Transcript Slackers Cancer Molecular Biology Fact Stack - U

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
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•
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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
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•
•
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.