Barrier (BBB)
NCTR scientists — in collaboration with scientists from the University of Arkansas at Fayetteville and Universidad Autonoma de San Luis Potosi and Universidad Juarez Autonoma de Tabasco in Mexico — have developed an in vitro BBB model that simulates the BBB damage resulting from TBI observed in vivo. The model consists of primary rat-brain microvascular endothelial cells grown on a flexible substrate, which is then exposed to different percentages of deformation induced by biaxial stretch to model mild, moderate, and severe TBI. The results of the study show a stretch-dependent increase in cell death and apoptosis. The BBB regulates the passage of substances from the blood to the brain and vice versa. Disruption of this barrier, as can occur after severe head injuries (TBI), can induce neuroinflammation and cell death. This study demonstrates the utility of the in vitro BBB model in simulating TBI and supports the use of biaxial stretch as a valuable tool to study the mechanisms of TBI and potential therapies. A manuscript describing the newly developed model was published in Molecular Neurobiology.
For more information, please contact Hector Rosas-Hernandez, Ph.D, or Syed Ali, Ph.D., Division of Neurotoxicology, FDA/NCTR.

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Award-Winning Publication on the Effects of Chemotherapeutics in an Animal Model
Scientists from FDA’s National Center for Toxicological Research and Center for Drug Evaluation and Research, and the University of Arkansas for Medical Sciences have demonstrated that two commonly used chemotherapeutics (cyclophosphamide and doxorubicin), administered alone or in combination, did not induce behavioral alterations in a female-mouse model reflective of human breast-cancer patients. The study was designed to investigate the memory and attention problems that some female breast-cancer patients experience after chemotherapy – sometimes known as “chemo” brain. Thus, the selected chemotherapeutics were administered intravenously at clinically-relevant doses and the mice were assessed using a comprehensive test battery to detect effects on learning and memory, general activity, and motor coordination. The results of this study show no significant behavioral alterations and provide new insights into two commonly used chemotherapeutics. The lead author of the article —Timothy Flanigan, Ph.D. — was awarded the Developmental Neurotoxicology Society’s “2018 Richard Butcher New Investigator Award” for this publication. The article is available online at Toxicological Sciences.
For more information, contact Sherry Ferguson, Ph.D., Acting Director, Division of Neurotoxicology, FDA/NCTR.

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Fluidic Biomarkers of Neurotoxicity
In a consortium effort with the Health and Environmental Sciences Institute (HESI), NCTR scientists collaborated with experts from other government agencies, academia, and industry to search for non-invasive biomarkers of neurotoxicity that can be evaluated in circulating biofluids, such as serum, plasma, urine, and cerebrospinal fluid. In the first set of studies, several unique candidates have been identified and an initial summary of these findings was published in Experimental Biology and Medicine. Preliminary findings from this work were presented as a symposium at the Winter Toxicology Forum 2017 in Washington D.C. and a workshop on the study was presented at the 2018 Society of Toxicology Annual Meeting.
For more information, please contact Syed Z. Imam, Ph.D., Division of Neurotoxicology, FDA/NCTR.

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Alzheimer's Disease – FDA Research on Ethnicity and Gender Differences
NCTR scientists, Drs. Sherry Ferguson and Vijayalakshmi Varma, presented a webcast lecture titled “Ethnicity- and Gender-Related Differences in Alzheimer’s Disease” as part of the FDA Grand Rounds series. Alzheimer’s Disease (AD) has a higher incidence in women at later ages and poses a greater threat to African American and Hispanic communities. This presentation discussed NCTR’s novel research into proteins implicated in AD and their levels in post-mortem African-American and Caucasian brain tissues from both genders to explore ethnicity- and gender-related differences. Research studies such as these are crucial to a precision-medicine approach to treating neurodegenerative diseases like AD.
For more information please contact Sherry Ferguson, Ph.D., Acting Director, Division of Neurotoxicology, FDA/NCTR or Vijayalakshmi Varma, Ph.D., Division of Systems Biology, FDA/NCTR or watch the webcast on www.FDA.gov.

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Multi-Electrode Array (MEA) Analysis for Neurotoxicity
NCTR scientists have successfully set up a high-throughput MEA system to record electrical functions of brain cells as a read-out for neurotoxicity, and have demonstrated that certain neurotoxic agents can alter electrical functions of cultured human-brain cells, such as neuronal firing rates, neuronal spikes, and electrical bursts. The MEA system is a unique emerging technology in the drug-development industry to evaluate the neurotoxicity of a drug or other compound and to predict their safety and efficacy. These NCTR studies can help support agency reviewers with validation or interpretation of MEA data submitted by industry and inform decisions about the safety and efficacy of such drug candidates.
For more information, please contact Syed Z. Imam, Ph.D., Division of Neurotoxicology, FDA/NCTR.

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NCTR... Improving Understanding of Liver Toxicity

Role of Cytochromes in Dronedarone-Induced Liver Toxicity
Dronedarone, a drug used to treat patients with cardiac arrhythmias, is associated with liver injury. Research scientists in NCTR’s Division of Biochemical Toxicology investigated the role of drug metabolism in dronedarone-induced liver toxicity. Cytochrome P450s (CYPs) are enzymes that metabolize external substances, such as medications that are ingested and internal substances, such as toxins that are formed within cells. In this NCTR study, a panel of 14 HepG2-derived human cell lines that stably express individual CYPs was used to identify the metabolic activity of each CYP toward dronedarone.  A key finding of the study was that three CYP isoforms, or protein variants — CYP3A4, 3A5, and 2D6 — were involved in the metabolism of dronedarone and that metabolism by these CYPs decreased dronedarone’s toxic effects on human cells. Thus, implying that individuals with low levels of CYP3A4, 3A5, and 2D6 enzymes may be more susceptible to dronedarone-induced liver toxicity. An article on this study was recently published in Archives of Toxicology.
For more information, please contact Lei Guo, Ph.D., Division of Biochemical Toxicology, FDA/NCTR. 

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Therapeutic Bile Acids and the Risks for Liver Toxicity
Bile acids have long been used to treat many disorders, such as gallstones, cholestatic liver disease (when substances normally excreted into bile are retained), and more recently used to treat diabetes and obesity. Several bile-acid derivatives (e.g., obeticholic acid) have been recently approved or submitted to FDA for approval. However, the use of bile acids also carries risk, particularly toxicity to the liver. Scientists from FDA’s NCTR and Center for Drug Evaluation and Research and the Hannover Medical School in Germany have published a review article that presents the uses of bile acids in therapy, as well as the associated toxicity risks. The authors discuss toxicity observed in clinical trials data, and data mined from surveillance programs designed to detect toxicity of drugs on the market. The authors further discuss the variation of molecular mechanisms of action of bile acids across different species, illuminating the difficulties of predicting effects in one species from those observed in others. The article is now available online at Alimentary Pharmacology & Therapeutics.
For more information, please contact Minjun Chen, Ph.D., Division of Bioinformatics and Biostatistics, FDA/NCTR.

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Monograph Published on Drug-Induced Liver Toxicity 
Drug-induced liver injury (DILI) has been one of the most vexing problems in toxicology for the pharmaceutical industry and their regulators for many decades. Many drugs fail in development due to DILI, and others are taken off the market after regulatory approval when DILI appears. When a drug fails, people who would not experience toxicity are denied its potential therapeutic benefits. Monographs such as this work edited by DILI experts Minjun Chen, Ph.D. from NCTR and Yvonne Will, Ph.D. from Pfizer are paramount in moving the field forward by summarizing the most current, relevant science. The book is not only a comprehensive review, but encompasses DILI over a drug’s life cycle — from drug discovery to clinical trials to post-market and clinical settings. The methodologies to test DILI risk are systematically discussed, including those in cells, animals, emerging genetic methods, and human clinical trials. The book, titled Drug-Induced Liver Toxicity was published by Humana Press, a part of Springer Nature in hard copies and online.
For more information, please contact Minjun Chen, Ph.D., Division of Bioinformatics and Biostatistics, FDA/NCTR. 

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Early and Sensitive Biomarkers of Liver Toxicity Discovered
NCTR scientists used a well-known chemical toxic to the liver – thioacetamide (TAA) –  which could be a liver carcinogen in humans, to discover microRNA biomarkers of liver toxicity. After administering the chemical to rats, scientists used next-generation sequencing to discover early and sensitive microRNA biomarkers for liver injury and tumor progression. These biomarkers could improve cancer diagnosis, prognosis, and management. A paper summarizing the findings of this study can be found in Scientific Reports and research on this topic continues in 2018.

For more information, please contact Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics, FDA/NCTR.

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