Genomics in Drug Discovery and Development 1st Edition by Dimitri Semizarov 0470096047 9780470096048

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ISBN 10: 0470096047

ISBN 13: 9780470096048

Author: Dimitri Semizarov

Early characterization of toxicity and efficacy would significantly impact the overall productivity of pharmaceutical R&D and reduce drug candidate attrition and failure. By describing the available platforms and weighing their relative advantages and disadvantages, including microarray data analysis, Genomics in Drug Discovery and Development introduces readers to the biomarker, pharmacogenomic, and toxicogenomics toolbox. The authors provide a valuable resource for pharmaceutical discovery scientists, preclinical drug safety department personnel, regulatory personnel, discovery toxicologists, and safety scientists, drug development professionals, and pharmaceutical scientists.

Genomics in Drug Discovery and Development 1st Table of contents:

1. Introduction: Genomics and Personalized Medicine
Dimitri Semizarov

1.1. Fundamentals of Genomics
1.2. The Concept of Personalized Medicine
1.3. Genomics Technologies in Drug Discovery
1.4. Scope of This Book
References

2. Genomics Technologies as Tools in Drug Discovery
Dimitri Semizarov

2.1. Introduction to Genomics Technologies
2.2. Gene Expression Microarrays: Technology
2.2.1. Standard Microarray Protocol
2.2.2. Monitoring the Quality of Input RNA for Microarray Experiments
2.2.3. Specialized Microarray Protocols for Archived and Small Samples
2.2.4. Quality of Microarray Data and Technical Parameters of Microarrays
2.2.5. Reproducibility of Expression Microarrays and Cross-Platform Comparisons
2.2.6. Microarray Databases and Annotation of Microarray Data
2.2.6.1. Target Identification
2.2.6.2. Disease Classification
2.2.6.3. Compound Assessment
2.3. Gene Expression Microarrays: Data Analysis
2.3.1. Identification of Significant Gene Expression Changes
2.3.2. Sample Classification and Class Prediction with Expression Microarrays
2.3.3. Pathway Analysis with Gene Expression Microarrays
2.3.4. Common Problems Affecting the Validity of Microarray Studies
2.4. Comparative Genomic Hybridization: Technology
2.5. Comparative Genomic Hybridization: Data Analysis
2.6. Microarray-Based DNA Methylation Profiling
2.7. Microarray-Based MicroRNA Profiling
2.8. Technical Issues in Genomics Experiments and Regulatory Submissions of Microarray Data
2.8.1. Study of a Drug’s Mechanism of Action by Gene Expression Profiling
2.8.2. Early Assessment of Drug Toxicity in Model Systems
2.8.3. Biomarker Identification in Discovery and Early Development
2.8.4. Patient Stratification in Clinical Trials with Gene Expression Signatures
2.8.5. Genotyping of Patients in Clinical Studies to Predict Drug Response
2.9. Conclusion
References

3. Genomic Biomarkers
Dimitri Semizarov

3.1. Introduction to Genomic Biomarkers
3.2. DNA Biomarkers
3.2.1. DNA Copy Number Alterations
3.2.1.1. DNA Copy Number Alterations in Cancer
3.2.1.2. DNA Copy Number Alterations in Other Diseases
3.2.1.3. Identification of DNA Copy Number Biomarkers in Drug Discovery
3.2.2. Mutations
3.2.2.1. p53 Mutations
3.2.2.2. K-ras Mutations
3.2.2.3. EGFR Mutations
3.2.2.4. Bcr-abl and KIT Mutations
3.2.3. Epigenetic Markers
3.3. RNA Biomarkers
3.3.1. Gene Expression Biomarkers Validated as Diagnostic Tests
3.3.2. Other Examples of Gene Expression Biomarkers
3.4. Clinical Validation of Genomic Biomarkers
References

4. Fundamental Principles of Toxicogenomics
Eric Blomme

4.1. Introduction
4.2. Fundamentals of Toxicogenomics
4.2.1. Principle of Toxicogenomics
4.2.2. Technical Reproducibility
4.2.3. Biological Reproducibility
4.2.4. Species Extrapolation
4.3. Analysis of Toxicogenomics Data
4.3.1. Compound-Induced Gene Expression Changes
4.3.2. Visualization Tools
4.3.3. Class Prediction
4.3.4. Network and Pathway Analysis
4.4. Practical and Logistic Aspects of Toxicogenomics
4.4.1. Species Considerations
4.4.2. Toxicogenomics Studies
4.4.2.1. Sample Considerations
4.4.2.2. Experimental Design in Toxicogenomics Studies
4.5. Toxicogenomics Reference Databases
4.5.1. Utility of Reference Databases in Toxicogenomics
4.5.2. Design and Development of Toxicogenomics Reference Databases
4.5.3. Existing Toxicogenomics Databases
4.5.3.1. Chemical Effects in Biological Systems (CEBS)
4.5.3.2. ArrayTrack®
4.5.3.3. Gene Expression Omnibus
4.5.3.4. ArrayExpress
4.5.3.5. DbZach
4.5.3.6. ToxExpress®
4.5.3.7. DrugMatrix®
4.6. Conclusion
References

5. Toxicogenomics: Applications to In Vivo Toxicology
Eric Blomme

5.1. The Value of Toxicogenomics in Drug Discovery and Development
5.2. Basic Principles of Toxicology in Drug Discovery and Development
5.2.1. Preclinical Safety Assessment
5.2.1.1. Genetic Toxicology
5.2.1.2. Single-Dose Toxicity
5.2.1.3. Repeat-Dose Toxicity
5.2.1.4. Reproductive Toxicity
5.2.1.5. Carcinogenicity
5.2.2. Discovery Toxicology
5.3. Toxicogenomics in Predictive Toxicology
5.3.1. Prediction of Hepatotoxicity
5.3.1.1. Hepatotoxicity: an Important Toxicology Problem in Drug Discovery and Development
5.3.1.2. Predictive Genomic Models of Hepatotoxicity
5.3.1.3. Additional Toxicogenomics Approaches to Predict Hepatotoxicity
5.3.2. Prediction of Nephrotoxicity
5.3.2.1. Kidney as a Target Organ of Toxicity
5.3.2.2. Predictive Genomic Models of Nephrotoxicity
5.3.3. Prediction of In Vivo Carcinogenicity
5.3.3.1. Value Created by Toxicogenomics in the Assessment of Carcinogenicity
5.3.3.2. Predictive Genomic Models of Carcinogenicity
5.3.4. Gene Expression-Based Biomarkers in Other Tissues and the Promise of Hemogenomics
5.3.5. Integration of Toxicogenomics in Discovery Toxicology
5.4. Toxicogenomics in Mechanistic Toxicology
5.4.1. Toxicogenomics to Investigate Mechanisms of Hepatoxicity
5.4.2. Intestinal Toxicity and Notch Signaling
5.4.3. Cardiac Toxicity
5.4.4. Testicular Toxicity
5.5. Toxicogenomics and Target-Related Toxicity
5.5.1. Target Expression in Normal Tissues
5.5.2. Target Modulation
5.5.2.1. Genetically Modified Animals
5.5.2.2. Tool Compounds
5.5.2.3. Gene Silencing
5.6. Predicting Species-Specific Toxicity
5.7. Evaluation of Idiosyncratic Toxicity with Toxicogenomics
5.8. Conclusion
References

6. Toxicogenomics: Applications in In Vitro Systems
Eric Blomme

6.1. Introductory Remarks on In Vitro Toxicology
6.2. Overview of Current Approaches to In Vitro Toxicology
6.3. Toxicogenomics in In Vitro Systems: Technical Considerations
6.3.1. Reproducibility
6.3.2. Genomic Classifiers
6.3.3. Testing Concentrations
6.3.4. Throughput and Cost
6.4. Proof-of-Concept Studies using Primary Rat Hepatocytes
6.5. Use of Gene Expression Profiling to Assess Genotoxicity
6.5.1. Toxicogenomics Can Differentiate Genotoxic Carcinogens from Nongenotoxic Carcinogens
6.5.2. Toxicogenomics Can Differentiate DNA-Reactive from Non-DNA-Reactive Compounds Positive in In Vitro Mammalian Cell-Based Genotoxicity Assays
6.5.3. Toxicogenomics Assays May Be Less Sensitive than the Standard Battery of In Vitro Genetic Toxicity Tests
6.6. Application of Gene Expression Profiling for In Vitro Detection of Phospholipidosis
6.7. Toxicogenomics in Assessment of Idiosyncratic Hepatotoxicity
6.8. Do Peripheral Blood Mononuclear Cells Represent a Useful Alternative In Vitro Model?
6.9. Current and Future Use of In Vitro Toxicogenomics
6.9.1. Improved Gene Expression Platforms
6.9.2. Standardization of Protocols and Experimental Approaches
6.9.3. Performance Accuracy
6.9.4. Battery of Gene Expression Signatures
6.9.5. Clear, Actionable Data Points
6.10. Conclusions
References

7. Germ Line Polymorphisms and Drug Response
Dimitri Semizarov

7.1. Introduction to Germ Line Polymorphisms
7.2. Polymorphisms and Drug Response in Oncology
7.2.1. UGT1A1 Polymorphism and Response to Irinotecan
7.2.2. FGFR4 Polymorphism and Response to Chemotherapy
7.2.3. Mdr-1 Polymorphism and Response to Paclitaxel
7.2.4. DPD Polymorphisms and Response to 5-Fluorouracil
7.2.5. TPMT Variants and Response to Thiopurines
7.2.6. MTHFR Polymorphisms and Response to Chemotherapy
7.2.7. Tandem Repeat Polymorphisms in the TS Gene and Response to Drugs Targeting Thymidylate Synthase
7.2.8. Use of Cancer Cell Lines to Identify Predictive SNPs
7.3. Polymorphisms and Response to Anticoagulants
7.4. Polymorphisms in Neuroscience
7.5. Polymorphisms and Drug Response in Immunology
7.6. Polymorphisms and Response to Antiviral Agents
7.6.1. Anti-HIV Drugs
7.6.2. Interferon Therapy in Hepatitis C
7.7. Conclusion
References

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