Foundations 2 Week 4 part 2

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  1. What is a Koilocyte?
    • A Koilocyte is a squamous epithelial cell that has undergone a number of structural changes, which occur as a result of infection of the cell by human papillomavirus (HPV).
    • Koilocytes may have the following cellular changes:
    • Nuclear enlargement (two to three times normal size)
    • Irregularity of the nuclear  membrane contour
    • A darker than normal staining pattern in the nucleus, known as Hyperchromasia
    • A clear area around the nucleus, known as a perinuclear halo.
  2. Correlate PAP smear sensitivity and specificity.
    • Sensitivity (TP/ TP+FN): 47%
    • Specificity (TN/TN+FP): 95%
  3. Contrast the characteristics of quadrivalent and bivalent HPV vaccines.
    • Both are non-infectious and contain no viral DNA. Contains viral protein L1 that assembles into a virus like particle.
    • Bivalent: Contains L1/VLPs for types 16, 18. It is 93-100% effective against types 16, 18 precancers.
    • Quadrivalent: Contains l1/VLPs for types 6, 11, 16, 18. 99% effective against types 6, 11 genital warts, 93-100% effective against types 16, 18 precancers.
  4. Describe the clinical use of HPV vaccines.
    • When should it be given? When the patient chooses. Ages 11-12 recommended.  The second dose is given 2 months later, the 3rd dose is given 6 months after the first (4 months after the second). If a dose is missed, give next dose as soon as possible at least 12 weeks after the previous dose.
    • It is available for females and males, ages 9-26. Only prevents types not already acquired. Do not give to pregnant women (no data) or to patients with yeast/vaccine allergies.
  5. How are mutations involving introns or insertions written?
    • Mutations involving an intron can be signified with a + or -, indicating the number of positions away from the exon.  “ins” is used to indicate an insertion (eg, 6154insC).
    • A mutation is any change, especially when function is decreased to less than 50% of normal.
  6. Describe 7 different types of mutations
    • Depurination: A purine (A or G) is randomly kicked out of the sequence.  It may be replaced with a different nucleotide.
    • Deamination of Cytosine: Cytosine may lose an amine, which can be replaced with an oxygen to produce Uracil. Uracil then pairs with Adenine (instead of Guanine), introducing an error.
    • ROS: ROS (from mitochondria) can react with DNA causing Guanine→8-oxoguanine. 8-Oxoguanine can pair with adenine or cytosine, introducing errors.
    • UV: UVB and UVC can cause thymine dimers (two adjacent thymines bond together).  This can be corrected by nucleotide excision repair.
    • Alkylation and cross linking: Alkylating agents can add an alkyl group to position 6 of guanine.
    • Replication machinery errors: Replication slippage in microsatellites causing deletions or insertions. Triple repeat nucleotides (trinucleotide repeat mutations, eg CGG-CGG-CGG) have the same problem, causing anticipation (the disease worsens in successive generations).
    • Fragile X syndrome: Triple repeats on the long arm of the X chromosome (Xq27.3, exhibiting an X-linked inheritance pattern) causes a prominent jaw, retardation, large ears, and large testes. It enlarges when passed from a MOTHER to child, not father to child.
  7. How are errors repaired?
    • Due to repairs, a cell can replicate about 50 times before dying, with 3.2 nucleotide errors with each division.
    • Base Excision Repair: Excises a bad nucleotide, repairing depurination and cytosine deamination errors.
    • Nucleotide Excision Repair: Repair thymine dimers and large chemical adducts (ie, polycyclic carbons, etc)
    • Mismatch Repair: MLH1, MSH2, MSH6, PMS2 correct mismatched pairs.
    • DNA RecQ Helicase family: Prevents mutations by suppressing recombination. Bloom syndrome can occur from a defect.
    • PARP1: PARP1 enzyme causes ssDNA repair
    • Double stranded break repair: Occurs through non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination
  8. What are the components that form microtubules and how do microtubules lengthen and shorten?
    • Microtubules are elongated polymeric structures composed of rings of 13 polar α-tubulin + ß-tubulin dimers.  They are aligned head to tail, with ß-tubulin connecting to the next α-tubulin (think legos!).  Microtubules grow on the ß side of the chain by attaching more α-tubulin/ß-tubulin complexes, with the α side of the chain usually attached to the Microtubule Organizing Center (MTOC).
    • These subunits can be polymerized or depolymerized (allowing them to polymerize in other locations). Depolymerization is caused by low temperature or high pressure, polymerization is encouraged by high temperatures or low pressure.  MAPs (microtubule associated proteins) can also modify the speed of polymerization/depolymerization and anchor the microtubules to specific organelles.
  9. What is dynamic instability?
    Microtubules are constantly growing or shrinking until they find an acceptable target (a MAP protein?) on the growing end. This is known as dynamic instability.  Binding to MAPs stabilizes the microtubule.
  10. What are the functions of microtubules in cells?
    • Intracellular vesicular transport (e.g., movement of secretory vesicles, endosomes, and lysosomes),
    • Movement of cilia and flagella,
    • Attachment of chromosomes to the mitotic spindle and their movement during mitosis and meiosis,
    • Cell elongation and movement (migration)
    • Maintenance of cell shape, particularly its asymmetry.
  11. What are molecular motor proteins and how do they function?
    • ATP-powered molecular motor proteins that use microtubules like train tracks to move transport vesicles, mitochondria, and lysosomes.
    • Dyneins move toward the minus end (toward the MTOC)
    • Kinesins move toward the plus end (toward the periphery)
  12. What is the clinical implication of dynein dysfunction in cilia?
    • Dynein is responsible for causing cilia movements.  
    • A defect can cause Kartagener’s syndrome, presenting dysfunction of microtubules and sperm motility.
  13. How does drug induced alteration of microtubule polymerization impact neutrophil function?
    • Drugs (like paclitaxel, aka taxol) can stabilize microtubules, arresting development in various stages.
    • Other drugs (like vinblastine and vincristine, aka oncovin) can destabilize microtubules, preventing mitosis.
  14. How does F-actin form from G-actin?
    • Free actin molecules in the cytoplasm are called G-actin. Polarized filament actin is called F-actin.  Filaments have a fast growing plus (barbed) end and a slow growing minus (pointed) end.
    • Actin-Binding Proteins (ABPs) interact with G-actin to prevent or enhance polymerization.
  15. What is the function of the following actin-binding proteins: fascin and fimbrin; gelsolin, tropomodulin, spectrin, and myosin I and II?
    • Fascin and fimbrin: Cross-link (bundle) actin filaments into parallel arrays (actin filament bundles)
    • Gelsolin: An actin filament-severing protein. It cuts long actin filaments into short fragments at high [Ca2+].
    • Tropomodulin: Actin-capping protein. It binds to the active end of actin myofilaments to prevent further additions.
    • Spectrin: An actin cross-linking protein. It cross links actin filaments with each other.
    • Myosin I and II: Actin motor proteins. Myosin II forms thick filaments in muscle cells. Myosin I provides motor functions in specialized non-muscle cells/
  16. What is the general structure of intermediate filaments and their roles in cells?
    • Intermediate filaments are nonpolar ropelike filaments with a diameter between that of microtubules and actin filaments.  They have a long rod-shaped domain and globular domains at either end.
    • The rod-shaped domains twist together to form dimers (like two wires placed side by side and then twisted together). The dimers combine into tetramers and then are staggered and stacked into a coil of 8 tetramers.
    • Intermediate filaments are cytoskeletal components.
  17. What cell types contain keratins (Classes 1 and 2 intermediate filaments)?
    Simple epithelia, stratified epithelia, and structural keratins (aka, hard keratins, found in hair and nails).
  18. What cell types contain Class 3 intermediate filaments?
    Many cell types, including all mesoderm derived cell types, muscle cells, and nerve cells.
  19. What cell types contain Class 4 intermediate filaments?
    Also called neurofilaments, they are expressed in the axons of nerve cells.
  20. How do Class 5 intermediate filaments differ from the other classes?
    Lamins are found in the nucleoplasm of almost all differentiated cells, and is associated with the nuclear envelope.
  21. What disease states are associated with alteration of intermediate filaments?
    Alzheimer’s disease (neurofibrillary tangles), Alexander disease (mutation in the GFAP gene, resulting in cytoplasmic inclusions in astrocytes).
  22. What is the structure of microtubule-organizing centers (MTOC)?
    • The MTOC contains centrioles and an amorphous pericentriolar matrix of more than 200 proteins, including γ-tubulin that is organized in ring-shaped structures. Each γ-tubulin ring serves as the starting point (nucleation site) for the growth of one microtubule that is assembled from tubulin dimers; α- and ß-tubulin dimers are added with specific orientation to the -tubulin ring.
    • The minus end of the microtubule remains attached to the MTOC, and the plus end represents the growing end directed toward the plasma membrane.
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  23. What are the two major functions of centrioles?
    Centrioles provide basal bodies for cilia and flagella and align the mitotic spindle during cell division.
  24. What is the structure of the centriole?
    Centrioles consist of nine fused triplets of microtubules.
  25. How does alteration in receptor structure and number influence cancer cell proliferation?
    Increased receptors or stronger binding will strengthen signals to proliferate.
  26. How can activation of B-Raf or PI3-kinase isoforms in signalling pathways alter cancer cell proliferation?
    Activation of these proteins causes proliferation.
  27. What is the impact of loss of function of PTEN or mTOR have on cancer cell proliferation?
    PTEN and MTOR inhibit PI3 activity, so loss of function of PTEN or mTOR results in increased cell proliferation.
  28. How does the RB protein control of cell proliferation as compared to TP53 relative to growth-inhibitory signals?
    RB and TP53 are both tumor suppressors. RB responds to signals from within, but mostly from without the cell (ie, extracellular signals).  TP53 responds to signals and stress only from within the cell.
  29. How does loss of contact inhibition control of cell proliferation?
    • Cells in contact can suppress tumor growth in one another as demonstrated in chimeric mice missing RB proteins in chimeric clusters of cells.  Nearby cells with the NF2 gene produce Merlin proteins which couple cell-surface adhesion molecules together. LKB1 is also involved in contact inhibition.
    • The loss of contact inhibition therefore promotes cancer.
  30. What are the two major effector circuits in apoptotic machinery?
    • The extrinsic apoptotic program: Receives and processes extracellular death-inducing signals, e.g. Fas ligand/Fas receptor
    • The intrinsic apoptotic program: Receives death-inducing signals from inside the cell.  Considered a more important barrier to cancer pathogenesis
  31. What is the role that the mitochondria play in apoptosis?
    Mitochondria release cytochrome C, which induces cell death.  Mitochondria also have an BAK surface receptor that inhibits cytochrome C release.
  32. How do cancer cells go around apoptosis?
    • They use several strategies, including...
    • The loss of TP53 tumor suppressor
    • By increasing the expression of antiapoptotic regulators (eg, Bcl-2, Bcl-xL) or survival signals (lgf1/2)
    • by downregulating proapoptotic factors (Bax, Bim, Puma)
    • by short-circuiting the extrinsic ligand-induced death pathway.
  33. How are autophagy and apoptosis linked?
    Autophagy and apoptosis are often signalled together.  For example, the signaling pathway involving the PI3-kinase, AKT, and mTOR kinases, which is stimulated by survival signals to block apoptosis, similarly inhibits autophagy.  Beclin-1 triggers either autophagy or apoptosis, depending on the cell’s status.
  34. How might necrosis influence tumor cell proliferation?
    Necrotic cell death releases proinflammatory signals into the surrounding tissue, causing inflammatory cells and growth factors to be released.  This causes angiogenesis and tumorigenesis.
  35. What is the role of telomeres and telomerase in facilitating tumor cell immortality?
    Telomerase is expressed much more in immortal cells, preventing telomeres from shortening. Telomeres protect the ends of chromosomal DNA from end-to-end fusions, so shortening telomeres limits the life of a cell.
  36. What factors stimulate angiogenesis?
  37. What are two things that can upregulate VEGF gene expression?
    hypoxia, oncogenic signaling
  38. What are three examples of factors that inhibit angiogenesis?
    • TSP-1
    • fragments of plasmin (angiostatin)
    • type 18 collagen (endostatin)
  39. What cell types play a role in angiogenesis during tumorigenesis?
    Pericytes, a variety of bone-marrow derived cells (macrophages, neutrophils, mast cells, myeloid progenitors, vascular progenitor cells)
  40. Where are the outcomes of EMT?
    Epithelial-mesenchymal transition is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal cells.  EMT has been shown to occur in wound healing and in the initiation of metastasis for cancer progression.
  41. What is the role of the stromal cells in invasion and metastasis?
    • stromal cells are connective tissue cells of any organ.
    • Stromal cells adjacent to the epidermis release growth factors that promote cell division. This keeps the epidermis regenerating from the bottom while the top layer of cells on the epidermis are constantly being "sloughed" off of the body. Certain types of skin cancers (basal cell carcinomas) cannot spread throughout the body because the cancer cells require nearby stromal cells to continue their division.
    • Stroma provides an extracellular matrix on which tumors can grow.
  42. Describe the role(s) of inflammation in tumorigenesis.
    • Inflammation results in...
    • Growth factors for proliferation
    • Survival factors to limit cell death
    • Pro-angiogenic factors to promote angiogenesis
    • Matrix modifying/ digesting enzymes to facilitate angiogenesis, invasion, and metastasis
    • Inductive signals for activation of EMT
  43. How is glucose uptake by cancer cells increased?
    Cancer cells upregulate Glut1, a glucose transporter.
  44. How does hypoxia influence fuel metabolism in cancer cells?
    Hypoxia increases the levels of the HIF1α and HIF2α transcription factors, which in turn upregulate glycolysis.
  45. What is the “Warburg effect”?
    • The Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria.
    • Malignant cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin.
    • This occurs even if oxygen is plentiful.
    • PET scans use this principle and monitor uptake of 2-18F-2-deoxyglucose (FDG)
  46. Describe how tumor cells avoid immune destruction.
    • Tumor cells…
    • Paralyze infilterating NK and Tc cells by secreting immunosuppressive factors (TGF-b)
    • Recruit anti-inflammatory cells that are actively immunosuppressive (Tregs and MDSCs)
  47. How does the tumor microenvironment influence each of the hallmarks of cancer?
    • Stromal cells cause angiogenesis
    • Nearby lymphatics serve as a key to seeding
    • Pericytes-poor pericyte coverage allows for cancer cell invasion
    • Immune cells actually help the tumor grow, release EGF (tumor growth factor), VEGF, FGF2, MMPs/ Myeloid cells suppress CTL and NK activity (MDSCs)
    • Fibroblasts and myofibroblasts-secrete ECM, enhance cell proliferation and angiogenesis
    • Heterotypic signaling (cross talk between cancer and normal cells) allows cancerous cells to stimulate cells to produce necessary growth/angiogenic factors.
  48. Compare and contrast descriptive with analytic epidemiology.
    • Descriptive epidemiology: The study of cancer’s distribution in human populations through surveillance.
    • Analytic epidemiology: The study of cancer’s determinants in human population.
  49. Describe the overarching risk factors for cancer
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  50. Describe the molecular epidemiology and the advantages/disadvantages of biomarker-based data
    • Molecular epidemiology: The examination of biological markers of exposure, disease, and points in between.  Biomarkers include cytokines, acute phase proteins, SNPs, Fatty acid in blood, tumor histology, prostate-specific antigen (PSA) test, breast density, etc.
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  51. How are epithelial cancers named?
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  52. Where is keratonized and non-keratonized stratified squamous epithelium found?
    • Keratinized stratified squamous epithelium is found in the skin.
    • Non-keratinized stratified squamous epithelium is found in the oral cavity including the tongue and lips, cornea, true vocal cords, esophagus; vagina; cervix, and anus
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Foundations 2 Week 4 part 2
Foundations 2 Week 4 part 2
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