A5103130158- Carcinogens and Genotoxicity Assessment
- Molecular Biology Techniques and Applications
- Gene expression and cancer classification
- Drug-Induced Hepatotoxicity and Protection
- DNA Repair Mechanisms
- Computational Drug Discovery Methods
- Genetically Modified Organisms Research
- Pharmacogenetics and Drug Metabolism
- Liver Disease Diagnosis and Treatment
- Drug Transport and Resistance Mechanisms
- Liver physiology and pathology
- Microscopic Colitis
- Effects and risks of endocrine disrupting chemicals
- Inflammatory Bowel Disease
- MicroRNA in disease regulation
- Cancer-related Molecular Pathways
- Metabolism and Genetic Disorders
- Liver Disease and Transplantation
- Diet and metabolism studies
- Alzheimer's disease research and treatments
- Pharmaceutical and Antibiotic Environmental Impacts
- Virus-based gene therapy research
- bioluminescence and chemiluminescence research
- Genomics, phytochemicals, and oxidative stress
- Biochemical and Molecular Research
Georgetown University Medical Center
2007-2025
Georgetown University
2007-2025
Prothena (United States)
2024-2025
Takeda (United States)
2018-2022
Pfizer (United States)
2010-2020
University of Michigan
2014
Maastricht University
2014
Drug Safety Research Unit
2013
Harvard University
1996-2011
Eli Lilly (United States)
2004
Current blood biomarkers are suboptimal in detecting drug‐induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts healthy volunteers (n = 192 n 81), subjects who safely took potentially hepatotoxic drugs without adverse effects 55 92) patients 98, 28, 143) were assayed for microRNA‐122 (miR‐122), glutamate dehydrogenase (GLDH), total...
Hepatotoxicity remains a major challenge in drug development. Although alanine aminotransferase (ALT) the gold standard biomarker of liver injury, alternative strategies to better predict potential for severe drug-induced injury (DILI) are essential. In this study, we evaluated utility glutamate dehydrogenase (GLDH), purine nucleoside phosphorylase (PNP), malate (MDH), and paraxonase 1 (PON1) as indicators cohorts human subjects, including healthy subjects across age gender, with variety...
To assess the potential of individual bile acids (IBA) and their profiles as mechanistic biomarkers liver injury for humans in real world situations, we interrogated samples collected under minimum controlled conditions (ie subjects were not fasted). Total (TBA) have been considered to be decades, more recently, monitoring IBA has proposed differentiation variety etiologies injury. We established a LC-MS/MS methodology analyze nine IBA, generated reference ranges, examined effects age,...
Bile acids (BAs) have been studied as potential biomarkers of drug-induced liver injury. However, the relationship between levels individual BAs and specific forms injury remains to be fully understood. Thus, we set out evaluate cholic acid (CA), glycocholic (GCA), taurocholic (TCA) in rodent toxicity studies. We developed a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay applicable rat mouse serum evaluated comparison with classical hepatotoxicity (alanine...
The development of in vitro molecular biomarkers to accurately predict toxicological effects has become a priority advance testing strategies for human health risk assessment. application transcriptomic promises increased throughput as well reduction animal use. However, the existing protocols predictive transcriptional signatures do not establish appropriate guidelines dose selection or account fact that toxic agents may have pleiotropic effects. Therefore, comparison transcriptome profiles...
Drug-induced liver injury (DILI) is a leading cause of acute failure and the major reason for withdrawal drugs from market. Preclinical evaluation drug candidates has failed to detect about 40% potentially hepatotoxic compounds in humans. At onset humans, currently used biomarkers have difficulty differentiating severe DILI mild, and/or predict outcome individual subjects. Therefore, new biomarker approaches predicting diagnosing humans are urgently needed. Recently, circulating microRNAs...
Interpretation of positive genotoxicity findings using the current in vitro testing battery is a major challenge to industry and regulatory agencies. These tests, especially mammalian cell assays, have high sensitivity but suffer from low specificity, leading rates irrelevant (i.e., results that are not relevant human cancer hazard). We developed an transcriptomic biomarker-based approach provides biological relevance assay data, particularly for chromosome damage propose its application...
Serum activities of alanine and aspartate aminotransferases (ALT AST) are used as gold standard biomarkers for the diagnosis hepatocellular injury. Since ALT AST lack liver specificity, onset injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated potential glutamate dehydrogenase (GLDH) a specific alternative biomarker In our study, serum GLDH subjects Duchene muscular dystrophy (DMD) was equivalent to age matched healthy subjects, while increased...
Microarrays provide an unprecedented opportunity for comprehensive concurrent analysis of thousands genes. The global the response genes to a toxic insult (toxicogenomics), as opposed historical method examining few select genes, provides more complete picture toxicologically significant events. Here we examine utility microarrays providing mechanistic insights into cells DNA damage. Our data indicate that value technology is in its potential insight mode action genotoxic compound....
The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and U.S. Food Drug Administration, aimed at evaluating qualifying biomarkers for variety of toxicological endpoints. Carcinogenicity Working Group Consortium has concentrated on sharing data to test predictivity two published hepatic gene expression signatures, including signature by Fielden et al. (2007, Toxicol. Sci. 99, 90–100) predicting nongenotoxic...
The genotoxicity testing battery is highly sensitive for detection of chemical carcinogens. However, it features a low specificity and provides only limited mechanistic information required risk assessment positive findings. This especially important in case findings the vitro chromosome damage assays, because may be also induced secondarily to cell death. An increasing body evidence indicates that toxicogenomic analysis cellular stress responses an insight into mechanisms action...
Evaluating the risk of chemical carcinogenesis has long been a challenge owing to protracted nature pathology and limited translatability animal models. Although numerous short-term in vitro vivo assays have developed, they failed reliably predict carcinogenicity nongenotoxic compounds. Extending upon previous microarray work (Fielden, M. R., Nie, A., McMillian, M., Elangbam, C. S., Trela, B. Yang, Y., Dunn, R. T., II, Dragan, Fransson-Stehen, Bogdanffy, et al. (2008). Interlaboratory...
Deletions and other genome rearrangements are associated with carcinogenesis inheritable diseases. The pink-eyed unstable ( p un ) mutation in the mouse is caused by duplication of a 70-kb internal fragment gene. Spontaneous reversion events homozygous / mice occur through deletion duplicated sequence. Reversion premelanocytes embryo detected as black spots on gray fur offspring were inducible carcinogen x-rays, ethyl methanesulfonate, methyl nitrosourea, benzo[ ]pyrene, trichloroethylene,...
We report novel polymyxin analogues with improved antibacterial in vitro potency against resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell assay (hRPTEC) was used to inform structure-toxicity relationships further differentiate analogues. Replacement the Dab-3 residue Dap-3 combination relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as fatty acyl replacement yielded analogue 5x, which...
The use of integrated approaches in genetic toxicology, including the incorporation gene expression data to determine molecular pathways involved response, is becoming more common. In a companion article, genomic biomarker was developed human TK6 cells classify chemicals as genotoxic or nongenotoxic. Because are not metabolically competent, we set out broaden utility for with requiring metabolic activation. Specifically, chemical exposures were conducted presence rat liver S9. ability...
MicroRNAs (miRNAs) released into the peripheral circulation upon cellular injury have shown a promise as new class of tissue-specific biomarkers. We were first to demonstrate that next-generation sequencing analysis serum from human subjects with acetaminophen-induced liver revealed specific signature circulating miRNAs. consequently hypothesized different types hepatic impairments might feature distinct signatures miRNAs and this approach be useful minimally invasive diagnostic "liquid...