1. Slackers Cancer Molecular Biology Fact Stack Mike Ori

2. Disclaimer These represent my understanding of the subject and have not been vetted or reviewed by faculty. Use at your own peril. I can’t type so below are common missing letters you may need to supply e r l I didn’t use greek letters because they are a pain to cut and paste in.

3. What are the key risk factors for colon cancer

4. Age Genetics Chronic bowel inflammation – Crohns – UC Diet

5. What are the two types of intestinal polyps

6. Hyperplastic – Smaller (< 5mm) – Better differentiation Adenomatous – Larger (>5mm) – Size and dysplasia correlate with disease risk – Increased malignant potential.

7. Outline the genetic steps required for the development of colon cancer

8. Epigenetic changes Loss of growth control – Loss of WNT signaling Pathway APC is in WNT pathway – RAS mutations Increases MAP kinase Increases PI3 kinase – Loss of suppressors TGF-B P53 APC/B-catenin Genetic instability (?) – APC? Loss of apoptosis (?) – P53/B-catenin

9. What is the function of the WNT pathway

10. The WNT pathway controls growth of epithelial cells via the APC and B-catenin proteins.

11. Describe the interaction of APC and B-catenin

12. APC binds free B-catenin to prevent B-catenin from initiating transcription in the nucleus. B-catenin is a component of adherens junctions and may help to signal the completion of the epithelial layer. Presumably when B-catenin is present, the layer is incomplete and cell growth ensues to fill in the layer.

13. Describe the frequency of mutation of wnt and apc in sporadic cancers

14. Wnt pathway defective in 100% APC defective in 70%

15. Describe the role of RAS in tumor development

16. RAS is a g-protein that leads to activation of downstream signaling pathways that lead proliferation

17. Describe the role of TGF-B in tumorgenesis

18. TGF-B normally halts the cell cycle in G1 to prevent proliferation and to activate differentiation or apoptosis. Loss of TGF-B allows for uncontrolled growth

19. What are the two forms of hereditary colon cancer

20. Familial adenematous polyposis (FAP) Hereditary non-polyposis colorectal cancer (HNPCC)

21. Why do molecular biologists make bad football coaches

22. Because their “simplified” playbook looks like this

23. What are the two types of genetic instability found in colon cancer

24. Chromosomal instability Microsatellite instability

25. What is the failure of microsatellite instability

26. MIN results from failure of the mismatch repair mechanism

27. What is the failure in chromosomal instability

28. CIN results from defects in chromosomal segregation.

29. Relate FAP and HNPCC to MIN and CIN

30. FAP – CIN – APC gene HNPCC – MIN – MSH2, MLH1, PMS2 genes

31. How many mutations are likely involved in the transformation to malignancy

32. 5-6 mutations

33. Draw a sample timeline and gene pathway leading to malignancy

35. List the major types of diagnostic errors

36. Differentiate retrospective vs prospective thinking

37. Retrospective thinking such that used in CPC’s and by novice examiners relies on broad spectrum data collection with analysis performed late in the process. Prospective thinking modifies the hypothesis during the data gathering process as a result of the collected data. This in turn modifies the data collection process.

38. What is a heuristic

39. Choose the correct answer A statue of a bull commonly found in Minoan culture A small fluid filled cyst that forms as a result of falling on the coccyx. A problem solving technique that emphasizes experience

40. What are common pitfalls of heuristics

41. Availability – Ease of recall Anchoring – Initial impressions Framing effects – How the problem is framed affects the thinking process Blind obedience – Remember authority figures are in charge, not all knowledgeable

42. Why are mistakes by clinicians often unrecognized

43. Happen in distant past Not recognized as mistakes by provider PT does not return to same provider

44. What is the role of follow-up in clinical practice

45. Provides space and time Additional data collection (tests) Research Trial therapy results

46. Who is responsible for test follow-up?

47. You ordered it, you own it.

48. What are the three stages of memory?

49. Encoding – Attending to the event Storage – Saving it for later Recall – Getting it back out

50. Describe the ability of the mind to process conceptual vs factual information

51. The mind is good at storing the concept (gist) of a set of facts but is relatively poor at storing the facts. An interesting aside, computers in contrast are very good at storing facts but not relating them conceptually.

52. Define impression management

53. The activities we undertake to control the impressions others have of ourselves.

54. Define self-enhancement

55. Performing actions intended to bolster the positive impression others have of us. Giving money to the poor, performing pro bono work

56. Define self verification

57. Understanding the impression others have of us and relating that back to how we see ourselves. Ideally the two will match.

58. Which type of shock is dobutamine most useful and why

59. Dobutamine is a B1 agonist (weak B2) that is useful in cardiogenic shock because it increase rate and force of contraction

60. Describe the role of dopamine in shock

61. Useful in cardiogenic shock. Interacts with dopaminergic receptors to vasodilate mesenteric and renal arterioles thus increasing renal perfusion. At moderate levels it acts as a B2 and at high levels it acts as an a1 agonist

62. What is the role of phenylephrine in shock

63. Phenylephrine is a a1 agonist that is sometimes used in septic shock as a pressor.

64. What is the role of epi and NE in hypovolemic shock

65. Relatively little. The body usually has tremendous sympathetic outflow as a result of the shock state and trauma and thus has plenty of epi/ne circulating.

66. What are the expected values for cardiac output, left ventricular end diastolic volume, and mixed venous O2 in hypovolemic, cardiogenic, and septic shock

67. OutputLVEDV/wedgeMVO2SVR HypovolemicLow High CardiogenicLowHighLowHigh SepticHighNormal?HighLow

68. What physical findings are present in metabolic syndrome

69. Impaired glucose tolerance Obesity Hyperlipidemia Hypertension

70. How does metabolic susceptibility relate to metabolic syndrome

71. Metabolic susceptibility is believed to be a necessary component in the development of metabolic syndrome. Its presence is inferred because some similar individuals do not progress to metabolic syndrome.

72. What role do fatty acids play in the development of insulin resistance

73. Chronically elevated fatty acids induce insulin resistance by increasing the availability of substrates that alter down-stream signaling. Specifically, excess NADH and acetyl-CoA disrupt pyruvate dehydrogenase to effectively cutoff the use of glucose as a fuel.

74. What is the role of adiponectin in metabolic syndrome?

75. Adiponectin is an anti-inflammatory cytokine that decreases in obesity. One of its roles is to decrease lipogenesis. Thus obese individuals have an increased tendency to lipogenesis.

76. What is the role of resistin in metabolic syndrome

77. Resistin is an autocrine factor that protects full adipocytes. In metabolic syndrome the large number of full adipocytes causes resistin to take on a more systemic effect wherein it begins to affect muscle cells.

78. Describe the role of insulin, TNF-a, and IL-6 in VLDL synthesis

79. VLDL is synthesized in the liver. Both TNF-a and IL-6 increase its synthesis and both are increased in obesity. Normally, insulin would activate lipoprotein lipase in the periphery to encourage the uptake of the fatty acids in the VLDL but in insulin resistance, this action is diminished. Thus, the body creates more VLDL’s than usual but they are not degraded. As the levels of VLDL increase some will be broken down; resulting in increased LDL.

80. Describe the role of insulin in liver of metabolic syndrome

81. Insulin normally promotes the mobilization of glucose transporters to the membrane, the conversion of glucose to glycogen, and the conversion of acetyl-coa to fatty acids. With insulin resistance, glucose uptake and glycogenolysis are both impaired.

82. Explain the origin of the prothrombotic state associated with diabetic patients

83. Excess production of TNF-a and IL-6 coupled with a decrease in adiponectin leads to an inflammatory state. This in turn causes the liver to synthesize more fibrinogen and plasminogen activator inhibitor 1.

84. List the management goals for diabetic patients

85. A1C < 7% LDL < 100 Systolic BP < 130

86. List the macronutrient proportions for patients with diabetes

87. CHO = 50% Fat = 30% Protein = 20%

88. What are the common receptors used in the prognosis and treatment of breast cancer

89. Estrogen receptor Progesterone receptor Her2/Neu/ErbB2

90. What is a gatekeeper

92. Seriously, what is a gatekeeper

93. A gene that acts by directly suppressing cell proliferation

94. What is a caretaker

95. A gene that functions to maintain genenome stability

96. Is BRCA1/2 a gatekeeper or caretaker

97. Caretaker

98. What is the function of BRCA1/2

99. They are involved in homology directed repair of DS DNA breaks

100. What attributes are beneficial for screening and diagnostic tests

101. Screening tests need to be cheap, quick, easy, and sensitive. They do not have to be very specific. The ideal diagnostic tests need to be sensitive and specific. If they aren’t sensitive then they at least need to be specific. Is a home pregnancy test a screening or a diagnostic test?

102. What are the common viruses associated with cancer.

103. HIV action HTLV1Adult T-cell leukemiaNone listed HPVSquamous cell carcinomasViral escape via immune suppression EBVLymphomasCo factor HBVHepatocellular carcinomaNone listed HCVHepatocellular carcinomaNone listed KSVKaposi sarcomaCofactor via cytokines HIVLymphoma, SCC, Body cavity lymphoma, primary CNS lymphoma, kaposi

104. What are the molecular events leading to cancer from viruses

105. HTLV1TAX gene drives replication. /\ cyclin D, /\ NF-kappa-B HPVViral E6 and E7 interfere with P53 and P21 EBVViral LMP1 acts like CD40 ligand to drive proliferation, viral EBNA2 /\ cyclin D, Viral IL10 prevents macrophage activation of T-cells HBVNo oncogenes. Chronic inflammation HCVNo oncogenes. Chronic inflammation KSVViral VEGF. P53 suppression. Viral cyclin D analogue HIV

106. Differentiate descriptive and inferential statistics

107. Descriptive – Describe qualities about the data but cannot be used to infer Inferential – Can be used to draw conclusions

108. Define nominal and ordinal data

109. Nominal – Data described by labels of no numerical significance. – Numerical operations are not possible even if the data appear to be numeric. For instance, the subtraction of two zip codes has no meaning. Only mode has meaning Ordinal – A rank ordered category such as least to most, worst to best, pain levels, satisfaction, etc – There is intrinsic order but the value between each item is variable. For instance, what is the quantitative difference between somewhat satisfied and satisfied. – Some numerical operations are allowed Mode and median have meaning

110. Describe the types of metric data

111. Physical measurement or counting All numerical operations are allowed – Mode – Median – Mean Variable has equal intervals between values. Interval – Metric data with an arbitrary zero Ratio – Metric data with a meaningful 0

112. What is the worst statistical error type, type I or type II

113. Type I is worst – Reject the null hypothesis (H0) even though its true. So we found something that isn’t there. In other words, we’ll treat with snake oil. Note that type II accepts the null hypothesis even though its false. Thus we will withhold a useful treatment because we fail to recognize that it is useful.