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Mechanisms of Disease
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- 1What are INTEGRINS and what is their association with invasion & metastasis?Cell surface glycoproteins. Reduced/altered expression in some cancers lead to reduced interaction between cell & stroma so cells able to move more freely
- 2What are CADHERINS & what is their association with invasion & metastasisCalcium dependent glycoproteins present on the cell membrane - allow cells to interact with one another. Reduced/altered expression in some cancers allowing cells to move away from each other
- 3List 3 mechanisms for tumour cell spread1. Reduced interaction with other cells
2. Reduced interaction with stroma
3. Increased motility - 4Define carcinogenesisThe process that results in the transformation of a normal cell into a neoplastic cell ~ by causing permanent non-lethal genetic alterations
- 5List 3 functions of p53 (tumour suppressor gene) when NOT mutated1. Induces apoptosis in cells whose DNA defects are irreparable
2. Induces transcription of genes involved in DNA repair
3. Delays/stops progression through the cell cycle of cells with defective DNA/damaged cells - 6Describe the normal molecular events associated with Rb (a tumour suppressor gene)When active (unphosphorylated) it is bound to and therefore sequesters E2F, which is usually involved in triggering cell division. If phosphorylated, it is inactive, detaches from E2F - which can then go on & initiate cell division & growth
- 7List 3 oncogenes & associated malignancyRAS (usually deactivated by GTP hydrolysis) - 90% of pancreatic adenocarcinomas & 50% of colon adenocarcinomas
C-MYC - Translocation (8 - 14) - Burkitt's Lymphoma, breast & colon & lung
Her2 - (cell membrane receptor) amplified in breast cancer - 8List 3 differences in behaviour between benign & malignant cellsRetain function versus lost function
No invasion versus ability to invade
No metastasis versus metastasis - 9List 3 differentiating features of benign versus malignant cells, in terms of macroscopic appearanceNo necrosis versus necrosis
Well defined versus ill defined edge
No haemorrhage versus haemorrhage - 10Differentiate between the microscopic features of benign versus malignant cellsMalignant - variation in nuclear size, shape & chromasia
Loss of differentiation
High mitotic count/activity - 11Differentiate between the microscopic features of benign versus malignant cellsMalignant - variation in nuclear size, shape & chromasia
Loss of differentiation
High mitotic count/activity - 12List the 3 requirements for tumour development1. There must be a change to DNA or gene expression
2. This change must lead to changes in cell growth & behaviour
3. This change must be non-lethal and passed on to daughter cells - 13What gene is implicated in Ataxia Telangiectasia and what does it normally do?ATM (serine threonine kinase) - normally prevents progress through cell cycle if defects in DNA have not been repaired i.e. DNA repair checkpoints. It responds to defects in DNA (especially double strand breaks) by activating various proteins involved in apoptosis, cell cycle arrest & DNA repair
- 14Define atherosclerosisIntimal lesions of the arteries, caused by atheroma, that leads to hardening of the vessel wall
- 15Define arteriolosclerosisSmall artery disease, hardening of arterioles, seen in DM & hypertension
- 16Define atheromaA chronic, intimal lesion of arteries that causes narrowing of the vessel lumen & weakening of the vessel wall
- 17List the 4 constituents of an atherosclerotic plaqueSmooth muscle cells
Inflammatory cells
Extracellular matrix
Lipids - 18BRIEFLY describe cellular events associated with atheromatous plaque development1. Endothelial injury
2. Lipid permeates & is oxidised
3. M.phages take up oxidised lipids (foam cells)
4. SMC migration & proliferation
5. Lipid accumulation
6. SMC calcification - 19List 4 complications of cerebral artery atheromaTIA
RIND
CVA
Vascular dementia - 20List 4 laboratory abnormalities that might be present in the setting of DIC1. Low platelets
2. Raised PT & APPT
3. Low fibrinogen
4. Raised FDPs - 21Define cellular INVOLUTIONReduction in cell number (c.f. hyperplasia)
- 22Give two examples of physiological hyperplasia1. Hormonal, e.g. endometrial
2. Compensatory, e.g. after partial hepatectomy - 23What type of inheritance does haemophilia A show?X-linked recessive
- 24List 2 types of physiological hypertrophy1. Hormonal, e.g. uterus (in combinations with hyperplasia) during pregnancy
2. Functional demand increased, e.g. mechanical or skeletal muscle - 25List 6 causes of cell atrophy1. Lack of nutrition
2. Denervation
3. Lack of blood flow
4. Reduced workload
5. Lack of endocrine stimulation
6. Ageing - 26Define metaplasiaReversible change from one cell type to another. Can be pathological or physiological.
- 27Define neoplasiaAbnormal growth of cells that continues even when the initiating stimulus is taken away
- 28What is the definition of a 'thrombus'A solid mass of blood constituents that forms in the vascular system within life. Composed of platelets, fibrin & blood cells
- 29List the 3 components of Virchow's Triad1. Abnormal endothelial wall
2. Abnormal blood flow
3. Abnormal blood constituents - 30List the 5 potential fates of a thrombus1. Propagation
2. Fibrinolysis
3. Organisation
4. Recanalisation
5. Embolism - 31What is the definition of an embolism?A mass which travels through the vascular tree & becomes lodged so as to obstruct blood flow
- 32List 3 potential types/outcomes of pulmonary embolism1. Obstruction of medium or small PA with/without lung infarction
2. Massive/saddle embolism - obstruction of main PA - sudden death
3. Multiple small emboli - pulmonary hypertension - 33List 5 symptoms of PEBreathlessness
Collapse
Chest pain
Cough
Haemoptysis - 34List 4 signs of PETachycardia
Tachypneoa
Hypotension
Raised JVP - 35List 7 types of embolism, other than thrombus1. Fat
2. Atheroma
3. Nitrogen
4. Tumour
5. Air
6. Amniotic fluid
7. Foreign material - 36Briefly describe DICDisseminated Intravascular Coagulation - complication of critical illness - multiple small emboli throughout vasculature, leads to exhaustion of clotting factors & resultant bleeding from e.g. skin, GIT, respiratory tract. Clots can also block organs - organ failure
- 37What is the definition of haemostasis?The maintenance of the blood in a fluid, clot-free state. Induction of rapid & localised haemostatic plug at the site of injury
- 38What mechanisms keep blood from clotting normally?1. Intact endothelial wall
2. Dilution of clotting factors
3. Removal of active clotting factors by the liver
4. Anticoagulant mechanisms - 39Describe the role of the platelet in clotting (4 stages)1. Activation (on contact with subendothelial material
2. Adherence to subendothelial tissue via interaction with vWF
3. Aggregation (platelets clump together via interactions between GP2a-3b platelet receptor in combination with fibrinogen )
4. Release of factors that stimulate continued further aggregation - 40What two roles does the endothelial wall play in preventing clotting?1. Physical barrier
2. Secretion of:
a. Thrombomodulin
b. Heparan
c. Enzymes
d. Prostacyclin - 41Differentiate between the actions of Tc & Th cellsTh (CD4) cells respond to MHC 2 proteins & secrete cytokines which initiate events that result in destruction of antigen (EXOGENOUS)
Tc (CD8) cells respond to MHC 1 proteins & become activated and able to destroy antigen (ENDOGENOUS) - 42Differentiate between the actions of Th1 & Th2 lymphocytesTh1 lymphocytes can activate macrophages but not help B cells
Th2 lymphocytes can help B cells but not activate macrophages - 43List 2 functions of B cells in chronic inflammation1. Production of antibodies, which then mark antigens for opsonisation, interact with killer cells & trigger the classical complement pathway
2. Presenting of antigen to CD4 (Th) lymphocytes - 44List the 3 types of healing & repair1. Fibrous repair
2. Regeneration
3. Resolution - 45Define 'labile' cellsContinuously dividing throughout life
E.g. skin, gut epithelium, cervix, endometrium, urinary tract - 46Define 'quiescent' cellsGenerally not dividing (in Go) but can undergo rapid division if stimulated to do so
E.g. osteocytes, chondrocytes, kidney cells, liver cells, fibroblasts, endothelial cells, smooth muscle cells - 47Define 'permanent' cellsCannot divide in adult life. Have left the cell cycle
E.g. cardiac muscle, neuronal, skeletal muscle - 48List the 5 stages of healing & repairAngiogenesis
Mitogenesis
Chemotaxis & motility
Fibrogenesis
Remodelling - 49Describe the process of angiogenesis in healing & repairPre-existing capillaries bud into area OR develop from endothelial precursors
VEG-F - 50What is granulation tissue?The specialised tissue of healing & repair.
Contains:
1. Fluid-rich
2. Antibodies & growth factors
3. Macrophages & myofibroblasts
4. Proliferating capillaries
5. Other inflammatory cells - 51Describe the processes of chemotaxis & mitogenesis in healing & repairFibroblasts migrate & proliferate
Collagen laid down
TGF-beta
FIBROVASCULAR GRANULATION TISSUE - 52Describe the process of fibrogenesis in healing & repairFibroblasts continue to produce collagen. Fibroblasts align so that collagen is uniform, increasing tensile strength.
FIBROUS GRANULATION TISSUE - 53Describe the remodelling process in healing & repairMMPs cleave collagen
PDG-F - 54List 2 factors that can stimulate apoptosis1. Extrinsic - e.g. TNF
2. Intrinsic - e.g. hormone withdrawal/growth stimulatory signal withdrawal - 55What factors comprise the anti-oxidant defence system?Vit A, Vit E, Vit C, Glutathione
- 56List the 3 features of acute inflammation1. Haemodynamic changes (RUBOR, CALOR)
2. Permeability changes in endothelium (TUMOR)
3. Recruitment & migration of neutrophils - 57List 4 roles of the macrophage in chronic inflammation1. Secrete factors involved in tissue destruction (e.g. proteases) & repair (e.g. VEG-F)
2. Secrete cytokines to recruit inflammatory mediators (e.g. PAF)
3. Phagocytosis
4. Antigen presenting (MHC 1 & 2) - 58List 6 non-immunological defences1. Skin sebum
2. Low pH of stomach & vagina
3. Mucociliary clearance system
4. Complete emptying of the bladder & inhibition of urine flow up the ureters
5. Commensal flora, e.g in vagina & bowel & skin
6. Skin - 59Describe what are meant by 'haemodynamic changes' in acute inflammationVasodilation due to vasodilatory mediators, e.g.NO, leads to hyperaemia - RUBOR & CALOR
- 60Describe what is meant by 'changes in endothelial permeability' in acute inflammationIn response to histamine & PAF, endothelial cells swell & partially retract, allowing fluid, salt & protein (e.g. albumin, immunoglobulins) to enter damaged area (TUMOR). Inflammatory fluid is known as exudate
- 61List and describe 3 types of exudate1. Purulent (pus containing)
2. Fibrinous (fibrinogen containing)
3. Transudate (low protein content) - 62Describe the process of 'neutrophil migration & recruitment' in acute inflammation1. Margination
2. Adhesion
3. Emigration
4. Chemotaxis - 63Describe the process of phagocytosis by neutrophils in acute inflammation1. Neutrophils recognise dead/foreign material via mannose receptors or opsonins & Fc/C3b & bind to it - engulf it into phagosome
2. Fuse with lysosome - phagolysosome - series of reactions (O2 dependent & non O2 dependent) - lysis - 64List 7 outcomes of acute inflammation1. Resolution
2. Suppuration
3. Organisation & repair
4. Chronic inflammation
5. Death
6. Septicaemia
7. Calcification - 65Describe the process of resolution of acute inflammation1. Exudate drains to lymphatics
2. Plasmin degrades fibrin
3. Neutrophil apoptosis
4. Regeneration - 66What is caseous necrosis?An accumulation of an amorphous structure within an area of debris
- 67Describe the pathophysiology of fat necrosisResults from the action of lipases into adipose tissue. Free fatty acids accumulate & precipitate as calcium salts (saponification). E.g. pancreatitis/trauma
- 68Define gangrene & list two typesA type of necrosis that is visible grossly.
Mostly coagulative? Dry gangrene
Mostly liquefactive or in a wet body cavity? Wet gangrene - 69Describe coagulative necrosis1. Cell death but basic shape & architecture remains
2. Solid consistency maintained
3. Necrotic cells removed by inflammatory cells
4. Tissue regeneration from neighbouring cells or scar tissue - 70Describe liquefactive necrosis1. Complete dissolution of necrotic tissue
2. Massive infiltration of neutrophils & abscess formation
3. Release of reactive oxygen species & proteases
(ISCHAEMIC NECROSIS IN BRAIN) - 71What are heat shock proteins?A class of functionally related proteins which are upregulated when cells are exposed to elevated temperatures or other stressors. Protect proteins from stress-related damage and remove damaged proteins.
- 72List 3 reversible mechanisms of cell damageReversible:
1. Reduced protein synthesis
2. Loss of ATP - e.g. inhibition of Na/K pump
3. Anaerobic metabolism - lactic acid build up - 73List 2 irreversible mechanisms of cell injury1. Massive intracytoplasmic calcium influx
2. Activation of enzymes, e.g. ATPase - 74List 5 factors that lead to generation of free radicals1. Normal cellular metabolism
2. Nitric Oxide
3. Transition metal, e.g. Fe+++
4. Toxins - e.g. carbon tetrachloride
5. Irradiation - 75List 4 mechanisms of removal of free radicals1. Spontaneous decay
2. Anti-oxidants, e.g. vitamin A/E/glutathione
3. Transport proteins, e.g. ferritin
4. Enzymes, e.g. catalase - 76List 3 mechanisms of free radical-induced damage1. Membrane lipid peroxidation
2. Interaction with proteins
3. DNA damage - 77Define 'free radical'Any species capable of independent existence that contains one or more unpaired electrons
- 78Describe the role of the complement systemPart of the innate immune system
A triggered enzyme cascade, ultimately resulting in the activation of a MEMBRANE ATTACK COMPLEX, which lyses invaders.
Functions: opsonization, chemotaxis, cell lysis & clumping of antigen-bearing agents - 79List 3 complement proteins and state their role1. C3b - binds to the surface of pathogens targets them for opsonisation by phagocytes
2. C5a - chemotactic - recruits inflammatory cells
3. C5b - initiates membrane attack complex (C5b, C6, C7, C8 & C9) - 80List the 6 causes of cellular injury & give an example of eachImmune - e.g. cytokines
Physical - e.g. direct trauma/heat
Infectious - e.g. prions
Nutritional - e.g. malnutrition
Chemical - e.g. arsenic & reduced ATP
Hypoxic - e.g. ischaemic (MI) - 81List 3 differences between necrotic & apoptotic cell death?1. Pathological versus Physiological/pathological
2. Enzymatic destruction versus internally controlled
3. Cell contents leak out versus nuclear dissolution
4. Death of contiguous groups of cells versus death of single cells
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- Mechanisms of Disease Fichas sobre Mechanisms of Disease, creado por laura.marsland el 13/05/2013.
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