National Center for Toxicological Research (NCTR)

Jefferson, VA, United States

National Center for Toxicological Research (NCTR)

Jefferson, VA, United States
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Goodsaid F.M.,U.S. Food and Drug Administration | Mendrick D.L.,National Center for Toxicological Research (NCTR)
Science Translational Medicine | Year: 2010

The gap between development of exploratory biomarkers and their acceptance in drug development and regulatory review is a hurdle in the development of better therapies. The U.S. Food and Drug Administration has developed a regulatory process for biomarker qualification to accelerate the process by which new biomarkers are integrated in the development of therapies.


Walters J.L.,National Center for Toxicological Research (NCTR) | Paule M.G.,National Center for Toxicological Research (NCTR)
Neurotoxicology and Teratology | Year: 2017

Thousands of infants and children undergo complicated surgical procedures that require prolonged periods of anesthesia and/or sedation each year. A growing body of preclinical research suggests pediatric anesthetics are harmful to the developing brain; yet, the extent to which these effects generalize to the clinical setting remains unclear. As there will be a continuing need for surgical and other interventions requiring sedation and/or anesthesia during the neonatal period, it seems clear that research efforts should focus on determining the extent to which general anesthetics can affect the developing brain as well as determining strategies for preventing or ameliorating the adverse effects associated with exposure to such agents. The purpose of this paper is to provide a review of the preclinical literature examining the effects of general anesthesia on brain and behavioral development. This paper will detail the effects of different anesthetic agents on various indices of neurotoxicity and functional outcomes as well as provide a review of potential protective compounds and suggestions for areas of future research. © 2016


Yang X.,National Center for Toxicological Research (NCTR) | Doerge D.R.,National Center for Toxicological Research (NCTR) | Fisher J.W.,National Center for Toxicological Research (NCTR)
Toxicology and Applied Pharmacology | Year: 2013

Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100. μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. © 2013.


Talpos J.C.,National Center for Toxicological Research (NCTR)
Drug Discovery Today | Year: 2017

Research indicates that relieving the cognitive and negative symptoms of schizophrenia is crucial for improving patient quality of life. However effective pharmacotherapies for cognitive and negative symptoms do not currently exist. A review of ongoing Phase III clinical trials indicates that, despite numerous compounds being investigated for cognition in schizophrenia, few are actually novel and most are not backed by empirically driven preclinical research efforts. Based on these trials, and a general disinvestment in development of novel therapies for schizophrenia, the likelihood of a major advancement in treating cognitive differences in schizophrenia does not look promising. Possible ways in which the remaining resources for development of novel treatment for schizophrenia can best be leveraged are discussed. © 2017


Ferguson S.A.,National Center for Toxicological Research (NCTR) | Sarkar S.,National Center for Toxicological Research (NCTR) | Schmued L.C.,National Center for Toxicological Research (NCTR)
Behavioural Brain Research | Year: 2013

The APP/PS1 double transgenic mouse is an Alzheimer's Disease-like model. However, cognitive deficits measured at one age do not necessarily indicate age-related progressions. Further, results of the most widely used behavioral assessment, water maze performance, are generally limited to 1-2 endpoints. Here, male APP/PS1 and noncarrier wildtypes (n=11/group) were assessed at 7-15 months of age for water maze, open field, and motor coordination performance. Body weights and motor coordination were comparable for both groups throughout. Beginning at approximately 9 months of age, the transgenic group exhibited hypoactivity in the open field which continued throughout. Latency to locate the platform and swim path length were longer in the transgenic group; however, these appeared to be more related to increased floating and thigmotactic behavior and only partially related to a cognitive impairment. Age-related decrements in performance were not substantial; however, substantial plaque numbers were measured in six representative 16-month-old transgenic mice. The stability of water maze performance may be related to the longitudinal testing and repetitive experience, which previous research has demonstrated can confer beneficial effects on behavior and plaque deposition in transgenic Alzheimer's Disease models [1]. These results emphasize the importance of measuring multiple water maze endpoints and demonstrate the feasibility of longitudinal assessments in this model. © 2013.


Pogribny I.P.,National Center for Toxicological Research (NCTR) | Rusyn I.,University of North Carolina at Chapel Hill
Advances in Experimental Medicine and Biology | Year: 2013

Tumorigenesis, a complex and multifactorial progressive process of transformation of normal cells into malignant cells, is characterized by the accumulation of multiple cancer-specific heritable phenotypes triggered by the mutational and/or non-mutational (i.e., epigenetic) events. Accumulating evidence suggests that environmental and occupational exposures to natural substances, as well as man-made chemical and physical agents, play a causative role in human cancer. In a broad sense, carcinogenesis may be induced through either genotoxic or non-genotoxic mechanisms; however, both genotoxic and non-genotoxic carcinogens also cause prominent epigenetic changes. This review presents current evidence of the epigenetic alterations induced by various chemical carcinogens, including arsenic, 1,3-butadine, and pharmaceutical and biological agents, and highlights the potential for epigenetic changes to serve as markers for carcinogen exposure and cancer risk assessment. © 2013 Springer Science+Business Media New York.


Pogribny I.P.,National Center for Toxicological Research (NCTR)
Experimental Oncology | Year: 2010

The development of cancer is a complex multifactorial process traditionally viewed as the stepwise accumulation of genetic alterations. However, recent advances in field of cancer research have established that all major human cancers, in addition to a large number of genetic alterations, exhibit prominent epigenetic abnormalities. This review presents current evidence that epigenetic alterations are not only key features of cancer cells, but they also may be key events in the initiation of carcinogenesis. The early appearance of cancer-linked epigenetic changes that are similar to those found in malignant cells provides a unique opportunity to use them as biomarkers in early cancer detection, indicators of carcinogenic exposure, and in the assessment of the carcinogenic potential of environmental chemical and physical agents. Copyright © Experimental Oncology, 2010.


Tryndyak V.P.,National Center for Toxicological Research (NCTR) | Beland F.A.,National Center for Toxicological Research (NCTR) | Pogribny I.P.,National Center for Toxicological Research (NCTR)
International Journal of Cancer | Year: 2010

The conversion of early stage tumors into invasive malignancies with an aggressive phenotype has been associated with the irreversible loss of E-cadherin expression. The loss of E-cadherin expression in human tumors, including breast cancer, has been attributed to promoter CpG island hypermethylation and direct inhibition by transcriptional repressors. Recent evidence demonstrates that up-regulation of E-cadherin by microRNA-200b (miR-200b) and miR-200c through direct targeting of transcriptional repressors of E-cadherin, ZEB1, and ZEB2, inhibits epithelial-to-mesenchymal transition (EMT), a crucial process in the tumor progression. We demonstrate that microRNA miR-200 family-mediated transcriptional up-regulation of E-cadherin in mesenchymal MDA-MB-231 and BT-549 cells is associated directly with translational repression of ZEB1 and indirectly with increased acetylation of histone H3 at the E-cadherin promoter. The increase in histone H3 acetylation may be attributed to the disruption of repressive complexes between ZEB1 and histone deacetylases and to the inhibition of SIRT1, a class III histone deacetylase. These events inhibit EMT and reactivate a less aggressive epithelial phenotype in cancer cells. Additionally, disruption of ZEB1-histone deacetylase repressor complexes and down-regulation of SIRT1 histone deacetylase up-regulate proapoptotic genes in the p53 apoptotic pathway resulting in the increased sensitivity of cancer cells to the chemotherapeutic agent doxorubicin. © 2009 UICC.


Pogribny I.P.,National Center for Toxicological Research (NCTR)
Breast Cancer Research | Year: 2010

Breast cancer is the most prevalent malignancy in women. The success of breast cancer treatment relies on the ability to detect the disease and correct molecular abnormalities at an early stage of disease development. A recent article describes a marked decrease in the levels of ferroportin in breast cancer. More importantly, the presented results demonstrate convincingly the incredible diagnostic and prognostic value of ferroportin and hepcidin gene expression in breast cancer and suggest that determination of these two molecular markers may be used as guidance toward individualized therapy for breast cancer patients. © 2010 BioMed Central Ltd.


Alusta P.,National Center for Toxicological Research (NCTR)
Journal of magnetic resonance imaging : JMRI | Year: 2010

To examine preprocessing methods affecting the potential use of Magnetic Resonance Spectroscopy (MRS) as a noninvasive modality for detection and characterization of brain lesions and for directing therapy progress. Two reference point re-calibration with linear interpolation (to compensate for magnetic field nonhomogeneity), weighting of spectra (to emphasize consistent peaks and depress chemical noise), and modeling based on chemical shift locations of 97 biomarkers were investigated. Results for 139 categorized scans were assessed by comparing Leave-One-Out (LOO) cross-validation and external validation. For distinction of nine brain tissue categories, use of re-calibration, variance weighting, and biomarker modeling improved LOO classification of MRS spectra from 31% to 95%. External validation of the two best nine-category models on 47 unknown samples gave 96% or 100% accuracy, respectively, compared with pathological diagnosis. Preprocessing of MRS spectra can significantly improve their diagnostic utility for automated consultation of pattern recognition models. Use of several techniques in combination greatly increases available proton MRS information content. Accurate assignment of unknowns among nine tissue classes represents a significant improvement, for a much more demanding task, than has been previously reported.

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