Week 6 Flashcards
function of PTEN and consequences of mutation?
normally inhibits PI3K
mutation = endometrial carcinoma
example of GOF mutation in cyclins and CDKs?
D cyclin and CDK4 promote progression from G1-S
example of LOF mutation in cyclins and CDKs?
TSG mutation (p.16, RB, TP53) that inhibit G1-S
what part of the cell cycle does Rb protein control?
transition from G1 to S
function of E2F?
required for synthesis of DNA replication enzymes
when Rb is bound to E2F - transcription and translation is stopped
how do GF affect Rb proteins?
GF phosphorylate Rb- detaching it from E2F = allowing gene transcription/ mRNA translation and transition to S phase
what is contact inhibition?
the cell to cell connection of E cadherin to the next epithelial cell
loss of contact inhibition contributes to metastasis and local invasion
function of APC?
encodes factors that negatively regulate WNT pathway in colonic epithelium by forming a complex that degrades B-catenin
what is associated with a NF2 mutation?
neurofibromatosis type 2
how does TGF-B carry out its inhibitory functions?
activates inhibitors of CDK and suppressors of MYC
what is CDKN2a?
negative regulator of cell entry and progression
encodes TSG and ARF (stabilizes p53)
what is another name for Fas
CD95
why re mutations in apoptosis more important in blood cancers?
because it regulates the number of lymphocytes
how do cells become senescent in terms of replication?
shortened telomeres are interpreted by DNA repair machinery as double stranded breaks leading to cell cycle arrest via p53 and Rb and senescence
how does hypoxia stimulate angiogenesis?
via H1F1-alpha
how do cancer cells degrade the basement membrane?
they express matrix mellaproteases in higher amounts than normal cells
what is the basis for PET imaging?
warburg effect
what is micro satellite instability?
regions of receptive DNA sequences prone to shortening or extension when mismatch repair enzymes are defective
what is imatinib ?
BCR-ABL kinase inhibitor
how do we know what drugs are being used?
needle syringe program reporting hospitalization s monitoring scehmes - IDRS, EDRS, household surveys forensic capture sewage monitoring
what are the 3 pillars of harm minimization?
demand reduction
supply reduction
harm reduction
what are the 3 approaches to harm minimization?
priority actions
priority populations
priority substances
psychological steps for dependance? (8)
exposure to substance with abuse potential
positive aspects of neurochemical activation outweight negative aspects in the ind
environmental context is conducive to repeated use
repeated use results in receptor adaptation
downstream neurological function alters to adjust for receptor adaptation
tolerance- need more drug for same effect
tolerance fuels desire for more drug use
dependence - normal function requires increased level of binding
withdrawal - removal of substance produces adverse effects
general features of withdrawal from CNS stimulant/ depressant.
sweating N&V, appetite disturbances restless, irritable, angry depression, anxiety loss of self-control muscle/ abdo cramps
how does alcohol cause seizures?
alcohol chronically stimulates GABA-A receptors so once you withdraw you can get seizures
what is the specific gravity of alcohol?
0.789
what are some discriminating features of FAS?
short palpebral fissure flat midface short nose indistinct philtrum thin upper lip
what are some associating features of FAS?
epicentral folds
low nasal bridge
minor ear abnormalities
micrognathia
what is FLAGS in brief intervention of alcohol?
feedback listen advice goals strategies
what is the pharmacotherapy used in alcohol?
naltrexone- opioid receptor antagonist - decreases the effects of endogenous opioids = decreases feelings of rewards from alcohol
acamprosate- inhibits NMDA receptor and activates GABAA receptors - decreases the ‘need’ for alcohol
disulfiram - inhibits acetaldehyde dehydrogenase
what component does wernickes encephalopathy affect?
physiological component - nystagmus and ophthalmopleia
what components does korsokoffs psychosis affect?
psychological component/ behavioural component
often later at the irreversible stage
what are some symptoms of mild withdrawal in alcohol?
anxiety, agitation, nausea, tremor, tachycardia, hypertension, disturbed sleep
what are some symptom fo severe withdrawal by alcohol?
vomiting, severe agitation, disorientation/ confusion, paranoia, hyperventilation and delirium
when to use diazepam and oxazepam in alcohol withdrawal?
use diazpam during withdrawal and then taper off for management
if liver is impaired use oxazepam
what are the different strengths of beer?
full: 4.8%
mid: 3.5%
low: 2.7%
what are the different strengths of wine?
red: 13%
white: 11.5%
champagne: 12%
what components in cannibis extracts exhibit therapeutic effects? when are they used?
cannabinol and cannabidiol
- epilepsy, MS, chemo induced nausea
MOA of nicotine?
agonist of nACH-R in CNS
MOA of NRT?
agonist of nACH-R
MOA of veranacline? adverse effects?
partial agonist at a4b2 nACH-R
serious psychotic symptoms
MOA of bupropion?
nACH-R antagonist
inhibits DAT= decrease DA uptake = increased in synaptic cleft
which HLA-As must we match in transplantation?
HLA-A,B, DR
how many HLA alleles should you try and match?
at least 6 but aim for 12
HLA-A,B, DR essential
HLA-C, DQ would be good
how to interpret results of lymphocyte cross matching?
so recipient serum mixed with donor lymphocytes and add complement
if donor specific Ab not present - complement is not activated and cannot lyse cells
if donor specific Ab are present then Ab will bind to lymphocytes and complement is activated to lyse cells and the cells take up dye
what are some cell based assays used to determine if recipient Ab are present against donor Ag?
complement mediated lysis of donor cells (classical complement pathway)
flow cytomery based methods
what are some ways anti-HLA levels can change?
blood transfusions, previous transplants, pregnancies (make HLA Ab against paternal HLA)
what are the 3 main occasions for immunosuppression in transplantation?
induction
maintenance
tx of acute and chronic rejections
immunosuppressive agents: Ab therapies?
IL2-R antagonist (basiliximab) - often used for induction therapy - binds IL2-R on alpha chain of T lymphocytes and prevents IL2 mediated acitvation
lymphocyte deleting AB - anti-CD3 mAB = deplete T cells from recipient Ab against CD3
calcineurin inhibitors?
tacrolimus and cyclosporine = decrease synthesis of pro-inflammatory cytokines
mTOR inhibitors?
sorilimus
block T cell activation
antiproliferative agentS?
mycophenolates and azathioprine
used to stop tumour cell and T cell proliferation
what kind of graft rejection occurs when AB react with endothelium?
hyperacute graft rejection
what mechanism is used to decrease the chance of sensitized HLA Ag after blood transfusion?
blood transfusions with leuco-depleted blood product which decreases the chances of recipient becoming sensitized to donor HLA
consequences of long term use of calcineurin inhibitors?
nephrotoxicity
how does the blockade of costimulatory signal in T cells help transplant survival?
block induces transplantation tolerance and prevents allograft rejection (eg, anti-CD40 mAB or CTLA4 block to CD80/86)
what is graft vs host disease?
mature T cells injected in allogeneic transplant see the recipients cells in BM are foreign and initiate an immune response = inflammation (rashes, diarrhea, pneumotitis)
drugs to stop sustaining proliferative signalling?
EGFR inhibitors
drugs to stop evading growth suppressors?
cyclin dependant kinase inhibitors
drugs to stop avoiding immune destruction?
activating anti-CTLA4 mab
how to stop enabling replicative immunity?
telomerase inhibitors
how to stop tumour promoting inflammation?
selective anti-inflammatory drugs
how to stop activating invasion metastases?
inhibitors HGF k-met
how to stop inducing angiogenesis?
VEGF inhibitors
how to stop genome instability and mutations?
PARP inhibitors
how to stop resisting cell death
pro-apoptotic BH3 mimetics
how to stop deregulating cellular energetics?
aerobic glycolysis inhibitors
significance of ABL-BCR translocation?
ABL normally codes for TK pathway, so once BCR binds to it the TK pathway is constitutively active
what are some elevated biomarkers for alcohol dependance?
MVC
GGT
LFTs
symptoms of nicotine withdrawal?
dysphoria/ depressed mood anxiety weight gain insomnia difficulty concentrating breathlessness decreased HR
what does renal transplant pathology look like?
lots of inflammatory cells
little purple nuclei
predominately T cells (hyper acute will have neutrophils)
nuclei all around the BV
what was the original transplant drug and why are we moving away from it?
calcineurin inhibitors however long term use causes nephrotoxicity so new Abs target IL2-R signalling or production = stops T cell proliferation
define some features of the effector stage in transplants?
cell mediated, Ab, complement
Macrophages and T cells initiate an inflammatory response
Ag presentation to T cells increases as expression of adhesion molecules, MHCII, chemokine and cytokines is unregulated
this promotes shedding of intact, soluble MHC molecules that may be involved in the activation of indirect allorecognition pathway
T cell cytokines promote macrophages infiltration, EC activation and more T cells = amplification of response
another name for microlymphocytotoxicity assay?
lymphocyte cytotoxicity assay
what are some sign of kidney graft rejection?
short term: infection, abcesses, hematuria, abdominal hernia
later: pylonephritis, kidney stones and kidney dysfunction
what are the main differences between BMT and HSCT?
BM- take stem cells directly
HSCT- take stem cells from peripheral circulation (give GCSF to give the BM a jump start to pump more SC in peripheral blood)
3 main groups of complications associated with BM/HSCT?
infections
non-infectious
GVHD (so use T cell depleted SC)
