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Pharmacology - General Medicine - Detailed Proteomics in clinical trials and practice: present uses and future promise. Azad NSet al., 2006. Mol. Cell. Proteomics 5(10):1819-1829.
Abstract The study of clinical proteomics is a promising new field that has the potential to have many applications, including the identification of biomarkers and monitoring of disease, especially in the field of oncology. Expression proteomics evaluates the cellular production of proteins encoded by a particular gene and exploits the differential expression and post-translational modifications of proteins between healthy and diseased states. These biomarkers may be applied towards early diagnosis, prognosis, and prediction of response to therapy. Functional proteomics seeks to decipher protein-protein interactions and biochemical pathways involved in disease biology and targeted by newer molecular therapeutics. Advanced spectrometry technologies and new protein array formats have improved these analyses and are now being applied prospectively in clinical trials. Further advancement of proteomics technology could usher in an era of personalized molecular medicine, where diseases are diagnosed at earlier stages and where therapies are more effective because they are tailored to the protein expression of a patient's malignancy. Comments: Challenges and opportunities in proteomics data analysis. Domon, B & Aebersold, R, 2006. Mol. Cell. Proteomics5(10):1921-1926. Accurate, consistent, and transparent data processing and analysis are integral and critical parts of proteomics workflows in general and for biomarker discovery in particular. Definition of common standards for data representation and analysis and the creation of data repositories are essential to compare, exchange, and share data within the community. Current issues in data processing, analysis, and validation are discussed together with opportunities for improving the process in the future and for defining alternative workflows. The mixed promise of genetic medicine. Elliott CN, 2007. N. Engl. J. Med. 356(20):2024-2025.
This editorial presents the pros and cons of genomic medicine. Short overview of big clinical picture. Genetic testing. Burke WN, 2002. Engl. J. Med. 347(23):1867-1875.
Review article that discusses genetics, related pathology, and clinical testing. Discusses interpretation and application to preventive care. Further, brief discussion of informed consent and genetic consoling.
The pharmacogenetics research network: from SNP discovery to clinical drug response. Giacomini KM et al., 2007. Clin Pharmacol Ther. 81(3):328-45
The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism. Connecting the dots using gene-expression profiles. Gullans SR, 2006. N Engl J Med. 355(19):2042-4.
Discusses the use of the connectivity map of gene expression profiles in human cells and attempts to correlate profiles and disease.
Realizing the promise of genomics in biomedical research. Guttmacher AE, Collins FS, 2005. JAMA 294(11):1399-402
Commentary on current and future genome initiatives, technologies, and effects on health care and society. Genomic medicine--a primer. Guttmacher AE, Collins FS, 2002. N Engl J Med. 347(19):1512-20
This is a review article by pioneers in the field that presents a history of genomic medicine, a glossary of commonly used terms, and an excellent summary of genetic variations, mutations, and the human genome. Lastly a short discussion of genes associated with common diseases. Prohibiting genetic discrimination. Hudson KL, 2007. N Engl J Med. 356(20):2021-3
This article discusses the Genetic Information Nondiscrimination Act. Has the result of a survey responding to “How much do you trust your doctor, genetic researchers, heath insurer, and employer to have access to your genetic test results. Do we need genomic research for the prevention of common diseases with environmental causes? Khoury MJ et al., 2005. Am J Epidemiol. 161(9):799-805.
Concerns have been raised about the value of genomic research for prevention and public health, especially for complex diseases with risk factors that are amenable to environmental modification. Given that gene-environment interactions underlie almost all human diseases, the public health significance of genomic research on common diseases with modifiable environmental risks is based not necessarily on finding new genetic "causes" but on improving existing approaches to identifying and modifying environmental risk factors to better prevent and treat disease. Such applied genomic research for environmentally caused diseases is important, because 1) it could help stratify disease risks and differentiate interventions for achieving population health benefits; 2) it could help identify new environmental risk factors for disease or help confirm suspected environmental risk factors; and 3) it could aid our understanding of disease occurrence in terms of transmission, natural history, severity, etiologic heterogeneity, and targets for intervention at the population level. While genomics is still in its infancy, opportunities exist for developing, testing, and applying the tools of genomics to clinical and public health research, especially for conditions with known or suspected environmental causes. This research is likely to lead to population-wide health promotion and disease prevention efforts, not only to interventions targeted according to genetic susceptibility. Population screening in the age of genomic medicine. Khoury MJ et al., 2003. N Engl J Med. 348(1):50-8
This review article describes current and evolving principles of population screening in genetics. Also, ethical, legal, and social issues encompassing screening and genomic medicine are discussed. The emergence of epidemiology in the genomics age. Khoury MJ et al., 2004. Int J Epidemiol. 33(5):936-44.
This article discusses the complementary relationship of epidemiology and genomics. The authors focus on cross-fertilization of epidemiological principles and methods to characterize genomic trends and impact on populations. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Lamb J et al., 2006. Science 313(5795):1929-35 To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project. Personalized medicine: elusive dream or imminent reality? Lesko LJ, 2007. Clin Pharmacol Ther. 81(6):807-16
The market for molecular diagnostic tests is predicted to grow at extraordinary rates over the next 10 years, fueled by pharmacogenetics and the elusive dream of personalized medicine. The challenge is managing the expectations of the medical community and the public at large that have already been set by speculation, promises, and the repeated exposure to headlines about genetic discoveries. Personalized medicine is a paradigm that exists more in conceptual terms than in reality, with only a few marketed drug-test companion products and not very many actual clinical practices set up to personalize medicine in the way that supporters have intended. Nevertheless, the reality of personalized medicine has become more imminent because of the increased awareness of the shortcomings in the delivery of drugs with adequate benefit/risk to patients, a better molecular understanding of how to optimize drug selection and dosing, and an increased demand for integrating more clinically relevant genetic information into the drug development process to improve both innovation and productivity. This paper focuses on personalized medicine by (1) looking at some converging changes taking place in the health-care landscape that are creating a scientific and social infrastructure to enable personalized medicine, (2) considering challenges that need to be addressed with regard to clinical evidence standards for validating genotype-phenotype associations, and (3) considering how clinical pharmacology can help construct a rational personalized medicine framework. As therapeutic experts, clinical pharmacologists can work to assure that "good therapeutics follows good diagnostics". They are well equipped to provide timely genetic education to others and to interpret genetic data so that actionable decisions, especially about drug dosing in individual patients, can be implemented in clinical practice. Proteomics-based development of biomarkers in cardiovascular disease: mechanistic, clinical, and therapeutic insights. Mayr M et al., 2006. Mol Cell Proteomics 5(10):1853-64.
This review article presents a discussion of the proteomic analysis of different pathological cardiovascular phenotypes. Further association of these proteomic phenotypes to biomarkers, and its impact on diagnosis are presented. Gene and cell-based therapies for heart disease. Melo LG et al., 2004. FASEB J. 18(6):648-63
Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Recent developments in understanding the molecular mechanisms of myocardial disease have led to the identification of new therapeutic targets, and the availability of vectors with enhanced myocardial tropism offers the opportunity for the design of gene therapies for both protection and rescue of the myocardium. Genetic therapies have been devised to treat complex diseases such as myocardial ischemia, heart failure, and inherited myopathies in various animal models. Some of these experimental therapies have made a successful transition to clinical trial and are being considered for use in human patients. The recent isolation of endothelial and cardiomyocyte precursor cells from adult bone marrow may permit the design of strategies for repair of the damaged heart. Cell-based therapies may have potential application in neovascularization and regeneration of ischemic and infarcted myocardium, in blood vessel reconstruction, and in bioengineering of artificial organs and prostheses. We expect that advances in the field will lead to the development of safer and more efficient vectors. The advent of genomic screening technology should allow the identification of novel therapeutic targets and facilitate the detection of disease-causing polymorphisms that may lead to the design of individualized gene and cell-based therapies. Can personalized drug therapy be achieved? A closer look at pharmaco-metabonomics. Nebert DW, Vesell ES, 2006. Trends Pharmacol Sci. 27(11):580-6. Erratum in: Trends Pharmacol Sci. 2007, 28(2):50.
Between 1930 and 1990, several dozen high-penetrance, predominantly monogenic disorders were identified and characterized, which led some investigators to speculate that individualized drug treatment was just around the corner. Informative DNA tests were sought to determine genetic predisposition to toxicity and cancer, thereby identifying individuals in which a drug was likely to be effective and those at increased risk of drug toxicity. These assays represent the leading edge of phenotype-genotype association studies, which are a major goal of clinical pharmacology and pharmacogenomics. Because of the complexity of the genome, however, the task is more challenging than anticipated originally. In the past decade we have come to appreciate how difficult it is to determine unequivocally either an exact phenotype or genotype. In the near future it seems unlikely that, by themselves, either transcriptomics or proteomics will be particularly helpful in achieving individualized drug therapy. However, recent advances in metabonomics are exciting and show promise. In the future, and perhaps in combination with proteomics, metabonomics might complement genomics in achieving personalized drug therapy. Journal link: Available through Science Direct | PMID The art and science of personalized medicine. Piquette-Miller M & Grant DM, 2007. Clin Pharmacol Ther. 81(3):311-5
This editorial discusses the historical perspective of variation of human drug response and its impact on individualized medicine. Further, barriers to application of pharmacogenomic information to clinical practice is presented. Journal Link: Available through Nature | PMID DNA testing, banking, and genetic privacy. Roche PA & Annas GJ, 2006. N Engl J Med. 355(6):545-6
This article presents a perspective of ethical issues associated with genomic profiling. Cardiovascular genomics. Sabatine MS et al., 2006. Circulation 113(11):e450-5
This is a review of the effects of genetic variations on heart disease. Also, examples and limitations of using genetic approaches to characterizing and managing heart disease are discussed. Inheritance and drug response. Weinshilboum R, 2003. N Engl J Med. 348(6):529-37
This review article provides an excellent background to pharmacogenomics presenting mechanisms of alteration of drug metabolism Genes on the Web--direct-to-consumer marketing of genetic testing. Wolfberg AJ, 2006. N Engl J Med. 355(6):543-5
This article describes advantages and disadvantages of commercialization of direct marketing of genetic testing to the consumer. The proteomic search for diagnostic biomarkers: lost in translation? Zolg W, 2006. Mol Cell Proteomics 5(10):1720-6.
This article discusses the development and implementation of using proteomics as biomarkers to make a clinical diagnosis and management. |
