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39 Cards in this Set
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southern blot
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detect DNA after electrophoresis
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RFLP (restriction fragment length polymorphism) analysis
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identify disease related genes using restriction digestions
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PCR
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amplify DNA; DNA primers used to amplify mRNA, readily allows for identification of mutations - deletions, insertions
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FISH (fluorescence in situ hybridization)
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identify gene location on a chromosome; fluorescently labeled DNA probes hybridized to human chromosomes to identify particular genes that might be in the wrong place or are amplified
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SNP (single nucleotide polymorphisms)
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DNA variations at a single base, average frequency of 1 per 1,000 base pairs
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DNA arrays
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glass slides that contain thousands of genes; fluorescently labeled RNA or DNA probes are hybridized to glass slides containing thousands of gene fragments, gauge expression level of mRNA
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EST (expressed sequence tags)
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small bits of RNA copied from each mRNA transcript from a specific tissue, sequenced, and loaded into a database; gene expression pattern
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ELISA (enzyme linked immunosorbent assay)
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titer proteins, identify/titer viruses
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mutation
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an alteration of DNA sequence that is present only rarely in the population (<<1%)
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polymorphism
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an alteration of DNA sequence that is present commonly in the population (> 1%)
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CYP2D6
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phase I enzyme that metabolizes 20-25% of all drugs including anti-depresseants (tricyclics), anti-arrhythmics, beta-blockers, and neuroleptics. inactive in 2-10% of the population
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CYP2C9
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phase I enzyme that metabolizes 15% of all drugs including tolbutamide, warfarin, phenytoin and NSAIDs. 40% of Caucasian population carry defective alleles.
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warfarin
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anticoagulant used to prevent clotting after a heart attack, stoke, or major surgery. highly variable responses, danger=excessive bleeding (CYP2C9 alleles account for 10% variability)
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vitamin K epoxide reductase (VKORC1)
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clotting factor that is a key warfarin target, 25% of warfarin variability due to VKORC1
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CYP3A4
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phase I enzyme that metabolizes 50% of all drugs, inhibited by grapefruit (bioflavonoids and furanocoumarins)
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N-Acetyltransferase 2 (NAT2)
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phase II enzyme, inactive in small percentage of population due to two mutant alleles identified by RFLP.
isoniazid = peripheral neuropathy hydralazine = lupus sulfonamide = hypersensitivity reactions |
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pharmacodynamic variability
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drug variability due to polymorphisms/mutations at the site of drug action
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Phase I
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test in humans, small sample size to assess safety and dosage levels
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Phase IIA
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desired clinical effect and safety concerns are examined, small sample size, expensive
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Phase IIB
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further efficacy and dose ranging with a larger sample size
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Phase III
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very large sample size, millions of dollars, could take years
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Phase IV
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post-marketing follow-up to keep track of adverse events, large sample size
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clozapine
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atypical antipsychotic for schizophrenia for patients who do not respond well to normal meds.
advantage=reduced extrapyramidal side effects disadvantage=agranulocytosis in 2% of patients, could be fatal |
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Gleevac = imatinib
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inhibits the Bcr-Abl tyrosine kinase that is constitutively turned on to reduce proliferation and activate apoptosis. FISH used to detect translocation resulting in longer chromosome 9 and shorter chromosome 22 (Philadelphia chromosome)
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Herceptin = trastuzumab
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humanized monoclonal antibody directed against the Her2 (human epidermal growth factor receptor) elevated in a sub-set of breast cancer patients. FISH analysis to determine gene amplification.
Increases risk of congestive heart failure. |
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Epogen = erythropoietin = recombinant protein
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recombinant protein that stimulates production of red blood cells, used to treat chronic kidney failure on dialysis
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Activase (tissue plasminogen activator) = recombinant protein
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thrombolytic agent indicated for patients who have had a heart attack or stroke
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Etanercept (Tumor necrosis factor, alpha) = Enbrel = recombinant protein
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soluble TNF-alpha receptor used to treat rheumatoid arthritis, can bind TNF-alpha fused to parts of human immunoglobulins
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Nerve growth factor (NGF) = recombinant protein
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stimulates nerve growth, used in neuronal degenerative diseases
Parkinson's, viral delivery of glial derived neurotrophic factor (GDNF) |
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cetuximab (Erbitux)
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chimeric monoclonal antibody against EGFR used to treat solid tumors associated with colorectal cancer by inhibiting signaling.
Risk=skin eruption |
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bevacizumab (Avastin)
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humanized monoclonal antibody against vascular endothelial growth factor (VEGF) used to treat colorectal and lung cancers by reducing angiogenesis and inhibiting tumor growth.
Risks=HTN, bleeding, thrombosis, and proteinuria |
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viral delivery
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indicated in diseases where expressing something extra is beneficial,
1.diseases caused by lack of enzyme activity, cystic fibrosis and X-SCID 2.diseases in which provision of a growth factor is beneficial, Parkinson's |
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adenovirus
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most commonly used viral delivery vector
A=high titer stocks, infects most cells D=very immunogenic, infection only persists for several months, virus does not integrate |
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adeno-associated virus (AAV)
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A=small virus that infects many cell types, no immune response, persists many months, may integrate
D=difficult to generate titers sufficient to infect cells |
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retrovirus
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vector type used to treat immune deficiencies
A=generated in high titer, readily integrates into dividing cells, long lasting D=only integrates into dividing cells, site of integration unpredictable |
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lentivirus
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type of virus associated with HIV
A=infects virtually every cell type (including neurons), transgene expression persists for years, easy to generate high titer, harmful HIV genes removed D=site of integration unpredictable |
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herpesvirus
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A=infects neurons
D=large and difficult to use, interest declined w/lentivirus |
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antisense oligonucleotide (ASO)
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single-stranded chemically synthesized DNA-like molecule 17-22 nucleotides in length designed to be complementary to selected gene mRNA...decreased mRNA leads to inhibition of expression of that gene
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RNA interference (siRNA)
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commercially synthesized dsRNA 21-27 nucleotides that are recognized by RISC. Complex finds mRNA that matches associated siRNA and degrades leading to reduced expression of protein...gene silencing.
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