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81 Cards in this Set
- Front
- Back
What is an SNP and what is its relevance to pharmacogenomics?
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SNP = Single Nucleotide Polymorphism
May be associated with diseases/genetic traits; can assess risk w/o sequencing whole genomes |
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Define pharmacogenomics.
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The application of genomic methods to study variability in drug responses
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Define pharmacogenetics.
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The study of how inherited
variation in genes affects drug response |
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Why does it suck to be a slow acetylator?
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1. get lupus more often
2. procainamide-induced antinuclear ab's 3. isoniazid polyneuropathy |
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What is the most common hereditary enzymatic disorder?
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency; sensitivity to oxidizing drugs, fragile RBC's
African americans |
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Advantage of G6PD deficiencies?
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Partial immunity to malaria
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Consequence of Thiopurine methyltransferase (TPMT) deficiency?
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can't break down thiopurines fast enough --> get TGN's (thioguanine nucleotides)
cytotoxic b/c function as base analogs |
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What allele is associated with Alzheimer's Disease?
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Apolipoprotein E-ε4
associated with increased onset of familial Alzheimer's and no benefit from cholinesterase Tacrine |
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What is PLX4032?
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Melanoma drug
Designed using gene sequencing to specifically target cancerous BRAF kinase enzyme and leave WT alone |
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Transition Mutation
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purine --> purine
pyrimidine --> pyrimidine A <--> G C <--> T/U |
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Transversion Mutation
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purine <--> pyrimidine
A <--> T/U C <--> G |
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Effect of 5-Br (5-Bromouracil)?
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Point mutation
Replaces T but pairs with G --> A/T to G/C mutation |
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Effect of base deamination?
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C --> U + NH3
G/C --> A/U base pair point mutation |
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Effect of alkylation of DNA?
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Nitrogen mustards and nitrosureas
impairment of transcription, replication, or repair mechanisms --> lose base pair |
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Examples and effect of DNA intercalating agents?
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Acridine dyes, Anthracycline abx (Actinomycin D)
slip into DNA ladder --> frameshift mutations during replication; blockage of polymerases. Effect is reversible. |
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Bleomycins MOA?
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Chelate iron --> intercalate into DNA and covalently bind T --> iron generates free radicals --> break DNA strand
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Examples and effects of DNA crosslinking agents?
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mitomycin C, cisplatin, nitrogen
mustards irreversibly (covalently) bonds and blocks transcription of DNA |
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Modes of gene amplification in response to drug?
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-mini-chromosome with extra copies
-extra copies of gene replicated on same chromosome |
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What genes are typically amplified in response to drug?
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-drug target
-efflux pumps (membrane transporters) -oncogenes (Her2/neu in breast cancer) |
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Take home points about antisense oligonucleotides?
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18-21nt ssDNA binds target mRNA
must be present in great molar excess to work may modify phosphoester bond or sugar backbone to +stability, block translation, induce RNases etc. |
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Take home points about Ribozymes?
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enzyme made of RNA
bind and cleave/destroy/fix target RNA's can clone into cell with constitutive promoter, works against viral genes in host cell (HIV) |
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Take home points about drugs that induce Triple Helix formation?
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intercalate w/DNA strand and interfere w/transcription (turn off promoter etc)
nonstandard base pairing. need less drug (target gene not mRNA) mothership vs drones |
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Take home points about siRNA?
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Small Interfering RNA's
long dsRNA introduced into cell, cleaved by DICER strands separate and bind RISC (RNAi Silencing Complex) --> induce degradation of target mRNA by SLICER |
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Principle behind Etanercept?
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Enbrel, for RA
"decoy" higher affinity TNF receptor bound to Fc region of IgG --> TNF binds Etanercept preferentially |
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Function of Corticosteroids?
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inhibit T cell proliferation, expression of cytokines
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Function of Cyclosporine?
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Fungal polypeptide that interferes w/lymphocyte proliferation
organ transplant rejection, psoriasis, severe atopic dermatitis |
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Requirements for antigenicity?
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-Foreign
-Size: larger = more antigenic (also small HAPTEN bound to large carrier molecule; polymerization of drug molecules) -metabolism into more antigenic compounds |
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Quick definition of humoral immune response?
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B-cell and antibody-mediated response
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Quick definition of cellular immune response?
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Cytotoxic/Killer T and Helper T cell mediated response
Also involves NK Natural Killer T cells. |
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True or False: Severe allergic reaction can occur upon primary exposure.
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False
Need primary exposure and formation of IgG --> immune memory to stage severe atopic response |
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Examples of Pseudoallergic responses?
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-drug activates allergy-related system (ex. triggers mast cells to release histamine)
-drug can cause cell damage and mimic immune mediated effects |
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Type I hypersensitivity reaction
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Anaphylactic Reaction
Ag binds IgE on mast cells --> anaphylaxis, bronchospasm, edema |
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Type II hypersensitivity reaction
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Cytolytic reaction
Ag binds cell membranes and IgG/M --> agglutination, complement-mediated lysis blood transfusions; hemolytic diseases mimics pseudoallergic rxn |
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Type III hypersensitivity reaction
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Arthrus Reaction
high conc of Ag-Ab complexes deposited on tissues, clogs capillaries, etc.--> skin rash, glomerulonephritis, LOCAL rxns lymphocytes target Ab's --> tissue casualties |
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Type IV hypersensitivity reaction
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"Delayed" Cell Mediated reaction
NO antibodies involved! WBC's recruited to site of inflammation; takes days to manifest (not mins to hours) |
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Most common source of drug allergy?
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Penicillins
1-10% of population is allergic. |
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What is wnt? What is beta-catenin?
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Wnt = extracellular signaling molecule. Inhibits degradation of B-cat.
Beta-catenin = intracellular transcription factor that is usually Phos and degraded. |
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Action of beta-catenin?
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Transcription factor. When active, promotes cell REGENERATION and PROLIFERATION.
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Significance of Wnt/B-cat signaling in Alzheimer's disease?
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signaling is attenuated in Alzheimer's disease; activating it may be beneficial
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Therapeutic applications of Wnt/B-cat signaling modulation?
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-encourage damaged/wounded tissue regeneration
-ameloriate alzheimer's dz sx -enhance effectiveness of hematopoietic stem cell therapy |
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Function of levamisol?
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tx colorectal cancer; stimulates T cell proliferation and activation
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Therapeutic applications of Recombinant proteins, eg. interferon/IL-2?
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IFN: stimulate cytotoxic T cell activities;
IL-2: Stimulate B/T cell differentiation and proliferation |
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Which portion of immune response is mostly effective against extracellular invasions?
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Humoral Immune Response
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Which portion of immune response is mostly effective against inracellular invasions and tumor cells?
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Cellular Immune Response (Killer/Cytotoxic T cells)
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General principle of Ames test?
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Detect mutagenicity of drug by observing frequency of his- auxotrophic bacteria mutating and reverting to WT
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How is Ames test modified to detect mutagens generated via oxidative metabolism?
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Same thing but add microsomes from liver homogenate (add liver juice to plate 'cause it's got P450s in it)
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How is Ames test modified to detect mutagens generated via reductive metabolism?
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Same thing but add enzymes from bacterial gut flora that usually carry out reductive metabo in humans
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General principle of Mammalian Cell Culture Test?
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Normal cells lack HGPRT --> killed by 8-azoguanine.
Expose cells to test chemical for a while then dump 8-azoguanine on it and see if you got HGPRT mutants |
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What is the major obstacle to killing cancer cells?
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Cells' ability to repair DNA!
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Average error rate (1 per __ nt's) in cell DNA replication?
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1 in 10,000.
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Nucleotide Excision Repair
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broadest DNA repair mecha
helicases open DNA @ damage site; RPA holds it open endonucleases cut out damaged nt's and ~30nt in surrounding area. DNA pol fills in gap correctly |
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Base Excision Repair
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more specific than NER; fixes damage resulting from normal cell activities.
-glycosylases cut out ONLY damaged bases -endonuclease opens DNA strand -DNA pol fills in; ligase seals the nicked strand |
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Double Strand Break Repair
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fixes damage from x-rays, chemicals, drugs, etc.
MUST be fixed before mitosis! 1. homologous recombination: use homologous xsome as template to fix damaged portion 2. sticky end joining (just slap it back together) |
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Repair of damage caused by alkylating agents
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Usually methylated guanines.
MGMT (O6-MethylGuanine Methyltransferase) removes methylated guanine from sugar base so it isn't used as a template. MGMT is destroyed in the process. |
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Mismatch Repair
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Cell scans DNA for damage.
DNA pols know to use methylated strand (older strand) as correct template to fix damage |
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How can methylguanine screw with Mismatch Repair?
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Methylguanine is an incorrect base but since MMR detects methylation it will be seen as "correct" by repair machinery
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Which syndromes result from inherited defects in Base Excision Repair?
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NONE
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Which syndromes result from inherited defects in Nucleotide Excision Repair?
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Xeroderma Pigmentosa
Cockayne Syndrome |
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Which syndrome results from inherited defects in Double Strand Break Repair?
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Ataxia telangiectasia
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Which syndrome results from inherited defects in Mismatch Repair?
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Hereditary Colon Cancer
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Retinoids: why are they teratogenic?
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involved in regulating early embryonic development via signal transduction pathways that regulate a wide range of genes
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Why are hormonal drugs/antagonists teratogenic?
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Mess up hormonal signaling pathways necessary for normal development
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Pregnancy Category A
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Totally ok to use at all stages of pregnancy
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Pregnancy Category B
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animal or human studies say not much risk
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Pregnancy Category C
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animal studies show teratogenicity, no well controlled human studies
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Pregnancy Category D
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has been shown to cause harm. cost/benefit analysis
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Pregnancy Category X
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NEVER OK
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Xeroderma Pigmentosa
Type/qty of mutation? Cancer risk? |
impaired NER --> can't repair UV induced thymine dimers --> severe photosensitivity, neurodegeneration
any of 7 genes involved; autosomal recessive mutations >1000x higher risk of skin cancer. |
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Cockayne Syndrome
Type/qty of mutation? Cancer risk? |
UV sensitivity, organ degeneration, early aging,
single autosomal recessive mutation NO increase in cancer (UV damage repair system is intact) |
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Ataxia telangiectasia
Type/qty of mutation? Cancer risk? |
defective DSB repair --> myriad of problems
single autosomal recessive mutation (ATM, mutated) predisposed to cancer, immunosuppression, neurodegeneration, etc. |
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Werner’s Syndrome
Type/qty of mutation? Cancer risk? |
defective DNA repair --> high # of xsome abnormalities; early aging, drug sensitivities
one autosomal recessive mutation No increased cancer risk |
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Bloom’s Syndrome
Type/qty of mutation? Cancer risk? |
defective DNA repair --> high # of xsome abnormalities; butterfly marking on face, drug sensitivities
one autosomal recessive mutation No increased cancer risk |
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Fanconi Anemia
Type/qty of mutation? Cancer risk? |
Defective DNA strand break repair --> anemia
multiple genes; autosomal recessive 20% develop cancer |
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Why are RBC's fragile in those with G6PD insufficiency?
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Membrane proteins damaged by oxidizing drugs --> fragile --> lyse when passing through spleen, capillaries, etc.
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What types of drugs are hazardous to those with G6PD deficiency?
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oxidizing drugs
(ex. Primaquine, antimalarial used during Korean War) |
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What genes mentioned in lecture are most commonly amplified in response to drugs?
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Those coding for DHFR (Dihydrofolate reductase) during tx w/Methotrexate
Alternately: membrane transporters (drug efflux pumps) --> drug resistance |
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Function of Antithrombin III (AT-III)?
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Cleave and inactivate clotting factors, incl. thrombin (duh).
Affinity for thrombin is increased when AT-III is bound to heparin. |
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How does TSH exert its effects?
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increases cAMP in thyroid cells --> increased secretion of T3/T4
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How does TRH exert its effects?
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Binds receptors on TSH producing cells in anterior pituitary --> Trigger IP3/Ca2+ signaling pathway --> TSH release
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What genes mentioned in lecture are most commonly amplified in breast cancer tumors?
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Her2/neu
abnormal levels in ~30% of all breast cancers |
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Function of RNAse H?
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cleave RNA/DNA heteroduplexes in cytosol.
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