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283 Cards in this Set
- Front
- Back
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Symptoms of familial adenomatous polyposis (FAP)
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Precancerous polyps in adolescence
Polyps of stomach & duodenum Too many teeth Congenital hypertrophy of the retina pigment epithelium Epidermoid cysts & bone tumoes or cysts (Gardner syndrome) Desmoid tumors (benign soft tissue sarcomas from tendons & ligaments) Medulloblastoma of brain (Turcot) |
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Cause of FAP?
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Germline mutation in APC gene.
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Buck v. Bell
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1927 Supreme Court decision that determined that it was constitutional to involuntary sterilize people
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Negative eugenics
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Discourage reproduction by persons w/genetic defects or presumed to have inheritable undesirable traits
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Positive eugenics
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Encourage reproduction by persons presumed to have inheritable desirable traits
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Principles of Bioethics: name them
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Respect for autonomy
Beneficence Justice (equality & access) |
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What is the mutation responsible for many NTD?
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MTHFR mutation: 677C-->T resutling in ala22val.
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What gene confers immunity to HIV?
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CCR5 mutation: 32bp deletion. Virus cannot enter cell. Allele present in 10% of caucasians.
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MCR1 gene modifies what gene?
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CNK2A gene, which increases risk of cutaneous melanoma to 85%. MCR1 variants have red hair and very pale skin. MCR1 is responsible for synthesis of black eumelanin.
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doxorubicin
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anthracyclin that has several pleiotropic effects (intercalates w/DNA, induction of single & double-stranded breaks, reacts w/P450 to produce free radicals, and interacts w/cell membranes)
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daunorubicin
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anthracyclin that has several pleiotropic effects (intercalates w/DNA, induction of single & double-stranded breaks, reacts w/P450 to produce free radicals, and interacts w/cell membranes)
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epirubicin
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anthracyclin that has several pleiotropic effects (intercalates w/DNA, induction of single & double-stranded breaks, reacts w/P450 to produce free radicals, and interacts w/cell membranes)
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idarubicin
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anthracyclin that has several pleiotropic effects (intercalates w/DNA, induction of single & double-stranded breaks, reacts w/P450 to produce free radicals, and interacts w/cell membranes)
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What is the complication associated with anthracyclins?
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Cardiomyopathy is a critical toxicity of anthracyclins which is related to total dose
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List the anthracylins.
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doxorubicin, daunorubicin, epirubicin, and idarubicin.
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Describe the action of bleomycins.
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Antibiotic, CCNS cytotoxic glycopeptides which induce fragmentation of DNA & accumulation of cells in G2. Minimal side effects, so popular in combo. w/other drugs.
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List the nitrogen mustards.
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mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil.
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List the nitrosoureas.
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carmustine, lomustine, semustine.
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What are the consequences of DNA alkylation?
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mispairing of guanine w/thymine residues during DNA synthesis, depurination by excision of guanine residues (random bases are inserted), cross linking of DNA, no replication (bifunctional alkylating agents only (nitrogen mustard))
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List the platinum coordinating complexes.
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cisplatin, carboplatin, oxaliplatin.
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How do platinum coordinating complexes function?
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Hydrolysis in the cell activates them and they from DNA adducts which inhibit DNA replication, leading to strand breaks. Normal cells have time to repair this damage but tumor cells do not.
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Focus of clinical studies of chemotherapeutic drugs is on:
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specific drug combos, dose-levels, dosing schedule, and sequencing of drugs.
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BEP
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Used for testicular cancer.
Bleomycin Etoposide Cisplatin |
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FEC
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Used for breast cancer.
Fluorouracil Epirubicin Cyclophosphamide |
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MVAC
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used for bladder cancer.
Methotrexate Vinblastine Doxorubicin (AdriamycinR) Cisplatin |
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CAV
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Used for lung cancer.
Cyclophosphamide Doxorubicin (AdriamycinR) Vincristine |
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Imatinib
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Gleevec. Inhibits several tyrosine kinases. Particular effective in bcr-abl mutations in CML. Also, c-kit in GIST, PDGFRB in CMML, and PDGFRA in eosinophilic leukemia.
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Dasatinib.
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Second-generation tyrosine kinase inhibitor for bcr-abl gene.
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Nilotinib
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Second-generation tyrosine kinase inhibitor.
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Bevacizumab
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Antibody against VEGF
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Sutinib.
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Also known as Sutent. VEGFR kinase inhibitor.
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Sorafinib
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Nexavar.
VEGFR/Raf kinase inhibitor. |
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Erlotinib
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Inhibits EGFR-1 in non small-cell lung cancer.
Also known as Tarceva. |
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Trastuzumab
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Herceptin.
Targets EGFR-2 (Her2/Neu) Used for breast cancer. |
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Rituximab
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Rituxan.
Targets CD20. Used for Non-Hodgkin's lymphoma |
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Gemtuzumab
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Mylotarg.
Targets CD33. Used for AML. |
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Alemtuzumab
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Campath.
Targets CD52. Used for CLL. |
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Cetuximab
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Erbitux.
Targets EGFR-1. Used for cancer of the colon, head and neck. |
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Bortezumib
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Velcade.
Inhibitor of the proteasome. Used for multiple myeloma and mantle cell lymphoma. |
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Vorinostat
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Zolinza.
Inhibits HDACs. Used for T-cell lymphoma. |
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Decitabine
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Dacogen.
Inhibits DNA methyltransferases. Used for myelodysplastic syndrome (MDS). |
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Azacytidine
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Vidaza.
Inhibits DNA methyltransferases. Used for myelodysplastic syndrome (MDS). |
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Methotrexate
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CCS agent.
Inhibits DHFR and shuts of DNA/RNA synthesis. |
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5-fluorouracil
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CCS agent that acts in S phase.
Resembles uracil and thymine. 5-fluorouraciltriphosphate is incorporated in to mRNA while 5-FdUMP inhibits thymidylate synthase-->inhibition of DNA synthesis. |
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Vinca alkaloids
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CCS agents (M phase)
Vincristine and Vinblastine. MT destabilizers. Cells arrested in metaphase. Revolutionized treatment of childhood leukemia. |
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Taxanes
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CCS agent (M phase)
Paclitaxel and docetaxel. From Pacific yew tree. MT stabilizers. Used in breast and ovarian cancer. |
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Etoposide and teniposide
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CCS agents (G2 phase)
Epipodophyllotoxins. Inhibit topoisomerase II & induce double stranded breaks. |
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Topotecan and irinotecan
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CCS agents (G2?)
Camptothecans Inhibit topo I Cells w/o TOPO I are resistant to camptothecans. |
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Define gene therapy
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Technique for correcting defective genes responsible for disease development.
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Define "vector" and list the types.
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Definition: carrier molecule used to deliver the therapeutic gene to the target cells.
Types: viruses, direct introduction, liposomes, receptor-mediated, and artificial chromosome. |
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Describe what happened with Gelsinger.
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Gelsinger had partial ornithine transcarbamylase deficiency. He joined trial later and had increased liver enzymes. Trial participants received adenoviral does on sliding scale. He received a higher dose-->developed liver failure-->died.
Gelsinger should not have been included in the study to begin with. |
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Describe the retroviral trials from 2003.
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Boys with X-SCID were treated with gene therapy via retrovirus. Stable insertion into genome was via bone marrow cells. All patients developed leukemia later in life b/c retrovirus inserted in region that caused leukemia.
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List the problems with gene therapy.
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Gene transfer is short lived.
Immune response can be difficult. The viral vectors can cause problems. Multigene disorders are difficult to treat via gene therapy. |
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Describe the Leber's congenital amaurosis.
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Disease=congenital blindness due to problem inthe retina of the eye.
RPE65 gene is cause of this particular variant. Needle injected AAV vector containing functional RPE65 gene in retina. Tested in dogs then humans. More successfull in dogs than humans. |
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Define "stem cell"
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Stem cell is a cell that is capable of self-renewal, ensuring a lifetime supply of descendants for replenishment or repair. A stem cell may differentiate into other types of cells specific to that organ or tissue.
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Totipotent embyronic stem cells: definition.
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the first 2-4 cells of an embyro. Have the potential to develop into a complete organism.
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Pluripotent embryonic stem cells: definition.
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Cells destined to be in the embryo can no longer produce the placenta (16 cell stage).
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Describe somatic cell nuclear transfer.
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Transfer nucleus from donor adult somatic cell to enucleated ovum. Produced Dolly.
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What issues did Dolly have?
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Genetically older at 5 years than a 5yo ewe (telomeres 20% shorter)
Obesity Arthritis Euthanized b/c she had lung cancer caused by a virus that usually affects sheep much older. |
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Programmed mature cells: what are they and what are their issues?
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Induced pluripotent stem cells (iPS): uses adult donor cell and nucleus which is genetically identical to the donor. Requires transfection w/stem-cell specific genes (Oct4, Sox2, cMyc, and Klf4)
Problem: once transferred to mice all tumor develop b/c cMyc is constitutively activated. |
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List the epigenetic mechanisms of trasncriptional regulation.
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DNA methylation of promoter
Histone modifications RNA regulation |
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What does an acetylated histone result in?
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The availability of a gene for transcription.
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What is the role of epigenetic process in the development of cancer?
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CpG island methylation in the promoter region increases as tumor develops as the histone modification pattern increases. Aberrant epigenetic silencing of tumor-suppressor genes plays a role in cancer developement.
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What is the role of epigenetic therapy in cancer?
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HDAC and DNA methyltransferase inhibition can restore proper gene expression.
BUT it can also affect other cellular processes. |
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What are the commonly hypermethylated genes in AML?
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p15, calcintonin, E-cadherin, ER, MyoD, p16, RARbeta, WT-1.
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Describe the importance of AML1/ETO+ AML.
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AML1 recruits a transcriptional activation complex to target genes including IL-3 & GM-CSF. The mutant fusion AML1/ETO instead recruits a transcriptional repressive complex including HDAC and DNMT in t(8;21) AML.
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What is valproic acid?
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Seizure agent & very weak inhibitor of histones.
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What is SAHA?
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Vorinostat, which is a HDAC inhibitor. Used for CTCL. (cutaneous T cell lymphoma)
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What is 5-azacytidine?
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5-azacytidine is approved of MDS treatment.
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What is CTCL?
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Malignant disorder of T-lymphocytes marked by infiltration of T-cells into skin. Predominant symptoms are cutaneous & can be severe: pruritis, skin breakdown, and impaired immunity.
Has four stages. May be indolent or aggressive |
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What did the paper by Ley TJ in Nature provide us with?
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The linkage of 10 genes to leukemia, 8 of which had never been associated with leukemia before.
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What is bisulfite sequencing?
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Determines methylation pattern of DNA. Converts cytosine residues to uracil but leaves 5-methylcytosine residues unaffected.
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Define pharmacogenetics.
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Focus on single genes.
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Define pharmacogenomics.
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Focus on many genes, use of genome-wide approaches to gene identification.
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What affects the drug response phenotype?
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1. Complex polygenic trait that can be affected by either GOF or LOF mutations.
2. Enviromental: drug-drug interactions. 3. Phenocopying: WT allele + enzyme inhibition by 2nd drug=high drgu conc. |
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What is the importance of CYP2C9?
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Hydroxylates 16% of clinical drugs.
Some drugs require specific levels w/narrow windows. warfarin phenytoin tolbutamide (Orinase-->insulin release stimulator) |
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What causes variability in warfarin metabolism?
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Warfarin contains two isomers: R- and S-. R has multiple metabolism pathways but S has fewer. All of the S-warfarin metabolism pathways use CYP2C9.
Also, a SNP in VKORC1 affects warfarin metabolism. These two variations are tested to help determine appropriate dosage. |
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What is VKORC1?
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Vitamin K epoxide reductase.
Explains 25% of warfarin variance. |
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What is the importance of CYP2D6?
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Responsible for the metabolism of 20-25% of clinical drugs.
Includes many antipsychotic drugs, metaprolol, and tamoxifen. |
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What inhibits CYP2D6?
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Cocaine
Fluoxetine (prozac) paroxetine (paxil) protease inhibitors (used to treat HIV) |
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What is the impact of variation on metabolism of drugs by CYP2D6?
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There are a number of different variants split into four categories: poor, intermediate, efficient, and ultrarapid metabolizers.
Relative dosage adjustments are recommended based on metabolism rate. |
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What is the impact of the use of ecstasy on CYP2D6?
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Ecstasy (MDMA) inhibits reuptake of serotonin & facilitates serotonin release. MDMA is metabolized by CYP2D6 and also inhibits CYP2D6. So, two consecutive doses of MDMA may result in an OD.
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What is the effect of MDMA?
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No hallucinations.
Toxicity is serotonin syndrome which includes increased m. rigidity, hyperreflexia, hyperthermia, increased HR & BP. |
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What is the importance of CYP3A?
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Responsible for the metabolism of 50-60% of clinical drugs. Expressed mostly in liver & intestines.
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What impact do drugs have on CYP3A?
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Many drugs induce increased expression of CYP3A4 and CYP3A5. So, induction by one drug increases the rate of metabolism of all CYP3A drugs, resulting in increased drug metabolism.
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What is the relationship between CYP3A and drug metabolism in different populations?
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Nonwhites particularly have high levels of CYP3A5 which results in increased drug clearance and the requirement of high dosages for effectiveness.
80 SNPs have been identified in CYP3A5. |
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What is the importance of variation in NAT1?
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NAT1 is an acetyltransferase which acetylates aromatic amines (tobacco carcinogens).
There is variability in NAT1. Increased NAT1 activity confers lower risk of lung cancer due to smoking. |
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What is the importance of NAT2?
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NAT2 is a acetyltransferase which acetylates isoniazid (an anti-TB drug) and other aryl amines. Phenotypic variations produce both rapid and slow inactivators of isoniazid. The slow acetylators have increased risk of hepatotoxicity.
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What is TPMT?
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Thiopurine S-methyltransferase.
Responsible for the inactivation of thiopurines including mercaptopurine and azathiopurine. |
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What is the importance of TPMT?
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Thiopurines are used for treatment of a variety of diseases. Low levels of TPMT can result in dangerous leukopenia with normal dosage amounts of thiopurines.
Alleles: *3=lowactivity while *1=high. Heterozygote=intermediate activity |
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What is the relationship of ALL and TPMT?
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Children with intermediate or low TPMT levels had better response to treatment b/c they had high mercaptopurine levels. Now, TPMT genotyping is standard of care in treatment of ALL. *1/*1 patients (high TPMT levels) receive higher doses of mercaptopurine.
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What is the goal of pharmacogenomics?
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Personalized/individualized medicine.
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What are biomarkers?
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Substances produced by tumor cells or by other cells of the body in response to cancer, or to a benign or noncancerous condition.
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What is CA 19-9?
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Carbohydrate biomarker for pancreatic cancer found in the serum.
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What is CA 125?
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Glycoprotein biobarker for ovarian cancer found in serum.
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What important protein biomarkers are found in the serum?
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PSA, CEA, CA125, CA19-9, beta-HCG, AFP, monoclonal Ig.
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What important protein biomarkers are found in the tissue?
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ER, PR, HER2/NEU, CD20, CD117.
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What does monoclonal Ig serve as a marker for?
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B cell lymphoma & leukemia, myeloma.
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What is AFP serve as a marker for?
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hepatocellular carcinoma, non-seminomatous (GCT)
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What is CEA a marker for?
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colorectal carcinoma.
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What is the primary use for serum tumor markers?
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Follow a patient's progress.
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What is HER2/NEU?
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Protein in epidermal GF receptor in many breast cancers.
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What is CD20?
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CD20 is a biomarker used in gastric lymphoma.
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What is CD117-cKIT?
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Arises from cells that connect nervous plexuses in the cell wall. found in GIST.
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What are the types of molecular biomarkers?
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chromosomes, DNA mutations, and miRNA.
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What is the use of a multiple mutational analysis?
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Determine whether a patient with synchronous tumors has metastatic disease or two primary tumors.
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What is gene profiling?
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Use of several biomarkers to determine the risk of recurrence of a certain disease.
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What is the implication of KRAS mutations on response to EGFR-inhibiting drugs such as Cetuximab?
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A mutated KRAS bypasses the EGFR-mediated inhibition and induces cell proliferation. Resistance to EGFR-targeted drugs can come from a mutation in KRAS. Paricular common in adenocarcinomas of the lung.
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What is the ideal approach for biomarker validation?
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Well designed prospective, well-controlled clinical study with standardization of every step of the process.
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What is qualitative data?
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Also known as categorical or discrete.
Includes nominal (eg. eye color, sex) or ordinal (stage, eg. good, bad, better). |
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What is quantitative data?
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Also known as continuous or numerical.
Numeric: many pseudo-continuous. Interval: SAT score Ratio Time-dependent (survival) |
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What type of confidence interval is ideal and how can it be achieved?
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A small CI is ideal. A smaller CI can be attained by using a bigger sample size.
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What is an exploratory study?
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Exploring patterns in data, no real hypothesis. Can't generate final conclusions.
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What is an inferential study?
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Study's goal is to test a hypothesis. Hypothesis must be determined ahead of time. Usually, one establishes a null hypothesis and attempts to disprove it.
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What is Type I error?
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Alpha probability.
False positive. Reject a true null hypothesis. |
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What is type II error?
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beta probability.
False negative. Power= (1-beta) Accepting a false null hypothesis. Inadequate sample size increases beta. |
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What is necessary when citing a P value?
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Also include a confidence interval.
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What is the odds?
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Odds=(probability of an event happening)/(probability of an event not happening)=(p)/(1-p)
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What is an odds ratio?
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OR=ad/bc
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What is the relationship of OR and RR?
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OR>>RR for common events & tends to overestimate risk.
RR cannot be calculated for some studies if total number at risk is not known. OR estimates RR. |
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What does Kaplan-Meier analysis do?
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Uses estimator to estimate survival because you don't know true survival because of incomplete observations.
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What was the importance of Erlotinib?
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The hazard ratio of was .018, which indicated a protective effect of the use of erlotinib + gemcitabine vs. gemcitabine alone. However, this added up to an average of only 12 day increase in survival. This did not include a test for the EGFR receptor mutation that erlotinib was active on.
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What is the HR?
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Hazard ratio.
It is generated from the entire distribution-->not just the median. Ranges from 0-->infinity. HR is skewed (not symmetric). |
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What is a phase I clinical trial?
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Establishes a safe dose and establishes that target is effected at recommended dose.
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What is a phase II clinical trial?
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Determines safety and efficacy of drug & determines if target change is assocaited w/early outcome.
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What is a phase III clinical trial?
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See if long-term outcome is beneficial to patient.
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What is one factor that affects survival rates of cancer?
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Minority status and age.
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What was used to determine the presence of GIST?
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C-KIT immunohistochemistry.
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What drug was found to be effective in treating GIST and what was its original indication?
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Gleevec (imatinib).
Imatinib blocks ATP-binding sites on KIT receptor. Originally indicated for CML. |
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What is one complication of imatinib therapy?
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Patients need to continue Gleevec forever-->can develop resistance.
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What is primary mediastinal large B-cell lymphoma?
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PMLBCL.
Expresses CD20. Appears to behave like a combination of Non-Hodgkins and Hodgkins lymphomas. |
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What is the treatment for CD20+ lymphomas?
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Rituximab.
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What treatment did the patient with PMLBCL receive?
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CHHOP + radiation + rituximab.
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What is one cause of neuroblastomas?
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Amplification of MYCN gene.
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What types of amplification can be seen in MYCN?
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Double minutes
Homogenously staining regions |
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What are double minutes?
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Small separate chromosomes containing an amplified gene.
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What are homogenously staining regions?
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Regions of large insertions of a number of copies of an amplified gene.
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What is the cause of CML?
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GOF activation of a Tyr kinase via fusion of 5' BCR on chromosome 22 with 3' ABL on chromosome 3.
This mutation is t(9;22)-->Philadelphia chromosome. |
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What is the result of t(11;14)?
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B-cell type CLL due to OE of cyclin D1
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What is the result of t(14;18)?
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B cell type CLL & follicular lymphoma due to OE of BCL2-->apoptosis inhibition.
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What is mutated in Burkitt lymphoma?
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MYC is OE'ed.
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What is MEN2 caused by?
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GOF mutation in RET gene.
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What are the variants of MEN2 and what are their implications?
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MEN2A is less severe than MEN2B (which has an earlier age of onset). Familial MTC is another variant. MEN2A has the mutation in the extracellular domain while the others have the mutation in the cytoplasmic domain. MEN2B implicates earlier thyroidectomy.
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What is the Knudson 2-hit hypothesis?
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The first mutation results in no disease phenotype. A second mutation leads to cancer.
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What are the characteristics of tumor-suppressor genes?
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Mutations are recessive at the cellular level and dominant at the pedigree level.
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What are the symptoms of FAP?
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Numerous precancerous polyps in adolescence. Extracolonic polyps may develop in other areas such as stomach & duodenum. Increased risk of other cancers.
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What causes FAP?
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Germline mutation in APC gene.
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What does APC do?
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APC is an antagonist of the WNT signaling pathway. It binds & degrades beta-catenin which prevents excess transcription. Mutations result in uncontrolled transcription.
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What are the symptoms of HNPCC?
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Lynch syndrome.
Tumor site is in proximal colon; adenomatous polyps initiate cancer but occur in small quantities, women have increased risk of endometrial cancer. |
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What causes HNPCC?
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Defect in DNA mismatch repair system.
MSH2 or MLH1, MSH6, PMS2. |
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What is an indicator a defective DNA mismatch repair?
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Microsatellite instability.
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What is juvenile polyposis?
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Juvenile polyps=a type of polyp.
Hamartomatous polyps in the GI tract that are benign. Increased risk of intestinal cancer. |
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What causes juvenile polyposis?
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Mutations in SMAD4 or BMPR1A.
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What is Peutz Jegher syndrome?
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Hamartomatous polyps in the jejunum, menaocytic spots on lips & buccal mucosa.
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What causes Peutz Jeghers syndrome?
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Mutation in LKB1 (STK11) which affects differentiation of intestinal epithelilal cells.
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What does a mutation in PTEN cause?
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Cowden syndrome. PTEN is responsible for negative control of the P13K signaling pathway.
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What is Li-Fraumeni syndrome?
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Germline mutation in p53.
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What is caused by a homozygous mutation in MCR1?
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Reduced ability to synthesize eumelanin & 100x increased risk for melanoma.
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What does a person who is heterozygous for mutations in both MCR1 and CDKN2A have to worry about?
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An 85% risk of melanoma.
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What are linked genes?
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Genes which are so close together on a chromosome that they are unlikely to be separated due to recombination.
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What is the action of CCR5?
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Receptor which allows HIV to enter host cells.
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What does a 32bp deletion in CCR5 cause if it is heterozygous?
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A person whose progression to AIDS will be prolonged. Also, increases susceptibility to West Nile Virus.
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What effect does being MTHFR 677TT have on CAD?
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A 16% increased risk of CAD if folate levels are low.
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What are the five SNPs which cause increased risk of CAD?
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KIF6, MVH15, PALLD, SNX19, and VAMP8
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What is the importance of APOEe4 in Alzheimer disease?
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APOEe4 homozygosity results in an increased incidence of late-onset Alzheimers.
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What is dysplasia?
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Disordered cell growth.
Characterized by abnormal basal appearing cells w/hyperchromatic nuclei, prominent nucleoli, increased N/C, and increased mitoses. |
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What role do cadherins play in metastasis?
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Cadherins are cell adhesion molecules that bind to cytoplasmic actin. Replacement of normal E-cadherin with N-cadherin is associated with invasion.
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What role do integrins play in metastasis?
|
Bind to laminin or fibronectin.
Integrins also function in the MAP kinase pathway. Altered integrin expression is associated with cancer. |
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What are CAMs?
|
Immunoglobulin superfamily proteins which bind to other cell CAMs or integrins involved in cell-cell adhesion. Altered expression increases cell motility.
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What are selectins?
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Transmembrane proteins which bind to sialylated carbohydrates attached to mucin-like moleucles.
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What enzymes are involved in digestion of the basement membrane during tumor invasion?
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Proteases, MMPs.
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What types of proteases are involved in metastasis?
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serine proteases (plasmin, urokinase, plasminogen activator) and cathepsins (BDC)
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What are MMPs?
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Family of zinc and calcium dependent endopeptidases. Usually involved in embyronic development nad tissue repair.
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What are TIMPs?
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Tissue inhibitors of MPs. Act by complexing with MMPs. Disturbed MMP/TIMP balance can lead to disease.
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What is von Hippel-Lindau syndrome?
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Increased risk for renal cell carcinoma.
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What HTLV-1?
|
An oncogenic RNA virus that causes T cell leukemia and lymphoma.
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What is a direct-acting initiator?
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An initiator in which no chemical transformation is needed for effect.
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What is an indirect-acting initiator?
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An initiator in which chemical transformation in necessary for effect.
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What is an initiatior?
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An electrophile that reacts w/nucleophilic sites to induce DNA adducts.
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What does GST do?
|
Inactivates many polycyclic aromatic hydrocarbons.
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What is a promoter?
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Induces cell proliferation but is not mutagenic.
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What does UVB do?
|
Induces formation of pyrimidine dimers which are repaired by NER.
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What is a complication of therapeutic radiation of the thymus?
|
Thyroid cancer later.
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What HPV strains are highly carcinogenic?
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16, 18.
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Which HPV strains produce low-grade dysplasia?
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6 11
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What is E6?
|
An early viral gene product of HPV 16 nd 18 which binds p53 and increases its degradation.
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What is E7?
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An early viral gene product of HPV 16 or 18 which binds Rb and induces the release of E2F.
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How does EBV cause Burkitt lymphoma?
|
c-myc is activated.
LMP-1 prevents apoptosis by upregulating bcl2 and activating cmyc. |
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What is Hbx?
|
Hbx protein can be produced by Hep B and binds p53-->stops growth suppression.
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Where is HTLV-1 endemic?
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Japan & Caribbean
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What does 2D-DIGE do?
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Helps visually analyze differences in protein concentration between cancers and normal cells.
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What does SELDI-TOF do?
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Makes a pattern of proteins. Cannot identify peaks but can use mixture of proteins.
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What does MALDI-TOF do?
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Identifies a protein.
CANNOT use protein mixtures. |
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What is ESI-LC-MS used for?
|
Identification for differences in protein expression patterns.
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What is PEDF?
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Anti-angiogenic protein that is decreased in prostate cancer patients.
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What is a ROC curve?
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Plot of TP rate on Y and FP on X. Should not have a slope of 1. Area under of curve should be greater than .5.
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What are heterotypic interactions?
|
Communication between different types of cells, including tumor cells.
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What is the threshold for oxygen diffusion?
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2mm
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What monitors oxygen tension in cells?
|
VHL proteins.
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What do VHL proteins signal for the production of in hypoxic conditions?
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VEGF proteins.
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What do VEGF proteins do?
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1. Stimulate proliferation of endothelial cells.
2. Stimulate the migration of endothelial cells to areas of high [VEGF] |
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What is TGF-beta?
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An angiogenic factor.
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What is beta-FGF?
|
An angiogenic factor.
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What mediates the expression of VEGF from a signal from VHL proteins?
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HIF-1.
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What is SDF-1?
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A chemotactic factor released by myofibroblasts that attracts endothelial cells.
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What is thrombospondin-1?
|
An anti-angiogenic factor released in to ECM.
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Why do cryptic secondary tumors sometimes arise after removal of the primary tumor?
|
The primary tumor produces antiangiogenic facotrs that inhibit secondary tumor growth.
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What are the antiangiogenic factors?
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thrombospondin-1, arrestin, tumstatin, angiostatin, endostatin.
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From where are many antiangiogenic factors derived?
|
Proteolytic cleavage of normal ECM proteins.
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What cyclins bind to Cdk1?
|
cyclin A, cyclin B, and cyclin B3, in that order.
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What are the steps to activation of Cdk1?
|
1. Cdk1 binds a cyclin
2. Thr14 and Tyr 15 are phosphorylated 3. Thr160 is phosphorylated 4. Thr14 and Tyr15 are dephosphorylated. 5. Cascade. |
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How are Cdks turned off?
|
Cyclins are destroyed via polyubiquination after being labeled by the same cyclin/cdk group.
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What is p53?
|
p53 is a tumor-suppression gene which stimulates the synthesis of Cdk-inhibitory proteins.
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What inhibits Cdk2/Cyclin E?
|
p21
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What is the INK4 family of CKI's?
|
Targets Cdk4 and Cdk6 by disrupting association w/D-type cyclins.
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What pair of Cdk/cyclin partners regulate the restriction point?
|
Cdk4(6)/Cyclin D
Cdk2/Cyclin E |
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What pair of Cdk/cyclin partners regulate the G1-S phase transition?
|
Cdk2/Cyclin E
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What pair of Cdk/cyclin partners regulate the S-G2 phase transition?
|
Cdk2/Cyclin A
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What pair of Cdk/cyclin partners regulate the chromosome condensation & nuclear envelope breakdown?
|
Cdk1/Cyclin A
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What pair of Cdk/cyclin partners regulate the spindle assembly?
|
Cdk1/Cycling B
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What pair of Cdk/cyclin partners regulate the anaphase?
|
Cdk1/Cyclin B3
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What pair of Cdk/cyclin partners regulate the CAK activity?
|
Cdk7/cyclin H
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What pair of Cdk/cyclin partners regulate the neuronal differentiation?
|
Cdk5/cyclin G
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What differentiates v-src from c-src?
|
v-src has a 19aa substitution in c-src with 12 unrelated aa's. This includes the loss of Tyr527, which inhibits the tyrosine kinase actvity.
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What is the importance of the Ras oncogene?
|
A single mutation at position 12 or 61 can create an oncogene.
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What is p53 activity closely related to?
|
bcl-2 & the ability to trigger apoptosis.
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What is in the tunica intima?
|
A single layer of flattened squamous epithelial cells (the endothelium) and the underlying subendothelial CT.
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What is in the tunica media?
|
Smooth muscle cells, elastic fibers,collagen, and proteoglycans.
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What is in the tunica adventitia?
|
Fibroblasts, collagen, and elastic fibers.
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What are the three types of arteries?
|
Elastic (conducting), muscular (distributing), and arterioles.
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What is in the tunica intima of elastic aa.?
|
thick.
Endothelial lining Sub-endothelial layer of CT Internal elastic membrane (lamina) |
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What is in the tunica media or elastic aa.?
|
Thickest.
Smooth mucsle cells in layers. Elastin in form of fenestrated sheets of lamella between muscle layers Collagen fibers & ground substance. |
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What is in the tunica adventitia of the elastic aa.?
|
Thin Ct layer about 1/2 the thickness of tunica media.
Collagen fibers Elastic fibers (not in lamellae) Fibroblasts and macrophages |
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What is in the tunia intima of muscular aa.?
|
Thinner than in elastic aa.
Endothelial lining Sparse sub-endothelial CT Prominent internal elastic membrane |
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|
What is in the tunica media of muscular aa.?
|
Smooth muscle cells
Collagen fibers Elastic material (sparse) External elastic membrane may be evident. |
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What is in the tunica adventitia of muscular aa.?
|
About as thick as the tunica media.
Elastic fibers Collagen fibers and ground substance Fibroblasts & adipocytes. |
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|
What is in the tunica intima of arterioles?
|
Endothelial lining
Basal lamina Sparse subendothelial CT VERY SMALL VESSEL |
|
|
What is in the tunica media of arterioles?
|
one or 2 layers of helically arranged smooth m. cells
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|
What is in the tunica media of arterioles?
|
Sparse.
Only fibroblasts & ECM. |
|
|
What is are the metarterioles?
|
Terminal part of the arterioles.
Also known as the precapillary sphincter area. Smooth muscle layer is discontinuous. |
|
|
What are the three types of capillaries?
|
continuous, fenestrated, and discontinuous.
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|
|
Where are continuous capillaries found?
|
Most of the body.
|
|
|
Where are fenestrated capillaries found?
|
Endocrine glands, gallbladder, intestines.
|
|
|
Where are discontinuous capillaries found?
|
Liver, spleen, bone marrow
|
|
|
What characterizes continuous capillaries?
|
junctional complexes and caveolae.
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|
|
What characterizes fenesterated capillaries?
|
Fenestrations.
Fenestrations are 60-100nm channels. |
|
|
What characterizes discontinuous capillaries?
|
Larger, more irregularly shaped than the other two types.
Wide gap between adjacent endothelial cells. Specialized cells may be associated with discontinuous capillaries. |
|
|
What is the vasa vasorum?
|
A network of blood vessels that supply the larger arteries and veins.
|
|
|
What are postcapillar venules?
|
15-50 micrometer vessels that receive blood from capillaries.
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|
|
What is the contents of the tunica intima of a large vein?
|
endothelium & CT
|
|
|
What is the contents of the tunia media of a large vein?
|
Smooth muscle in layers, collagen fibers.
|
|
|
What are the contents of the tunica adventitia of a large vein?
|
CT, some elastic fibers, smooth m., thicker than tunica media.
|
|
|
What is the size of a medium vein?
|
1mm-<1cm
|
|
|
What are the formed elements of blood?
|
Cells and their derivatives.
|
|
|
How big are erythrocytes?
|
7-8 microns.
|
|
|
What leukocytes are classified as granulocytes?
|
Neutrophils, basophils, eosinophils.
|
|
|
What leukocytes are classified as agranulocytes?
|
Lymphocytes and monocytes.
|
|
|
How big are neutrophils?
|
10-12 microns.
|
|
|
What is the characteristic feature of neutrophils?
|
Polymorphonuclear. Nucleus has 3-5 loobes.
|
|
|
What characterizes tertiary granules?
|
Gelatinase and alkaline phosphatase
|
|
|
What are the three types of neutrophil granules?
|
Azurophilic, specifc, and tertiary
|
|
|
What is the role of neutrophils?
|
Phagocytes.
|
|
|
What is characteristic of eosinophils?
|
Large refractile granules. Generally have a bilobed nucleus.
|
|
|
What is the function of eosinophils?
|
Killing parasitic worms and internalization of antigen-antibody complexes.
|
|
|
What is characteristic of basophils?
|
"S" shaped nucleus often obscured by a number of cytoplasmic granules. Smaller than eosinophils or neutrophils. Express IgE.
|
|
|
How big are monocytes?
|
10-12microns. They are the largest leukocytes.
|
|
|
What is the function of monocytes in blood?
|
They are travelling from bone marrow to specfic organs to differentiate into macrophages.
|
|
|
What is a characteristic feature of monocytes?
|
kidney-shaped nucleus.
|
|
|
What is the size range of lymphocytes?
|
6-18microns.
|
|
|
What are the categories of lymphocytes?
|
B cells and T cells.
|
|
|
Where do T cells mature?
|
Thymus.
|
|
|
What do B lymphocytes do?
|
Prodcution of antibodies and differentiate into plasma cells.
|
|
|
What is the function of T lymphocytes?
|
Cell-mediatedi mmunity.
|
|
|
What produces platelets?
|
Megakaryocytes via demarcation channels.
|
|
|
How big are platelets?
|
2 microns.
|
|
|
What is a benign squamous papilloma?
|
Benign squamous epithelium-derived papilloma covered with layers of neoplastic cells.
|
|
|
What characterizes neoplastic lesions from squamous cells?
|
Intercellular bridges normal seen in stratified squamous epithelium
|
|
|
What charcterizes squamous cell carcinoma?
|
Keratin pearls and whirls.
|
|
|
What do adenocarcinomas look like?
|
Donuts. Lumn formed by tumor cells. Also, signet ring appearance.
|
|
|
What characterizes fibroblast tumors?
|
spindle-shaped cells w/spindle-shaped nuclei
|
|
|
What are smooth muscle cell tumors?
|
Benign: leiomyoma
Malignant: leiomyosarcoma |
|
|
What is a choristoma?
|
mass of ectopic dermal tissue: normal tissue in wrong place
|
|
|
What is a hamartoma?
|
disroganized normal tissue at normal site
|
