Mechanisms of Disease Flashcards
(215 cards)
1
Q
Sensitivity
A
True +ve rate proportion of the people that have the disease test +ve. Ie this is the ability to detect everyone who has the disease
2
Q
Sensitivity formula
A
TP
TP + FN
3
Q
Specificity
A
True -ve rate proportion of people who don’t have the disease test -ve. Ie this is the ability to distinguish who has the disease
4
Q
Specificity formula
A
TN
TN + FP
5
Q
False +ve and false -ve
A
False +ve is a person identified by the test to have the disease who is infarct normal
False -ve disease sufferers who are missed by the test
6
Q
D-dimer
A
Breakdown product of fibrin from blood clot useful in diagnosis of PE. High sensitivity i.e. everyone with a PE will have a raised d-dimer. Low specificity many other causes of raised d-dimer.
7
Q
Positive predictive value
A
TP
TP + FP
8
Q
Negative predictive value
A
TN
TN + FN
9
Q
Positive likelihood ratio
A
Sensitivity
1-Specificity
Values > 1 imply the test is useful
10
Q
Negative likelihood ratio
A
1-Sensitivity
Specificity
Values <1 imply the test is useful
Likelihood that test will be negative in somebody with the disease compared to someone who is healthy
11
Q
ROC curve
A
Slope = likelihood ratio
Area underneath = power of the test
12
Q
Pregnancy and developing breasts
A
200x increased risk of cancer
13
Q
Plain films
A
+ve - quick accessible, great for bones
-ve - only 2D representation, pt factors i.e. inspiration, posture
14
Q
CT
A
+ve - quick accessible, mass data, useful for blood supply using radioactive contrast
-ve - contrast can be nephrotoxic be aware if using in renal impairment, high doses of radiation beware in pregnancy and children
15
Q
USS
A
+ve - quick, safe, no radiation, by the bedside, used to guide interventional procedures
-ve - difficulty to interpret, operator dependent, struggles to be used on obese people
16
Q
MRI
A
+ve specific for soft tissue, very good for spinal, no radiation
-ve CI metal!!, slow take approx 30mins, pt needs to be still, very claustrophobic
17
Q
CURB 65
A
Confusion (AMTS<8) Urea < 7mmol Resp rate >30 BP <90/6 65+
18
Q
Bilateral consolidation CXR
A
Consider legionella. May have neutropenia, lymphopenia, dry cough. Test for antigen in urine
Mx = ciprofloxacin
19
Q
Air bronchogram
A
Air filled bronchi (dark) are made visable due to opacification of the alveoli. Caused by pathological process where either fluid, pus or blood fills the alveoli
Causes = pneumonia, pulmonary oedema, bronchcarcioma, ILD, pulmonary haemorraghe
20
Q
Cryptogenic organsising pneumonia (COP)
A
PC - similar to infectious pneumonia, fever, wt loss, fatigue, chest pain and SOB often over the course of severe months
CXR resembles consolidation, very hard to distinguish from pneumonia. Classically unilateral or bilateral patchy areas. -ve culture! increased CRP or ESR
Mx - steroids!
21
Q
Lights criteria for pleural effusions
A
Exudate = protein >35g/L, pleural protein: serum protein >0.5, pleural LDH: serum LDH >0.6
Causes - infection, malignancy,inflammatory - SLE, RA
Transudate protein <30g/L causes = cirrhosis,HF, renal failure, hypothyroidism, Meigs
22
Q
CT head interpretation
A
Acute bleed = white, Hypodense areas often develop over time sign of infarction
Examine cisterns carefully for blood. Look for midline shift of the cortex
23
Q
NG tubes
A
Should sit in the stomach to provide nutrition is incorrectly placed may = aspiration pneumonia.
Must pass straight down past the corina
24
Q
ET tube
A
Catheter inserted into the trachea to establish and maintain a patent airway. Needs to sit approximately 1-2cm above the corona to equally ventilate both lungs. If poorly placed can lead to collapse of contralateral lung and improper ventilation
25
Karyotyping
Looks at whole chromosomes for aneuploidy, translocations, ring chromosomes and mass deletions
- Easy to identify trisomys
26
FISH
Detects sections of chromosomes that are abnormal. Uses flourescent probes to look for specific mutations in DNA. Need to know what you're looking for
- Williams, Prader-willi etc
27
Whole exome sequencing
This can be used to look for single nucleotide changes, they offer huge scope to look for cancer driver, single gene mutation
Huge number of polymorphism which never manifest a phenotype, heterogeneity is a problem. Huge amount of data!
28
VUS
Variant of uncertain of significance presents problems. This is due to limited data and unreported information there is uncertainty between normal and mutation
This a problem if a persons phenotype is borderline but the genetic test gives a result of VUS or normal. This shows either the diagnosis based on the phenotype is wrong or even worse is that the test has not confirmed anything!
29
Precision
Repeatability of a measurement
30
Accuracy
How close the result is to the actual value.
31
Systematic error
Determined by the calibration and specificity
32
Marfans
AD genetic connective tissue disorder. PC scoliosis, high arched palate, sclerodactyl, tall, pectus cavatum or excavatum, flexible joints. Aortic root dissection, ectopic lentil, mitral valve prolapse, spontaneous pneumothorax
Mutation @ cr15 FBN1 preventing fibrillin 1 needed to maintain elastic and extracellular matrix
Mx - surveillance via yearly echo +/- elective surgery
B-blocker or ARBs to reduce aortic load
33
Cytology
Study of structure, function and chemistry of cells - doesn't look at specific architecture
- Ascites/pleural fluid, CSF, peritoneal washing, fine needle aspirate, cervical screening programme
34
Histology
Needs a biopsy or piece of tissue, examines the morphology and architecture of the specimen
35
When does a death need reporting to the coroner
Unknown causes of death
Violent or sudden unexplained death
No medical certificate
Person hasn't been seen in 14days or not visited by a medical practitioner during illness
Asbestos exposure
Death during anaesthesia from surgery before they woke up
36
GCS
Eyes /4 - spontaneous(4), to speech (3), to pain(2), no response (1)
Verbal /5
Motor /6
37
GCS
Eyes /4 - spontaneous(4), to speech (3), to pain(2), no response (1)
Verbal /5 - orientated (5), confused (4), inappropriate words(3), incomprehensible sounds(2), no response(1)
Motor /6 obeys commands(6), moves localised to pain(5), flexion withdrawal(4), decorticate flexion(3), decorticate extension(2), no response(1)
38
Hospital autopsy
Interest from clinician to aid research. Consent required through next of kin
39
Coroner autopsy
Consent not required. Aims to determine how a person died and whether a legal investigation into the cause of death is needed
40
Lactate in sepsis
High values indicate a poor prognosis esp if pt fails to respond to fluids. Lactate levels increase due to increased production by macrophages, reduced clearance, action of adrenaline on B2 adrenoreceptors on Na+/K+/ATPase
41
Acute respiratory distress syndrome (ARDS)
Acute diffuse inflammatory lung injury eating to increased pulmonary vascular permeability and loss of aerated lung tissue with hypoxemia and bilateral radiographic opacities.
42
Pathophysiology of ARDS
Widespread inflammation triggered by trauma, sepsis, pancreatitis. TNFa produced by alveolar macrophages, recruits neutrophils leading to release of free radicals and cytokines. This mass inflammation leads to aveolar infiltration, pulmonary oedema, reduced surfactant produced gives a higher chance of airway collapse. This overall leads to reduced gas exchange and ventilation
43
PC ARDS
Severe life threatening disorder, RF = SOB and hypoexmia. Crucially it is acute, no HF cause, CXR shows bilateral opacities
Mx = ventilation and +ve pressure
44
Adrenaline CPR
1:10000 1mg 10ml IV
45
Adrenaline anaphylaxis
1:1000 0.5mL IM
46
Mx anaphylaxis
0.5mL 1:1000 IM adrenaline
| 200mg IV hydrocortisone and 10mg IV chlorophemaine
47
Mx post anaphylaxis
2x epipens with 18month sell by date, patient and adult education how and when to use
Ring 999 stat if happens
Check trypase 1-6hrs post attack. This is released along with histamine from mast cells during an attack
48
Why check trypase
Helps confirm the diagnosis of anaphylaxis. Can be used to rule out the diagnosis of mastocytosis
49
Type I hypersensitivity
IgE mediated fast response occurs in minutes. 1st contact leads to IgE antibodies being produced from B cells and priming mast cells. On 2nd contact mass degranulation and histamine release
50
Type II
IgM and IgG mediated antibodies against cell surface antigens trigger destruction via complement and phagocytosis
51
Type III
Immune complex deposition
52
Signs of PE on ECG
Sinus tachycardia, S1Q3T3, RH strain shown be axis deviation or T wave inversion, RBBB, P pulmonale (peaked p wave)
53
Investigating PE in pregnancy
USS of both legs if +ve for clot no further investigation needed
If CXR normal = V/Q if abnormal = CTPA
CTPA = radiation dose gives increased risk of breast cancer in future life. Avoid if FHx of breast cancer
V/Q = lower risk of maternal breast cancer, increased risk of childhood cancer
Very hard decision especially if IVF, recurrence miscarriage, 1st pregnancy
54
Infants under 6months post UTI
USS during infection if recurrent, resistant to treatment or atypical organism
USS 6 weeks post UTI to check for structural damage
DMSA and MCUG 4-6months post UTI if atypical organisms, resistant to treatment or recurrent
55
CSF results bacterial meningitis
Cloudy, high WCC (polymorphs), low glucose (below 50%), high protein
56
TB/fungal meningitis
Turbid, mixed WCC mixed polymorphs and lymphocytic, protein >1.5, glucose <50%
57
Viral meningitis
Clear, high lymphocytes, normal glucose, normal protein
58
Assessing capacity
Understand, retain, use and weigh up their choice, communicate their decision
Capacity can fluctuate with time
59
ESR
Erthyrocyte sedimentation rate distance RBC fall after 1hr
Age (+10 if female)
2
High sensitivity low specificity = chronic inflammation, vasculitis, infection, malignancy
60
Spinal cord compression
10% of pt with prostate, lung, breast, thyroid, renal or myeloma develop this. Crucial to act quickly otherwise paralysis will result
PC = severe back pain often precedes neurology
inability to pass urine or defecate. UMN symptoms numbness and weakness in legs, fast reflexes and hypertonia. Upgoing planters
MRI - needed to comfirm diagnosis and rule out abcess, disc prolapse, haematoma or fracture
Mx 10mg IV dexamethasone stat + PPI for gastric cover
- radiotherapy or surgery to treat
61
Cauda equina
Compression of the spinal cord below L1. LMN signs due to bilateral innervation of long sacral nerve
Loss of sacral sensation, poor anal tone = bad sign, flaccid tone, slow reflects
62
UMN vs LMN signs
UMN - hypertonia, hyperreflexia, spastic, babinski +ve
LMN - hypotonia, hyporreflexia, fasciculations and wasting
63
Normocytic anaemia
Reticulocytes <2% = leukaemia and aplastic anaemia
| Reticulocytes >2% = haemolytic anemia, renal disease, haemorrhage
64
Preventing acute coagulopathy
Transexemic acid, ensure maintaining body temperature and ionised Ca2+, Aim for BP >90 maintain with vasopressors if needed
65
Triggers for a trauma call
Significant bleeding, cardiac arrest, GCS <14, airway compromise, paralysis, pelvic #, multiple victim, mechanism of injury
66
Traumatic bleeding
Self perpetuating triangle of acidosis, hypothermia and coagulopathy. Hypothermia decreases the efficacy of platelets which leads to a coagulopathy, the coagulopathy leads to raised lactate levels which in turn causes an acidosis which leads to hypo perfusion, hypotension and vasoconstriction. This leads to lower volume of circulation blood = hypothermia
67
Pathophysiology of major bleeding
Loss of circulating blood volume means MAP falls, this leads to low BP and hence reduced oxygen delivery to tissues. Baroreceptors detect this fall activating the sympathetic nervous system to vasoconstrict the arteriole and via adrenaline acts as an iontrope. Mass cortisol and adrenaline release to maintain HR. Reduced renal perfusion leads to RAS activation in an attempt to retain Na+ and H20 to increase circulation volume
68
Signs of brain injury
Brainstem herniation - CN III palsy, hyperventilation, lower extremities rigidity, dilated pupils
Increasing ICP = low GCS, projectile vominting, seizures, Cushings reflex - with increasing ICP high BP with a relative bradycardia indicated imminent herniation
69
Management of increased ICP
Remove the mass lesion - i.e. haematoma,
Reduce CSF volume via drainage
Reduced brain parenchymal volume via osmotic therapy with mannitol
Reduce cerebral blood flow
- venous = head up, avoid jugular compression
- arterial = sedation, CPP monitoring, avoid fever and ventilate
Last ditch = decompression with removal of bone flap, hypothermia, hyperventilate aiming for C02 4.5-5.5
70
Cerebral perfusion pressure
CPP = MAP - ICP
The brain maintains CPP over a huge range of blood pressure by dilation and constriction of its own vessels. CCP needs to be around 60-70mmHg. As the pressure inside the cranium increases the ventricles compress, CSF shifts into the spinal reservoirs. The increasing pressure due to oedema and swelling leads to compression of the cerebral vasculature.
71
Sepsis Red Flags
RR >25, SBP <90,
| Lactate >2, HR >130, reduced GCS
72
Problems in ICU
DVT/PE - difficult to identify signs and symptoms of PE if pt is ventilated. Risk for trauma pt due to endothelial damage, coagulopathy from inflammation, immobility, often surgery and stress response from extreme injury
AKI - Hypoperfusion, constrast, drugs
GI bleed - stress ulcers, ventilation 48hrs+ esp those on steroids etc. Protect with PPI's
Pressure ulcers - poor nutrition and skin integrity, need 2hrly turning and mobilisation asap
73
Ventilator associated pnuemonia
Often severely immunocompromised >72hrs from admission. Staph aureus.
74
Psychological problems ICU
80% pt suffer from delirium. Treat triggers ensure well hydrated, not constipated, ween opioids we possible, minimal sleep disturbance and sensory input
20% have PTSD post ICU stay often with delusional memories to fill in the gaps
75
Drivers of overdiagnosis
Technology = incidental findings on scans, patient pressure groups, poor evidence based practise, new interventions and politics!
76
1st line of defence
Intrinsic epithelial barrier. Strong tight junctions and cilia to waft pathogens out of the lungs. Normal commensal gut flora that outcompete bacteria using resources. Strong stomach acid kills most bacteria ingested
77
Innate immune system
Activated when foreign pathogen breaches the skin. Consists of macrophages, dendritic cells and NK. No specific includes cellular and chemical response leading to acute inflammatory reaction
78
Granulocytes
Neutrophils - simple killer cells attracted by TNFa and receptive to complement
Eosinophils - Respond to allergens very receptive to IgE, will kill IgE coated pathogens
79
Monocytes (Macrophages)
Monocytes become macrophages when they exit the bloodstream and arrive at their target tissue. Crucially this is when they differentiate and express CD14
80
Macrophages MOA
Senitel cells that live under the epithelium. Once barriers are broken they are unregulated by the release of IFNg leading to increase MHC II expression, They act as APC, by recognising PAMPs on the surface of the foreign antigens binding with PRR. They phagocytose pathogens and via a lysomsome containing reactive oxygen species destroy them.
81
Macrophages secrete
IL-1, IL-6, IL12, TNFa = major pro inflammatory cytokines
82
Proinflammatory cytokines
IL-1 = activates vascular endothelium and lymphocytes
IL-6 = increased antibody production, lymphocyte activation and fever!!
IL-8 = Neutrophil chemotaxis!!
IL-12 = Activates NK cells and TH1
TNFa = Increased vascular permeability and lymph drainage, increased complement and IgG levels
IL4/5 = promote IgE production and eosinophilic reactions
83
NK cells
Large granular lymphocytes that produce IFNg activating macrophages. Macrophages produce TNFa and IL-12 which activate and perpetuate the NK response
They target viral/malignant cells with dysfunctional or absent MHC I and induce apoptosis via toxic granules
84
MCH I
Expressed on all bodily tissues allowing the immune system to recognise self from non-self
85
Complement
Classical pathway = antigen-antibody complexes
Lectin = Activated when mannose binding lectin binds to the carbohydrate mannose molecule on pathogens surface
Alternative = C3 directly on pathogen surfaces
Crucially all 3 pathways produce C3 convertase which cleaves C3 into C3a and C3b activating the rest of the cascade
86
Actions of complement
C3a, C4a and C5a potentiate the inflammatory response, they also trigger mast cell degranulation and histamine release
C3b acts to opsonise pathogen binding antibodies to their surface this forms immune complex and facilitates their removal to the spleen
C5b imitates the membrane attack complex (MAC) leading to osmotic lysis of the cell
87
Features of the inflammatory response
Vasodilation and increased blood flow
Increased vascular permeability – this allows an inflammatory cell infiltrate to extravasate and reach the site of infection - oedema
Release of inflammatory mediators such as bradykinins and prostaglandins which increase pain sensitivity and cause hyperalgesia
Neutrophil chemotaxis – neutrophils migrate to the site of infection and begin their clean-up operation, phagocytosing pathogens and debris
Microvascular coagulation – this is induced by local tissue damage, and acts to confine the infection and prevent its spread
Systemic features such as fever and raised inflammatory markers such as CRP and ferritin – this produces unpleasant “flu-like” symptoms such as hot flushes, sweats, chills, rigors, headache, nausea, myalgia, arthralgia and fatigue.
Upregulation of costimulatory molecules such as MHC-II and B7 to encourage activation of the adaptive immune system
88
Antigen presentation
Dendritic cells are crucial to this process. They are sentinels like macrophages and are activated by IFNg or PRR stimulation. Once they have phagocytose a pathogen they up regulate MHC II, B7 costimulator molecules and migrate to the lymph nodes where they await to be sampled by a passing T cell with a complementary PRR (Toll like receptor)
89
T cell activation
The T cells TLR binds to the MHC II expressing the antigen. To be activated it needs another signal from a costimulatory molecule. In a state of systemic inflammation B7 molecules are abundent and provide the 2nd stimulatory signal binding to CD28 receptors on the T cell.
90
Th1 vs Th2
Th1 presence of IL-12 and IFNg
Th2 presence of IL-4
91
Plasma cells
Factories for antibodies. Antibodies are specific to antigens and allow neutralisation of toxins, opsonisation of pathogens and activate complement
92
Specific antibodies
IgA - High levels in mucosal secretions
IgG - High levels in the blood, cross the placenta
IgE - secreted by mast cells to trigger immune response to allergens
IgM - default antibody
IgD - Low levels in the serum interacts with mast cells and basophils
93
Antibody structure
2 x heavy chains which dictates the class of antibody. initially they express IgM but can undergo class switching
2 x light chains
Both chains have variable and constant regions. The variable regions are specific to each antibody and allow it to confer antigen specificity. VDJ recombination of protein sections of the variable regions of the chains. Undergo affinity maturation
94
Autoimmunity
Loss of discrimination between self and non-self. Tolerance is maintained both centrally and peripherally. The process perpetuates leading to more damage. Only treatment is to immunosupress
95
Central tolerance
Occurs during lymphocyte development for T cells = thymus and B cell = BM. Involves deleting auto reactive lymphocytes before they develop into immunocompetent cells. The are exposed to self antigen produced by thyme epithelial cells or dendritic cells. T cells that bind strongly to self antigen are deleted (-ve selection) and weakly binding T cells mature in to Treg. T cells that pass this section process pass into the periphery
96
Peripheral tolerance
Tregs and tolerogenic dendritic cells dispose of self reactive cells which often lack CD40 and express low levels of MCH I
97
Autoreactivity
Presence of immune response of reacting with self antigen
98
AIRE
Non expression of self antigen leads to failure of central tolerance. AIRE is a gene that transcribes medullary thymus epithelial cells.
PC - polyendocrinopathy, chronic mucosal candidiasis, hypoparathyroidism and 1 adrenal failure
99
IPEX
Failure of peripheral tolerance due to Treg failure from a mutation in FOXP3
PC - psoriatic dermatitis, bullous pemphigoid, hypothyroidism, lymphadenopathy, AI endocrinopathy
100
Type I hypersensitivity
Reproductible symptoms and signs initiated by exposure to a defined stimulus at a dose tolerated by a normal person. Often food -nuts, dust, drugs, animal fur
101
PC Type I
Rhinoconjuctivitis, asthma and urticaria = atopy
Angioedema in severe cases - anaphylaxis
Bronchostriction and increased mucus secretion = SOB, chest tightness, wheeze and stridor
Vasodilation and increased permeability = oedema, tachycardia, hypotension and arrest
Increased peristalsis = N/V, abdo pain and diarrhoea
102
Pathology of Type I
Mediated by IgE.
1st contact leads to phagocytosis of allergen by APC, this expresses the allergens antigen on its surface and migrates to the lymph node to present to T cells. Differentiation to Th2 allowing activation of B cells and production of IgE. This binds to mast cells and sensitise them.
2nd contact = IgE crosslinking leads to mass mast cell degranulation and excessive histamine release
103
Emergency Mx of anaphylaxis
PC = life threatening rapid breathlessness, swelling with skin and mucosal changes
Crucial to remove trigger esp if drip
IM adrenaline 1:1000 0.5ml, IV hydrocortisone 200mg, chloramphine 10mg
104
Inv of anaphylaxis
Skin prick testing for allergens
IgE allergen testing
Patch testing
105
Type II hypersensitivity
Antibody mediated cytotoxic reactions involving IgM and IgG against cell surface or extracellular matrix antigens. Leads to opsonisation and phagocytosis via complement mediated recruitment of leukocytes and MAC
Eg Goodpastures, hamolytic anemia
106
Goodpastures (anti-GBM)
Antiglomerular basement membrane antibodies against type IV collagen leads to systemic effects @ alveolar and glomerular basement membranes
BM = protein collagen base that is crucial to anchor epithelial cells. IgG antibodies activate the complement cascade by binding to the a3 collagen helix, chemokine attract neutrophils which destroy the BM
107
PC Goodpastures
Malaise, fever, wt loss and fatigue
Lungs - cough, progressive SOB, haemoptysis due to pulmonary haemorrhage
Kidney - nephritic syndrome (haematuria and low level proteinuria), HTN and uraemia
Inv = anti GBM antibodies
biopsy - crescentic GN
Mx = corticosteriods, plasmapherisis
108
Type III hypersensitivity
Immune complex mediated deposition
| Eg - SLE, RA, GN
109
Mechanism of Type III
IgG antibodies specific for DNA and nucleoproteins. Mass production of antibody by B cells. Small complexes are immunogenic and often missed by the macrophages, they deposit in the BM leading to an inflammatory response attracting neutrophils and cytokines in an effort to phagocytose the complex. The neutrophils degranulate releasing enzymes causing further inflammation.
110
PC SLE
Oral ulceration, discoid rash, photosensitive malaria rash, oligoarthritis symmetrical, fever, wt loss, Raynauds
Serositis - pericarditis, peritonitis and pleurisy
Lupus nephritis = RPGN
Anaemia, leukopenia and thrombocytopenia
Invx = ANA 95% (low specificity), antidsDNA = SLE!
111
Type IV hypersensitivity
T cell mediated, Th1 cells secreted cytokines which activate macrophages and cytotoxic T cells
Eg - contact dermatitis, T1DM, MS
112
Spectrophotometry
Reaction produces or consumes a substance absorbing UV or visible light at a certain wavelength
```
+ve = fast, cheap and full automated
-ve = haemolyis, icterus and lipidemia can ruin samples and lead to interference
```
Used for LFTs, urea, CK, lipid profiles, Ca2+, Mg2+
Mass spectrometry can be used to identify specific molecular fragmentation patterns
113
Immunoassays
Used to measure the presence or concentration of a macromolecule in solution via antibodies. These bind to specific parts of target antigen and are flourescently labelled. The solution is subsequently washed off and only the bound complexes remain
+ve = high sensitivity, can be used for many analyses - e.g. TFTs, PSA, hepatitis serology, troponin T, BNP
-ve = cross reactivity, often hahahah to be done manually hence can be expensive
114
Monoclonal vs polyclonal immunoassays
Monoclonal = single antibody, specific epitope, high cost but very specific
Polyclonal = Isolated from animals mixture of antibodies, cheap, higher affinity but loads of variability
115
ELISA
Uses antibodies to detect hep B, HIV, rotavirus in stool. Conformational colour change
116
Competitive and sandwich assays
Sandwich assay = signal produced is directly proportional to amount of analyte
Competitive assay = signal produced is inversely proportional to amount of assay
117
Immunohistochemistry
Imaging for antigen in a tissue specimen. Widely used for detecting abnormal cells found in cancerous tumours. ER, PR, PSA, CD-20 for B cell lymphoma
118
Humeral immunity (Th2)
Naive T cells differentiate under the influence of Il-2 and IFNg to Th2. B cells circulating in the lymph bind to their corresponding T cell presenting the antigen on MHC II. A second signal from CD40 molecules allows activation. The Th2 produces IL-4, Il-5 and Il-2 cytokines which promote B cell proliferation
B cells migrate to the medullary cord in the BM forming a germinal centre. They transform into plasma cells which mass produce IgM antibodies, class switching of antibodies occurs to provide cover in different areas followed by somatic hypermutation and affinity maturation
The most well developed antibodies formed from affinity maturation will survive to become memory cells
119
Cell mediated immunity
Specific adaptive response directed by Th1 cells producing cytotoxic CD8 t cells designed to fight intracellular viral and protozoans
120
T cell maturation
Only undergo VDJ recombination
121
T cells and APC
Once T cells leave the thymus they encounter APC. They bind via MHC II presenting the antigen. A co-stimulatory CD40 molecule is also required. This interaction leads to the production of IFNg which allows macrophages to increase their production of free radical and superoxide ions increasing their killing power
122
Activation of CD8 cytotoxic
The APC expressing the pathogens antigen on its MCH I receptor bind to the complementry TCR receptor on a cytotoxic T cells. CD28 and B7 co stimulatory molecules are present. The actions of Il-2 a potent T cell growth factor produced by Th0 cells helps potentiate the process of activating the T cells
123
Activate CD8 cytotoxic T cells
The recognise specific antigens the cell infected with the foreign pathogens displays on its MHC I and destroy the cell through several mechanisms
- Fas ligand interactions lead to the activation of the death induced signalling complex
- Form an immunological synapse releasing perforin which via granzymes and granulysin lead to apoptosis and DNA fragmentation
IFNg release which prevents viral replication without destroying the cell and leading to release of large numbers of viral
124
Cessation of the immune response
Intrinsic cell death - failure of survival signals leads to mitchochondria swelling and releasing cytochrome c activating caspase and cleaving DNA
Extrinsic = activation of death receptors
125
Immunodeficiency
A failure to achieve immune function to provide efficient self listed host defence against the biotic and abiotic environment while preserving tolerance to self
126
Primary immunodeficiency
Consist of mendelian treats conferring predisposition not multiple infectious diseases nature of which depends on the severity of the disorder. Present from birth
127
Secondary immunodeficiency
```
These are acquired and can present at any age. Some are reversible others aren't.
Malnutrition
HIV - AIDS
Chemo and radiotherapy
Malignancy - BM invasion
Myelodysplasic syndromes
Chronic infections
Post splenectomy
```
128
Congenital antibody deficiency
X-linked and AR hypogammaglobulinemia. PC often 6-9 months after birth due to circulating maternal antibodies protecting child for 1st few months of life. Recurrent infections with strep pneumonia, mycoplasma and Hib
Mx - monthly IV immunoglobulins
129
Acquired antibody deficiency
Protein losing states i.e. nephrotic syndrome, anti CD20 drugs such as rituximab
130
Congenital complement defiency
Recurrent pyogenic infections strep and Hib most common as polysaccharide coat needs to be opsonised before removal. C5-C9 deficiency susceptible to nessieria.
Mx - vaccination and replacement
131
Extracellular clearance
Complement, Ab and neutrophils
132
Acquired complement deficiency
Chronic infections and SLE
133
Congenital neutrophil deficiency
Failure to make neutrophils = HAX-1, ELA-2, WAS
Failure to migrate = leukocyte adhesion deficiency I-III
PC = chronic granulomatous infections, deep abcesses, suppurative lymph adenitis
134
Mx for neutrophil, antibody and complement deficiency
Abx and anti fungal prophylaxis, replacement IgG, set cell transplant
135
T cell deficiency
T cells are required to clear intracellular pathogens such as viral, protozoal and some bacterial
Listeria, HSV, EBV, mycobacterium, pneumocystiis jiroveci
136
Primary and secondary T cell deficiency
Primary
- Complete = SCID
- Partial = wiskott aldrich, di-george, ataxia telengestasia
Secondary = AIDS, chemo/radiotherapy, lymphoma
137
Severe combined immunodeficiency disorder
Complete T and B cell failure often fatal by 1y/o.
PC = FTT, persistent viral and gut infections, impaired cytokine signalling, VDJ recombination
BM transplant is the only treatment
138
Wiskott Aldrich syndrome
AR disease classically seen with eczema, thrombocytopenia, immune deficiency and bloody diarrhoea (secondary to the thrombocytopenia). WASp gene
139
Di george syndrome
22q11.2 deletion poor T cell mediated response due to congenital absence of a thymus
PC = cleft palate, cardiac abnormalities - TOF
hypocalcaemia due to hypoparathyroidism, learning disorders
140
Mx T cell deficiency
Fungal and Ab prophylaxis, vaccines, stem cell transplant
141
AI lymphoproliferative syndrome
Defect in apoptosis means the body is unable to clear T and B cells which were activated to clear infection. This leads to accumulation in the spleen, liver and lymphatic system. Due to defects in FAS and FAS ligand
PC = lymphadenopathy and hepatosplenomegaly, increased risk of lymphomas, Linked to AI haemolytic anaemia, neutropenia and thrombocytopenia
142
Hereditary periodic fever syndrome
Mendelian disorder featuring episodes of fever and serial or synovial inflammation that last <72hrs
AR - PAPA, familial mediterranean
AD - TNF receptor 1-associated fever
143
Haemophagocytic lymphohistiocytosis
Life threatening uncontrolled proliferation of lymphocytes and macrophages leading to a cytokine storm
PC = fever, splenomegaly
cytopenia of 2/3 cell lineages
No evidence of malignancy on biopsy
144
Hyper acute rejection
Within 48hrs. Often happens within minutes due to pre-formed antibodies alloantigens against group ABO or non self HLA. This leads to mass activation of complement and coagulation cascade. Thrombosis and occlusion of blood vessels occur leading to organ death
Surgery to remove needed
145
Acute cellular rejection
Type IV hypersensitivity usually within weeks to months
i) Acute cellular = T cell mediated leading to leukocytic infiltration of the organ
ii) Acute humoral = Antibody mediated . cases are increasing due to anti T cell drugs preventing case of acute cellular rejection
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PC acute rejection
Graft tenderness, fever. If renal may = gradually increasing creatinine levels
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Chronic rejection
This occurs in every transplant organ the time scale can differ from months to years. Secondary to endothelial damage gradual thickening and fibrosis of the grafts blood vessels. Concentric arteriosclerosis and intimal fibrosis. Alloreactive T cells produce CCLS attracting macrophages via IL-1 and TNFa
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Direct alloantigen presentation
Donor APC from transplant migrates to lymph nodes, recipient T cells with corresponding TCR recognise the donors MHC I/II and with a costimulatory signal migrates to the graft and attacks via a direct cytotoxic response
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Indirect alloantigen presentation
Recipient APC processes peptides from inflamed/dead cells. The APC presents the peptides via MCH I to T cells in the lymph nodes. This differentiates and attacks the graft
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Avoiding rejection
ABO and HLA matching to prevent hyper acute rejection
Immunosuppression
- Steroids
- Calcineurin inhibitors = Tacrolimus and cyclosporin
If pre-existing Ab plasmapheresis and rituximab (anti CD20)
- Anti-proliferatives = MMF and azathioprine
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Balance of immunosuppresion
Too much = death from infection
| Too little = organ rejection
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GvHD
Graft contains immunologically competent cells, the host appears foreign to the graft. It has alloantigens that can stimulate the graft. This leads to the graft attacking the host. Crucially the graft has to be from an immunologically different donor and the recipient is immunocompromised.
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High risk for GvHD
Solid organ transplants - Liver
Allogenic haematopoetic stem cell transplant
Transfusion of unirradiated products
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Pathogenesis of GvHD
Damage to host tissues leads to mass cytokine production, APC recognise the host Ag and present it to the donor T cells. The T cell is activated and induces NK and neutrophils to attack the hosts tissue. This inflammation potentiates the response.
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Acute GvHD
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Hepatic = asymptomatic rise in bilirubin, AST and ALT
GI = Anorexia, dyspepsia, diarrhoea and intestinal bleeding
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Dermatological = painful erythematous macule on soles, palms and trunk. Confluent with erythema, sub epidermal bullae and vesicles
- Staged 1-4 based on % skin involvement and vesicle presence
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Prevention of GvHD
Choose donor by matching HLA carefully, deplete donor T cells. Immunosupress with MMF and steroids
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Graft vs leukemia effect
The more you irradiated the T cells in the HSCT to less effective they will be against the cancer
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Chronic GvHD
70-90% cases are due to progression of acute GvHD.
Ocular - keratoconjuctivitis, ocular erosions
Pulmonary - Obstructive lung disease, wheezing, chronic cough, bronchiolitis obliterates
Hepatic - hyperbilirubineamia, pruritus and jaundice
Neuro - cramps, weakness and neuropathic pain
GI - oesophageal strictures, wt loss
Derm - atrophy and ulceration of oral mucosa, joint contractures, lichenoid lesions of skin, buccal and labial mucosa
Linked to AI disorders - SLE, Sjogrens, RA, PBC
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Alzheimer PC
PC 20% of people >80y/o have a degree of alzheimers
progressive cognitive decline, agnosia, amnesia and aphasia.
Post mortem diagnosis showing cortical atrophy, enlargement of ventricles and deepening of sulci
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Pathogenesis of AD
Accumulation of amyloid B senile plaques. These are inert and hydrophobic and disrupt the communication between neurones. Tau neurofibrillary tangles are implicated too. Tau is a protein which stabilises the microtubule cytoskeleton allowing transport of proteins and molecules throughout the cell. Tau is hyperphosphorylated which promotes aggregation and reduced microtubule binding
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Amyloid targets ?
Every brain cell has APP molecules B and g secretase chop these APP molecule leading to the production of B amyloid. It was hoped that by targeting B/g secretes inhibition the progression of AD could be halted
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Frontotemporal dementia
Marked degeneration of frontal and temporal lobes seen on autopsy with occipital and parietal sparing.
PC = social and behavioural changes, spatial and memory problems, reduced comprehension
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Multi system atrophy
MSA is a neurodegenerative disorder characterised with tremors, ataxia, slow movement and muscle rigidity. Seen in 50-60y/o
It presents with autonomic failure =postural hypotension, urinary retention, dilated pupils, constipation and impotence
Crucially there is very little response to L-dopa
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Parkinson's disease and dementia with lewy bodies
Both present with rigidity, resting tremor, akinesia and cognitive impairment
Due to loss of the dopaminergic neuroes in the substantia nigra. Lewy bodies are accumulations of a synucelin they collect and deposit in synapses leading to impaired transmission of impulses
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Lysosomal storage disorders
Rare inherited metabolic disorders that are due to lysosomal enzyme dysfunction. This leads to progressive accumulation of metabolites within the lysosomes. This causes macrophage dysfunction and gradual organ dysfunction. They are often AR.
No cure
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Tay-Sachs PC
Destruction of nerve cells in the brain and the spinal cord. Manifests around 6 months with baby losing the ability to crawl or roll over, progresses to seizures hearing loss and inability to move
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Gauchers
1q22 recessive leading to progressive neurological defects, hepatosplenomegaly and parkinsionism
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Iron metabolism
Tightly regulated uptake of 1-2mg daily from intestines. Absorption regulated by hepcidin. Fe is exported by ferroportin bound to transferrin and stored as ferritin
Hepcidin is produced when adequate levels of iron have been absorbed by the body. In its presence ferroportin channels are down regulated leading to reduced iron absorption from the gut. It also prevents iron leaving the macrophages and liver
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PC Haemochromatosis
AR seen in 1/3000 people. Often due to HFE or C282Y mutations leading to increased iron absorption from intestine.
PC - bronzed skin, arthralgia, DM, cardiomyopathy, cirrhosis. Hypogonadotrophic hypogonadism due to deposition in pituitary. Female gender is protective until menopause
Inv = high ferritin and high transferrin saturations
Mx - venesection
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Neuroferrinopathy
Mutation of the iron storage protein ferritin leads to accumulation of ferritin throughout the body. AD
PC = chorea, dystonia and parkinsonism, @ autopsy iron deposits can be visibly seen in cortex
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Copper metabolism
2.5mg daily closed system with intestinal and binary secretion. Deficiency = extra-pyramidal side effects and peripheral neuropathy
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Wilsons disease
AR defect in ATP7B which transports copper to transporter proteins on the ER. Without this copper cant be loaded on to ceuroplasmin
PC = cirrhosis, ataxia due to deposition in the basal ganglia, kayser-flasia rings, renal damage - nephrocalcinosis
Inv - low serum Cu, high urine copper and low ceruloplasmin
Mx = penicillamine
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Functions of endothelium
Angiogenesis and tissue repair, cell adhesion, preventing and inducing coagulation, fibrinolysis and thrombogensis
Vasoreactivity to regulate tissue perfusion
Exchange of gas, nutrients and waste
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Blood vessels
Endothelium is the inner layer on the intima. BP and flow velocity stay constant and high in the arteries own to a thick muscular wall which propagate the pressure wave the LV creates. When the surface area for exchange dramatically increases in the capillary network there is a fall in flow rate facilitating exchange.
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Endothelium and junctions
Derived from mesoderm. They lie end to end in the direction of blood flow perpendicular to the circular arrangement of SM. Joined by
- Tight junctions to prevent leakage/passage
- Gap junctions for communication
- Adherens junctions hold the cells together and provide structure
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Continuous endothelium
BBB, blood vessels, lungs, muscle
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Blood brain barrier
Protected by highly specialised endothelial layer forming very tight adherent junctions with high numbers of astrocytes and pericytes
Tight junctions are 50-100x stronger. Small and lipid soluble molecule can easily cross the BBB. Otherwise active or receptor mediated transport is needed.
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Fenestrated endothelium
Inner ear, renal and intestines
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Renal endothelium
Role is filtration, the glomerulus is a network of small capillaries with huge SA. Glomerular pressure is regulated by afferent and efferent arterioles despite a fluctuating MAP.
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Sinusoidal endothelium
Liver, spleen, BM
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Mass spectrometry
peptide, immunosuppressant drugs and steroid hormones
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Angiogensis
Mature endothelial cells can divide in situ and migrate locally in response to VEGF and PDGF. Low oxygen states stimulate VEGF production. Tumour cells exploit this by being hypoxic and production growth factors to stimulate VEGF by having their own blood supply they can grow and metastasis .
Primary brain tumours rarely metastasis due to the strength of the BBB
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Vasodilators and vasoconstrictors
Autoregulation facilitates the smooth flow of blood and products to tissues
NO and prostenoids = vasodilators
Endothelin = vasoconstrictor
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Regulation of platelet coagulation and aggregation
High sheer stress leads to a cascade of prothrombotic factors. After an insult vWF bonds to exposed collagen fibres allowing platelets to aggregate together and form the platelet plug. This encourage fibrin to bind
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Immune response and endothelium
Immune cells are transported around in the arterial circulation and return to the lymph via the SVC. At sites of inflammation retained by adherins and selectins which tether the lymphocytes, stop it rolling and allow ICAM extravasation across endothelium
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Sepsis
Pro inflammatory cytokines IL-1, IL-6 and TNFa are released by macrophages and neutrophils. They trigger a cascade and increased in Ca2+ which phosphorylates cadherins relaxing tight junctions. This increases membrane permeability leading to leakage of fluid, oedema and reduced BP.
NO and prostacyclin stimulate mass vasodilation to allow transport of immune cells leading to hypoperfusion.
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Carcinogensis
Multi-step process resulting from a gradual accumulation of errors. Risk increases with age. Can begin in a single cell which multiplies and possesses a survival advantage
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Hypertrophy
Increase in cell size
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Hyperplasia
Increase in cell number
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Metaplasia
Change in cell type. Ie squamous to glandular
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Dysplasia
Disrupted cell architecture and cytological changes often viewed as pre malignant
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Chemical carcinogenes
Cigarette smoke, azo dyes, nitrosamines
Initiation requires replication of cells where repair of chemically induced DNA damage has failed.
Promotion reversible process requiring multiple exposures to produce a growth advantage without DNA mutation. Produces transient changes only
Progression irreversible involving multiple complex DNA changes and chromosome alterations
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Smoking and cancer
Increased risk of bladder, lung, laryngeal, breast and cervical cancer
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Ionising radiation
High frequency, high energy damages DNA by displacing atoms producing ion pairs. Sources include background and medical (X-ray, CT)
Rapidly dividing tissue such as breast, BM and thyroid are more susceptible.
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Non-ionising radiation
UVB most significant. Linked to increase risk of BCC, SCC and melanoma. Esp in white skinned population and those with extreme sunburn at young age
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EBV
Hodgkin lymphoma, burkitts, craniopharingioma
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HHV8
Kaposi's and Castlemans
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Liver flukes
Cholangiocarcinoma
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H.pylori
Gastric cancer and lymphoma
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Tumour supressor gene
Normally act to inhibit cell survival and proliferation by controlling the cell cycle, promoting apoptosis and regulating telomeres. For change in cellular function to occur both copies of the gene need to be affected!! - "recessive"
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Proto-oncogene
Normally promote cell survival and proliferation activated at times of injury and embryonic development.
Oncogenes are mutated copies that allow proliferation , gain in function mutations only require one hit.
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1. Sustained proliferation signalling
Most fundamental trait. Produce growth factor ligands, increase receptor levels on cell surface, alter structure of receptor molecules and activate additional downstream pathways
EGFR and HER2 oncogene closely linked to tyrosine kinase receptors. Dimerisation due to ligand binding leads to intrinsic intracellular transduction cascades.
Drugs can inhibit EGFR hence inhibiting the tyrosine kinase receptors and halting growth
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2. Evading growth suppression
Cancer must circumvent powerful mechanisms that suppress growth. These include tumour suppressor genes, contact inhibition and TGF-B pathways
Cancer cells with defect in RB1 gene are missing a gatekeeper to the cell cycle which usually prevents progression from G1 to S. Cancer cells have mutations which lead to the incorrect assembly of tublin networks crucial for contact inhibition
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3. Resisting cell death
Loss of TP53 tumour suppressor. This is the largest initiator of apoptosis in its absence central control of apoptosis is lost. Promotion of necrosis to gain advantage from growth stimulating factors
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Necrosis
Premature cell death leads to rupture and release of cell contents into local environment. This leads to recruitment of inflammatory immune cells promoting angiogenesis, cell proliferation and release of stimulatory factors
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Autophagy
Catabolic process where cell constituents are degraded within the cell by lysosomes. The cellular metabolites are recycled and used for metabolic purposes
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Apoptosis
Dissemble of the cell due to removal of IL-3, TG-1 and inappropriate activation of cyclin E without cyclin . induces chromatin margination, break up of the nuclear envelope and cell fragmentation
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4. Replicative immortality
Most cells have a finite lifespan due to telomere length. Cancer cells have the ability to lengthen their telomeres using Stem cells and TERT. Longer telomeres protect the DNA from end to end fusion
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4. Replicative immortality
Most cells have a finite lifespan due to telomere length. Cancer cells have the ability to lengthen their telomeres using Stem cells and TERT. Longer telomeres protect the DNA from end to end fusion
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5. Inducing angiogenesis
Tumours require a blood supply to grow above 1mm3. They need nutrient, o2 and to remove metabolic waste and CO2. VEGF is produced in hypoxic states from stimulation of hypoxia inducing factors allowing blood vessel proliferation to provide oxygen to the hypoxic tissue
VEGF leads to leakage in the BM followed by endothelial budding. nascent vascular sprouts form and elongate towards to tumour. A lumen is formed and SM and pericytes form the vessels walls.
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6. Activating invasion and metastasis
E-cadherin is crucial in assembly of epithelial cell sheet s and maintaining quiescence of cells. Cadherins are types of cell adhesion molecule important in the formation of adherens junctions. Down regulation of e-caderin has been linked to metastasis.
Weak BM = easier for tumour to invade the BM and enter the blood supply
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7. Genome instability and mutation
Gene disorders. DNA repair mechanisms are crucial due to constant damage to
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9. Deregulating cellular energies
Under anaerobic conditions glycolysis is favoured to produce ATP. Cancer cells reprogram their glucose metabolism to aerobic glycolysis. This is 18x less efficient. Upregulation of GLUT1 = larger glucose supply
Glycotic intermediatarys can be used for synthetic pathways to produce amnio acids and nucleosides
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10. Avoiding immune detection
Immune system is a significant barrier to tumour formation and progression. Deficiencies in development or impaired function of cytotoxic T cells, and NK are linked to tumour incidence. Cancer may disable the immune system by recruiting natural immunosuppressive cells such as Treg and MDSC
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Mass spectroscopy
High specificity and sensitivity large range of analytes used for steroid hormones and toxicology
