Presentation on theme: "Slackers Cancer Molecular Biology Fact Stack Mike Ori."— Presentation transcript:
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 e r l I didn’t use greek letters because they are a pain to cut and paste in.
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
How many mutations are likely involved in the transformation to malignancy
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.
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
OutputLVEDV/wedgeMVO2SVR HypovolemicLow High CardiogenicLowHighLowHigh SepticHighNormal?HighLow
What physical findings are present in metabolic syndrome
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
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
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 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
What are the molecular events leading to cancer from viruses
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
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.