WEEK 8 FLASHCARDS

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89 Terms

1
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what is precision medicine

considering genetic, environmental and lifestyle variability for disease treatment and prevention

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what is multiomics

integrative analysis using data from multiple omics technologies and computational tools

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what is genomics

study of the full genome of an organism

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what is transcriptomics

study of RNA transcripts from gene expression

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what is proteomics

study of proteins, structures and functions

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what is metabolomics

study of small molecule metabolites within biological systems

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key tools used in ‘omics’

  • high throughput sequencing

  • mass spec

  • NMR

  • bioinformatics

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applications of genetic research

diagnostics

pharmacogenetics

gene therapy

drug development

disease prevention

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what is a biomarker

objectively measured indicator of biological state or response to treatment

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ideal characteristics of a biomarker

safe

easy to measure

cost effectove

modifiable

consistent across all populations

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what is proteomics used for

  • discovering protein biomarkers

  • understanding disease

  • developing therapies for disease

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what are post translational modifications

chemical changes after protein synthesis

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tools used in proteomics

  • mass spec

  • gel electrophoresis

  • liquid chromatography

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what is mass spec used for

analysis of proteins and metabolites

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components of mass spec

inlet

source

analyser

detector

data system

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examples of ionisation methods used in mass spec

  • Elelctrospray

  • MALDI

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advantage and disadvantage to using plasma as a clinical sample

  • accessible

  • but is dominated by a few proteins ie albumin.

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why is tissue useful as a clinical sample

site specific

hard to access and monitor

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why is CSF used as clinical sample

  • best sample for neurological disorders but highly invasive

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what is the metabolome

  • total set of metabolites in biological sample

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why study metabolome ?

closest reflection of phenotype, sensitive to changes

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types of metabolites

polar - amino acids

non polar - lipids, steroids

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why is metabolomics complex

  • wide dynamic range, diverse structures, changing with age and envt

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whys it difficult to identify metabolites

no single technology can cover full metabolome

25
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stages in omics based drug target discovery

disease models→ omics data → bioinformatics → functional analysis→ potential targets → validation

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goal of precision oncology

tailor cancer therapy based on individual patient omics

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how are treatment decisions guided in precision medicine

integrating clinical, genomic and epidemiological data to generate scores predicting treatment efficacy.

28
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cytostatic vs cytotoxic

cytostatic- stop growth

cytotoxic - kill cells

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why doesnt one drug fit all patients

cancer heterogeneity

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first step in genomic testing for cancer

DNA isolation through blood draw

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what is WGS, when is it used

Whole genome sequencing - to detect copy number changes, rearrangements and non coding mutations

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Why is FFPE tissue limitation to sequencing

gives low quality DNA ehich is unsuitable for whole genome sequencing

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what can next generation sequencing detect

structural variants, translocations, genetic mutations copy number variants

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what is transcriptome sequencing for

analyse gene expression, fusion genes, splice variants

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what does methylation sequencing do

detects DNA methylation patterns, which affects gene expression.

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goal of gene expression profiling

  • identify high and low risk pts and predict survival/ recurrence

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what is a gene expression signature

pattern of expression used to predict phenotype or treatment response.

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how are gene expression profiles validated

  • comparing to animal models

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what is DNA methylation

addirion of methyl groups to cytosine bases, can silence gene expression

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how does histone acetylation affect DNA

  • relaxes the structure, making it more transcriptionally active

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classes of epigenetic enzymes

writers

erasers

readers

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why target epigenome in cancer therapy?

reactivate tumour suppressors

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what are DNMT inhibitors

  • reduce DNA methylation to restore normal gene expression

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what can targeting chromatin impact

  • immune checkpoints

  • cytoplasmic signalling

  • transcription factors

  • drug sensitivity

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effect of activating endogenous retroviruses via epigenetic therapy

increases immune recognition of cancer cells

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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 .

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what is the NCI-60 cell panel used for

to build expression based predictors of drug sensitivity or resistance

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potential of genomics guided therapy

  • outperform standard treatment by tailoring therpay tp individual patients

49
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paclitaxel drug class and MOA

taxane

stabilises microtubules, promoting assembly and inducing cell cycle arrest.

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what does paclitaxel treat

ovarian, breast , lung, pancreatic can

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why does paclitaxel need special formulation

it is water insoluble

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what is used to solubilise paclitaxel in traditional formulations

  • ethanol and cremophor EL

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what is cremophor EL- why is it problematic

  • surfactant

  • causes severe hypersensitivity reactions

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how is hypersensitivity prevented in cremophor EL formulations

pretreatment with corticosteroids , H1 and H2 antagonists, slower infusion rates.

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what is nab-paclitaxel

  • albumin bound nanoparticle formulation that avoids cremophor EL, uses albumin for solubility and reduces side effects.

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what receptor does albumin bind to for targeted delivery

GP60 on endothelial cells

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role of caveolin 1 in nab-paclitaxel delivery

facilitates the uptake of calveolin 1 1 via transcytosis across the endothelium

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how does nab-paclitaxel enter tumours

passive EPR effect and active GP60 mediated transcytosis

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what is the main cellular uptake method for nanomedicines

endocytosis

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what is clathrin dependent endocytosis

Ligand receptor mediated uptake of molecules into cells through clathrin-coated vesicles.

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what is caveolin dependent endocytosis

bypasses lysosomes , uses caveolin to transport molecules directly to the cytoplasm.

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what is macropinocytosis

non specific uptake of extracellular fluid

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which pathway does nab-paclitaxel use to enter tumour cells

macropinocytosis and gp60 mediated caveolae transport

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what are the barriers to nanoparticle delivery

vascular clearance

endothelial tight junctions

ECM

high IFP

cellular uptake mechanisms

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what are the 3 components of a targeted drug delivery system

ligand for targeting, linker, cargo- drug

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passive vs active targeting

  • passive uses EPR effect

  • active uses surface ligands to bind specific receptors.

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what is organelle targeting

delivering drugs directly to organelles using nanoparticles

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what is SGT-53

catoinic liposome with wild type p53 DNA and a targeting antibody for transferrin receptor

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why target transferrin receptor

overexpressed in rapidly dividing cancer cells due to high iron demand.

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what is SGT-53 decorated with

single chain antibody fragment that specifically binds to the transferring receptor.

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why is nanoparticle size important for nucelar delivery

nuclear pore complexes allow particles <10nm through.

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common dysfunctions in the nucleus

disrupted morphology, nuclear envelope damage, transcription/ translation errors, cell cycle issues

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lysosomal / endosome dysfunctions

substrate accumulation, trafficking disruption, decreased hydrolase activity, swelling

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mitochondrial dysfunctions

oxidative stress

membrane depolarisation

mtDNA mutations

fusion/ fission errors

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ER related dysfunctions

misfolded proteins

calcium imbalance

cholesterol accumulation

protein synthesis errors

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golgi dysfunctinos

protein accumulation

fragmentation

trafficking impairment

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how are endosomes and lysosomes targeted

  • endocytosis

  • acid sensitive nanoparticles

  • proton sponge effect

  • pore forming

  • swelling carriers

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mitochondrial targeting strategies

use of lipophilic cations

mitochondrial targeted peptides

passove membrane potential exploration

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nuclear targeting strategies

functionalisation with NLS peptides

using particles <10nm, small molecules

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ER targeting strategy

sylfonyl ligands , ER targeted peptides , direct transport , membrane-coated nanoparticles

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golgi targeting strategy

cysteine rich ligands, KDEL-mimicking peptides, receptor binding sequences.

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what is charge shifting in pH responsive nanocarriers

particles become cationic at acidic pH → drug release.

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what are acid labile linkers used for

release drugs in acidic environments - like tumours

84
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what are MMP responsive nanocarriers

exploit MMPs overexpressed enzymes to trigger drug release or enhance targeting

85
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key strateft in redox responsive nanomedicine

disulfide bond cleavage in high GSH/ROS environments → drug release and ferroptosis.

86
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what is magnetic hyperthermia

uses magnetic nanoparticles that vibrate under magnetic fields to heat and kill tumour cells

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what is photothermal therapy

uses light to heat photothermal nanoparticles and kill cancer cells

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what is photodynamic therapy

light activates photosensitisers in tumour cells→ generates ROS→ cell death.

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why are nanomedicines slow to market

undefined regulations, newness of the field.