Slackers Cancer Molecular Biology Fact Stack Mike Ori 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 • erl • I didn’t use greek letters because they are a pain to cut and paste in. • What are the key risk factors for colon cancer • Age • Genetics • Chronic bowel inflammation – Crohns – UC • Diet • What are the two types of intestinal polyps • Hyperplastic – Smaller (< 5mm) – Better differentiation • Adenomatous – Larger (>5mm) – Size and dysplasia correlate with disease risk – Increased malignant potential. • Outline the genetic steps required for the development of colon cancer • 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 • What is the function of the WNT pathway • The WNT pathway controls growth of epithelial cells via the APC and B-catenin proteins. • Describe the interaction of APC and B-catenin • 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. • Describe the frequency of mutation of wnt and apc in sporadic cancers • Wnt pathway defective in 100% • APC defective in 70% • Describe the role of RAS in tumor development • RAS is a g-protein that leads to activation of downstream signaling pathways that lead proliferation • Describe the role of TGF-B in tumorgenesis • 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 • What are the two forms of hereditary colon cancer • Familial adenematous polyposis (FAP) • Hereditary non-polyposis colorectal cancer (HNPCC) • Why do molecular biologists make bad football coaches • Because their “simplified” playbook looks like this • What are the two types of genetic instability found in colon cancer • Chromosomal instability • Microsatellite instability • What is the failure of microsatellite instability • MIN results from failure of the mismatch repair mechanism • What is the failure in chromosomal instability • CIN results from defects in chromosomal segregation. • Relate FAP and HNPCC to MIN and CIN • FAP – CIN – APC gene • HNPCC – MIN – MSH2, MLH1, PMS2 genes • How many mutations are likely involved in the transformation to malignancy • 5-6 mutations • Draw a sample timeline and gene pathway leading to malignancy • List the major types of diagnostic errors • Differentiate retrospective vs prospective thinking • 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. • What is a heuristic • 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 • What are common pitfalls of heuristics • 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 • Why are mistakes by clinicians often unrecognized • Happen in distant past • Not recognized as mistakes by provider • PT does not return to same provider • What is the role of follow-up in clinical practice • • • • Provides space and time Additional data collection (tests) Research Trial therapy results • Who is responsible for test follow-up? • You ordered it, you own it. • What are the three stages of memory? • Encoding – Attending to the event • Storage – Saving it for later • Recall – Getting it back out • Describe the ability of the mind to process conceptual vs factual information • 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. • Define impression management • The activities we undertake to control the impressions others have of ourselves. • Define self-enhancement • Performing actions intended to bolster the positive impression others have of us. • Giving money to the poor, performing pro bono work • Define self verification • Understanding the impression others have of us and relating that back to how we see ourselves. Ideally the two will match. • Which type of shock is dobutamine most useful and why • Dobutamine is a B1 agonist (weak B2) that is useful in cardiogenic shock because it increase rate and force of contraction • Describe the role of dopamine in shock • 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 • What is the role of phenylephrine in shock • Phenylephrine is a a1 agonist that is sometimes used in septic shock as a pressor. • What is the role of epi and NE in hypovolemic shock • 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. • What are the expected values for cardiac output, left ventricular end diastolic volume, and mixed venous O2 in hypovolemic, cardiogenic, and septic shock Output LVEDV/wedge MVO2 SVR Hypovolemic Low Low Low High Cardiogenic Low High Low High Septic High Normal? High Low • What physical findings are present in metabolic syndrome • • • • Impaired glucose tolerance Obesity Hyperlipidemia Hypertension • How does metabolic susceptibility relate to metabolic syndrome • 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. • What role do fatty acids play in the development of insulin resistance • 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. • What is the role of adiponectin in metabolic syndrome? • 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. • What is the role of resistin in metabolic syndrome • 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. • Describe the role of insulin, TNF-a, and IL-6 in VLDL synthesis • 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. • Describe the role of insulin in liver of metabolic syndrome • 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. • Explain the origin of the prothrombotic state associated with diabetic patients • 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. • List the management goals for diabetic patients • A1C < 7% • LDL < 100 • Systolic BP < 130 • List the macronutrient proportions for patients with diabetes • CHO = 50% • Fat = 30% • Protein = 20% • What are the common receptors used in the prognosis and treatment of breast cancer • Estrogen receptor • Progesterone receptor • Her2/Neu/ErbB2 • What is a gatekeeper • Seriously, what is a gatekeeper • A gene that acts by directly suppressing cell proliferation • What is a caretaker • A gene that functions to maintain genenome stability • Is BRCA1/2 a gatekeeper or caretaker • Caretaker • What is the function of BRCA1/2 • They are involved in homology directed repair of DS DNA breaks • What attributes are beneficial for screening and diagnostic tests • 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? • What are the common viruses associated with cancer. HIV action HTLV1 Adult T-cell leukemia None listed HPV Squamous cell carcinomas Viral escape via immune suppression EBV Lymphomas Co factor HBV Hepatocellular carcinoma None listed HCV Hepatocellular carcinoma None listed KSV Kaposi sarcoma Cofactor via cytokines HIV Lymphoma, SCC, Body cavity lymphoma, primary CNS lymphoma, kaposi • What are the molecular events leading to cancer from viruses HTLV1 TAX gene drives replication. /\ cyclin D, /\ NF-kappa-B HPV Viral E6 and E7 interfere with P53 and P21 EBV Viral LMP1 acts like CD40 ligand to drive proliferation, viral EBNA2 /\ cyclin D, Viral IL10 prevents macrophage activation of T-cells HBV No oncogenes. Chronic inflammation HCV No oncogenes. Chronic inflammation KSV Viral VEGF. P53 suppression. Viral cyclin D analogue HIV • Differentiate descriptive and inferential statistics • Descriptive – Describe qualities about the data but cannot be used to infer • Inferential – Can be used to draw conclusions • Define nominal and ordinal data • 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 • Describe the types of metric data • 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 • What is the worst statistical error type, type I or type II • 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.