The enhanced value of combining conventional and “omics” analyses in early assessment of drug-induced hepatobiliary injury

Ellinger‐Ziegelbauer, Heidrun; Adler, M.; Amberg, Alexander; Brandenburg, Arnd; Callanan, John J.; Connor, Susan C.; Fountoulakis, Michael; Gmuender, Hans; Gruhler, Albrecht; Hewitt, Philip; Hodson, Mark P.; Matheis, Katja; McCarthy, Diane; Raschke, Marian; Riefke, Bjoern; Schmitt, Christina S.; Sieber, Max; Sposny, Alexandra; Suter, Laura; Sweatman, Brian C.; Mally, Angela

doi:10.1016/j.taap.2010.09.022

Cited by 56 publications

(27 citation statements)

References 38 publications

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“…Microarray identified the molecular mechanism behind dyslipidemia caused by protease inhibitors, and elucidated the mechanism of enhanced lipidemia associated with enhanced proteasome system [48]. To identify predictors of drug toxicity and facilitate informed decision making, large-scale gene array projects combined with conventional toxicology (toxicogenomics) have been performed at the InnoMed PredTox Consortium [49–51]. Another study called STALWART revealed that an increase in CD4 count or IL-2 therapy is not sufficient to reduce opportunistic infections or death by AIDS [52], suggesting that additional immunoprotection strategies are required.…”

Section: Gene Array Technology In a Nutshellmentioning

confidence: 99%

“…Led by the nonprofit Critical Path Institute, Predictive Safety Testing Consortium is a successful public-private partnership that focuses on qualifying preclinical safety biomarkers related to drug-induced nephrotoxicity [49, 50]. Similar large-scale collaborations need to be encouraged to find biomarkers for HIV-1 disease progression.…”

Section: Gene Array Technology In a Nutshellmentioning

confidence: 99%

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Gene Array Studies in HIV-1 Infection

Mehla

Ayyavoo

2011

Curr HIV/AIDS Rep

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HIV-1–infected individuals exhibit remarkable variation in the onset of disease. Virus replication and disease progression depend on host cellular transcription and gene regulation in virus-specific target cells. Both viral and host factors are implicated in this differential regulation. Gene arrays and transcriptome analyses might shed light on why some infected individuals remain asymptomatic while others progress rapidly to AIDS. Here we review developments in HIV research using gene array technologies and the unifying concepts that have emerged from these studies. Gene set enrichment analysis has revealed gene signatures linked to disease progression involving pathways related to metabolism, apoptosis, cell-cycle dysregulation, and T-cell signaling. Macrophages contain anti-apoptotic signatures. Also, HIV-1 regulates previously under-emphasized cholesterol biosynthesis and energy production pathways. Notably, cellular pathways linked to a subset of HIV-infected individuals known as non-progressors contribute to survival and anti-viral responses.

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Section: Gene Array Technology In a Nutshellmentioning

confidence: 99%

Section: Gene Array Technology In a Nutshellmentioning

confidence: 99%

Gene Array Studies in HIV-1 Infection

Mehla

Ayyavoo

2011

Curr HIV/AIDS Rep

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“…Pattern recognition in biochemical signals from transcriptomic, proteomic, and metabolomic experiments will lead to the identification and validation of the biomarkers relevant to monitor defined toxicity in humans and animals (Ellinger-Ziegelbauer et al, 2011;Peng et al, 2013). Pattern recognition in biochemical signals from transcriptomic, proteomic, and metabolomic experiments will lead to the identification and validation of the biomarkers relevant to monitor defined toxicity in humans and animals (Ellinger-Ziegelbauer et al, 2011;Peng et al, 2013).…”

Section: Strength and Limitations Of Omics Technologiesmentioning

confidence: 99%

Modern methodologies and tools for human hazard assessment of chemicals

2014

EFS2

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This scientific report provides a review of modern methodologies and tools to depict toxicokinetic and toxicodynamic processes and their application for the human hazard assessment of chemicals. The application of these methods is illustrated with examples drawn from the literature and international efforts in the field. First, the concepts of mode of action/adverse outcome pathway are discussed together with their associated terminology and recent international developments dealing with human hazard assessment of chemicals. Then modern methodologies and tools are presented including in vitro systems, physiologically-based models, in silico tools and OMICs technologies at the level of DNA/RNA (transcriptomics), proteins (proteomics) and the whole metabolome (metabolomics). Future perspectives for the potential applications of these modern methodologies and tools in the context of prioritisation of chemicals, integrated test strategies and the future of risk assessment are discussed. The report concludes with recommendations for future work and research formulated from consultations of EFSA staff, expert Panels and other international organisations.

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“…49 When ''omics'' are used either alone or better yet in conjunction with other technologies (systems biology approach), they can rapidly fill the gap in the development of new minimally invasive and easily accessible biomarkers in preclinical and clinical studies. 24,48,85 Systems biology is the combination of the ''omics'' platforms, bioinformatics, and other biologic data, which focuses on interactions within and between the mechanisms that combine to give rise to the function and behavior of a biological system. 34,89 Deciphering complex, highly networked, and pleiotropic pathways that give rise to adverse events aids in the identification of specific biomarkers, which ultimately helps us understand the patient risks and improves the overall safety testing process.…”

Section: Transcriptomics Metabonomics/metabolomics and Proteomicsmentioning

confidence: 99%

Safety Biomarkers in Preclinical Development

Sasseville¹,

Mansfield²,

Brees

2013

Vet Pathol

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The identification, application, and qualification of safety biomarkers are becoming increasingly critical to successful drug discovery and development as companies are striving to develop drugs for difficult targets and for novel disease indications in a risk-adverse environment. Translational safety biomarkers that are minimally invasive and monitor drug-induced toxicity during human clinical trials are urgently needed to assess whether toxicities observed in preclinical toxicology studies are relevant to humans at therapeutic doses. The interpretation of data during the biomarker qualification phase should include careful consideration of the analytic method used, the biology, pharmacokinetic and pharmacodynamic properties of the biomarker, and the pathophysiology of the process studied. The purpose of this review is to summarize commonly employed technologies in the development of fluidand tissue-based safety biomarkers in drug discovery and development and to highlight areas of ongoing novel assay development.

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The enhanced value of combining conventional and “omics” analyses in early assessment of drug-induced hepatobiliary injury

Cited by 56 publications

References 38 publications

Gene Array Studies in HIV-1 Infection

Gene Array Studies in HIV-1 Infection

Modern methodologies and tools for human hazard assessment of chemicals

Safety Biomarkers in Preclinical Development

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