1/88
Looks like no tags are added yet.
Name | Mastery | Learn | Test | Matching | Spaced |
---|
No study sessions yet.
what is precision medicine
considering genetic, environmental and lifestyle variability for disease treatment and prevention
what is multiomics
integrative analysis using data from multiple omics technologies and computational tools
what is genomics
study of the full genome of an organism
what is transcriptomics
study of RNA transcripts from gene expression
what is proteomics
study of proteins, structures and functions
what is metabolomics
study of small molecule metabolites within biological systems
key tools used in ‘omics’
high throughput sequencing
mass spec
NMR
bioinformatics
applications of genetic research
diagnostics
pharmacogenetics
gene therapy
drug development
disease prevention
what is a biomarker
objectively measured indicator of biological state or response to treatment
ideal characteristics of a biomarker
safe
easy to measure
cost effectove
modifiable
consistent across all populations
what is proteomics used for
discovering protein biomarkers
understanding disease
developing therapies for disease
what are post translational modifications
chemical changes after protein synthesis
tools used in proteomics
mass spec
gel electrophoresis
liquid chromatography
what is mass spec used for
analysis of proteins and metabolites
components of mass spec
inlet
source
analyser
detector
data system
examples of ionisation methods used in mass spec
Elelctrospray
MALDI
advantage and disadvantage to using plasma as a clinical sample
accessible
but is dominated by a few proteins ie albumin.
why is tissue useful as a clinical sample
site specific
hard to access and monitor
why is CSF used as clinical sample
best sample for neurological disorders but highly invasive
what is the metabolome
total set of metabolites in biological sample
why study metabolome ?
closest reflection of phenotype, sensitive to changes
types of metabolites
polar - amino acids
non polar - lipids, steroids
why is metabolomics complex
wide dynamic range, diverse structures, changing with age and envt
whys it difficult to identify metabolites
no single technology can cover full metabolome
stages in omics based drug target discovery
disease models→ omics data → bioinformatics → functional analysis→ potential targets → validation
goal of precision oncology
tailor cancer therapy based on individual patient omics
how are treatment decisions guided in precision medicine
integrating clinical, genomic and epidemiological data to generate scores predicting treatment efficacy.
cytostatic vs cytotoxic
cytostatic- stop growth
cytotoxic - kill cells
why doesnt one drug fit all patients
cancer heterogeneity
first step in genomic testing for cancer
DNA isolation through blood draw
what is WGS, when is it used
Whole genome sequencing - to detect copy number changes, rearrangements and non coding mutations
Why is FFPE tissue limitation to sequencing
gives low quality DNA ehich is unsuitable for whole genome sequencing
what can next generation sequencing detect
structural variants, translocations, genetic mutations copy number variants
what is transcriptome sequencing for
analyse gene expression, fusion genes, splice variants
what does methylation sequencing do
detects DNA methylation patterns, which affects gene expression.
goal of gene expression profiling
identify high and low risk pts and predict survival/ recurrence
what is a gene expression signature
pattern of expression used to predict phenotype or treatment response.
how are gene expression profiles validated
comparing to animal models
what is DNA methylation
addirion of methyl groups to cytosine bases, can silence gene expression
how does histone acetylation affect DNA
relaxes the structure, making it more transcriptionally active
classes of epigenetic enzymes
writers
erasers
readers
why target epigenome in cancer therapy?
reactivate tumour suppressors
what are DNMT inhibitors
reduce DNA methylation to restore normal gene expression
what can targeting chromatin impact
immune checkpoints
cytoplasmic signalling
transcription factors
drug sensitivity
effect of activating endogenous retroviruses via epigenetic therapy
increases immune recognition of cancer cells
why is patient selection important for targeted therapy
to treat the patients who will respond well to the therapy - eg trastuzumab only in Her2+ patients .
what is the NCI-60 cell panel used for
to build expression based predictors of drug sensitivity or resistance
potential of genomics guided therapy
outperform standard treatment by tailoring therpay tp individual patients
paclitaxel drug class and MOA
taxane
stabilises microtubules, promoting assembly and inducing cell cycle arrest.
what does paclitaxel treat
ovarian, breast , lung, pancreatic can
why does paclitaxel need special formulation
it is water insoluble
what is used to solubilise paclitaxel in traditional formulations
ethanol and cremophor EL
what is cremophor EL- why is it problematic
surfactant
causes severe hypersensitivity reactions
how is hypersensitivity prevented in cremophor EL formulations
pretreatment with corticosteroids , H1 and H2 antagonists, slower infusion rates.
what is nab-paclitaxel
albumin bound nanoparticle formulation that avoids cremophor EL, uses albumin for solubility and reduces side effects.
what receptor does albumin bind to for targeted delivery
GP60 on endothelial cells
role of caveolin 1 in nab-paclitaxel delivery
facilitates the uptake of calveolin 1 1 via transcytosis across the endothelium
how does nab-paclitaxel enter tumours
passive EPR effect and active GP60 mediated transcytosis
what is the main cellular uptake method for nanomedicines
endocytosis
what is clathrin dependent endocytosis
Ligand receptor mediated uptake of molecules into cells through clathrin-coated vesicles.
what is caveolin dependent endocytosis
bypasses lysosomes , uses caveolin to transport molecules directly to the cytoplasm.
what is macropinocytosis
non specific uptake of extracellular fluid
which pathway does nab-paclitaxel use to enter tumour cells
macropinocytosis and gp60 mediated caveolae transport
what are the barriers to nanoparticle delivery
vascular clearance
endothelial tight junctions
ECM
high IFP
cellular uptake mechanisms
what are the 3 components of a targeted drug delivery system
ligand for targeting, linker, cargo- drug
passive vs active targeting
passive uses EPR effect
active uses surface ligands to bind specific receptors.
what is organelle targeting
delivering drugs directly to organelles using nanoparticles
what is SGT-53
catoinic liposome with wild type p53 DNA and a targeting antibody for transferrin receptor
why target transferrin receptor
overexpressed in rapidly dividing cancer cells due to high iron demand.
what is SGT-53 decorated with
single chain antibody fragment that specifically binds to the transferring receptor.
why is nanoparticle size important for nucelar delivery
nuclear pore complexes allow particles <10nm through.
common dysfunctions in the nucleus
disrupted morphology, nuclear envelope damage, transcription/ translation errors, cell cycle issues
lysosomal / endosome dysfunctions
substrate accumulation, trafficking disruption, decreased hydrolase activity, swelling
mitochondrial dysfunctions
oxidative stress
membrane depolarisation
mtDNA mutations
fusion/ fission errors
ER related dysfunctions
misfolded proteins
calcium imbalance
cholesterol accumulation
protein synthesis errors
golgi dysfunctinos
protein accumulation
fragmentation
trafficking impairment
how are endosomes and lysosomes targeted
endocytosis
acid sensitive nanoparticles
proton sponge effect
pore forming
swelling carriers
mitochondrial targeting strategies
use of lipophilic cations
mitochondrial targeted peptides
passove membrane potential exploration
nuclear targeting strategies
functionalisation with NLS peptides
using particles <10nm, small molecules
ER targeting strategy
sylfonyl ligands , ER targeted peptides , direct transport , membrane-coated nanoparticles
golgi targeting strategy
cysteine rich ligands, KDEL-mimicking peptides, receptor binding sequences.
what is charge shifting in pH responsive nanocarriers
particles become cationic at acidic pH → drug release.
what are acid labile linkers used for
release drugs in acidic environments - like tumours
what are MMP responsive nanocarriers
exploit MMPs overexpressed enzymes to trigger drug release or enhance targeting
key strateft in redox responsive nanomedicine
disulfide bond cleavage in high GSH/ROS environments → drug release and ferroptosis.
what is magnetic hyperthermia
uses magnetic nanoparticles that vibrate under magnetic fields to heat and kill tumour cells
what is photothermal therapy
uses light to heat photothermal nanoparticles and kill cancer cells
what is photodynamic therapy
light activates photosensitisers in tumour cells→ generates ROS→ cell death.
why are nanomedicines slow to market
undefined regulations, newness of the field.