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YEAR 2 > Interactions -MD2B4 > Flashcards

Interactions -MD2B4 Flashcards

1
Q

What does clonal mean?

A

genetic changes are inherited when cells divide

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2
Q

what is progression in relation to tumorigenesis

A

‘cellular evaluation’ - progressive accumulation of genetic changes resulting in tumour progression from normal cells to benign tumour to malignant to metastatic tumour

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3
Q

name some hallmarks of cancer (10)

A 
resisting cell death
evading growth suppressors
activating invasion metastasis
sustained proliferative signalling
avoiding immune destruction 
tumour-promoting inflammation 
genome instability and mutation 
introducing angiogenesis
enabling replicative immmortality
deregulating cellular energetics
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4
Q

what are the 3 DNA methylation changes that can be detected in cancer cells?

A
  1. gene-specific hypo- and hyper- methylation
  2. global hypomethylation across the genome
  3. increased incidence of mutations
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5
Q

what is the impact of gene-specific hypomethylation?

A

the gene is transcribed

removal of methylation = activation of oncogenes

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6
Q

give an example of the impact of gene-specific hypomethylationq

A

BCL-2 oncogene is hypomethylated and over transcribed in human B-cell chronic lymphocytic leukemia and breast cancer

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7
Q

what is the impact of gene-specific hypermethylation?

A

the gene is supressed

methylation = suppression of tumour genes

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8
Q

give an example of the impact of gene-specific hypermethylation

A

DNA repair: MGMT, MLH1, BRCA1 -suppressed and no longer expressed and so there is dysregulation in DNA repair leading to cancer

Apoptosis and survival

GSTP1 is methylated in >90% of prostate cancers

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9
Q

what are the impacts of genome-wide hypomethylation?

A

it happens early on and progresses over time - detected in all cancer types

hypomethylation of repetitive regions causes genome instability (deletion, insertion…)

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10
Q

what happens to cytosine when its methylated?

A

it is methylated to form 5-methylcytosine which is unstable

it can undergo spontaneous deamination and forms a thymine base

so methylation gives rise to a spontaneous mutation converting cytosine to thymine

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11
Q

what happens to methylation as cancer progresses?

A

global methylation decreases

gene-specific hypermethylation at CpG islands in promotors occurs

alteration and dysregulation of histone modifications

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12
Q

why are epigenetic mistakes clinically relevant?

A

epigenetic mistakes change and progress over time
significant clinical implications
used for detection, classification, prognosis, and treatment

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13
Q

what are common features of a tumour cell population?

A

heterogenous

0.1-0.8% of of the tumour cells are made up of cancer stem cells (cancer-initiating cells)

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14
Q

what are the capabilities of cancer stem cells?

A

drug resistant
self-renewal
differentiation
tumorigenicity when transplanted into animal host

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15
Q

what do cancer stem cells differentiate into?

A

self renewing cells and differentiated cells that make up the bulk of the tumour

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16
Q

what mechanisms can cacncer stem cells origionate through?

A

de-differentiation of somatic or differentiated cancer cells
mutations and epigenetic changes in normal stem cells or progenitor cells

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17
Q

what are the most commonly mutated classes of genes in cancer?

A

epigenetic regulators

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18
Q

how is epigenetics used in early cancer diagnosis?

A

detection of CpG island hypermethylation in biological fluids and serums

example: GSTP1 in urine specimens of patients with putative prostate cancer

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19
Q

how is epigenetics used in cancer prognosis?

A

hypermethylation of specific genes
whole DNA methylome profiles
Histone modification map

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20
Q

how is epigenetics used in tumour response predictions

A

CpG island hypermethylation as a marker of response to chemotherapy, hormone therapy and targeted therapy

example: MGMT in patients with glioma and temozolomide treatment -predicts outcomes/response to treatment

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21
Q

how is epigenetics used in follow up cancer appointments?

A

detection of CpG island hypermethylation in biological fluids and serum

e.g., p15 methylation in acute myeloid leukemia - reoccurance

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22
Q

what are Epidrugs?

A

small-molecule inhibitors that target epigenetic machinery

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23
Q

are dna methylation and histone modifications reversible?

A

yes

unlike mutations which are not

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24
Q

what are the main classes of epidrugs?

A

DNA methyltransferase inhibitors (DNMTi)

histone deacetyltransferase inhibitors (HDACi)

histone acetyltransferase inhibitors (HATi)

The aim is to activate tumour suppressor genes, deactivate oncogenes, prevent proliferation and trigger apoptosis in cancer cells

alter active site of enzymes to inhibit them

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25
Q

what is the role of DNMT inhibitors?

A

aberrant DNA hypermethylation

reactivate the hypermethylated genes, leading to their activation and cancer cells reprogramming that ultimately lead to proliferation arrest and cell death

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26
Q

what is the role of HDCAis inhibitors in cancer?

A

reverse transcriptional repression of multiple genes involved in cell cycle progression, differentiation aand apoptosis

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27
Q

what are the role of HDAC inhibitors

A

reverses transcriptional repression of multiple genes involved in cell cycle progression, differentiation and apoptosis

4 different classes

vorinostat is FDA approved for the treatment of cutaneous t cell lymphoma

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28
Q

name 2 biomedical non modifiable risk factors

A

genetic susceptibility

hormonal factors in females

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29
Q

name some lifestyle risk factors for cancer

A 
smoking
alcohol
physical inactivity
chronic infections
diet
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30
Q

name some environmental risk factors for cancer

A

sunlight - skin/melanoma
radiation - leukaemia, breast, thyroid
occupational exposure - nasal cavity
pollution - skin, lung, bladder

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31
Q

what is absolute risk

A

the chance that a person will develop a disease during a given time
general indicator as to how many people are at risk in general populaiton

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32
Q

what is relative risk?

A

compares the risk of disease between 2 groups of people

compares one group with a certain risk factor for a disease to another groups risk

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33
Q

what is incidence and how is it calculated

A

estimates how many people will be diagnosed with cancer within certain time period

identify nimber of people diagnosed over a range of years, place numbers in statistical model to predict further incidence

given as a rate
can be age adjusted

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34
Q

what is prevalence

A

estimates how many people have or have had cancer (ALL people with cancer)

shown as a percentage

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35
Q

what are non-modifiable risk factors?

A

unmodifiable intrinsic risk factors - unavoidable spontaneous mutations that arise because of random errors in DNA replication

occur in different organisms at diffferent rates

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36
Q

what are the two types of non-intrinsic risk factors?

A

exogenous - modifiable/external- carcinogens, viruses, lifestyle factors

endogenous - partially modifiable - immune, metabolism, DNA damage responses, hormone levels

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37
Q

half of all cancers are in people over 70, true/false

A

true

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38
Q

what do faulty BRCA genes increase the risk of?

A

BRCA1 and 2: breast, ovarian, pancreatic and prostate

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39
Q

what are BRCA1 and BRCA 2 genes?

A

Tumour suppressor genes

mutations means that cells can grow out of control and lead to cancer develpoment

only 1 in 400 have the fault

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40
Q

~70% in every 100 women with a faulty BRCA1/2 gene will develop by aged 80

true/false

A

true

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41
Q

what is another term for lynch syndome?

A

non-polyposis colon cancer (HNPXX)

INCREASES RISK OF BOWEL CANCER

70 in 100 people with Lynch syndrome will develop bowel cancer

most will develop before aged 50

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42
Q

what does Li fraumeni syndrome increase the risk of? and what gene?

A

TP53 gene. - tumour supressor
breast
bone
brain

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43
Q

what are the 5 key modifiable risk factors?

A 
tobacco use
alcohol consumption 
excess body weight 
physical activity
healthy eating
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44
Q

how many cancer cases arise from modifiable risk factors?

A

~1/2

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45
Q

what is primary cancer prevention?

A

addresses the cause so the disease does not occur e.g., avoid certain behaviours/activities

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46
Q

what is secondary cancer prevention

A

identified the disease before the onset of symptoms and keeps it from becoming more extensive e.g., screening

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47
Q

what is tertiary cancer prevention?

A

reduces complications and progression of disease once it has become clinically apparant

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48
Q

rank the top 5 cancer risk factors

A
  1. smoking
  2. excess body weight
  3. drinking alcohol
  4. UV radiation
  5. physical inactivity
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49
Q

how many cases of cervical cancer are modifiable?

A

100%

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50
Q

what causes 19% of all cancers?

A

smoking

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51
Q

what does excess body weight affect?

A 
inflammation in the body
cell and blood vessel growth
cells' ability to live longer
levels of hormones that can fuel cell growth
factors that regulate cell growth 
the ability of cancer cells to spread
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52
Q

how does alcohol raise cancer risk?

A

alcohol is converted to acetaldehyde that can damage DNA inside cells
alcohol can act as an irritant
cells that are damaged mah try and repair themselves which may lead towards DNA changes
lead to oxidative stress - ROS
liver damage

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53
Q

combination of alcohol and smoking on cancer risk

A

alchohol may help other harmful chemicals such as those in tobacco smoke, enter the cells lining the upper digestive tract

alcohol may also slow down the bodies ability to break down and get rid of some harmful chemicals

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54
Q

what are the three main groups of UV radiation

A

UVA
UVB
UVC

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55
Q

which UV rays have the most energy but arent a risk factor?

A

UVC

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56
Q

Which form of UV radiation causes skin cancers?

A

UVB

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57
Q

what reduces the risk of 13 different cancers?

A

exercise

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58
Q

what are the 5 types of observational study?

A 
cohort
case-study
cross-sectional
gene-wide association
gene-environemnt §
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59
Q

what is a cohort study

A

group of people with something in common
usually an exposure or involvement in a defined populaiton group
study to obtain additional evidence to refute or support the existence of an association between suspected cause and diseases

cohort is identified prior to to appearance of disease being investigated
groups observed for defined period of time

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60
Q

what is a prospective cohort study?

A

2 groups - exposed and unexposed
both free from condition from the outset
observed for specifc period of time

long duration
funding for long period
drop out

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61
Q

what is a reterospective cohort study?

A

outcomes have all occured before the start of the investigation
investigator goes back to the past to select the study group and traces them forward through time

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62
Q

what is an ambi-directional cohort study?

A

combines prospective and reterospective

cohort is identified from past records and assesses the date for the outcome. same cohort is followed up pprospectively into the future for further assessment of outcome

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63
Q

what is relative risk?

A

incidence risk among exposed group/incidence risk among non-exposed group

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64
Q

what is attributable risk?

A

incidence risk among an exposed group minus the incidence risk among non exposed group

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65
Q

what is bioavailability?

A

proportion of administered drug which reaches the systemic ciruclation unchanged and therefore available for distribution to the site of action

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66
Q

what method of drug adminiistration acheives 100% bioavailability?

A

intravenous injection

all the drug reaches the systemic circualtion unchanged

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67
Q

which method of drug admiinistration always acheives less than 100% bioavailability?

A 
oral route
common, safe, convenient, economical
exposure to pH, enzymes, gut activity
exposure to first pass metabolism 
absorption depejds on rates of GI transit
requires patient compliance
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68
Q

which methods of drug administration avoids first pass metabolism?

A 
mucosal routes
sublingual, buccal - spray under tounge
nasal, eye, vaginal, rectal 
rapid transit to systemic circulation
drug stability- pH in mouth is neutral compared to stomach

also inhalation routes

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69
Q

what is pharmacokinetics

A

study of drug movement within the body - what the body does to the drug

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70
Q

what is pharmacodynamics?

A

study of drug effects and mechanisms of action - what the drug does to the body

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71
Q

what are the 4 phases of pharmacokinetics (ADME)

A
  1. ABSORPTION
  2. DISTRIBUTION
  3. METABOLISM
  4. EXCRETION
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72
Q

Describe the absorption phase of pharmakokinetics

A

Drug must cross the GI tract and avoid metabolism by liver
Most drug absorption occurs via passive diffusion
Rate = permeability x SA x concentration difference

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73
Q

what factors affect GI drug absorption rate?

A

surface area/blood flow
GI motility - e.g., laxatives = rapid transit so less exposuer and absorption
Malabsoptive states - e.g., coeliac disease - reduces/impairs absorption
food type - meal composition - fat intake delays gastric emptying
lipid solubility of drug can increase absorption rate

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74
Q

what is first pass metabolsim?

A

The extent of drug metabolism occuring before the drug enters the systemic circulation

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75
Q

desribe the process of first pass metabolism

A

after absorption, orally administered drugs enter the portal system
drugs can be rapidly metabolised by enxymes in the liver
this reduces the level of drug reaching thr systemic circulation so has major affect on bioavailability

swallowed drug > digestive system > hepatic portal system > liver > rest of body

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76
Q

what is the drug distribution phase?

A

process of drug being transferred ffrom systemic circulation to the tissues

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77
Q

what is rate and distribution of drugs determined by?

A

ability of drug to pass through tissue membrane
lipid solubility of drug
binding of drug to plasma proteins
active transport of some drugs across cell membranes
presence of other drugs in the body
perfusion rate limitations

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78
Q

what is the effect of drugs binding to plasma proteins?

A

drugs can bind reversibly to plasma proteins
only non-protein bound drug molecules go on to traverses membranes to gain access
changes in protein binding can lead to changes in drug distribution

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79
Q

how much of the total drug plama must constitute of protein bound drugs

A

90%
E.G., warfarin used to treat coagulation disorders/risks - around 99% of this is protein bound - stays in blood so low distribution level

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80
Q

what increases drug half life dramatically?

A

high-protein-binding

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81
Q

what is the risk of protein dispalcement with co-admisitered drugs?

A

warfarin is usually 99% protein bound but if the pateint also takes aspirin which is a high protein binder, the asprin will displace the warfarin from the plasma proteins and therefore increasing the level of unbound protein in the blood. the effective concentration of warfarin increases and this toxicity can lead to excessive bleeding as its a drug that helps prevent blood clots

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82
Q

where is the main sight of drug metabolism?

A

liver

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83
Q

what are the 2 phases of drug metabolism?

A

phase 1: oxidation, reduction, hydrolysis, demethylation. products are more chemicslly reactive and more toxic than the parent drug, Cytochrome p450 enzymes are important

phase 2: conjugation, sulphonation, glucuronidation, acetylation. conjugates are often chemically polar and readily cleared by the kidney. retains them longer in the bloodstream

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84
Q

what are the effects of drug activity on drug metabolism?

A

Conversion of drugs to inactive compounds by liver; promotes excretion of converted drug molecules by kidneys

pro-drugs - inactive pro-drugs can undergo metabolism in the liver following ingestion to become pharmacologically active

active metabolites - e.g., codeine (inactive) is converted to morphine (active) in the liver

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85
Q

what are the features of pro-drugs

A

altered absorption kinetics
prevent adverse effects
improve distribution post ingestion

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86
Q

what factors affect drug metabolism?

A

liver disease
advancing age
genetic polymorphisms in drug metabolising enzymes
competition between drugs for the same metabolising enzymes

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87
Q

where is the major route of drug excretion?

A

kidney via urine

also via GI - bile

foecal drug excretion

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88
Q

what are minor routes of drug excretion?

A

lungs, sweat, tears, saliva, breast milk

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89
Q

what is rate of elimination?

A

amount of drug eliminated from the body per unit time

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90
Q

what is first order kinetics in drug elimination?

A

drug concentration is decreased exponentially
natural logarithm of drug concentration and time is linear
rate of elimination is proportional to the amount of drug in the body

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91
Q

how can drug half life be determined?

A

elimination curve

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92
Q

what is the half life of paracetamol?

A

~2 hours

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93
Q

what is the half life of chloroquine?

A

~6 WEEKS

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94
Q

how long does it usually take for drugs to be absent from the body?

A

after 5 half lives have elapsed?

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95
Q

what is half life of a drug?

A

meausre of the presence of the drug in the body rather than the duration of the action of the drug

the half life of the same drug remains the same no matter the dosage given

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96
Q

what are the 4 types of pharmacolgical actions of drugs?

A
  1. via direct effects of cellular receptor function
  2. via action on ion channels
  3. via action of membrane transport processes
  4. via enzyme inhibition
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97
Q

which receptors have fast responses and which are slow

A

cell membranes - fast responses

cell cytoplams - slower responses

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98
Q

what is a receptor agonist?

A

an agonist is a moleucle that binds to a recptors and activates it

can be partial - doesnt have the same extent of biological reponse

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99
Q

what is a receptor antagonist?

A

competitive antagonists compete for the same binding sites as the agonist

non-competitive antagonists alter the receptor binding site to reduce agonist activity

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100
Q

give 2 examples of receptor antagnonists

A

atenolol - therapeutic competitive inhibitor of the Beta-1 adrenergic receptor and is used to treat hypertension and cardiac arrhythmia

ketamine - therapuetic non-compeititve antagonist of the neuronal N-methyl-D-aspartate receptor and is used as an anaesthetic

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101
Q

what is the affect of drugs targetting ion channels

A

ion channels influnce the movement of ions into and out of cells across membranes

influences polarisaion of excitable cells and influences intracellular signallign cascades

drugs acting on ion channels affect neural transmission and muscle contractility

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102
Q

what are examples of ion channels inhibitors

A

sodium channel blockers - local anaesthesia e.g., lidocaine

calcium channel blockers -slow heart rate e.g., verapamil

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103
Q

what is the effect of drugs targeting transporters?

A

transporters mediate the movement of specific endogenous signlaling molecules and nutrients in and out of cells

so targetting this can cause accumulation or prevention

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104
Q

what is an example of drug targeting of transporters?

A

selective serotonin reuptake inhibitor (SSRI) anti-depressant drug, sertaline, blocks neironal serortonin transporter (SERT) leading to retention or serotonin in the nrual post-synaptic cleft.

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105
Q

what are examples of drug targeting enzymes?

A

ACE inhibitors - ramirpil blocks ACE

NSAIDs - iburpofen

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106
Q

what is the importance of the P450 isoenzyme? - drug -drug interactions

A

introduction of the P450 enzykmes by one drug can increase the rate of metabolism of another resulting in lower plamsa concentrations and reduced effects

upon withdrawal plasma concentrations of the other drug increase and toxicity can occur

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107
Q

what are common important drugs affected by P450 enzymes?

A 
Ciclosporin
Oral contraceptives
Warfarin
Phenytoin - epilepsy drug
Acetylcholinesterase inhibitors 
Theophyline - asthma 
Statins

COWPATS

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108
Q

What is pharmacogenetics?

A

Individual responses to drugs can vary

genetic polymorphisms exist in drug metabolising enzyme genes especially in cytochrome p450 enzymes

some can lack enzymes and so drugs have no effect
some can have extra copies and so are rapid metabolisers - enhanced effect
opens up the field of personalised medication

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109
Q

what proportion of > 65 year olds take at least one medication?

A

4 in 5

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110
Q

what percentage of older people take >4 medications simultaneously?

A

36%

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111
Q

what percentage of admissions for older adults are due to adverse drug reactions?

A

5-12%

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112
Q

what is an adverse drug reaction

A

undesirbale effect of a drug beyond its anticipated therapeutic effects

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113
Q

what are ADRs related to? (DoTS classification)

A

Dose
Time-course
Susceptibility

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114
Q

what is the theraputic index?

A

theraputic window - stay between to get deisred repsonse

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115
Q

what are some examples of drug sensitivity in older adults?

A 
reduced receptor responses
renal clearane reduced
altered immune response
slower gastric emptying 
reduced plasma albumin 
altered liver metabolism
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116
Q

what is the problem with drug disocovery?

A

attrition remains high
small moleucle drug approvals remain constant
new drug candidates must represent a significant advantage over standard of care
disease models fail to refelct complexity of human disease
cure vs disease control
lack of effective biomarker research

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117
Q

what is precision medicine?

A

not a one size fits all approach

takes into account individual variability

more accurate prediction about the treatment and prevention strategies for a particualer disease or group of people

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118
Q

what are advantages of precision medicine?

A

wider availability of doctors to use patients genetic and other molcular infomation as part of routine medical care

ability to predict whcih treatments will work best

improved approahces for preventing, diagnosing and treating a wide range of diseases

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119
Q

what are commercial challenges of precision medicine?

A

unlike traditional medicines where manuacturers can earn more selling these products to a large population, pprecsion medicine doesnt provide this opportunity

manufacturers often charge a lot of moneyy for their products like with orphan medications (rare diseases and some cancers)

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120
Q

what is an explanatory trial?

A

‘as-treated’ analysis
analyses only those who completed follow-up and complied with treatments
compares the physiological effects of the treatments

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121
Q

what is a pragmatic trial?

A

‘intention to treat’ analysis

Intention-to-treat analysis is a method for analyzing results in a prospective randomized study where all participants who are randomized are included in the statistical analysis and analyzed according to the group they were originally assigned, regardless of what treatment (if any) they received

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122
Q

as treated vs intention to treat

A

as treated - larger sizes of effect

intention - smalller effect sizes

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123
Q

what are key ethical issues in clinical trials?

A

clinician has to provide the best treatment for each individual patient

scientific integrity requires treatment to be chosen at random

clinical equipose: reasonable uncertainty about which treatment including non-treatment is better so randomisation dies not deny any patient the best treatment

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124
Q

what is informed consent? - what should be explained to patients before the trial

A

patient is invited to be in a trial
what the alternative treatments are
the treatment is allocated at random
patient can withdraw at any time

information should be given verbally and in writing with time to make a deicison

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125
Q

how many cells do we carry?

A

~3.72x10^23

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126
Q

what are the objectives of a cancer treatment?

A

> destroy/kill ALL cancer cells - possible complete cure

> destroy/kill MOST cancer cells - prolonging survival time

> destroy/kill SOME cancer cells - eliminating symptoms or preserving QOL

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127
Q

what are the categories of tumour rersponse (treatment efficacy)

A

> complete response: dissapearance of all signs of disease
partial response: reduction of tumour volume by at last 30%
stable disease: no significant change
disease progression: increase in tumour volume by at least 20% or new metastasis

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128
Q

what is meant by overall survival?

A

survival time from the start of treatment

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129
Q

what is disease-free survival?

A

survival time prior to tumour relapse after radical treatment

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130
Q

what is progression free survival?

A

survival time prior to tumour progression

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131
Q

how do you assess if one treatment is better than the other?

A

estimaet effects from sample of data and provide survival curves
estimate confidence interval around the estimate to rerlect uncertainty

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132
Q

what are methods of traditional cancer treatment?

A

radiation
surgery
chemotherapy

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133
Q

what are new methods of cancer therapy?

A

targeted drug therapy

precision medicine

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134
Q

what is chemotherapy?

A

administration of chemical agents to destroy cancer cells

aim to cure where possible and palliate where cure is impossible

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135
Q

what is neoadjuvent chemeotherapy?

A

administered prior ro surgery to facilitate resection (shrinking) and prevent mestastasis

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136
Q

what is adjuvent chemotherapy?

A

administered post operatively

debulking to kill micro-metastases

reduce risk of distant replapse

increase disease-free survival

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137
Q

what is palliative chemotherapy?

A

improving the qualtiy of the patients life by controlling symptoms prolonging life in a patient where cure isn’t possible

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138
Q

what is salvage chemotherapy?

A

potentially curative, high dose regimen given to a patient who has failed or recurred following a prior curativ regimen

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139
Q

what are antimetabolites? - mechanism of chemotherapy

A

limit the synthesis of nucleic acid precursors (needed for DNA replication)

e.g., methotrexate inhibits dihydrofolate reductase - reduces the synthesis of folate which is necessary for purine and pyrimidine production

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140
Q

what are topoisomerase enzymes? - mechanism of chemotherapy

A

they participate in the winding and unwinding of DNA and are inhibited by anthracyclines snd camptothecins

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141
Q

what agents cause stucutral damage to mature DNA?

A

alkylating agents, platinum derivatives

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142
Q

what do vinca alkyloids and taxanes do - chemotherapy mechanisms?

A

disturb function of mitotic spindle

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143
Q

what chemotharpeutic mechanism involves hormones?

A

homonal agents - block proliferation if hormone responsive cells

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144
Q

what is the mechanism of action for alkylating agents?

A

target DNA, produce alkylation through the formation of intermediates

not cell cycle phase specific - just damage DNA wherever they are in the cycle, causing cell death

e.g., cisplatin, carboplatin

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145
Q

what is the mechanism of action for antimetabolites?

A

interfere with DNA synthesis
structural analogues or inhibit sseveral enzymes
s-phase specific

e.g., methotrexate

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146
Q

what is the mechanism of action for mitotic spindle agents

A

bind to microtubular proteins inhibiting microtubule assembly, thereby interupting the mitosis phase of cell division

M phase speicific

e.g., docetaxel

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147
Q

What is the mechanism of action for topoisomerase inhibitors?

A

DNA topoisomerase 1 and 2 are essential enzymes for transcription, replication and mitosis - moduare the structure for winding of DNA

e.g., Topo 1 INHIBITORS

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148
Q

what do all mechanisms of action for chemotherspy have in common?

A

targeting DNA replication machinery and ability of cells to divide
the problem is that this is the mechanism of all growing cells in our body, not just cancer

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149
Q

what are the principles of combination chemotherapy?

A

> use drugs active as a single agent
use drugs with different mechanisms of action
use drugs with different mechanisms of resistance
use drugs with different side-effects
be aware of drug-drug interactions

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150
Q

is survival increased with combination therapy?

A

overall survival is significantly increased

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151
Q

what is category one cancer based on effectivness of chemotherapy?

A

evidence that single or combination of drugs alone or other therapeutic modalites will result in cure - deifined by a normal lifespan and prolongation of survival in most patients

germ cell, leukaemia, lymphoma

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152
Q

what is category two cancer based on effectivness of chemotherapy?

A

average survival is prolongued when chemotherapy is used in adjuvent to local surgery or radiotherapy in the early stages of disease

e.g., breast, colorectal, ovarian

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153
Q

what is category three cancer based on effectivness of chemotherapy?

A

evidnece that a single drug or combination will produce clinically useful responsievness in more than 20% of patients. may be of short duration

e.g., lung, bladder, prostate, stomach, cervical

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154
Q

what is category four cancer based on effectivness of chemotherapy?

A

tumours where locsl control mayu be improved bt uusing chemotherapy before, during or after surgery/radiotherapy

e.g., head and neck

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155
Q

what is category five cancer based on effectivness of chemotherapy?

A

tumours for which there are no effective drugs

objective response occur in less than 20% of patients

e.g., liver, melanoma, pancreatic, brain, thyriod

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156
Q

what is meant by a complete response to treatment? (chemo)

A

dissapearance of all target lesions

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157
Q

what is meant by a partial response to treatment? (chemo)

A

at least 30% decrease in the sum of the longest diameter of targeted lesions

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158
Q

what is meant by a stable disease (chemo)?

A

neither sufficient shrinkage to qualify for PR or significant enough increase to qualify for PD

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159
Q

what is meant by progressive disease (chemo)?

A

at least 20% increase in the sum of the LD of the targeted lesions

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160
Q

what are methods of chemotherapy delivery?

A

IV or oral

straight to site where needed:
local drug application - intra-arterial (hepatic infusion)
- intra-pertoneal (ovarian cancer)
- intra-pleural (pleural metastasis)

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161
Q

what is mucositis

A

common complication of cancer chemotherapy

begins 5-10 days post initiation of treatment and lasts 1-2 weeks
causes mucosal lining of the mouth to atrophy and break down, forming ulcers and sores

oral pain
burning
ulceration
difficulty eating, drinking, speaking

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162
Q

what is the problem with cytotoxic drugs?

A

drug resistance
resistance is often due to mutation or altered expression of genes whos products mediate:
> transport o a drug into/out of a cell
> metabilism and therefore intracellular concentration of the drug
> structure of the target protein (structural/enxyme) to which the drug binds to cause cytotoxicity
> protection from apoptosis

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163
Q

what are features of cancer stem cells?

A

quiescent, increased expression of anti-apoptotic proteins and increased activity of pro-survival pathways

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164
Q

what does the MDR1 gene encode? - multidrug resistance gene

A

P-glycoprotein (PGP): mediates transport of certain drugs out of the cell therefore reducing intracellular concentration and cytotoxicity

overexpression of PGP achieved through incresded expression of its mRNA with or without MDR1 gene amplification

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165
Q

what are processes of multi-drug resistance

A 
increased drug efflux
decreased drug influx 
tumour microenvironment 
drug targets - mutations, feedback activation 
drug metabolism - detoxifying 
gene regulation

resistance can be intrnsic or aquired
epigeneitc alterations can cause resistance - reversible by epigenetic modification?

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166
Q

how can drug resistance be overcome?

A

platinum drugs targeting resistance mechsanisms

more of drug in a way thats less toxic

more specific agents - pairing with drugs thhat are not resistant

drug resistance is also affected by the microenvironment

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167
Q

what are the characteristics of radical radiotherapy?

A

preserves normal anatomy
acute morbidity
less severe
localised disease
high dose therapy delivered in daily fractions over 7 weeks
e.g., larangeal carcinoma when patients are not fit to undergo radical surgery

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168
Q

what are the characteristics of adjuvent radiotherapy?

A

administered as an addition to potentially curative surgery
eradicate microscopic residual disease remaining in the tumour bed
used to reduce local relapse rates following partial masectomy

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169
Q

what are the characteristics of palliative radiotherapy?

A

control of distressing symptoms
not curative
improve QOL
relive pain

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170
Q

what is external beam radiation?

A

x-rays, gamma rays and electron beams from linear accelerators

high-intensity electron beams have greater penetration, less scatter, delivers high enerft to deep seated tumours while sparing nomral tissues

planned using CT scan to create 3D image

computor profeamme designs radiation beams that follow the shape of the tumour

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171
Q

what is brachytherapy?

A

internal radiotherapy

use of radioactive sources implanted directly into a tumour or body cavity to deliver localised radiotheapy

examples: iridium-192 needles or wires implanted into tumours of the breast, tounge, floor of mouth

sealed caesium -137 radioactive sources into the vagina, rectum to treat cancer of the vagina, cervix, uterus, rectum, animals

pellets of iodine-125 to treat prostate cancer

major disadvantage is staff handling radioactive sources

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172
Q

how is thyriod cancer treated?

A

Radioisotope
iodine-131
specific transport protein that allows uptake of this iodine in the thyriod and it will stay in that region

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173
Q

what is proton therapy

A

form of radiotherapy that uses protons instead of x-rays
high energy proton beams target tumours morre precisely
less damage to healthy tissues

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174
Q

what molecular mechanisms contribute to radioresistant phenotypes

A

evasion of apoptosis
altered mitochondrial and energy metabolism
inflammation
altered cell cycle

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175
Q

what are some early effects of radiotherapy (2-3 weeks)?

A

tiredness, lack of energy, depression

specific local effects related to area beign treated: skin- erythema, bowel - diarrhoea, bladder - urine frequency/dysuria, scalp - hair loss, mouth - mucositis

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176
Q

what are some late effects of radiotherapy?

A

loss of stem cell recovery
damage to small blood vessels resulting in occlusion
skin - fibrosis
bowel - stricture, perforation
bladder - fibrosis. haematuria
rare induction of second malignancy - leukaemia (3 yrs), solid tumour (10-30 yrs) post exposure

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177
Q

what are the 3 types of surgical oncology?

A

surgery for prevention - familial cancer, liver transplant
surgery for cancer cure - total eraditcation of primary tumour, regional lymphatics
surgery for palliation - surivice longer, better QOL, reduce occlusion of lumen

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178
Q

what is a tumour margin?

A

rim of normal tissue surrounding the tumour

sent off to pathology to ensure a good tumour margin and all tumour is removed

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179
Q

what is a lumpectomy?

A

proceudre used for breast cancer
minimal mutilation when cancer is detected early - small scar
lymph node disection and removal of breast required when cancer has spread
(mastectomy)

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180
Q

what are the main types of damage caused by ioinsing radiation?

A

base and sugar damage
single stand breaks
double strand breaks
covalent intra or inter strand cross linking

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181
Q

what factors affect the tumours response to radiation

A 
where the cell is in the cell cycle
what type of tumour
how fast is it growing 
type of microenvironment 
dosage of radiotherapy
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182
Q

what are therapeutic vaccines?

A

modified tumour cells, tumour associated antigens, dendritic cells, oncolytiic viruses

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183
Q

what are different methods of immunotherapy?

A 
therapeutic vaccines
immune system modulators
monoclonal antibodies
adoptive t cell transfer
immune checkpoint inhibitors
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184
Q

how are dendritic cells involved in immunotherapy?

A

they generate cytotoxic T cells which kill cancer cells by recognising specific antigens produced in the cell

cancer cells produce antigens that are seen as foreign and are presented as peptides that can be recognised by cytotoxic T cells

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185
Q

how are dendritic cell vaccines created for vaccine therapy?

A
  1. take blood from cancer patient
  2. remove monocytes (give rise to dendritic cells)
  3. stimulate with various factors in vitro
  4. they become dendritic cells
  5. feed the cells specific peptides (tumour antigens) or tumour lysate
  6. inject back into patient as a vaccine to induce a T cell immune repsonse agasint the tumour
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186
Q

how are dentritic cells used in treatment of prostate cancer?

A

Sipuleucel -T
use a fusion protein which is a combination of an antigen thats present in prostate cancer - prostatic acid phosphatase)- and granulocyte macrophage colony stimulating factor - stimulated dendritic cells

introduce into activiated dendritic cells int he patient and give them back as therapy

(take cells, modify, replace)

very expensive

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187
Q

how much longer is survival when using dendritic cells/sipuleucel-T in prostate cancer?

A

4 months longer

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188
Q

what are key mediators of cell communication in the tumour microenvironment?

A

cytokiines

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189
Q

what does CAR-T stand for?

A

chimeric antigen receptor t cells

190
Q

How does CAR T-cell therapy work?

A 
> T cell taken from patient
> gene for CAR receptor that binds to the cancer proteins s added to the T cell 
> CAR-T cells are grown in the lab - 
> give back to patient via infusion
> now t cells kill cancer cells
191
Q

what is CAR T-cell therapy used for?

A

certain blood cancers

e.g., leukaemia and lymphoma

192
Q

what are immune checkpoint inhibitors?

A

immune checkpoint pathways usually prevent T cells from becoming hyperactivated which can result in autoimmune disease

tumour specific t cells can be inhibited by the same pathways through inhibitory signals

allows immune system to kill the cancer cells

193
Q

describe the CTLA-4 immune checkpoint pathway

A

antigen-presenting cells in the lymph nodes have the protein B7-1/-2 and this is bound to CTLA-4 on the surface of T cells.

this interaction can be directly blocked by monoclonal antibodies such as Ipilimumab to block CTLA-4

and this allows T cell activation to kill cancer cells

194
Q

describe the relationship between PD-1 and PD-L1 IN for immune checkpoint inhibitors?

A

PD-L1 is on the surface of tumour cells and binds to PD-1 on the surface of T cells to prevent hyper-activation

this interaction can be directly blocked by monoclonal antibodies such as nicolumab to block PD-1 and Avelumab to block PD-L1

and as a result t cells are activated and can kill tumour cells

195
Q

what percentage of patients respond to ICI therapy?

A

30-40%

196
Q

what makes a tumour more immune responsive?

A

> inflamed tumour microenvironment
many infiltrating t cells and macrophages along with high levels of PD-L1 expression on the tumour cells

can be measured as biomarkers in tumour biopsies and used to identify patients who will have a more effective response to ICI therapy

197
Q

what are PARP inhibitors?

A

DNA repair pathways

synthetic lethality in familial and sporadic tumours

198
Q

what are the 3 types of tyrosine kinase inhibitors?

A

receptor tyrosine kinase
non-receptor tyrosine kinase
serine/threonine kinase inhibitors

199
Q

what do kinase inhibitors do?

A

target signalling pathways - particularly those driving cell proliferation

200
Q

what pathway do kinase inhibitors mostly target?

A

ERK-MAP kinase pathway through either directly inhibiting receptor tyrosine kinases such as EGF receptor or downstream components of the MAP kinase cascade

201
Q

what is mutated in 50% of melanomas?

A

BRAF gene

202
Q

what do BRAF inhibitors do?

A

target kinase and block its ability to activate the downstream signalling cascade that results in the proliferation of melanoma cells

203
Q

what are 3 types of epigenetic inhibitors?

A

histone methyltransferase inhibitors

histone deacetylase inhibitors

DNA methyltransferase inhibitors

204
Q

what is the role of proteosome inhibitors?

A

block the ubiquitin-proteosome pathway responsible for protein degradation and the production of growth-promoting proteins

205
Q

what do Bcl-2 inhibitors promote?

A

apoptosis

206
Q

what is chronic myelogenous leukaemia?

A

malignant cancer of the bone marrow

causes rapid growth of the blood-forming cells (myeloid precursors)

207
Q

What drives tumour formation in Chronic myelogenous leukaemia?

A

chromosomal translocation results in a fusion of the BCR gene with ABL kinase

208
Q

what is the mechanism of action of the drug Gleevec used for CML?

A

Competes with ATP binding to the ABL kinase which stops the ability of kinase to phosphorylate downstream effector molecules

effects progression of CML

very effective and little side effects

209
Q

What inhibitors of BCR-ABL are used for patients with Gleevec-resistant tumours?

A

AMN107 is 20 times more potent than Gleevec against unmutated BCR-ABL

210
Q

why are combination drugs commonly used in cancer therapy?

A

mutations can happen anywhere and happen all the time and so using a combination of drugs is used to increase the potency and reduce the ability for drug-resistants is more than one aspect to the pathway id targeted

211
Q

What is the BCR-2 pathway? and why is it a therapeutic target?

A

It controls apoptosis - tightly programmed cell death

this pathway becomes deregulated in cancer and so is a therapeutic target

212
Q

how is the BCR-3 pathway targeted for cancer treatment? and when is it used?

A

BH3 mimetic drugs
Induce apoptosis

Used only for relapsed and refractory tumours as it’s not ethical when there are possible other drugs - last resort.

213
Q

How is the PARP pathway used in cancer therapy?

A

Cancer cells have lost their ability to repair DNA via homologous recombination if they have lost either BRCA1/2 and instead rely on the PARP-1 pathway for base excision repair - the only dominant pathway left

The cancer drug then targets this pathway so the cancer cell can no longer repair its DNA - synthetic lethality

214
Q

What is BRACness is sporadic tumours?

A

DNA repair processes are disrupted by numerous mechanisms in sporadic tumours

Some sporadic tumours share traits with those occurring in BRCA1/BRCA2 mutation carriers

Possibility of using PARP inhibitors even though they don’t have the mutations

215
Q

what can be used to improve and personalise cancer therapy with small molecules

A

biomarkers

216
Q

what are 3 types of biomarkers?

A

diagnostic - detect or confirm the presence of a disease or condition of interest

predictive - identify individuals who are more likely to experience a favourable or unfavourable effect or drug

prognostic - used to identify the likelihood of a clinical event or disease or progression on patients who have the disease

217
Q

how do drugs get approved

A

NICE technology appraisal

single TA
Fast-track -TA
multi -TA

218
Q

What is the chance you will pass on the BRCA1/2 gene to your child?

A

50% as its an autosomal dominant gene

219
Q

what cancers are the BRCA1/2 gene mutations associated with?

A

BREAST AND OVARIAN

220
Q

how do you manage BRCA1/2 mutation if found at screening?

A

prophylactic bilateral mastectomy, oophorectomy

anto-oestrogen dugs - tamoxifen

221
Q

What gene is implicated in Li-Fraumeni syndrome?

what cancers does this predispose?

A

TP53 gene - tumour suppressor

breast, soft tissue sarcoma, leukaemia

222
Q

what genes are implicated in multiple endocrine neoplasia? and what cancers does this predispose

A

MEN1 and MEN2 - tumour supressor

pancreatic endocrine and thyroid tumours

223
Q

what are the limitations of genetic screening?

A

family tensions - who do you tell?
anxiety - will it ever happen?
false security - presumably im okay then?
unclear results - what does it mean?
discrimination - do i need to tell life insurance
high cost

224
Q

what is the process of cervical screening?

A

smear test
aged 25-64
every 3 years - or 5 years if over 50

invited by letter
cervical sample
check for HPV and abnormal cells

225
Q

what is the process of beast screening?

A 
females aged 50-71
every 3 years
invited by letter
mammogram or ultrasound
biopsy > check for abnormal cells
226
Q

what is the process of bowel screening?

A

56-60 to 74 years
every 2 years
postal kit
test for blood in stool

colonoscopy and treatment if positive result

227
Q

Limitations of screening for premalignant disease

A

not everyone attends screening - deprived areas, too busy, no sick pay, not health educated

sensitivity vs specificity

consequences of false positives/negatives

228
Q

Why is there no prostate screening in the UK?

A

There is no suitable test

PSA test - can be high in people that don’t have cancer e.g., a recent urine infection - false positive
and the next round of testing would be a prostate biopsy which is very invasive

in many men that get it, it’s slow-growing and doesn’t really bother them - overtreating?

229
Q

can cancers result from chronic infection?

A

yes

230
Q

what cancer can Hep B and C infection lead to?

A

hepatocellular carcinoma

231
Q

what cancer does helicobacter infection lead to?

A

gastric cancer

232
Q

What is the protocol for the HPV vaccine?

A

target: girls and boys aged 12-13
two doses - 6-24 months after first

prevents cervical, mouth, throat and vaginal cancers
genital warts

233
Q

what is an example of upstream smoking prevention?

A 
tackle wider influences on health through public policy
> tobacco taxation increase
> increase the legal age for purchase
> health warnings on packets
> prevention
234
Q

what is an example of downstream smoking prevention?

A

deal directly with adverse health behaviours

advice to pregnant women and teenagers who smoke

smoking cessation clinics

235
Q

how many people in the UK are living with a cancer diagnosis?

A

3 million

set to rise to 4 million by 2030

236
Q

describe the psychosocial impact of caner

A

recognises how cancer can affect each aspect of a person’s life (domains)

> psycholigical
social
personal
spiritual effects

237
Q

what are disruptors to the biological clock?

A

light
meal timing
activity

238
Q

what are synchronisers for the biological clock?

A

diffusable factors - hormones
temperature
Parasympathetic NS

239
Q

what is the association between shift work and breast cancer risk?

A

working more than 10 years of shift work with 3 night shifts a week has significant cancer risks associated

shift work that involves circadian disruption is carcinogenic

240
Q

Is shift work a risk factor for T2D?

A

even if you control the lifestyle, the more years of working shifts, the risk increases for T2D

241
Q

What is the importance of single-cell clocks and cell cycle coupling in cancer?

A

normally the cell cycle is linked to the biological clock so division can only happen at certain points

in cancer cells this relationship is lost and so the cell can divide at any time

242
Q

what is the effect of chronic jetlag?

A 
neuroendocrine dysfunction to the liver
sympathetic nerveous system tone 
activation of CAR
fatty liver disease
hepatocarcinogenesis
243
Q

disruption of bioloigcal clocks

A

24/7 society - social jet lag, shift work, trans meridian travel

probably a carcinogen

can lead to diseases and then patients enter a vicious cycle

can be a biomarker

244
Q

how can you fix disrupted biological clocks?

A

can be attempted by behaviour changes (food, activity, light exposure)

pharmacotherapy

might alleviate symptoms or even fix diseases

treatment target

245
Q

name some consequences of less sleep?

A 
irritability
immune system dysfunctions 
cognitive impairment 
risk of heart disease
decreased reaction time 
risk of type 2 diabetes
246
Q

what sleep disorders are obesity related to?

A

sleep-disordered breathing

obstructive sleep apnoea

247
Q

What is the impact of sleep problems and obesity?

A

change in individuals’ metabolic profile
accumulation of adipose tissue
the increase is rapid - therefore unlikely to be genetic

248
Q

what regualtes the circadian clock?

A

physical, mental and behavioural changes follow a roughly 24 cycle, responding primarily to light and darkness in the environment

groups of interacting molecules in cells throughout the body

249
Q

where is the master clock and what does it do?

A

located in the brain and it coordinates all the body clocks so they’re in synch

called the suprachiasmatic nuclei (SCN) and controls the production of melatonin

250
Q

how are peripheral clocks synchronised?

A

humoral, nutrient and automatic wiring

251
Q

what does the peripheral clock coordinate?

A

food absorption, glucose clearance, fat accumulation, insulin secretion, lipogenesis

252
Q

what is the impact of light on clock outputs?

A

glutamate and PACAP are co-released in the SCN upon photic stimulation

253
Q

give examples of some external cues that influence clock outputs

A

feeding, social interaction, sleep deprivation, exercise

254
Q

what is the impact of a positive energy balance?

A

obesity

255
Q

what is the impact of a negative energy balance?

A

leanness

256
Q

what are the biological impacts of shift work?

A

as you’re eating when you would normally be sleeping

night-time eating and sleep disruption
/restriction can cause circadian disruption. all this contributes to an increase in adiposity, increased circulating triglycerides and fatty acids and abnormal glucose metabolism 1

257
Q

what hormone inhibits hunger?

A

leptin - promotes satiety

258
Q

what hormone is known as the hunger hormone?

A

ghrelin - increases appetite and food intake

259
Q

what controls the appetite-stimulating/inhibiting neuronal circuits?

A

the arcuate nucleus in the hypothalamus

260
Q

what is the impact of short sleep duration? (hormones and hunger)

A

decreased leptin
increased ghrelin
increased hunger and appetite

261
Q

what is the orexin system?

A

Involved with appetite control

orexin neurones regulate arousal
orexin A and orexin B have potent wake-promoting effects and stimulate food intake

The orexin system activates the appetite-promoting neuropeptide Y

In animal models, sleep deprivation results in increased orexinergic activity

262
Q

what can cause glucose intolerance and insulin resistance?

A

short term partial sleep restriction

263
Q

what does sleep debt have a harmful effect on?

A

carbohydrate metabolism and endocrine function

sleep debt increases severity of age-related chronic disorders

264
Q

what is the state of the brain during slow-wave NREM sleep?

A

the brain is still functional and can listen, but its eyes are shut

we are unaware of the surroundings

reduced responsiveness

265
Q

what are the features of REM sleep?

A

> cortex is active
still not aware of surroundings
if woken at this stage - likely to remember dreams
effectively paralysed, inhibition of alpha motor neurons - stop acting out sleep

266
Q

is sleep an active or passive process?

A

active

267
Q

what are the 3 distinct phases of brain acitivty?

A

Wakefulness
Slow-wave NREM sleep
REM sleep

268
Q

what are the features of an EEG during NREM sleep?

A

low frequency, high amplitude
4 stages (1-4)
from lighter to heavier sleep the amplitude increases and the frequency decreases

269
Q

what are the features of stage 2 sleep?

A

spindles and K complexes

light sleep

270
Q

what are the features of an EEG during REM sleep?

A

high frequency, low amplitude

desynchronised cell firing

271
Q

what occurs during REM sleep?

A

rapid eye movements
skeletal muscle paralysis
loss of muscle tone
muscle twitches

272
Q

What are the 3 processes that make us sleep?

A

homeostatic - sleep propensity
circadian - body clock
ultradian - sleep architecture

273
Q

how long do babies have no circadian rhythm for?

A

first 4-6 weeks of life

274
Q

what are the characteristics of narcolepsy?

A

lack of orexin producing cells - control movement between REM and NREM

Autoimmune

275
Q

what are the tetred of symptoms for narcolepsy?

A

irresistible sleepiness

cataplexy

hypnagogic hallucinations

sleep paralysis

276
Q

what is cataplexy?

A

sudden onset of muscle weakness when awake
facial weakness to complete collapse
breathing, hearing and vision unaffected

277
Q

what is OSA? and what are the characteristics?

A 
obstructive sleep apnoea 
repetitive partial or complete collapse of the upper airway during sleep 
snoring
repetitive, brief, unrecalled arousals
unrefreshing sleep, daytime sleepiness
278
Q

who is most affected by OSA?

A

Middle-aged men with large collar size

279
Q

what does OSA increase the risk of?

A

high blood pressure and strokes

280
Q

what is parasomnia?

A

sleepwalking/talking
bruxism
REM sleeping disorder
acting out dreams

281
Q

what is nociception?

A

the neural process of encoding noxious stimuli

how information about damage to the peripheral tissues is sent to the brain

282
Q

what is the process of nociception?

A

stimuli can be chemical, mechanical or thermal and these are picked up by nerve endings

the signal is then transmitted to the spinal cord to move the affected body part away from the stimulus

the signals travel in specialised pathways to the brain and are then processed

descending inhibitory pathway

283
Q

what is the difference between A-delta fibres and C fibres (sensory nerves)?

A

A-delta - fast myelinated

C-fibres - slower unmyelinated

284
Q

how can pain be classified? (2)

A

according to duration

according to cause

285
Q

how is pain categorised when classified by duration?

A

acute
chronic
acute on chronic

286
Q

how is pain categorised when classified by cause? (3)

A

primary vs secondary
nociceptive vs neuropathic vs central sensitisation
cancer vs non-cancer

287
Q

what is meant by acute pain?

A

pain of less than 6 weeks duration?
usually responds to treatment
often protective - move hand from hot surface

288
Q

what are the features of chronic pain?

A

persists or recurs for >3 months
difficult to treat
may have significant social and psychological implications

289
Q

what is chronic primary pain?

A

no alternative diagnosis
significant emotional distess
significant functional disability

290
Q

what is chronic secondary pain?

A

an underlying disease for which pain is a symptom

cancer pain

neuropathic pain

headache

visceral pain

msk pain

291
Q

name 2 simple analgesics?

A

paracetamol

NSAIDs (non-steroidal anti-inflammatory drugs)

292
Q

what is an example of a weak opioid?

A

codeine phosphate

293
Q

what are examples of strong opiods?

A

morphine, fentany

294
Q

when are antidepressant or antiepileptic drugs used in pain management?

A

when the pain is thought to arise from dysfunction of the PNS or CNS - neuropathic pain

295
Q

why are antidepressants used in pain management?

A

block central reuptake of neurotransmitters allowing increased descending inhibitory input

noradrenaline, serotonin

296
Q

what does sleep requirement vary according to?

A 
age
environmental demands
biological factors 
psychological factors
social factors
297
Q

how common is sleep disturbance in people in pain clinics?

A

90% of patients report sleep disturbance

298
Q

what is the relationship between sleep and pain?

A

bidrectoinal

299
Q

what population has the highest incidence of primary sleep disorders?

A

those who suffer with chronic pain

300
Q

what is sleep onset latency?

A

the time it takes after getting into bed to go from being fully awake to falling asleep

301
Q

what is sleep efficiency?

A

the amount of time spent actually sleeping while in bed

302
Q

what is the relationship between sleep and exercise?

A

bidrectional

poor sleep may contribute to low physical activity levels

exercise has been long associated with better sleep

303
Q

what are the acute effects of exercise?

A

increased respiratory rate, tidal volume, ventilation
ncreased heart rate, cardiac output, stroke volume,

increased blood flow to working muscles
increase in metabolic by products. - lactate, H+ions 
increased sweat
increased muscle recruitment 
increase fuel metabolism 
increased oxygen consumption
304
Q

Why might it help to be physically fitter?

A

effects cardiac and autonomic function during sleep
effects on melatonin
effect of exercise on mood during the night

305
Q

what happens to circulating trophic factors in a sleep-deprived state?

A

circulating trophic factors are supressed such as IGF-1 and brian derived neurotophic factor (BDNF)

306
Q

what is the efffect of reduced circulation of trophic factors during sleep deprivation?

A

negatively impacts muscle recovery from exercise

307
Q

what happens to muscles during sleep deprived states?

A

loss of muscle mass
due to type 2B muscle fibre atrophy
reduced muscle regeneration after damage

308
Q

what is the effect of OSA on exercise?

A

exhibit acute exercise responses such as reduced ability to exercise, lower aerobic and anaerobic capacity compared to healthy individuals

309
Q

what is the highest point of crying in the crying curve for new borns?

A

6 weeks

310
Q

how much of crying is inconsolable in the first 0-3 months?

A

40%

311
Q

how much does a baby’s weight change in the first 3-6 month and then 12 months?

A

double weight in first 3-6 months

trebled by 12 months

312
Q

what is the oxytocin reflex?

A

oxytocin increases and eventually milk production in response to their baby crying (posterior pituitary) - ready for feeding? - n shaped curve.

313
Q

what is the 1st bio-behavioral shift?

A

3-6 months
adaptation to the extra-uterine world

crying for attention
sleep staging and self soothing
feeding - transition to solids

314
Q

what is the 2nd bio-behavioral shift?

A

9-12 months
attachment consolidation
social referencing
crying, sleeping, feeding and attachment system

315
Q

what is a regulatory problem?

A

when regulation is not accomplished after the 1st biobehavioral shift - e.g, can’t stop crying

316
Q

what are common regulatory problems between 3-9 months?

A

excessive crying
food refusal
sleep onset and night waking problems

317
Q

what is the impact of multiple or persistent regulatory problems in childhood when it comes to adulthood?

A

more likely to have attention problems later in life - ADHD
depression
avoidant personality
antisocial personality

318
Q

what creates an avoidant personality?

A

Differing default mode network

Differences in social cognition networks in those that have multiple persistent regulatory problems

319
Q

what are attachment disorganisation symptoms at 18 months

A

parents leave - separation anxiety
parent returns - reunion behaviour

insecure attachment - resistant vs avoidant - trouble making emotional connections with others

disorganised attachment develops from a parent’s consistent failure to respond appropriately to their child’s distress, or from a parent’s inconsistent response to their child’s feelings of fear or distress.

320
Q

what is disorganised attachment?

A

develops from a parent’s consistent failure to respond appropriately to their child’s distress, or by a parent’s inconsistent response to their child’s feelings of fear or distress.

321
Q

what is insecure attachment?

A

trouble making emotional connections with others

322
Q

what is the cascade model?

A

Shows bio-behavioural shifts

The earlier in the course of the problem amendments are made, the more likely you are to getting back on track

323
Q

what scale is used to assess how sleepy you are?

A

Epworth Sleepiness scale

324
Q

what is nociceptive pain?

A

pain resulting from traumatic injury to tissue - large inflammatory responses and localised effects

time-limited - ends when tissue is repaired

325
Q

what is neuropathic pain?

A

pain resulting from neuronal damage/change

debilitating bouts of sharp-shooting or burning pain

tingling or pins and needles (paraesthesia)/numbness and throbbing

often chronic

326
Q

what are examples of nociceptive pain?

A 
arthritis
endometriosis 
low-back
ulcers
angina
327
Q

what are examples of neuropathic pain?

A

cancer
complex regional pain syndrome
phantom limb
shingles

328
Q

what carries pain and temperature signals to the brain?

A

spinothalamic tracts

329
Q

what is gate control?

A

the mechanism by which activation of mechanoreceptors or activation of descending tracts can reduce the transmission of pain at the level of the spinal cord

330
Q

how does gate control work?

A

increases activation of local inhibitory interneurons or directly inhibiting the transmission neurones of the spinothalamic tract

331
Q

what are the 4 main properties of NSAIDs?

A

ANTI-INFLAMMATION

ANTI-PYRETIC - reduces fever

ANALGESIC - rapid pain relief - CNS AND PNS

ANTI-COAGULANT

332
Q

What is the role of an anti-coagulant (NSAIDs)

A

prevents thromboxane dependant platelet aggregation

333
Q

what is the mechanism of action of NSAIDs?

A

preventing the breakdown of arachidonic acid by inhibiting cycle-oxygenase enzymes (COX). - this decreases the production of prostaglandins and thromboxane

334
Q

what happens at the neuronal level under painful conditions?

A

prostaglandins are produced which bind to prostanoid receptors

this triggers a second messenger cascade that increases the likelihood of the neuron depolarising and firing

by preventing prostaglandin production, the NSAIDs

335
Q

what are opiods used for clinically?

A

Analgesia
Anaesthesia
Antitussive effects - dampen cough reflex
Anti-diarrhoeal effects - slow down peristalsis of the gut - increase opportunity for water resorption

336
Q

what is the mechanism of action for opioid drugs?

A

bind to opioid receptors and mimic the effect of endogenous opioids such as the endorphins

337
Q

what are the 4 opioid receptors?

A

mu, kappa, delta, NOP - orphan receptor

338
Q

what is the effect of opioids binding to opioid receptors?

A

Decreased opening of voltage-dependent Ca2+ channels
Increased K+ outflow
Decreased Ca2+ release from intracellular stores
Decreased exocytosis of transmitter vehicles

339
Q

what is the overall effect of opioid drugs binding to opioid receptors?

A

hyperpolarisation of neurones reducing the likelihood of firing, decreasing transmission of the pain signal

They also increase activity in the descending inhibitory pathways to reduce transmission of the pain signal at the level of the spinal cord

340
Q

what does anti-pyretic means?

A

reduces fever?

341
Q

what does anti-tussive mean?

A

dampen down the cough reflex

342
Q

what are the characteristics of paracetamol?

A

good analgesic and anti-pyretic

little anti-inflammatory effects

343
Q

what is the mechanism of action of paracetamol?

A

same as NSAIDs - blocks the breakdown of arachidonic acid to prostaglandins via inhibition of COX enzymes

344
Q

what is the difference between NSAIDs and paracetamol?

A

NSAIDs have strong peripheral effects (PNS) and anti-inflammatory effects

paracetamol works in the CNS and has no short term reduction in inflammation

345
Q

what are the 2 groups of drugs used to treat neuropathic pain?

A

tri-cyclic antidepressants

antiepileptics

both act to increase the inhibition of the pain pathways but in different ways

346
Q

what is the mechanism of action of Tri-cyclic antidepressants?

A

block the reuptake of both 5HT and noradrenaline
this increases the levels of 5HT and NA which increases the activity in the descending pathways which can block transmission

347
Q

how do anesthetics work?

A

block pain transmission from reaching consciousness

suppress consciousness through a reduction of activity within the CNS, with agents acting on both inhibitory (GABA) and excitatory (glutamate) pathways

348
Q

how do local anaesthetics work?

A

blocking voltage-gated sodium channels of neutrons to prevent action potentials from firing

enter through the cell membrane unionised and then become ionised in the intracellular space

349
Q

what are the features of epidural anaesthesia?

A

reduces pain but still allows the mother to respond to changes in pressure

concentration dependant
lidocaine - great anaesthesia
midazolam is a muscle relaxant and a good sedative

350
Q

what are some side effects of NSAIDs?

A

GI upset
heart burn
nausea
vomitting

351
Q

why do NSAIDs cause GI upset?

A

the blocking of COX-1 enzymes; they are responsible for homeostasis of the gut muscosa which leads to damage of the lining of the stomach and intestines

352
Q

what are used to counter-act the GI effects of NSAIDs?

A

proton-pump inhiibitors

353
Q

what is the most common indication of NSAID intoxication?

A

tinnitus

354
Q

what are common side effects of Opioids?

A

most side effects are due to dampening down of neuronal activity

constipation - peristalsis is slowed
nausea and vomiting 
conscious depression and mood alteration - dampening or cortical activity
respiratory depression 
miosis - pinpoint pupils
355
Q

how is opioid intoxication reversed?

A

opioid antagonist
> naloxone
> naltrexone

356
Q

what proportion of the population experience migraines?

A

10%

357
Q

what are the 5 types of headaches?

A 
tension
cluster
migraine
sinus 
medication overuse
358
Q

what are the 5 types of headaches?

A 
tension
cluster
migraine
sinus 
medication overuse
359
Q

what are the features of tension headaches?

A

associated with physical and mental tension
any changes to vasculature e.g., dehydration or stress may lead to vasospasm or increases in pressure that are felt as a headache

360
Q

what are features of migraines?

A

onset is preceded by warning symptoms or auras

normally unilateral with a focal point generally behind the eyes

361
Q

what are used to treat migraines?

A

NSAIDs and anti-emetics (anti-sickness)

opioids are ineffective and avoided

362
Q

What are cluster headaches?

A

Headaches with rapid onset and strong severity

associated with changes in the ANS

363
Q

What is the WHO analgesic ladder?

A

Strategy proposed in 1986 to provide adequate pain relief for cancer patients

364
Q

what percentage of patients foes the pain ladder reduce morbidity due to pain for?

A

70-80%

365
Q

why do we need a pain ladder?

A

to have adequate knowledge about pain
prescribe appropriate medications
balance optimum dosage with the side effects of the drug
avoid misuse
include opioid rotation - reduce addiction issues

366
Q

what are the stages of the original WHO ladder?

A

step 1: NSAIDs - ibuprofen
step 2: weak opioids - tramadol
step 3: strong opioids - morphine

367
Q

what are adjuvents?

A

used to increase the immune response/potency of another drug

368
Q

what are examples of adjuvents?

A

anti-depressants

diazepam

369
Q

what are the benefits of the new adaptation of the pain ladder?

A

non-pharmacological interventions and neurosurgical procedures added such as nerve blocks, spinal stimulators
move up and down the ladder - bidirectional
around the clock administration as opposed to on-demand

370
Q

what are steps in the new adaptation?

A
  1. NSAIDs
  2. weak opioids
  3. strong opioids
  4. nerve blocks, epidurals
371
Q

what are patients unaware of their prognosis more likely to do?

A

PREFER AGRESSIVE CARE

RECEIVE AGGRESSIVE CARE

HAVE A WORSE QOL

372
Q

what are patients unaware of their prognosis less likely to do?

A

complete advance directives
receive care consistent with their preferences
receive hospice services

373
Q

what is PiPs?

A

prognosticator tool under development

predict death?

374
Q

what is a social death?

A 
can occur before or after physical death
disconnection from social life
> loss of social identity
> loss of social connectedness 
> loss of moral entitlement 
...

less than human or no longer human

375
Q

what is the medical approach to palliative care?

A

focus on pain and symptom management
emphasises role of specialist doctors and a medical model for end of life care
location-centric provision e.g., hospitals or hospices - sequestration

376
Q

what is the holistic approach to palliative care?

A

concern for physical, personal, spiritual and psychological issues of patients and their families experience in relation to dying

diffuse needs will require multiple approaches to care and support

care is provided wherever its needed

377
Q

what is hyper-professionalisation of dying?

A

dying has become a medical event rather than a natural process in which medicine has a part

palliative care has been focused on increasing it’s professional capacity

378
Q

what is the social model of desirability?

A

people are disabled by the way society treats them - rather than the disease model

change the way we structure society and these disabilities wouldn’t exist

379
Q

what is the importance of the potato famine?

A

changed the health environment

380
Q

what is the significance of sickle cell anemia?

A

weaponised and used as something to fear

381
Q

How many migrants are there globally?

A

1 billion

382
Q

what is a migrant?

A

individuals who leave their legal place of origin and cross international boundaries

383
Q

who is a refugee?

A

people fleeing armed conflict or persecution

cross-national borders to seek safety in near-by borders

384
Q

what is the difference between migrants and refugees?

A

MIGRANTS CAN RETURN HOME IF THEY WIsh

385
Q

what are 4 types of migrant?

A

economic migrant
social migrant
political migrant
environmental migrant

386
Q

what are some pull factors for migration?

A 
better services
higher employment 
better education 
reunite with family 
safe society 
less crime
fetile land 
political stability
lower natural hazard risk
387
Q

what are some push services for migration

A 
lack of services
low employment 
lack of safety
high crime
crop failure
flooding
poverty
388
Q

name the 5 migratory phases?

A 
pre-departure 
travel 
interception
designation
return
389
Q

what are common communicable diseases for migrants and refugees?

A 
TB
skin infections\GI illness
food and water-borne diseases
HIV
Heptatitis
endemic diseases in host country
390
Q

what are common non-communicable diseases for migrants and refugees?

A 
CV, hypertension, T2D
psychological disorder
STDs 
drug abuse, alcoholism
exposure to violence
pregnancy and related complications
391
Q

what are the impacts of cold weather on displaced persons?

A

hypothermia - temp<35
frostbite
increased risk of fracture
severe bacterial and viral infections

392
Q

what are the impacts of hot weather on displaced persons?

A

dehydration and exhaustion
life-threatening heat stroke
worsen existing conditions such as CV and respiratory diseases

393
Q

What is the healthy immigrant paradox?

A 
better health than the native populatio 
new immigrants' health capital?
lower mortality rate
high life expectancy
lower incidence and mortality due to cancer
Perinatal health outcomes
394
Q

what is gene flow?

A

migration of genetic variation from a certain population to another

creates diversity in a genetic pool

395
Q

what is genetic drift?

A

alteration of the frequency of a specific allele because of the organisms random sampling

396
Q

what are two mechanisms that cause genetic drift?

A

bottle effect

founder effect

397
Q

describe the bottle effect - genetic drift

A

population experiences a catastrophe and so a trait’s allele frequency has decreased since many organisms carrying that trait have been eliminated

398
Q

describe the bottle effect - genetic drift

A

population experiences a catastrophe and so a trait’s allele frequency has decreased since many organisms carrying that trait have been eliminated

399
Q

describe the founder effect - genetic drift

A

few members separate from the main population and form their own

Causes a significant drift of allele frequency depending on the mating preferences of the newly formed group

400
Q

how does gene flow occur?

A

migration

401
Q

what percentage of the worlds populaiton reside in a nation different to where they were born?

A

2%

>200 million people

402
Q

what is the danger of population migration?

A

plays a critical role in the spread of disease by initiating outbreaks of acute diseases, changing the prevalence of infectious diseases at a given location, changing the face of chronic disease

403
Q

why are refugees at risk of falling sick in transition or staying in new countries?

A

poor living conditions
inadequate food and water
increased stress
lack of integration

404
Q

what are common infectious diseases of migrants at first arrival?

A

TB
Mites
Food/water-borne infection - typhoid, hep A, E
Malaria

405
Q

what should happen at migrants first arrival?

A

screening based on syndromic approach for early indication of most common communicable conditions asap

406
Q

what are the health priorities of migrants at arrival instead of infectious diseases?

A

traumatic, obstetric, psychological disorderrs

407
Q

what are the 2 main drivers of infection?

A

prevalence of a given infection in country of origin

marginalisation and vulnerability to poverty related disease

408
Q

what are the common diseases associated with Hajj pilgrimage?

A

yellow fever
meningitis
seasonal flu

409
Q

what are longer-term indirect impacts of armed conflict?

A 
social wellbeing
physical and psychological health 
education
economic activity
social cohesion and trust
410
Q

what are the economic impacts of armed conflict?

A

reverse economic development
society diverts some of its resources from productive activities to destruction
for an average developing country, military spending increases from 2.8% to 5%

411
Q

what are the economic impacts of war?

A

economic policies
destruction of community ties
destruction of rule of law

412
Q

what are the political impacts of human conflict?

A

could inspire higher political engagement and social participation

more violence enhances in-group norms and preferences and participation

rising social cohesion in conflicting societies might not promote peace - strengthening cleavages that divide society

413
Q

what are social impacts of armed conflict?

A

wars impact how we regard and treat each other
undermines trust within localities - decreases in willingness to engage in impersonal exchange and reinforces reliance in kinship groups
divisive nature of armed conflict - increased discrimination, defined groups

414
Q

what are public health impacts of armed conflict?

A 
negative effects on nearly all aspects of physical health 
stunted growth in children
resurgence of contagious diseases
domestic violence 
number of HCP drop 
availability of healthcare reduced 
PTSD
aggressive and violent behaviour 
food insecurity - malnourishement
415
Q

what is large scale migration?

A

large group of people move in close proximity over a relatively short period of time

416
Q

what are some maco drivers of migration?

A

political
demographic
socio-economic
environmental

417
Q

name some meso drivers of migration

A

communication technology

land grabbing

418
Q

name some micro drivers of migration

A

education
religion
marital status
personal attitude

419
Q

what are common problems caused by rural to urban migration

A 
rapid population growth
high unemployment 
conflicts between locals and migrants - social problems
shortage of facilities and services
influx nerver stops - few people leave
lack of services to meet demand
420
Q

what percentage of the world populaiton live in informal settlements?

A

~25%

421
Q

what are some causal factors of slums?

A 
poor infrastructure
social exclusion
economic stagnation
poverty - slums are only option
gangs
social conflict
natural disasters
422
Q

what are some characteristics of slums?

A

insecure tenure
outskirts of city
least desirable land
overcrowded

423
Q

what are countermeasures to slums?

A

slum removal
slum relocation
slum upgrade
public housing projects

424
Q

what are pull and push factors of rural to urban migration?

A

pull factors - attracted to urban life: better standrd of living, employment, better health…

push factors - dissastisfaction wiith rural living: poor living conditions, arrid land, lack of services, poor job prospects q

425
Q

how does urbanisation negatively affect health?

A

pollution
overcrowding
high prices - poor living, food, water, heating, insulation, repairs
crime and social deprivation

426
Q

what is a key determinant of access of migrasnts to health services in a country?

A

legal status

427
Q

what is the International Health Regulation of 2005?

A

all countries should have effective disease surveillance and report systems and capacity for outbreak investigation, case management and response

428
Q

what environmental factors are leading to human migration?

A 
increasing GHGs
flooding
drought
frequency of climate related disasters
sea levels rising
429
Q

what are the 3 stages of frost-bite?

A

early stage- frost nip
intermediate stage
advanced stage

430
Q

what is early stage frostbite?

A

frost nip

pins and needles sensation
throbbing, aching, skin becomes cold, nub, white
tingling sensation

431
Q

what is the intermediate stage of frost bite?

A

prolongued exposure to the cold
temperatures cause more tissue damage
affected area will feel hard and frozen
when out of cold and tissue has thawed, skin will turn red and blister
superficial - top layers of skin and tissues

432
Q

what is advanced stage frost bite?

A

exposure continues
frostbite increasingly severe
skin is white, blue or blotchy
damage occurs under skin to tendons, muscles, nerves and bones
deep frostbite - urgent medical attention
as skin thaws, blood filled blisters form and turn into black scabs- tissue necrosis

433
Q

how many children die each year due to poor sanitation and hygiene?

A

5000

434
Q

what is the risk of ambient air pollution?

A

INCREASES RISK OF PRETERM BIRTH
LOW BIRTH WEIIGHT
INFANT MORTALITY

INCREASED RISK OF LUNG CANCER OR HEART DISEASE

435
Q

What are some interventions to adress air pollution?

A 
speed limit changes
low emission zones
promote electirc car use
compulsory vehicle standards
fuel taxation industry regualtion e.g., emissions cap
436
Q

what are interventions to reudce household air pollution?

A

improved cookstoves
improved kitchen ventilation
clean fuels
ban on wood and coal burning in the home

437
Q

who are the key partners and stakeholders for WASH?

A

member states: national and local govenment agencies
practitioners: water suppliers, sanitation services, waste water mamngement services, management of water resources, HCPs
institutions for research and development: scientists organised in expert advisory panels, academia, research groups
q

438
Q

what comonent of blood in particular can significantly affect the rate of srug distribution?

A

albumin

439
Q

what is the volume of distribution of a drug and why is it important?

A

theoretical value derived from the ratio of a drugs concentration in plasma and its concentration in the rest of the body

volume of plasma necessary to account for the total amount of drug in the patients body

represents a specific drugs propensity to eother remain in the plasma or redistribute to other tissue compartments of the body

439
Q

what is the volume of distribution of a drug and why is it important?

A

theoretical value derived from the ratio of a drugs concentration in plasma and its concentration in the rest of the body

volume of plasma necessary to account for the total amount of drug in the patients body

represents a specific drugs propensity to eother remain in the plasma or redistribute to other tissue compartments of the body

440
Q

what is phase 1 drug metabolism?

A

phase 1 drug metabolic reactions normally introduce or expose chemcially reactive groups to a drug molecule.

oxidation, reduction, hydrolysis

modified drug molecules are usually more chemically reactive but usually pharmacologically less active

441
Q

what is a drug that can be activated by phase 1 reactions

A

codeine to morphine

442
Q

what types of enzymatic reactions normally occur in phase2 drug metabolism?

A

conjugation of polar, hydrophillic chemical groups to drug molecules via the chemically reactive groups introduced onto the drug stucture by phase 1 reactions

e.g., acetylation

443
Q

what is the key physiological functional outcome of phase 2 drug metabolic reactions?

A

increased drug solubility in water to enhance eliminaion

retained in the blood stream more effectively and more easily eliminated via filtration by the kidney

444
Q

why is it important to review medication use regularly in patients over 65?

A

chronic kidney disease and decline in renal function is common in the over 65s

445
Q

what influence can the understanding of drug half-life have on treatment strategy?

A

guide to the time it takes for the drug to be eliminated from the body

half life serves a guide to calcualting loading doses of a drug during treatment

446
Q

Indicate three common and important different types of molecule that can be targeted by drugs

A

ion channels - proton pump inhibitors - verapamil (L-type calcium channels)
transporters - serotonin reuptake transporter - sertraline
enzymes - COX-2 - IBUPROFEN

447
Q

what is an agonist?a

A

a molecule that binds to a specific receptor and activates/stimulates it

can be a drug or natural ligand fo a receptor

448
Q

what is a partial agonist?

A

type of agonist molecule that cannot elicit the same level off biological response as a full agonist

449
Q

what is an antagonist?

A

diminish or abolish the effect of an agonist (often a natural ligand) via interaction with its receptor (usually competitive or non-competiitve)

450
Q

what is a gene-environment interaction study?

A

the GxE interaction is defined as the differential of genotype response in connection to environmental variation

451
Q

what are the different types of interaction?

A

produce or increase the expression of a risk factor

genotype exacerbates the effect of the risk factor - no effect of the genotype in unexposed persons

exposure exacerbates the effect of the genotype - no effect of the exposure in perosns with the low risk genotype

both the exposure and genotype are required to increase the risk

452
Q

what are advantages of gene-envrionment interactions studies?

A

important implications for public health

aids predicting disease rates and provides a basis for well-informed recommendations for disease prevention

453
Q

what are disadvantages of gene-environment interaction studies?

A

Lack of replication/reproducability
Additive vs multiplicative model > doesnt conclide whether environmental effects are addiditve, multiplicative or interactive

454
Q

what are geneomic wide association studies?

A

approach that involves scanning biomarkers such as SNPs from the DNA of many people to find genetic variation, associatoin with a particular disease field phenotype….

455
Q

what is the basic methodology of genome wide association studies?

A

> to detemine if either allele at a given SNP is overrepresented in either cases or controls
cases: those with the disease of interest
controls: individuals without the disease of interest
SNs that show a stronger association than expected by chance are regarded as markers of candidate genes

456
Q

what is the basic methodology of GWAS?

A
  1. gather sample
  2. DNA sample
  3. hybridize DNA to array
  4. identify all genotypes
  5. impute additional SNPs
  6. perform statistical analysis
  7. interpret findings
457
Q

what counts as a signficant result? - SNP contributing to a trait

A

statisitically significant if the value is below the p value of 0.05

very significant if below 5x10^-8

GOLD STANDARD: p<5x10^-8 with replication

458
Q

what are advantages of GWAS?

A

very succesful in identifying novel varient trait associations
can lead to the discovery of novel biological mechanisms
translating biological insights into medical advancements

459
Q

what are disadvantages of GWAS?

A

dont necessarily pinpoint causal varients and genes
cannot identify all genetic determinents of complex traits
limited clinical predicitive value

460
Q

what is precision medicine?

A

not a one size fits all approach
takes into account individual variability in genes, environment and lifestyle
allows more accurate prediction about the treatment and prevention strategies for a particular disease for a particualr group of people

461
Q

potential advantages of precision medicine

A

wider availabiltity of doctors to use patients genetic snd other molcular information as part of routine medical care

improved ability to predict which treatments will work best for speciric patients

better understanding of the underlying mechanisms by which various diseases occur

462
Q

what are some commercial challenges of preicison medicine?

A

manufacturers often charge large amounts of money for their products, like orphan medicines e.g., for rarrer diseases and some cancers

463
Q

What is a diagnostic biomarker?

A

detect or confirm the presence of a disease or condition of interest

464
Q

what is a predicitve biomarker?

A

identifty individuals who are more likley to experience a favourable or unfavourable effect to a drug

465
Q

what is a prognostic biomarker?

A

used to identify liklihood of a clinical event or disease progression in patients who have the disease or medical condition of interest

466
Q

what is discordant risk randomisation design?

A

looks at biomarker and clinical risk and if they align its a concordant risk on a spectrum of high to low

if the risks don’t align then its discordant risk - this is used in uiltiy design - two experimental arrms

467
Q

what is intermediate risk randomisation design?

A

patients cateogrised into risk categories based on their biomakers (low, intermediate, high)

intermediate group is then used in study designs

468
Q

what is a randomise all design?

A

patients are randomised to standard care or experimental arm

within each arm, patients are strateifed as the whether they are biomarrker positive or not

469
Q

what is interaction (biomarker-stratified) design

A

stratify groups according to biomarkers and then randomise into standard care and experimental arm

YEAR 2 (3 decks)

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