Executive Summary

Introduction

The Division of Chemistry contributes to new NCTR/FDA-directed research initiatives in mass spectrometry (MS)-based proteomics and nuclear magnetic resonance (NMR)-based metabonomics programs. These new facilities are now fully operational and complement the program Centers in Structural and Functional Genomics, Toxicogenomics, Hepatotoxicology, and other research divisions to elucidate mechanisms of toxicity. The Division also has programs on MS-based investigations in counter-terrorism, environmental chemistry, biomarkers, and sensor technology for rapid screening. Computational chemistry and artificial intelligence are also used in predictive toxicology and pattern recognition of bioterror agents. The Division continues to provide expertise in analytical chemistry and spectroscopy to the National Toxicology Programs (NTP) and other research programs Center-wide.

FY 2003 Accomplishments

The Mass Spectrometry Proteomics Laboratory was established in 2002 and collaborations have been initiated within NCTR (Center for Hepatotoxicology, Divisions of Chemistry, Microbiology, and Neurotoxicology) and externally. Projects have ranged from the identification of differentially expressed proteins to large-scale proteome mapping. Proteomics of rat liver mitochondria was chosen as a first project because of the critical importance of this organelle in cell function (E7183). We identified more than 1500 unique proteins, which will enable us to examine changes in protein expression and mitochondrial function in disease states or following drug treatments. MS approaches (nanoLC/MS/MS and de novo sequencing) were also used to identify proteins induced in Mycobacterium vanbaalenii PYR-1 that were exposed to pyrene, a toxic polycyclic aromatic hydrocarbon (PAH) (E7118). These studies will aid us to elucidate the mechanisms by which bacteria decontaminate environmental toxins.

The Mass Spectrometry Counterterrorism Program has used matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) MS and a pyrolysis metastable atom bombardment (MAB)-TOF MS to produce unique mass spectra of pathogenic Vibrio and Salmonella spp. A computational method was invented to improve the quality of MALDI spectral methods of these biological pathogens and to correctly identify bioterror agents (E07146). With this approach, bioterror agents or hoax materials, such as talc or flour, may be rapidly characterized. In collaboration with the Microbiology Division and the Arkansas Regional Laboratory’s (ARL) Microbiology staff, we are developing a method for microbial isolation that dramatically reduces analysis times of contaminated food to only a few hours.

In computational chemistry, the collaboration with the University of Arkansas for Medical Sciences (UAMS) continues on the brain tumor diagnostic method to achieve tissue characterization (E7131) and develop an early, noninvasive breast tumor detection method. Models have been developed using NMR spectral information and internal molecular structural connectivity information for predictive toxicology. A patent was submitted for the three-dimensional quantitative spectrometric data-activity relationship (3D-QSDAR) method (E7126). QSDAR modeling was used to predict the toxic equivalence factors (TEFs) for a small set of chlorinated dioxin molecules (E7077), that were assumed as nontoxic, and half of them predicted toxic with our model. FDA/ORA experimentally validated these predictions to the same level of magnitude, indicating the impressive accuracy of the QSDAR approach and the alarming toxicity of these substances. Rapid methods such as 3D-QSDAR may rapidly estimate toxicity of molecules and minimize the use of experimental animals.

A NMR-based Metabonomics Research Program has been established to aid the FDA in nonclinical and clinical drug safety assessment and drug efficacy issues. Metabonomics is a quantitative spectral “fingerprint” measurement of the dynamic endogenous metabolite response of living systems to pathophysiological stimuli or genetic modification. We are investigating metabolic changes in biofluids caused by drugs, analgesics and herbal products that may produce beneficial or deleterious health effects. Our program includes investigations on acetaminophen, tamoxifen, glitazone (with CDER), TCDD, doxorubicin (with CDER), cancer and liver diseases. Collaborations with UAMS scientists have been initiated to investigate the biological effects of ephedrine, ethanol, baby diets, cardiovascular disease and aging on health using the metabonomics approach.

In environmental chemistry research, collaboration with the Division of Molecular Epidemiology was established to assess the safety of hair dyes (E6978), which have been reported to increase the risk of developing bladder cancer with frequent usage. MS methods were developed to detect the bladder carcinogen 4-aminobiphenyl (4-ABP) in hair dyes. Some batches of para-phenylenediamine (PPD), a key reagent used in hair color development, were contaminated with 4-ABP and may be a source of 4-ABP contamination in hair dyes. We provided this analytical method to the cosmetic industry so that they may monitor the purity of PPD and other aromatic amine constituents used in hair dyes to assure the safety of hair coloring products. Investigations on the stability of biologically active constituents of herbal products containing St. John’s Wort were carried out and showed some key chemicals degrade under simulated gastric conditions, or in acidic fruit drinks, and through exposure to light. Food Quality Indicator (FQI), a rapid, chemical sensor to assess food quality (E7080) has been evaluated by The Canadian Center for Fisheries Innovation (CCFI), St. Johns, Newfoundland, Canada. Their findings show that FQI is rapid, sensitive, rugged, and simple enough that multiple analysts can obtain results of equal quality. A Cooperative Research and Development Agreement (CRADA) has been developed with Litmus for a commercial outlet and partial support for extension of the FQI technology. An interagency agreement has been established with the Federal Aviation Administration (FAA) to develop rapid sensor detection methods to screen for explosives in counterterrorism (E7081).

The Chemistry National Toxicology Program (NTP) Analytical Team and Mass Spectrometry Branch continued analyses of test articles of numerous NCTR/National Institute of Environmental Health Sciences (NIEHS) Interagency Agreement (IAG) studies and collaborations Center-wide. Analytical support was provided to toxicological investigations on Aloe barbadensis, ethinyl estradiol, zidovudine, lamivudine, Ephedra sinica (Ma Huang), nelfinavir, nevirapine, retinol palmitate, retinoic acid, and 13-cis-retinoic acid. Analytical methods were developed or validated to separate Ephedra alkaloids, isomers of retinol palmitate and retinoic acid. Guidance was provided to National Institute of Health (NIH) on the alkaloid content of Ephedra sinica to be used in studies being conducted at NIEHS and NCTR.

FY 2004 Plans

Proteomics:

• Development of bioinformatic tools to aid in the analysis of proteomics data.
• Identify protein markers associated with the toxicity of acetaminophen and other hepatotoxins (with the Center for Hepatotoxicology).

Counterterrorism:

• Develop automated systems for rapid sample isolation and cell preparation, and for robotic spectral acquisition. Other foodborne pathogens to be profiled include Enterohemorhagic E. coli and Listeria monocytogenes.
• Continue refinement of pattern recognition/mass spectral methods for the rapid identification of biological pathogens and hoax materials.

NMR-Based Metabonomics:

• Acetaminophen, a hepatotoxin, will be used in a NMR-based metabonomics study (E7150) in collaboration with the Center for Hepatotoxicology, Functional Genomics, Proteomics, Biometry, CDER, and UAMS.

Computational Chemistry:

• Develop and validate a Monte-Carlo-based computational technique that can predict the tertiary structures of proteins and effects of genetic polymorphisms (in collaboration with the Division of Molecular Epidemiology, UALR, and CBER).

Environmental Chemistry:

• Determine if 4-ABP in hair dyes is bioavailable and poses a public health risk.

Public Health Significance

Proteomic and metabonomic technologies will advance our understanding of mechanisms of antibiotic resistance, signature proteins in disease states, biochemical modifications of proteins associated with cellular metabolism, and protein function following drug treatments or toxicity. These data can aid in the establishment of FDA policies and interpretation of data provided during an investigational new drug (IND) or new drug applications (NDA) submission to the FDA. The NCTR counterterrorism research provides a rapid means of analysis of bacteria that may aid in rapid identification of biohazards. Rapid analytical methods and MS-based monitoring studies provided a means to assure product quality and safety for the consumer.  

Research Projects

PI: Ang, Catharina

Title: ADDEND: Development of Analytical Methodologies for Assessing Bioactive Herbal Ingredients in Functional Food Systems
Project Number: E0705611
Strategic Research Goal: Method Driven Research

Objective(s):

Expand the original protocol to include functional foods as additional substrates and to include active components of Echinacea and marker compounds as analytes. The scope of this protocol addendum covers the analytical methodology development aspect for St. John's Wort and Echinacea. Functional food items to be investigated may include tea, drink, soup, snack, cereal and candies.

Status: Started/Ongoing

Title: Analytical Methodology Development for Assessing Bioactive Herbal Ingredients in Functional Foods
Project Number: E0716101
Strategic Research Goal: Method Driven Research

Objective(s):

Develop qualitative and quantitative methods for determination of specific marker compounds, such as terpene trilactones (ginkgolides and biolobalide) and kava lactones in raw plant materials, dietary supplements and functional food products containing ginkgo, kava kava or their extracts. A minor objective of this proposed work is to include other minor compounds which do not meet the selection criteria but may be of safety concerns. These compounds include ginkgolic acids, ginkotoxin and urushiols in gingko products and unknown factors in kava.

Status: Started/Ongoing

Title: Influence of Hyperforin Concentration on Drug Interactions
Project Number: P00436
Strategic Research Goal: Method Driven Research

Objective(s):

Quantify hyperforin concentrations in plasma samples collected at University of Arkansas for Medical Sciences (UAMS) as a part of studies evaluating drug interactions between St. John's Wort and the conventional medicines.

Status: Started/Ongoing

PI: Beger, Richard

Title: Methods for Predicting Toxicological Properties of Molecules from Their NMR Chemical Shifts Through-Bond and Through-Space Distance Connectivity Patterns
Project Number: E0712601
Strategic Research Goal: Predictive Toxicology

Objective(s):

Produce models that use NMR data and infuse three-dimensional atom-to-atom through-bond connectivity and atom-to-atom through-space intramolecular distance information into a three-dimensional pattern that can be used by pattern recognition software to build a model of a biological or toxicological endpoint. The results of the 3D-QSDAR models will be compared to the results of QSDAR and QSAR models from protocols E0706801, E707701 and E0708301.

Status: Started/Ongoing

Title: ADDEND: Methods for Predicting Toxicological Properties of Molecules from Their NMR Chemical Shifts Through-bond and Through-space Distance Connectivity Patterns: Task Order 853 - Automated Analysis of NMR Chemical Shifts
Project Number: E0712611
Strategic Research Goal: Predictive Toxicology

Objective(s):

Produce and investigate models of biological activity that are produced based on the activity factors calculated from the minimum summed chemical shift deviations between a set of known compounds and an unknown compound to be predicted by the model. Task order #853 set up for programming to facilitate analysis of NMR chemical shifts; calculation of minimum shifts, pattern recognition on shift patterns.

Status: Started/Ongoing

PI: Buzatu, Dan

Title: Comparison of Principal Components Analysis (PCA) and Artificial Neural Networks (ANN) for Prediction of Qualitative and Quantitative Biological End Points from Spectromentric Data
Project Number: E0707701
Strategic Research Goal: Predictive Toxicology

Objective(s):

This study will introduce and evaluate a new ANN-based method for the correlation of spectrometric data to biological endpoints/activities. The evidence and methodology needed to expand the existing FDA-owned patent covering the use of spectrometric data for predicting biological endpoints will be provided.

Status: Started/Ongoing

Title: High Speed Parallel Distributed Neural Network Project
Project Number: E0713101
Strategic Research Goal: Method Driven Research

Objective(s):

Development of a high-speed computational platform for an Internet-based parallel-distributed artificial neural network. This is intended not only as an increase in the data-size handling capacity of the network, but equally important as a drastic enhancement of its efficiency. Improvements in both of these factors will enable the parallel neural network to become a powerful tool for elucidating important patterns in proteomic, genomic and other large size data-sets.

Status: Started/Ongoing

Title: The Development of Dynamic Mass Spectral/Pattern Recognition-Based Methods for the Rapid Identification of Bioterror Agents
Project Number: E0714601
Strategic Research Goal: Method Driven Research

Objective(s):

Develop the necessary computational capability to enable the rapid identification of pathogen/nonpathogen microorganisms, nonbiological hoax materials, and mixtures of all mentioned collected real world situations. An analysis will be done of the salient spectral features necessary for identifying these substances, and the effect of both instrumental and pattern definition techniques on the ability to use these features for rapid identification.

Status: Started/Ongoing

Title: Analysis of Proton MRS Data Using a Distributed Artificial Network
Project Number: E0719501
Strategic Research Goal: Predictive Toxicology

Objective(s):

Evaluate whether a self-optimizing, parallel distributed neural network can use the data from in vivo proton magnetic resonance spectroscopy (MRS) exams to provide additional information about a brain lesion. If so, this project will lead to improved brain tumor diagnoses from proton MR spectra.

Status: Project Under Review

PI: Feuers, Ritchie

Title: Methods for Support of a Functional Proteomics Facility at NCTR
Project Number: E0713501
Strategic Research Goal: Method Driven Research

Objective(s):

1. Establish and standardize for routine use procedures for whole cell and subcellular organellar isolation for a variety of tissues;
2. Develop and standardize specific and sensitive markers of cell type and organellar purity and yield;
3. Identify, adapt, develop and standardize appropriate 2-D protein separation techniques; and
4. Integrate results of specific aims 1-3 to provide “front-end” components of a functional proteomics facility.

Status: Started/Ongoing

PI: Siitonen, Paul

Title: Analytical Method Validation and Characterization of Ephedra Alkaloids in Ephedra sinica Staph - NTP Test Article Materials
Project Number: P00628
Strategic Research Goal: Agent Driven Research

Objective(s):

NIEHS/CFSAN/NCTR have identified six ephedra alkaloids of toxicological significance to be included for evaluation of Test Articles prior to the NTP Study. Several potential appropriate methods of analysis for epehdra alkaloids have been published by other scientists. Selection, validation and/or modification of these methods is required by the Division of Chemistry personnel prior to characterization of the ephedra test article for the NTP study. The Division of Chemistry has received NTP experimental test articles for maintenance of custody throughout the experiment. Published methods of analysis will be applied to the NTP materials or surrogate material to determine the reproducibility and ruggedness prior to selection and application to chemical characterization analyses for the NTP experiment. Numerous reports of adverse health effects linking ephedra containing supplement use and athletic training or weight loss have appeared in recent years. Validated methods are needed to determine levels of ephedra alkaloids prior to initiation of the NTP experiment.

Status: Started/Ongoing

PI: Turesky, Robert

Title: Human Risk Assessment of Heterocyclic Aromatic Amines: Exposure, Development of Novel Biomarkers of Cytochrome P450 1A2 Activity and DNA Adduct Formation
Project Number: E0709101
Strategic Research Goal: Agent Driven Research

Objective(s):

1. Analyze HAAs by HPLC-MS in previously unreported grilled foods that are indigenous to southern cooking style, including Cajun-type foods;
2. Establish sensitive biomarkers for interspecies extrapolation and human health risk by utilizing HPLC-MS methods to measure metabolites and excised DNA adduct of MeIQx and PhIP in human urine for cohort studies;
3. Determine if specific metabolites of MeIQx and PhIP in human urine are catalyzed by P45 aA2, which is believed to be the major P450 involved in the toxication of these chemicals;
4. Evaluate the effect of chemoprotective agents and dietary supplements on enzyme modulation, and its impact on HAA metabolism and DNA adduct formation in human hepatocytes for eventual chemoprotective studies in vivo; and
5. Interspecies metabolism to assess the capacity of human and rat P45 1A2 orthologues in metabolic activation and detoxication of HAAs to assess human risk.

Status: Started/Ongoing

Title: Dietary Factors in the Etiology of Human Cancer, Biomonitoring of Heterocyclic Aromatic Amines – CRADA-Funded portion of E0709101
Project Number: E0709102
Strategic Research Goal: Agent Driven Research

Objective(s):

1. Determine the extent of heterocyclic aromatic amine exposure via urine analysis and determine whether HAA may contribute to human cancer development based upon the nested case-control studies;
2. Develop analytical methods to measure the HAA metabolites and DNA adducts in urine; and
3. Correlate HAA metabolite profiles with genotype and phenotype data associated with xenobiotic enzymes associated with cancer risk, such as cytochrome P450 1A2, N-acetyltransferases.

Status: Project Under Review

Title: Toxicological Effects of Ochratoxin A
Project Number: E0709401
Strategic Research Goal: Predictive Toxicology

Objective(s):

1. Establish chemical and biological markers of oxidative stress to proteins using biochemical and mass spectrometry techniques;
2. Establish markers of oxidative damage to DNA by measurement of abasic site formation and oxidized DNA lesions by affinity detection and LC-MS methods;
3. Investigate changes in gene expression and protein expression in liver and kidney as a function of OTA treatment; and
4. Correlate differences in these above endpoints with in vivo mutagenesis using the Big Blue Rat experimental model.

Status: Started/Ongoing

PI: Wilkes, Jon

Title: Combining MAB/MS with Pattern Recognition to Sub-Type Bacteria
Project Number: E0707901
Strategic Research Goal: Method Driven Research

Objective(s):

This work is intended to demonstrate the validity of the combination of pyrolysis/metastable atom bombardment (MAB)/mass spectrometry (PyMAB/MS) with computerized pattern recognition (PattRec) for bacterial sub-typing. The work should produce a scientifically and technologically validated basis for commercial licensing of an NCTR-patented process: a method for assembling coherent spectral databases for use in rapid chemotaxonomy at the strain and sub-strain level.

Status: Started/Ongoing

Title: Evaluation of Pyrolysis MAB/Tof MS and MALDI/Tof MS for Rapid Characterization of Presumptive Bio-Terror Agent Samples

Project Number: E0714701

Strategic Research Goal: Method Driven Research

Objective(s):

The suitability of mass spectral data obtained from both pyrolysis metastable atom bombardment MS and matrix-assisted laser desorption/ionization time-of-flight MS techniques will be evaluated for the purpose of rapidly characterizing presumptive bio-terror agent samples. This includes analysis of the salient spectral features necessary for identifying microorganisms from contaminated samples and differentiating tainted samples from hoax sample materials collected from the environment, as well as evaluating the effects of both instrumental and pattern definition techniques on the ability to use these features for rapid identification.

Status: Started/Ongoing

Publications

Beger, R., Buzatu, D.A. and Wilkes, J.G., Combining NMR Spectral Information with Associated Structural Features to Form Computationally Non-Intensive, Rugged and Objective Models of Biological Activity, In: Discovery Handbook: Pharmaceutical Development and Research Handbook, Internet Electronic. Accepted: 8/31/2003 (E0712601)

Beger, R., Buzatu, D.A. and Wilkes, J.G., Using Simulated 2D 13C-13C NMR Spectral Data to Model a Diverse Set of Estrogens, J. Molecular Design, 2:435-453. Accepted: 5/1/2003 (E0712601)

Beger, R., Somervile, L., Krynetski, E.Y., Krynetskaia, N.F., Zhang, W., Marhefka, C.A. and Kriwacki, R.W., Structural and Dynamics of Thioguaninie-Modified Dupled DNA Containing a Single Central Thioguanine Modification, J. Biol. Chem., 278:1005-1011. Accepted: 6/1/2003 (N/A)

Billedeau, S.M., Heinze, T.M. and Siitonen, P.H., Liquid Chromatography Analysis of Erythromycin A in Salmon Tissue by Electrochemical Detection with Confirmation by Electrospray Ionization/Mass Spectrometry, J. Agri. & Food Chemistry, 51(6):1534-1538. Accepted: 12/18/2002 (E0698001)

Buzatu, D.A., Beger, R., Wilkes, J.G. and Lay, J.O., Predicting Toxic Equivalence Factors from 13C NMR Spectra for Dioxins, Furans and PCBs Using Multiple Linear Regression and Artificial Neural Networks, Environmental Chemistry & Toxicology, 23(1). Accepted: 5/24/2003 (E0707701) (to be published in December 15, 2003 issue)

Chiarelli, M.P., Li, L.A., Branco, P.S., Antunes, A.M., Marques, M.M., Goncalves, L.M. and Beland, F.A., Differentiation of Isomeric C8-Substituted Alkylaniline Adducts of Guanine by Electrospray Ionization and Tandem Quadrupole Ion Trap Mass Spectrometry, Journal of American Society for Mass Spectrometry. Accepted: 9/30/2003 (N/A)

Chou, M.W., Wang, Y., Yan, J., Yang, Y., Beger, R., Williams, L.D., Doerge, D.R. and Fu, P.P., Riddelliine N-Oxide Is A Phytochemical And Mammalian Metabolite With Genotoxic And Activity That Is Comparable To The Parent Pyrrolizidine Alkaloid, Toxicol. Lett, 5460:1-9. Accepted: 7/3/2003 (E0710401)

Cui, Y., Ang, C.Y., Beger, R., Heinze, T.M. and Leakey, J.E., In Vitro Metabolism of Hyperforin in Rat Liver Microsomal System, Drug Metabolism Disposition. Accepted: 8/29/2003 (E0708401)

Fu, P.P., Yang, Y., Xia, Q., Chou, M.W., Cui, Y. and Lin, G., Pyrrolizidine Alkaloids-Tumorigenic Components in Chinese Herbal Medicines and Dietary Supplements, J. Food Drug Analys., 10:198-211. Accepted: 11/13/2002 (E0710401)

Gamboa da Costa, G., Marques, M.M., Beland, F.A., Freeman, J.P., Churchwell, M.I. and Doerge, D.R., Quantification of Tamoxifen DNA Adducts Using On-Line Sample Preparation and HPLC-Electrospray Ionization Tandem Mass Spectrometry, Chem. Res. Tox., 16:357-366. Accepted: 1/7/2003 (E0701101)

Gamboa da costa, G.C., Marques, M.M., Freeman, J.P. and Beland, F.A., Synthesis and Investigation of α-Hydroxy-N,N-Didesmethylatamoxifen as a Proximate Metabolite in the Metabolic Activation of Tamoxifen to a Carcinogen, Chem. Res. Toxicol., 16:1090-1098. Accepted: 6/12/2003 (E0701101)

Kim, Y., Kim, S., Cerniglia, C.E. and Heinze, T.M., Adsorption and Clay-Catalyzed Degradation of Erythromycin A on Homoionic Clays, Journal of Environmental Quality. Accepted: 6/23/2003 (E0690101)

Leakey, J.E., Seng, J.E. and Allaben, W.T., Body Weight Considerations in the B₆C₃F₁ Mouse and the Use of Dietary Control to Standardize Background Tumor Incidence in Chronic Bioassays, Toxicology Applied Pharmacology. Accepted: 7/23/2003 (E0211701)

Leakey, J.E., Seng, J.E., Hussein, N., Allen, L.J., Allaben, W.T. and Latendresse, J.R., Dietary Controlled Carcinogenicity Study of Chloral Hydrate in Male B₆C₃F₁ Mice, Toxicology and Applied Pharmacology. Accepted: 7/23/2003 (E0211701)

Leakey, J.E., Seng, J.E., Toxicokinetics of Chloral Hydrate in Ad libitum-fed, dietary-controlled and calorically restricted Male B₆C₃F₁ Mice Following Short-Term Exposure Using Idealized Body Weight Curves that are Normalized by Modulation of Caloric Intake, Toxicology & Applied Pharmacology. Accepted: 7/23/2003 (E0211701, E0211711 and E0211722)

Lopachin, R.M., Jones, R.C., Patterson, T.A., Slikker, W. and Barber, D.S., Application of Proteomics to the Study of Molecular Mechanisms in Neurotoxicology, NeuroToxicology, 24(6) 761-775, 2003. Accepted: 8/5/2003 (N/A)

Mannila, M., Lang, Q., Wai, C.M. and Ang, C.Y., Supercritical Fluid Extraction of Bioactive Components from St. John's Wort (Hypericum perforatum L.) and Ginkgo biloba, Separation and Processes Using Supercritical Carbon by Dioxide: ACS Symposium Book Series No. 860, Chap. 9:130-144. Accepted: 3/11/2003 (N/A)

Moody, J.D., Fu, P.P., Freeman, J.P. and Cerniglia, C.E., Regio- and Stereoselective Metabolism Of 7,12-Dimethylbenz[A]Anthracene by Mycobacterium Vanbaalenii PYR-1, Applied and Environmental Microbiology, 69:3924-3931. Accepted: 4/1/2003 (E0707501)

Poirier, M.C., Divi, R.L., Beland, F.A., Churchwell, M.I., Doerge, D.R., Gamboa da costa, G.C. and Marques, M.M., Formation of Tamoxifen-DNA Adducts in Multiple Organs of Adult Female Cynomolgus Monkeys Dosed Orally with Tamoxifen for 30 Days, Cancer Research. Accepted: 7/1/2003 (NA)

Rafii, F., Heinze, T.M., Beger, R., Park, M. and Davis, C.L., Variation in Metabolism of the Soy Isoflavonoid Daidzein by Human Intestinal Microflora from Different Individuals, Archives of Microbiology, 180:11-16. Accepted: 4/14/2003 (E0700701)

Rafii, F., Wynne, R.A., Heinze, T.M. and Paine, D.D., Mechanism of Metronidazole-Resistance in Isolates of Nitroreductase-Producing Enterococcus gallinarum and E. casseliflavus from the Human Intestinal Tract, FEMS Microbiology Letters, 225:195-200, 2003. Accepted: 6/1/2003 (E0709301)

Seng, J.E., Agrawal, N., Horsley, E., Xia, S., Allaben, W.T., Leakey, J.E. and Leakey, T.I., Toxicokinetics of Chloral Hydrate in Ad Libitum-Fed, Dietary-Controlled and Calorically Restricted Male B₆C₃F₁ Mice Following Short-Term Exposure, Toxicology & Applied Pharmacology. Accepted: 7/23/2003 (E0211701)

Shvartsburg, A.A., Wilkes, J.G., Chemistry in Aldol Complexes of Metal Dications: Massive Dehydration of the Bisligand Species, Int. J. Mass Spectrometry, 225:155. Accepted: 11/24/2002 (E0712001)

Snellings, S.L., Takenaka, N., Kim, Y. and Miller, D.W., Rapid Colorimetric Method to Detect Indole in Shrimp with Gas Chromatography Mass Spectrometry Confirmation, Journal of Food Science, 68(4):1548-1553. Accepted: 1/21/2003 (E0699701)

Turesky, R., Freeman, J.P., Holland, R.D., Nestorick, D.M., Miller, D.W., Kadlubar, F.F. and Ratnasinghe, L., Identification of Aminobiphenyl Derivatives in Commercial Hair Dyes, Chemical Research in Toxicology, 16:1162-1173. Accepted: 6/27/2003 (E0714801)

Turesky, R., Richoz, J., Constable, A., Curtis, K.D., Dingley, K.H. and Turteltaub, K.W., The Effects of Coffee on Enzymes Involved in Metabolism of the Dietary Carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Rats, Chemico-Biological Interactions, 45:251-265. Accepted: 1/13/2003 (N/A)

Concept Papers

PI: Beger, Richard

Title: Case-Control Study of NMR Metabonomic Signatures for Prostate, Breast and Colorectal Cancer
Project Number: E0717601
Strategic Research Goal: Predictive Toxicology

Objective(s):

Demonstrate that there are unique NMR spectral signatures in urine and/or serum obtained from cancer patients compared to controls.

Status: Approved Concept Paper

PI: Edmondson, Rick

Title: Development of Automated High Sensitivity Nano LC/MS/MS Systems for Proteomics
Project Number: E0718201
Strategic Research Goal: Method Driven Research

Objective(s):

Status: Approved Concept Paper

Title: Managing Sample Complexity and Dynamic Range During Proteome Analyses
Project Number: E0718301
Strategic Research Goal: Method Driven Research

Objective(s):

Studies aimed at optimizing the analytical approaches adopted at NCTR regarding comprehensive proteome analysis.

Status: Approved Concept Paper