Mechanisms of Disease

Frage	Antworten
List 3 oncogenes & associated malignancy	RAS (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
List 3 mechanisms for tumour cell spread	1. Reduced interaction with other cells 2. Reduced interaction with stroma 3. Increased motility
What are CADHERINS & what is their association with invasion & metastasis	Calcium 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
What 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
Describe 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
List 3 functions of p53 (tumour suppressor gene) when NOT mutated	1. 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
Define carcinogenesis	The process that results in the transformation of a normal cell into a neoplastic cell ~ by causing permanent non-lethal genetic alterations
List 3 differences in behaviour between benign & malignant cells	Retain function versus lost function No invasion versus ability to invade No metastasis versus metastasis
List 3 differentiating features of benign versus malignant cells, in terms of macroscopic appearance	No necrosis versus necrosis Well defined versus ill defined edge No haemorrhage versus haemorrhage
Differentiate between the microscopic features of benign versus malignant cells	Malignant - variation in nuclear size, shape & chromasia Loss of differentiation High mitotic count/activity
Differentiate between the microscopic features of benign versus malignant cells	Malignant - variation in nuclear size, shape & chromasia Loss of differentiation High mitotic count/activity
List the 3 requirements for tumour development	1. 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
What 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
Define atherosclerosis	Intimal lesions of the arteries, caused by atheroma, that leads to hardening of the vessel wall
Define arteriolosclerosis	Small artery disease, hardening of arterioles, seen in DM & hypertension
Define atheroma	A chronic, intimal lesion of arteries that causes narrowing of the vessel lumen & weakening of the vessel wall
List the 4 constituents of an atherosclerotic plaque	Smooth muscle cells Inflammatory cells Extracellular matrix Lipids
BRIEFLY describe cellular events associated with atheromatous plaque development	1. 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
List 4 complications of cerebral artery atheroma	TIA RIND CVA Vascular dementia
List 4 laboratory abnormalities that might be present in the setting of DIC	1. Low platelets 2. Raised PT & APPT 3. Low fibrinogen 4. Raised FDPs
Define cellular INVOLUTION	Reduction in cell number (c.f. hyperplasia)
Give two examples of physiological hyperplasia	1. Hormonal, e.g. endometrial 2. Compensatory, e.g. after partial hepatectomy
What type of inheritance does haemophilia A show?	X-linked recessive
List 2 types of physiological hypertrophy	1. Hormonal, e.g. uterus (in combinations with hyperplasia) during pregnancy 2. Functional demand increased, e.g. mechanical or skeletal muscle
List 6 causes of cell atrophy	1. Lack of nutrition 2. Denervation 3. Lack of blood flow 4. Reduced workload 5. Lack of endocrine stimulation 6. Ageing
Define metaplasia	Reversible change from one cell type to another. Can be pathological or physiological.
Define neoplasia	Abnormal growth of cells that continues even when the initiating stimulus is taken away
What 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
List the 3 components of Virchow's Triad	1. Abnormal endothelial wall 2. Abnormal blood flow 3. Abnormal blood constituents
List the 5 potential fates of a thrombus	1. Propagation 2. Fibrinolysis 3. Organisation 4. Recanalisation 5. Embolism
What is the definition of an embolism?	A mass which travels through the vascular tree & becomes lodged so as to obstruct blood flow
List 3 potential types/outcomes of pulmonary embolism	1. 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
List 5 symptoms of PE	Breathlessness Collapse Chest pain Cough Haemoptysis
List 4 signs of PE	Tachycardia Tachypneoa Hypotension Raised JVP
List 7 types of embolism, other than thrombus	1. Fat 2. Atheroma 3. Nitrogen 4. Tumour 5. Air 6. Amniotic fluid 7. Foreign material
Briefly describe DIC	Disseminated 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
What 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
What 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
Describe 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
What two roles does the endothelial wall play in preventing clotting?	1. Physical barrier 2. Secretion of: a. Thrombomodulin b. Heparan c. Enzymes d. Prostacyclin
Differentiate between the actions of Tc & Th cells	Th (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)
Differentiate between the actions of Th1 & Th2 lymphocytes	Th1 lymphocytes can activate macrophages but not help B cells Th2 lymphocytes can help B cells but not activate macrophages
List 2 functions of B cells in chronic inflammation	1. 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
List the 3 types of healing & repair	1. Fibrous repair 2. Regeneration 3. Resolution
Define 'labile' cells	Continuously dividing throughout life E.g. skin, gut epithelium, cervix, endometrium, urinary tract
Define 'quiescent' cells	Generally 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
Define 'permanent' cells	Cannot divide in adult life. Have left the cell cycle E.g. cardiac muscle, neuronal, skeletal muscle
List the 5 stages of healing & repair	Angiogenesis Mitogenesis Chemotaxis & motility Fibrogenesis Remodelling
Describe the process of angiogenesis in healing & repair	Pre-existing capillaries bud into area OR develop from endothelial precursors VEG-F
What 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
Describe the processes of chemotaxis & mitogenesis in healing & repair	Fibroblasts migrate & proliferate Collagen laid down TGF-beta FIBROVASCULAR GRANULATION TISSUE
Describe the process of fibrogenesis in healing & repair	Fibroblasts continue to produce collagen. Fibroblasts align so that collagen is uniform, increasing tensile strength. FIBROUS GRANULATION TISSUE
Describe the remodelling process in healing & repair	MMPs cleave collagen PDG-F
List 2 factors that can stimulate apoptosis	1. Extrinsic - e.g. TNF 2. Intrinsic - e.g. hormone withdrawal/growth stimulatory signal withdrawal
What factors comprise the anti-oxidant defence system?	Vit A, Vit E, Vit C, Glutathione
List the 3 features of acute inflammation	1. Haemodynamic changes (RUBOR, CALOR) 2. Permeability changes in endothelium (TUMOR) 3. Recruitment & migration of neutrophils
List 4 roles of the macrophage in chronic inflammation	1. 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)
List 6 non-immunological defences	1. 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
Describe what are meant by 'haemodynamic changes' in acute inflammation	Vasodilation due to vasodilatory mediators, e.g.NO, leads to hyperaemia - RUBOR & CALOR
Describe what is meant by 'changes in endothelial permeability' in acute inflammation	In 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
List and describe 3 types of exudate	1. Purulent (pus containing) 2. Fibrinous (fibrinogen containing) 3. Transudate (low protein content)
Describe the process of 'neutrophil migration & recruitment' in acute inflammation	1. Margination 2. Adhesion 3. Emigration 4. Chemotaxis
Describe the process of phagocytosis by neutrophils in acute inflammation	1. 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
List 7 outcomes of acute inflammation	1. Resolution 2. Suppuration 3. Organisation & repair 4. Chronic inflammation 5. Death 6. Septicaemia 7. Calcification
Describe the process of resolution of acute inflammation	1. Exudate drains to lymphatics 2. Plasmin degrades fibrin 3. Neutrophil apoptosis 4. Regeneration
What is caseous necrosis?	An accumulation of an amorphous structure within an area of debris
Describe the pathophysiology of fat necrosis	Results from the action of lipases into adipose tissue. Free fatty acids accumulate & precipitate as calcium salts (saponification). E.g. pancreatitis/trauma
Define gangrene & list two types	A type of necrosis that is visible grossly. Mostly coagulative? Dry gangrene Mostly liquefactive or in a wet body cavity? Wet gangrene
Describe coagulative necrosis	1. 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
Describe liquefactive necrosis	1. Complete dissolution of necrotic tissue 2. Massive infiltration of neutrophils & abscess formation 3. Release of reactive oxygen species & proteases (ISCHAEMIC NECROSIS IN BRAIN)
What 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.
List 3 reversible mechanisms of cell damage	Reversible: 1. Reduced protein synthesis 2. Loss of ATP - e.g. inhibition of Na/K pump 3. Anaerobic metabolism - lactic acid build up
List 2 irreversible mechanisms of cell injury	1. Massive intracytoplasmic calcium influx 2. Activation of enzymes, e.g. ATPase
List 5 factors that lead to generation of free radicals	1. Normal cellular metabolism 2. Nitric Oxide 3. Transition metal, e.g. Fe+++ 4. Toxins - e.g. carbon tetrachloride 5. Irradiation
List 4 mechanisms of removal of free radicals	1. Spontaneous decay 2. Anti-oxidants, e.g. vitamin A/E/glutathione 3. Transport proteins, e.g. ferritin 4. Enzymes, e.g. catalase
List 3 mechanisms of free radical-induced damage	1. Membrane lipid peroxidation 2. Interaction with proteins 3. DNA damage
Define 'free radical'	Any species capable of independent existence that contains one or more unpaired electrons
Describe the role of the complement system	Part 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
List 3 complement proteins and state their role	1. 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)
List the 6 causes of cellular injury & give an example of each	Immune - 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)
List 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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