Midterm Flashcards
What are the four Rights of personalized medicine?
right patient
right drug
right time
right dose
What are the pros of personalized medicine?
more accurate diagnosis, safer, faster, lower s/e, increase efficacy
What are some challenges of personalized medicine?
patient engagement, privacy, cost, data ownership
Explain personalized medicine of tamoxifen?
used for breast cancer but needs CYP 2D6 to be active. some people are deficient in this
What are the cell cycle stages?
G1: grows and prepares
S: DNA replication
G2: grow
M: Mitosis
G0: Leaves cell cycle
What are the 2 checkpoints in cell cycle?
G1:before DNA Synth
G2: Prep for mitosis
When is the restriction point in the cycle?
commits to division
happens before S stage
How many chromosomes?
23 pair
What histones in chromosomes?
2 of H2A, H2B, H3 and H4 and H1 which clips it
What is transcription?
gene-> RNA
What is translation?
RNA->protein
What are Promoters?
promote expression, upstream
How can we suppress promoters?
methylation
What is encoding for genomes?
annotation of the pairs to make reading easier= AATTCCGGG to AAT TCC GGG
What are SNP’s?
single change
Most common genetic variation?
SNP
What are Copy number variations? What causes them?
variations in the number of copies of a gene
caused by recombination
What are insertions and deletions?
deletion of one or more or insertion of one or more
What are large scale variations?
LARGE portion repeated or gone
What is a hot spot of structural variations?
short arm of chromosome 1
What is bioinformatics?
merge biology and computers
Genetics vs genomics
look at one gene vs look at all genes
What is transcriptomics?
study of RNA and their functions
What is an exon vs intron?
exon- encodes
intron- does not encode/ spliced out
What is constitutive splicing?
exons retained in order
What is proteomics
study of proteins and their functions
What is top down vs bottom up?
top down= analyze without being broken down
bottom up= digest them into peptides first
What is metabolomics?
study of metabolites and their function
What is glycomics?
structure and function of glycans
What is a biomarker?
sign of normal OR abnormal
What is conventional medicine?
empirical therapy with universal drugs
What is PCR? steps?
quick method to make lots of copies of DNA
1. denature
2. anneal
3. synthesize
What is different about qPCR?
add fluorescent reporter- taqMan probe
What test uses PCR?
Abbott HIV-1 targeting 2 spots
Which is more money whole genome or whole exons?
whole genome
How do you sequence RNA?
make cDNA and then shatter it
What is the biggest gene?
duchene muscular dystrophy-X linked
What is a biochip? Which molecule cant be used?
array of biomolecules immobilized on surface
No RNA because unstable
What is a microarray?
uses DNA chip to sequence and analyze **
What does 23 and me use for biochip?
gene profiling array (DNA chip) affymetrix
What does AmpliChip CYP450 do?
biochip to see deletions and insertions of ALL CYP 450
What is a bio-Rad
protein chip
What is SELDI?
probe to immobilize then lazer to ionize
What is a kinome array?
when kinase rxn occurs with binding
What is an issue with protein chips?
more cost cause less stable
What is microfluidics?
use small amounts for biochips
What is FISH?
fluorescent prob
What biomolecules are you looking at for gene expression profiling?
RNA and protein
What are some gene expression tech?
DEG, SEG, SAGE, biopsy, rna splicing
What is a PET scan?
positron, use fluorodeoxyglucose as tracer
What is a drug?
substance with physiological effect
what is an aptamer?
chemical antibody
What makes a good drug?
potent and specific
What are the steps of drug development?
target selection-find stuff that binds to target- good ones are put through
then preclinical: Phase 1-2–3, approval, post marketing
How long to make a drug and how much money?
15 years, 1.5 billion
What is the most expensive part of discovery?
clinical
What is the data mining approach to identification?
identify important proteins in disease- look at databases
What is the genetic approach to identification?
identify genes that cause by comparing
What is the in vitro approach to identification?
identify targets
What is target validation?
does knock out of target give right effect
What is difference between knock out and knock down?
down= decreased, reversible
out= all and permanent
What is a choke point?
no other alternative pathways
Two methods to chemogenomic screen?
- have a chemical what does it effect
- I have a target what binds
What are the most successful targets?
enzymes and GPCRs
All targets are druggable?
NO
What makes a protein druggable?
binding site size
How can you predict druggability?
sequence based
structure based(pockets)
does it bind endogenous
high affinity drug(ligand based)
established target (precedence based)
Why has antibiotic research fallen off?
cant put high price on them
liability for side effects
rapid resistance
What is the pasteur act?
pay the company the value it is rather than the amount prescribed
What are the properties of targets in bacteria?
essential to survival, and only in bacteria
Explain CCR5 and HIV?
if you get the delta 32 version it is shorter so then the HIV cell cannot kill T cell
What is the K value paradox?
complexity does not correlate with number of chromosomes
What is the c value paradox?
complexity is not correlated with genome size
What is the n value paradox?
complexity is not correlated with gene number
Why are mice good models?
share a lot of same genes
What are common variations in CYP?
CYP2D6
CYP 2C9-warfarin
CYP 4F2- lowers vitamin K
What does VKORC1 do?
recycles Vit K
What is the function of CFTR and what does variation cause?
chloride channel in lung
variation= no transport or not enough, this will cause cystic fibrosis
How does Ataluren work?
overcome nonsense mutation(premature stop codon), so it reads through
What is the G551D mutation of CFTR? What drug fixes?
channels dont open correcly
kalydeco
What medication fixed CFTR mutations that lower the amount and helps them open correctly?
TRIKAFTA
What is an antisense oligonucleotide?
single stranded NA that hybridize with mRNA= inhibit expression
What name shows its an ASO?
rsen
fomivirsen
What are the mutations in the DMD gene (muscle dystrophy)?
large deletions and SNPs
Which gender does DMD affect?
male b/c x linked
If woman are carriers, how do they present?
some muscle weakness
How can Eteplirsen help with DMD?
skip exon 51(nonsense mutation)
What other med can help with DMD?
Ataluren-supressor tRNA that makes it place an AA instead of stopping
How does SMA happen?
neurodegenerative disease of spinal neurons due to SMN1 and SMN2
Which one has more function, SMN1 or 2? why?
SMNI has more cause more stable
What drug helps with SMA?
nusinersen that helps SMN2 the copy of SMN1
WHat does SMN2 lack?
exon 7
What are molecular glues? What are the uses?
encourage 2 proteins to come together
used if no druggable active site and need less levels
What is PROTAC?
glue that forces target to be ubiquitinylated and degraded in proteasome
What are the characteristics of cancer cells?
Proliferative
evade growth suppress
evade cell death
angiogenesis
immortal
metastasis
Benefits of small molecules
easier to cross membranes
act in or outside cells
What is the first drug for tyrosine kinase?
imatinib
How many small molecules interact with TK?
LOTS
What makes BCR ABL gene and what does this do?
translocation of piece of Chromosome 22 and 9
makes always on TK
How does imatinib work?
blocks ATP from donating to enzyme
What is BCR ABl mutations that are dependent and independent resisitance?
dependent= change imatinib binding site= p loop and T3151
Independent= change transport that imports drug = stops import
What is the only effective TRK inhibitor that can bypass BBB?
entrectinib
What is the front end of an antibody? What is back?
front=binds targets
Back= bind other immune cells
What are bispecific antibodies?
bind two usually bind to bad then bind to CD3 of t cell
Mechanism of antibody drugs.
can flag it for NK destruction
or deliver toxin to the cell
What drug is used for Her2?
trastuzumab= flags for killing
What role does pertuzumab have?
also blocks dimerization
What happens if EGFR1 inhibitor is used with a tumour with KRAS?
NO effect
How does bevacizumab work?
stops angiogenesis
What do MMP’s do for tumour?
dissolve ECM and build vessels
What happens if a tumour is very turgid?
reisstant to drugs
What does VEGF do?
vessel survive, increase permeability and angiogenesis
What CYP is a major player in metabolism and has alot of genetic variability?
CYP 2D6
What is the concept of tumour heterogenicity?
surface make up of cells are not constant neither in time as well
How can tumour heterogenicity effect personalized medicine?
make take sample from part of the tumour that doesnt have the target. The drug will not kill it all
How does antigen shedding work?
shedding the antigen can dodge the drug, by modulating.
How does antigen modulation work?
endocytosis the antigen back inside cell
IN relation to general cancer what is cancer stem cells?
more resistant
more metastasis
infinite proliferative
WHat are the issue with cancer vaccine development?
suppress immune system
look normal
large or advanced
each tumour is unique
people who are sick already have weakened immune system
What cancers have vaccines?
viral ones- HPV, HBV,
How does BCG vaccine work?
uses weakened bacteria to help boost bladder cancer
How does Sipuleucel-T vaccine work?
patients own dendritic cells that are stimulated to boost immune response to prostate cancer
What does MCH-1 tell us?
I am infected
What bacteria is involved in BCG vaccine?
mycobacterium bovis- TB
What does MCH-2 tell us?
i am immune cell
What is overproduced in prostate cancer?
PAP and PSA
How can we boost cytotoxic t cells?
modify to release perforins and granzyme to break down
CAR-T
What is CAR-T for usually?
liquid cancer
Side effects of CAR-T?
CRS= massive release of cytokines that results in fever and drop in BP
Mass die off of B cells= aplasia
Issues with CAR-T?
expensive, time consuming
tumour heterogeneity is bad
What happens if PD-L1 or PD-L2 bind to PD-1?
T cell apoptosis, downregulation, suppress anti tumour response
What is an example of PD-1 blockers?
nivolumab or pembrolizumab
How does CTLA-4 work and what drug blocks it?
CTLA inhibits T cell activation
drug- iplimumab
What are the 4 types of biomarkers?
Molecular
Radiographic
histological
Physiological
What are radiographic biomarkers?
from medical images so like CT scan or x ray
What is a histological biomarkers?
reflects molecular changes such as cancer grading
What is a physiological biomarker?
measures body processes such as BP
How long to develop biomarker?
3-4 years
Which stage of biomarker development is the most expensive?
clinical validation
What is multiomics?
combo of genomics etc
What is a susceptibility biomarker?
indicates potential of disease
ex BRCA gene
What is a diagnostic biomarker?
detect or confirm disease
Ex GFR, B amyloid
What type of biomarker is GFR?
diagnostic for CKD
What is a monitoring biomarker?
assess status of disease
What is an example of a monitoring biomarker?
level of CA-125 or PSA
What is a prognostic biomarker?
likelihood of health outcome
True or False: Prognostic biomarker predicts response to treatment
FALSE
What is a predictive biomarker? Ex?
identify those likely to respond
ex- HER2 gene= use HER2 therapy
Where does trastuzumab and pertuzumab work?
4
2
What is a pharmacodynamic/response biomarker?
drug interacts with target
ex BP
What is a safety biomarker?
presence of toxicity
ex albumin or S cr from nephrotoxic drug
What is a pharmacogenomic biomarker?
genetic differences
ex CYP P450
What is proteomics?
total set of [proteins and how they function and interact
What is primary protein structure?
AA sequence
What is secondary structure?
how it folds
Why study proteomics?
change in gene or RNA does not always translate into protein, post translational mods
What is functional, expression and structural proteomics?
F= how it functions
E= expression
S= structure
Why use electrophoresis?
separate based on charge and size
Pros of using X ray crystallography and cons?
pros- high resolution, see structure
Cons- time consuming, expensive
What does a protein microarray do?
purify, function and quanitfy
What is P4?
predictive
personalized
preventive
participatory
What is benefits of P4 mentality?
cost effective, lower rates of illness,
True or false P4 is curative
False- more preventative
What is systems medicine?
uses studys of the levels of life to integrate good care
What does omics mean?
interactions and functions of biomolecules
What does pharmacoproteomics?
deals with the changes of proteins due to drugs
Why is it better to look at proteins than DNA?
1 gene makes multiple proteins and Post TM
What is purpose of electrophoresis?
isolate crude identification and quantification
What is purpose of chromatography?
isolate crude identification and quantification
What do you need to do before mass spectrometry?
chromatography
What is purpose of immunoassay and mass spectrometry?
identify and quantify
What is a western blot?
gel put on paper to visualize
What moves slower in chromatography?
whatever is close to what stationary phase is
What is mass spectrometry?
see gas ions and sort based on charge and size
What is toxicoproteomics?
how chemical exposure modifies protein or expression
The Philadelphia chromosome is formed between chromosome 9 and chromosome 22 due to:
Translocation
In general, how many coding SNPs are present in a gene?
5
