Disease and Defense Unit 2-class of 2019

Question 1

what are adaptations (in general)?

Answer 1

reversible changes in size, #, phenotype, metabolic activity, cell function, environment. Can be physiologic or pathologic

Question 2

what are the 4 main adaptations (of cells)?

Answer 2

Think “Hham”: hypertrophy, hyperplasia, atrophy, metaplasia

Question 3

hypertrophy

Answer 3

increase in cell size—> increase organ size (limit eventually reached and can no longer compensate—> injury). can be physiologic or pathologic. may be reversible. example: uterus in pregnancy, heart in hypertension.

Question 4

Can hypertrophy occur with hyperplasia?

Answer 4

YES!

Question 5

hyperplasia

Answer 5

increase in number of cells (response to stimulus/injury). physiologic=hormonal or compensatory. pathologic=excessive hormonal or GF stimulation (these are very “hyper” cells). increase in cell number. can be physiologic or pathologic. may be reversible. often driven by hormones/growth factors. May be associated with increased risk of neoplasia. eg: mammary gland in puberty, endometrial neoplasia

Question 6

if stimulation is removed in pathologic hyperplasia, what happens?

Answer 6

abates. doesn’t happen with cancer

Question 7

atrophy

Answer 7

decrease/shrinkage in size/function capacity of cell. physiologic=loss hormonal stimulation, decreased workload. pathologic=denervation or diminished blood supply.

Question 8

mechanism of atrophy:

Answer 8

down with the protein synth and up with the protein degradation!!!!!

Question 9

metaplasia

Answer 9

reversible change where 1 cell type is replaced by another (“it’s so meta!”). typically because 1 cell is sensitive to stress, and another is better able to handle it. change from benign differentiated cell type to another, usually in response to injury. may be associated with increased risk of neoplasia. “in between” state. best observed and most observed in epithelia. seems to have a “field effect”. eg: columnar to squamous metaplasia, barrett esophagus

Question 10

what is metaplasia named for (the cells)?

Answer 10

what it ends up as

Question 11

reversible cell injury

Answer 11

if damaging stimulus removed, you can heal if damage isn’t too badly progressed to severe membrane damage/nuclear dissolution

Question 12

what classifies irreversible injury?

Answer 12

cell death! necrosis/apoptosis, other causes

Question 13

cellular swelling is caused by what…?

Answer 13

failure of ion pumps in plasma-which disrupts ionic/fluid homeostasis.

Question 14

what is fatty change?

Answer 14

accumulation lipid vacuoles in the cytoplasm of cells (especially those that do fat metabolism). Due to increased entry/synthesis of free Fa and decreased FA oxidation. non-specific, reversible.

Question 15

intracellular changes with reversible injury:

Answer 15

plasma membrane alterations, myelin figures, dilation of ER, nuclear alterations

Question 16

what are myelin figures?

Answer 16

phospholipid masses derived from damaged cell membranes

Question 17

what are the 2 big irreversible cell injury morphologies?

Answer 17

necrosis and apoptosis

Question 18

what are some intracellular changes associated with irreversible injury?

Answer 18

cytoplasmic changes (increased eosinophilia), loss of RNA basophilia in cytoplasm

Question 19

what are some nuclear changes associated with irreversible injury?

Answer 19

breakdown of DNA and chromatin, kayorrhexis (pynknotic nuclear fragments), karyolysis (nucleus dissolution)

Question 20

pynknosis is what?

Answer 20

nucleus shrinks, increased basophilia

Question 21

List the 5 patterns of tissue necrosis:

Answer 21

“Cassie Left Connie For Frank”.

Caseous, Liquefactive, Coagulative, Fibrinoid, Fat

Question 22

coagulative necrosis

Answer 22

GANGRENOUS!!!!!! (involves multiple layers). Architecture of tissue preserved for several days, dead cells are pale/ghost like, characteristic of infarcts, any white/yellow is still live tissue

Question 23

liquefactive necrosis

Answer 23

seen in focal bacterial/fungal infections, fungal infections. microbes stimulate accumulation of inflammatory cells. leukocyte enzymes digest the bacteria. there are no histeocytes/giant cells unless responding to microbes

Question 24

caseous necrosis

Answer 24

tuberculosis infections (and histoplasmosis). derived from white apron, necrotic area is fragmented/lysed cells. has histeocytes/giant cells.

Question 25

granulomas inflammation

Answer 25

amorphous granular debris enclosed in inflammation border. histologically distinctive pattern of chronic inflammation. fibrosis often forms around it

Question 26

fat necrosis

Answer 26

fat destruction due to activated pancreatic lipases. chest wall trauma, breast tissue, etc. fat hydrolyzed into free FA and precipitated with calcium into chalky, grey material

Question 27

fibrinoid necrosis

Answer 27

immune rxn where complexes of antigens/antibodies are deposited into artery walls. deposited immune complexes combine with fibrin and produce bright pink/amorphous appearance on H&E

Question 28

list the 6 mechanisms of cell injury:

Answer 28

ATP depletion, mitochondrial damage, influx of calcium, accumulation of ROS, increased membrane permeability, accumulation of damaged DNA/misfolded proteins. “ROS CAn MEet MItch After Dinner.”

Question 29

ATP depletion and cellular injury

Answer 29

Oxidative phosphorylation+ADP=ATP in mitochondria, or via glycolytic path in absence of O2. Tissues with greater glycolitic capacity can survive better. makes tissue susceptible to ischemic injury (think about DELICATE and not as renewable tissue)

Question 30

mitochondrial damage and cellular injury

Answer 30

failure of oxidative phosphorylation means: ATP depletion, ROS forms, high conductance channels formed destabilizing mitochondria, releasing of proteins and apoptosis

Question 31

influx of calcium and cellular damage

Answer 31

ischemia and toxins cause release from intracellular stores

Question 32

accumulation of ROS and cellular damage

Answer 32

damage by free radicals via 2 paths: 1) all cells during REDOX rxn during mito respiration, 2) phagocytic leukocytes. consequences=damage is based on removal rate. increased production=ineffective scavenging by enzymes=stress. Removal by spontaneous decay.

Question 33

increased permeability of cellular membranes and cellular damage causes damage where?

Answer 33

Important sites of damage: mitochondria, plasma membrane, lysosome

Question 34

spontaneous decay in ROS damage

Answer 34

SUPEROXIDE converts H2O2 by SOD. Decomposition to H2O by GLUTATHIONE, PEROXIDASE, CATALASE

Question 35

what is apoptosis?

Answer 35

programmed cell death where cells activate enzymes to degrade cellular nuclear DNA and nuclear cytoplasmic proteins (fragment/fall off!!!!). Doesn’t illicit an inflammatory response

Question 36

what are some physiologic causes of apoptosis?

Answer 36

programmed destruction (embryogenesis), involution of hormone dependent tissues (hormone deprivation), cell loss in proliferating cell=POP!!!, elimination of used up cells, elimination of self-reactive lymphocytes, death from cytotoxic T-lymphocytes

Question 37

what are some pathologic causes of apoptosis?

Answer 37

DNA damage with inadequate repair (eliminate instead of propagate), accumulation misfolded protein (ER stress), cell injury (viral infection, etc.), pathologic atrophy in parenchymal organs after duct obstruction

Question 38

what is the morphology of apoptosis?

Answer 38

picnotic nucleus that darkens (condensed chromatin), fragmentation, apoptotic bodies are phagocytosed or taken up by neighboring cells

Question 39

what is the mechanism of apoptosis?

Answer 39

1) mitochondrial path and | 2) death receptor

Question 40

describe 3 things mitochondrial apoptosis has:

Answer 40

anti apoptotic mechanisms (BCL2, BCL-XL, MCL1), pro apoptotic mechanisms (BAX, BAK), these lead to activation of initiator caspases (8,9; executioner)

Question 41

what is autophagy?

Answer 41

where a cell eats its own contents! Yum!. it’s an adaptive response/survival mechanism for times of deprivation. disregulated sometimes (cancer, disease, IDB, neurodegenerative disorders), role in host defense (degrades some pathogens: Mycobacteria, HSV-1, etc)

Question 42

what are four main paths of abnormal accumulation of substances in a cell?

Answer 42

1) inadequate removal; 2) accumulation of abnormal endogenous substance, 3) failure to degrade due to inherited enzyme deficiencies, 4) deposition/accumulation of abnormal exogenous substances

Question 43

hemosiderin

Answer 43

hemoglobin derived granular pigment. accumulates with excess of iron. found with Prussian blue

Question 44

lipofuscin

Answer 44

wear and tear pigment. accumulates with age/atrophy. its a complex of lipid an dprotein

Question 45

steatosis

Answer 45

accumulation of tryglycerides

Question 46

cholesterolosis

Answer 46

deposition of cholesterol in macrophages in gallbladder

Question 47

what is pathologic calcification?

Answer 47

abnormal deposition of calcium salts (and iron, magnesium, other minerals)

Question 48

dystrophic calcification

Answer 48

dead/dying tissue. absence of systemic derangement in calcium metabolism. appears purple to pink.

Question 49

psammoma body/calcification

Answer 49

sign of degeneration and cell turnover. laminate of calcification. seen in benign and malignant proliferations (meningioma, papillary thyroid carcinoma, serous carcinoma). outside of cell-aggregate of dead cells and contents.

Question 50

metastatic calcification

Answer 50

seen in normal tissues. secondary derangement to calcium metabolism. (precipitates and deposits out of tissue). hypercalcemia, hyperparathyroidism, Paget disease, etc.

Question 51

innate immune system

Answer 51

nonspecific defense mechanism. occurs immediately/very soon.

Question 52

what are they physical barriers of innate immune system?

Answer 52

skin, mediators in the blood, immune system cells

Question 53

adaptive immune system

Answer 53

antigen specific response. more complex-requires antigen processing. Specific cells must be made/designed for each antigen. Maintains memory cells for future encounters (for quick response). takes a while to develop!

Question 54

acute inflammation: onset, cellular infiltrate, tissue injury/fibrosis, local/systemic signs

Answer 54

onset: fast (minutes, hours), infiltrate: neutrophils, tissue injury: mild/self limited, local/systemic signs: prominent

Question 55

chronic inflammation: onset, cellular infiltrate, tissue injury/fibrosis, local/systemic signs

Answer 55

onset: slow (days), infiltrate: monocytes/macrophages/lymphocytes, tissue injury: severe and progressive, local/systemic signs: less prominent/may be subtle

Question 56

list the 4 stimuli for acute inflammation:

Answer 56

Infection, Trauma, Foreign Material, Immune Rxn. | “I Try For My Immunity”

Question 57

list some possible infections:

Answer 57

bacterial, viral, fungus, parasites, toxins

Question 58

list some possible trauma:

Answer 58

mechanical, chemical, thermal, nuclear, direct physical/chemical damage to cells

Question 59

list some foreign materials that could cause inflammation:

Answer 59

substance that directly stimulates inflammation and its associated “stuff”. microbes, etc.

Question 60

list some immune reactions:

Answer 60

host/environment antigens cause inflammation, immune reactions or hypersensitivity rxns, inappropriate response to inflammation/environment. These often persist, tend to be chronic.

Question 61

inflammation receptors

Answer 61

pattern recognition receptors present on large variety of cells. they pick up stuff (microbe-derived substance, toxins, necrotic cell material, etc).

Question 62

Toll Like Receptors (TLR)

Answer 62

10 receptors. they detect a variety of MICROBES (on plasma membrane, endosomes). TLR stimulated—> transcription factors—> mediators of inflammation and anti microbial products (stimulates inflammatory cytokines)

Question 63

Inflammasome

Answer 63

complex of proteins that mediate cell response esp in response to dead/damaged cells or microbes. (stuff=uric acid, ATP, decreased K, DNA). receptors in cytoplasm=important stimulators. Activates capsize 1—> IL1-beta—> inflammation

Question 64

Pro inflammatory receptors have what 3 locations?

Answer 64

plasma membrane, endosomes, cytosol

Question 65

vascular changes to inflammation

Answer 65

key component of reaction to bring cells and other material quickly to the site of injury/threat. this directly leads to many early clinical signs of infection

Question 66

what are the words of antiquity used to describe inflammation?

Answer 66

calor (warmth, increased flow), rubor (increased flow, congested capillary bed, erythema), tumor (permeability, exudate into tissue, swelling)

Question 67

describe permeability of vessels in inflammation

Answer 67

arterioles dilate, flooding capillaries. Histamine (mediator) acts on smooth muscle to stimulate the dilation (endothelial cells contract).

Question 68

transcytosis

Answer 68

material is taken from the intravascular space and transported through the endothelial cells via vesicles

Question 69

list the common cause, protein content, cell content, and specific gravity of Exudate

Answer 69

increased vascular permeability, increased protein content, increased cell content and inflammation and RBC, high specific gravity

Question 70

list the common cause, protein content, cell content, and specific gravity of Transudate

Answer 70

increased hydrostatic or decreased colloid osmotic pressure, decreased protein content, fewer cell content, low specific gravity

Question 71

exudate

Answer 71

result of increased permeability/leakiness of vessels related to inflammation—>proteins get pushed out!

Question 72

transudate

Answer 72

filtering of fluid, result from cardiac failure. decreased blood protein (oncotic pressure) from liver disease can cause. also caused by heart failure. filtered fluid due to vessel being “tight”

Question 73

lymph drain what???

Answer 73

accumulating edema and debris that inflammation produces

Question 74

what are the 4 phases of leukocyte recruitment?

Answer 74

margination/rolling, adhesion, transmigration, chemotaxis “MATCh”

Question 75

what is leukocyte recruitment?

Answer 75

targeting certain areas for migration of leukocytes in 4 phases, low level of natural peripheral movement, but is first step of ACUTE inflammation

Question 76

margination

Answer 76

leukocytes accumulate on endothelium (laminar flow-slower/larger go to periphery). Vascular permeability thicker, blood moves slower.

Question 77

rolling

Answer 77

stimulated endothelial cells have adhesion molecules with sugar affinity on leukocytes. endothelium induced to move these surfaces via chemical mediators. local tissues detect threat—>mediators released—>vessel is sticky

Question 78

what are the chemical mediators for rolling?

Answer 78

histamine—>p selectin. IL1—>E selectin

Question 79

adhesion

Answer 79

occurs when leukocytes reach area of activation that has been signaled by leakiness. alter interns on surface into a high-affinity state. (Icam-1 binds these). results in stable attachments sites of inflammation

Question 80

do adhesion and margination overlap?

Answer 80

YES! first margination, then adhesion

Question 81

transmigration

Answer 81

Think phantom of the opera-“Past the point of no return!!! No going back now!!!” after adhesion arrests leukocyte on endotheium. squeeze btw endothelial cells in venules (diapedesis).

Question 82

how do those darned leukocytes get through the endothelial cells of the venules?

Answer 82

secrete enzymes like collagenous to break up basement membrane of vessels

Question 83

chemotaxis

Answer 83

leukocytes move towards site of inflammation by following chemical gradients of greater density. start in vascular space—>diapedese—>move towards gradient. this is tied to the contractile elements of a cell, direction of greatest chemotactic density determines the movement.

Question 84

can endogenous and exogenous substances be chemotactic?

Answer 84

Heck yes! bacterial products, cytokines, compliment proteins (C5), arachidonic acid metabolites (LTB4)

Question 85

what are leukocytes?

Answer 85

inflammatory cells

Question 86

leukocyte activation

Answer 86

activate when encounter certain substances: microbial products, cellular debris, mediators, etc.

Question 87

what are the 4 things inflammatory cells can do that other cells can’t do?

Answer 87

1) readily phagocytize material, 2) be poised to kill/degrade engulfed materials (nomnonmnom), 3) readily secrete material into extracellular environment to kill or degrade tissue, 4) produce inflammatory mediators to amplify inflammatory process

Question 88

phagocytosis

Answer 88

recognition/attachment of particle to leukocyte—> engulfment and formation of vacuole—> killing/degrading vacuolated material

Question 89

what are 2 ways for phagocytes to bind material?

Answer 89

1) receptors for specific products/microbes/necrotic cells, | 2) receptors for opsonins

Question 90

what the heck are opsonins?

Answer 90

host proteins present in blood or produced locally that coat microbes (IgG, C3b, collectins)

Question 91

what do ROS convert oxygen into when they oxidize NADPH?

Answer 91

SUPEROXIDE ION (toxic oxidizer)

Question 92

what does superoxide ion spontaneously become?

Answer 92

HYDROGEN PEROXIDE

Question 93

when in the presence of myeloperoxidase and chloride ions, what does hydrogen peroxide become?

Answer 93

HYPOCHLOROUS RADICAL (strong oxidizer

Question 94

what toxic compounds kill microbes and break down other materials like elastase and lysozyme?

Answer 94

OTHER LYSOSOMAL ENZYMES

Question 95

what are NETs?

Answer 95

neutrophil extracellular traps. they are nuclear chromatin that act as scaffolding with embedded antimicrobial compounds providing and area of antimicrobial material that traps microbes. it takes the nucleus, extrudes complex, traps microbes, kills them

Question 96

what are the 3 general outcomes of inflammation?

Answer 96

resolution, chronic inflammation, scarring

Question 97

resolution of inflammation

Answer 97

only happens if the tissue can regenerate. occurs in a limited degree of injury (minimal damage). requires termination of inflammatory process

Question 98

chronic inflammation

Answer 98

generally occurs when the offending agent not removed by acute inflammation so the system transitions to chronic. can be prolonged, followed by resolution or scarring. doesn’t always follow acute inflammation.

Question 99

scarring

Answer 99

occurs when tissue can’t regenerate, after considerable destruction. results from tissue being filled in by connective tissue elements, can significantly impair function

Question 100

summarize for me how host tissue damage can occur (3 things)

Answer 100

tissue surrounding infectious agents, cleaning up necrotic tissue by inflammatory process may cause damage, inflammatory process directed against host tissue

Question 101

what are the general points about acute inflammation?

Answer 101

often presented as sequential steps, but can occur w/ chronic inflammation. mononuclear cell infiltrate (cells with small round nuclei), tissue destruction, repair

Question 102

what 3 settings are characterized by chronic inflammation?

Answer 102

persistent infections, immune mediated diseases, prolonged exposure to toxins

Question 103

persistent infections and chronic inflammation

Answer 103

some infections difficult to eliminate or stimulate a response to—> associated with delayed hypersensitivity reaction

Question 104

immune mediated diseases and chronic inflammation

Answer 104

autoimmune diseases, allergic diseases (endogenous response)

Question 105

prolonged exposure to toxins and chronic inflammation

Answer 105

exogenous substances that can’t be broken down/removed promote inflammation (constant low grade stimulation). endogenous substances may do this as well

Question 106

macrophage

Answer 106

blood monocyte. circulates for a day and gives rise to macrophages in tissues throughout body. sometimes given names specific to location (Kupffer cells in liver). All are same origin, basic function

Question 107

what are the roles of macrophages?

Answer 107

ingest microbes/cellular debris. initiate tissue repair (fibrosis/scar)

Question 108

classical activation of macrophages:

Answer 108

endotoxin, IFN-gamma, foreign material

Question 109

classical activation of macrophage production:

Answer 109

ROS, NO, lysozymal enzymes, proinflammatory cytokines

Question 110

classical activation of macrophage function:

Answer 110

killing microbes, chronic inflammation

Question 111

alternative activation of macrophage:

Answer 111

IL-4, IL-13 (from eosinophils, T-cells, mast cells)

Question 112

alternative activation of macrophage production:

Answer 112

growth factors for new vessels, fibroblast activation

Question 113

alternative activation of macrophage function:

Answer 113

tissue repair, fibrosis

Question 114

lymphocytes

Answer 114

barely noticeable in cytoplasm, involved large variety of inflammatory responses. many chronic disorders mediated by lymphocytes. activation is a function of adaptive immunity

Question 115

what are the 3 classes of CD4+T cells that promote inflammation?

Answer 115

TH1 CD4+ T lymphocytes secrete IFN-ɣ: activates classical pathway macrophages. TH2 CD4+ T lymphocytes secrete IL-4, IL-5, IL-13: activates alternative pathway macrophages; also activates eosinophils. TH17 CD4+ T lymphocytes secrete IL-17: recruitment of neutrophils and monocytes

Question 116

eosinophils

Answer 116

bright red granules, bilobed nuclei. recruitment is similar to neutrophils, but includes specific chemokines (eotaxin)

Question 117

what are the 2 notable scenarios you would notice eosinophils in?

Answer 117

parasitic infections (have major basic protein toxic to parasites), allergic reactions mediated by IgE

Question 118

mast cells

Answer 118

involved acute/chronic inflammation. network of cells in body, can quickly release mediators (histamine, arachidonic acid, etc), coated with IgE to trigger mediator release. well known for allergic involvement-wide distribution and quick response to infections

Question 119

granuloma

Answer 119

enlarged macrophages form a nodule, surrounded by lymphocytes. form around organisms and prevent their spread.

Question 120

can organisms/infections remain viable once sequestered by an granuloma?

Answer 120

YES!

Question 121

what would a granuloma lead you to investigate further?

Answer 121

inflammatory reactions not eradicated by reactions (leprosy, tuberculosis), some immune mediated diseases (crohns), foreign material, sarcoidosis (last resort diagnosis)

Question 122

what are the mediators produced that are responsible for many systemic effects?

Answer 122

TNF, IL-1, IL-6

Question 123

fever

Answer 123

vascular cells in hypothalmus are stimulated by pyrogens to produce prostaglandins (PGE2). Act locally to cause central increase of body temp. exogenous pyrogens cause leukocytes to release endogenous pyrogens (act on hypothalamus vasculature) and can also act directly on hypothalmus vasculature

Question 124

what is the increased acute phase of proteins in the blood in response to?

Answer 124

IL-6 hepatocytes. produce several proteins in greater abundance. clinically used to detect and monitor progress of inflammatory processes.

Question 125

what are 2 proteins that adhere to cell walls and act as possible opsonins?

Answer 125

C reactive protein (CRP), Serum Amyloid A (SAA)

Question 126

fibrinogen

Answer 126

binds RBCs to make them into stacks that sediment. this becomes the basis of the erythrocyte sedimentation rate (ESR) to test for inflammation

Question 127

leukocytosis

Answer 127

increased leukocytes in the blood. WBC increase systemically in inflammation. TNF and IL-1 cause more to be released from bone marrow. may see increased number of immature WBC (left shift of leukocytes).

Question 128

continued inflammation leads to increased production of??

Answer 128

colony stimulating factors (CSF). increase bone marrow production of leukocytes

Question 129

neutrophilia is/is in response to?

Answer 129

increased nuetrophils, bacterial infection

Question 130

lymphocytosis is/is in response to?

Answer 130

increased lymphocytes, viral infection

Question 131

eosinophilia is/is in response to?

Answer 131

increased eosinophils, asthma/parasitic infections

Question 132

leukopenia is/is in response to?

Answer 132

specific infections (eg: typhoid fever)

Question 133

give me a synopsis of mediators

Answer 133

produced at site of inflammation or by the liver to be activated at site of inflammation. once they are released they have a short lifespan. they are activated by specific receptors, some have broad and non-specific effects

Question 134

mediators can be:

Answer 134

reformed for secretion, synthesized on demand

Question 135

what are cell derived mediators?

Answer 135

vasoactive amines, ARACHIDONIC ACID METABOLITES, platelet-activating factor, cytokines, ROS, NO, lysosomal enzymes, neuropeptides

Question 136

what are plasma protein derived mediators?

Answer 136

COMPLIMENT, coagulation and kinin

Question 137

vasoactive amines

Answer 137

histamine and serotonin. Stored in cells for quick release/repsonse.

Question 138

serotonin

Answer 138

vasoconstriction to aid in clotting, present in platelet granules

Question 139

histamine

Answer 139

arterial dilator and endothelial contractor. Mast cells, basophils, platelets.

Question 140

when do mast cells release histamine?

Answer 140

physical features (mechanical, temp), immune (IgE bind), compliment (C3a, C5a), histamine releasing proteins (from leukocytes), neuropeptides, cytokines (IL-1 or 8)

Question 141

arachidonic acid metabolites (AA)

Answer 141

derived from cell membrane phospholipids, transformed into compounds that mediate inflammation and homeostasis. from leukocytes, mast cells, endothelium, platelets.

Question 142

how is AA deactivated?

Answer 142

spontaneous decay and enzymes

Question 143

what are the 2 paths that form AA?

Answer 143

1)cyclooxygenase (results in prostaglandins and thromboxanes), 2)lipoxygenase (results in leukotrienes and lipoxins)

Question 144

prostaglandins

Answer 144

vasodilation

Question 145

thromboxanes

Answer 145

vasoconstriction

Question 146

leukotrienes

Answer 146

vascular permeability. mediate specific functions of inflammation. LTB4=chemotactic for neutrophils. LTC4, LTD4, LTE4=vascular permeability

Question 147

lipoxins

Answer 147

inhibit endothelial adhesion/chemotaxis. generated as leukocytes enter tissue. antagonize leukotrienes-anti inflammatory.

Question 148

what popular medications block the AA formation paths?

Answer 148

NSAIDs block cyclooxyrgenase, glucocorticoids block phospholipase A2 (shut down whole path)

Question 149

prostaglandins and thromboxjnes

Answer 149

prostoglandins contribute to pain and fever symptoms. presence of enzymes determines the compounds of a specific AA path.

Question 150

cytokines

Answer 150

polypeptides that function as mediators in innate and adaptive immune system.

Question 151

list the 2 important acute inflammatory cytokines

Answer 151

TNF and IL-1

Question 152

What do TNF and IL1 do?

Answer 152

produced mostly in macrophages, mast cells, endothelial cells. stimulated by microbial products, immune complexes, endothelial cells. cause endothelial activation, induce systemic effects of inflammation

Question 153

chemokines

Answer 153

subset of cytokines. small proteins separated into 2 groups (CXC, CC) based on structure. function in chemotaxis, also activate leukocytes

Question 154

CXC

Answer 154

chemotactic for neutrophils

Question 155

CC

Answer 155

chemotactic for variety of cells

Question 156

what are 2 important chronic inflammatory cytokines?

Answer 156

IFN-γ, IL-12

Question 157

IFN-γ

Answer 157

stimulates classical macrophage activation

Question 158

IL-12

Answer 158

stimulates growth and function of T cells

Question 159

ROS

Answer 159

released from activated neutrophils and macrophages. NADPH oxidase path. Superoxide ion changes to OH ion. can be reduced to a radical or converted to hypochlorous radical (BLEACH) vial myeloperoxidase in neutorphils.

Question 160

NO

Answer 160

free radical that can be used to kill microbes. mediator vasodilation (antagonizes platelet activation, reduces leukocyte recruitment/attachment). Made by Nitric Oxide synthase (NOS) from L-arginine.

Question 161

type 2 inducible NOS

Answer 161

induced by macrophages and endothelial cells. responsible for NO inflammation

Question 162

type 3 endothelial NOS

Answer 162

constitutively expressed in endothelial cells

Question 163

Lysosomal enzymes

Answer 163

azurophil granules of neutrophils and granules of monocytes. contain enzymes that can kill microbes and digest ingested materials. can damage host tissues (acid proteases, neutral proteases are active outside cell).

Question 164

protease inhibitors are present where?

Answer 164

in blood/body tissues to limit damage to host tissues. Alpha-1-antitrypsin (neutrophil elastase inhibitor-emphysema), alpha-2-macroglobullin (inhibits proteinases-eg collagenase)

Question 165

neuropeptiedes

Answer 165

initiate inflammation, active in vascular tone/permeability. active in lung and GI.

Question 166

what are some examples of neuropeptides?

Answer 166

Substance P. secreted by nerves/inflammatory cells. binds neurokinin-1-receptor. generates pro inflammatory effects in immune and epithelial cells

Question 167

complement

Answer 167

large number of plasma proteins involved with inflammation nd immunity. opsonize pathogens and induce inflammatory response to fight infection. final complement forms MAC. increase vascular permeability and leukocyte chemotaxis

Question 168

the components of complement system (C1-9) circulate as _________ molecules in ______.

Answer 168

inactive. plasma. activated by proteolysis. once activated can proteolyses and amplify the reaction (self activate). Key factor is C3 converts cleaving C3 into a and b.

Question 169

list the 3 separate paths for C3 converts formation:

Answer 169

1) classical: fixation of C1 to antigen-antibody complex. 2) alternative: microbe cell wall components combine with plasma proteins. 3) lectin: plasma letting binds microbial mannose and stimulates classical path

Question 170

what are the results of activated complement (5 things)?

Answer 170

C3a, C5a increase vascular permeability (stimulate mast cells to release histamine). C5a stimulates lipogenous path for AA metabolism. leukocytes are activated via C5a, 4a, 3a to increase endothelial adhesion. C3b is opsonin for enhanced phagocytosis. MAC.

Question 171

how do you block C1 activation and complement?

Answer 171

C1 inhibitor, Decay accelerating factor (DAF), and factor H

Question 172

what is factor XII (Hageman factor?

Answer 172

an important clotting factor that activates the kinin system, leading to bradykinin (increases vascular permeability, dilation, pain). activates the clotting cascade!

Question 173

what is Kallikrein?

Answer 173

an intermediate product that is chemotactic. it activates factor 7 but can self activate

Question 174

Factor Xa

Answer 174

leads to vascular permeability

Question 175

thrombin

Answer 175

binds protease activated receptors on endothelial cells, activating them. cleaves fibrinogen (to make fibrinopeptides) to increase vascular permeability (chemotactic). cleaves complement factor 5 to form factor 5a.

Question 176

what is activated when he clotting system is activated?

Answer 176

the fibrinolytic system (active inflammatory mediators)

Question 177

anti-inflammation

Answer 177

factors serving to antagonize driving/facilitating mediators of inflammation to allow for a baseline. lipoxins, compliment regulatory proteins (C1 inhibitor), IL-10, TGF-beta

Question 178

lipoxins

Answer 178

antagonize leukotreines (anit-inflammatory mediator)

Question 179

IL-10

Answer 179

secreted by macrophages. down regulates activated macrophages

Question 180

TGF-beta

Answer 180

promotes fibrosis. anti-inflammatory as process moves to scarring.

Question 181

what is the basic definition of tissue repair/healing?

Answer 181

restoration of tissue architecture and function if possible after injury

Question 182

regeneration of injured cells and tissues involves cell ________ which is driven by growth factors and is critically dependent on _________ of extracellular matrix

Answer 182

proliferation, integrity

Question 183

what cell types proliferate during repair

Answer 183

remnants of injured tissue (to restore normal structure), vascular endothelial cells (new vessels for repair), fibroblasts (source fibrous tissue to make scar)

Question 184

list the 3 groups of tissues that have an intrinsic proliferative capacity:

Answer 184

labile (continuously dividing), stable, permanent

Question 185

labile tissue

Answer 185

continuous turnover from stem cells and proliferation of mature cells. injured cells replaced by residual cells and stem cells if basement layer is intact.

Question 186

what tissues have labile tissue?

Answer 186

bone marrow, surface epithelia: skin, oral cavity, GI, ducts, urothelium, etc

Question 187

stable tissues

Answer 187

quiescent tissue (minimal replication even though capable in response to injury/loss). exception is liver since has robust capacity to regenerate. most have limited regeneration capacity.

Question 188

what are some examples of stable tissue?

Answer 188

parenchyma of most solid organs: liver, kidney, pancreas. also endothelial cells, fibroblasts, smooth muscle

Question 189

permanent tissue

Answer 189

terminally differentiated, can’t proliferate. limited stem cell replication and differentiation that is insufficient for regeneration. forms scars instead

Question 190

what are some examples of permanent tissue?

Answer 190

neurons, cardiac muscle

Question 191

do mature tissues carry variable proportions of the 3 groups of proliferative tissues?

Answer 191

yes! most tissues have some regeneration and scar formation

Question 192

stem cells summary

Answer 192

characterized by self renewal and asymmetric replication (can make daughter cells that have 2 fates), embryonic and adult

Question 193

embryonic stem cells

Answer 193

most undifferentiated, present in inner cell mass of blastocyst. can form ecto,endo, meso

Question 194

adult stem cells

Answer 194

tissue stem cells. less undifferentiated than ES cells, found in organ or tissue. self renewal capacity. more restricted lineage potential. important for tissue homeostasis

Question 195

sources of cells to covered injured epithelium

Answer 195

skin: adjacent epithelial cells, hair follicle: follicles in skin

Question 196

growth factors

Answer 196

proteins that stimulate survival/proliferation of particular cells. may promote migration, differentiation, other cell responses.

Question 197

what (might) produce growth factors?

Answer 197

macrophages, lymphocytes, or parenchymal/stromal cells

Question 198

autocrine vs paracrine vs endocrine growth factor signalling

Answer 198

directly in cell, adjacent cells, distance/remote cells

Question 199

ECM definition

Answer 199

complex of several proteins that assembles into a network surrounding cells and makes up a large portion of any tissue. regulates proliferation, movement, differentiation of cells. is required for tissue regeneration and if it is damaged only a scar can form.

Question 200

list 3 components of ECM

Answer 200

1) fibrous structural proteins, 2) water hydrated gels, 3) adhesive glycoproteins

Question 201

what are the 2 basic forms of ECM?

Answer 201

interstitial matrix and basement membrane

Question 202

interstitial matrix

Answer 202

spaces btw connective tissues. made by mesenchyme. made of fibrillar and non fibrillar collagens. scaffolding (collagens, ellastins, proteoglycans)

Question 203

basement memberane

Answer 203

beneath epithelial, endothelial, smooth muscle cells. made by epithelium and mesenchyme. made of amorphous non-fibrilar type 4 collagen and laminin

Question 204

liver regeneration

Answer 204

robust. 40-60% of liver can be removed for transplant, can regenerate. can also regenerate if other injury/insults happen if framework intact. priming—> g0—> g1—> proliferation—> regeneration!

Question 205

scar formation

Answer 205

results when repair not possible by regeneration alone. replaces non-regenerated cells with connective tissue. sometimes just scar or combo of scar and cell regeneration

Question 206

what can cause scars?

Answer 206

tissue injury is severe or chronic, parenchymal cells and epithelia are damaged, non dividing cells are inured

Question 207

list the steps of scar formation (3):

Answer 207

angiogenesis, migration and proliferation of fibroblasts and deposition of connective tissue and agencies, maturation and reorganization of fibrous tissue

Question 208

give a very basic outline of angiogenesis:

Answer 208

vasodilation (triggered by NO), permeability by VEGF, separation of pericytes from albumin surface, sprout and migration to area of injury, proliferation, remodeling, recruitment of periendothelial cells, suppression

Question 209

what orchestrates the deposition of CT/scar?

Answer 209

locally procuced cytokines and GF: PDGF, FGF-2, TGF-BETA!!!!!

Question 210

what is the most important cytokine for synthesis and deposition of connective tissue proteins?

Answer 210

TGF-beta

Question 211

degradation of collagens/ECM components is accomplished by _________

Answer 211

MMP. matrix metalloproteinases. produced by a variety of cells, include interstitial collagenases, gelatinases, stromelysins. important for remodelling

Question 212

nutritional factors that influence tissue repair

Answer 212

impair collagen synthesis if shot tin protein and Vitamin C

Question 213

metabolic factors that influence tissue repair

Answer 213

delay repair if you have diabetes, are on glucocorticoids (inhibit TGF-beta production and diminish fibrosis)

Question 214

vascular factors that influence tissue repair

Answer 214

ischemia, venous drainage (poor perfusion if lack of resources). Thrombosis, arteriosclerosis and artherosclerosis, varicose veins

Question 215

what are 2 major considerations regarding whether repair will be effective or not?

Answer 215

if the inciting insult has been terminated or persists, if a new insult (infection) has been introduced

Question 216

what are some aberrations of cell growth and ECM production in healing?

Answer 216

hypertrophic scar (regresses from going outwards originally), keloid (does not regress)

Question 217

keloid

Answer 217

goes outside the bounds of initial repair. occurs in groups and families. pink/ropy collagen

Question 218

hypertrophic scars

Answer 218

look like keloids, but they regress. can cause contracture

Question 219

healing by first intention

Answer 219

epithelial regeneration is principal repair mechanism. superficial, clean wounds, not large. fibrous but not contracture. neutrophils—> fibrin clots—> angiogenesis—> granulation—> epithelial regeneration

Question 220

healing by second intention

Answer 220

combination of regeneration and scarring. contracture occurs via myofibroblasts to contract tissue together. inflammation is more intense, larger area to fill in and regrow

Question 221

NSAID (non-steroidal anti-inflammatory drug)

Answer 221

drugs whose therapeutic action is to reduce pain and inflammation caused by COX1 and 2, as well as decrease production of inflammatory prostaglandins and thromboxjnes

Question 222

can NSAIDs have undesirable side effects?

Answer 222

yes. prostaglandins mediate physiologic maintenance functions, and inhibition can cause predictable side effects in tissues (we know what it will do though so that’s good)

Question 223

what are some major therapeutic uses of NSAIDs?

Answer 223

analgesia, antipyretic effect, anti inflammatory, antithrombogenesis

Question 224

analgesia

Answer 224

inhibits inducible COX2 at injury site. low to moderate intense pain relief. intermediate dose, prn dosing.

Question 225

antipyretic effect

Answer 225

inhibits inducible COX2 in hypothalmus. fever reduction! (anti-pyretic, anti fire!) intermediate dosing, prn dosing.

Question 226

anti inflammatory

Answer 226

inhibition of inducible COX2 at sites of inflammation. treats RA. hi doses, scheduled dosing, based on half life

Question 227

antithrombogenesis

Answer 227

inhibits COX1 in platelets. primary and secondary MI risk reduction. low dose, daily.

Question 228

GI side effects NSAIDs

Answer 228

inhibits constitutive COX1 in gastric cells=ulceration, bleeding, nausea

Question 229

increased incidence of bleeding problems side effects NSAIDs are due to?

Answer 229

COX1 inhibit in platelets

Question 230

renal side effects NSAIDs

Answer 230

inhibition of COX 1, 2 in kidney cells=acute renal failure and interstitial nephritis

Question 231

uterine side effects NSAIDs

Answer 231

inhibition of COX2 in smooth m.= interference uterine contractions late term pregnancy

Question 232

increased thrombotic events side effects NSAIDs

Answer 232

unopposed inhibition of COX2 in vascular endothelial cells=potential for increased cardiovascular events, including MI and stroke

Question 233

traditional NSAIDS (reversible vs irreversible, action/classes)

Answer 233

reversible, COX1 AND 2. chemical classes are: “SOAPPy” (Salicylates, Oxicam derivatives, Acetic/carboxylic acids, Propionic acid derivatives, PYrazolone derivatives)

Question 234

salicylates

Answer 234

analgesic, antypyretic, anti-inflammatory

Question 235

pyrazolone derivatives

Answer 235

analgesic, antipyretic, anti inflammatory. more potent/longer lasting than aspirin, serious toxicities with misuse/chronic use

Question 236

acetine/carboxylic acids

Answer 236

analgesic, antipyretic, anti inflammatory. fewer toxic rxns than pyrazolone, but many more adverse rxns related to idomethicin. limited generally to arthritis that don’t respond

Question 237

oxicam derivatives

Answer 237

anlagesic, antiipyretic, anti inflammatory. potent, long half life (15-50hrs)

Question 238

propionic acid derivatives

Answer 238

analgesic, antipyretic, anti inflammatory. tolerated well, some OTC

Question 239

acetaminophen (reversible vs irreversible, action/classes)

Answer 239

NO inhibition COX1, 2 in PERIPHERY. inhibits COX2 in CNS. analgesic, antipyretic properties. less GI side effects

Question 240

COX2 selective inhibitors (reversible vs irreversible, action/classes)

Answer 240

Seslective, reversible COX2 inhibition. analgesic, antipyretic, anti inflammatory. less GI side effects.

Question 241

asprin (reversible vs irreversible, action/classes)

Answer 241

irreversible inhibition of COX1, 2. analgesic, antipyretic, anti-inflammatory, antithrombotic

Question 242

list some traditional NSAIDS:

Answer 242

ibuprophen, naproxen, ketoprofen

Question 243

traditional NSAID actions

Answer 243

anti inflammatory, antipyretic, analgesic effects. rapidly/completely absorbed (>90% protein bound, renal excretion or liver metabolism). as effective as ASA or acetaminophen for mild/moderate point.

Question 244

traditional NSAID side effects-GI

Answer 244

interfere with gastric cytoprotection via COX1 PGE sytnesis—> sypepsia and gastric ulceration. lowest risk with ibuprophen, highest with naproxen. food or antacids can help. PPI protect against gastroduodenal toxicity

Question 245

traditional NSAID side effects-Platelets

Answer 245

interfere with platelet aggregation by inhibition cox1 thromboxane a2 synthesis (promotes bleeding). effect is 4-7 days ( life of platelet). should keep patients on regular NSAID use off of anticoagulants or vice versa

Question 246

traditional NSAID side effects-Kidney

Answer 246

cause renal vasoconstriction by inhibiting COX1, COX2 PGE synthesis and loss of vasodilator actions-reversible renal insufficiency. can cause fluid retention, which can exacerbate heart failure. avoid if hypertension if diabetes, ckd, heart failure. lowest cardiovascular risk with naproxen.

Question 247

how do cox 2 selective inhibitors work? (celecoxib/celebrex in particular)

Answer 247

all possess anlageisc, antypyretic anti inflammatory action. selectively reversible for COX 2 over 1 by 5-7 fold for celexoib. well absorbed and well exreted. metabolized by cyp2c9, long half life. used for RA, osteoarthritis, acute pain. less gastroduodenal toxicity to doses that provide pain relief than non selective NSAIDS. could reduce antithrombotic PGI2 activity. increases risk of CVD and HF in dose dependent manner. can precipitate acute renal failure, avoid use in at risk patients. can trigger sulfa allergy

Question 248

how do cox 2 selective inhibitors work (acetaminophen in particular)

Answer 248

equal to aspirin as analgesic/antipyretic. less anti inflammatory properties, possibly selective for inhibition of CNS prostaglandin synthesis. mild to moderate pain. inadequate alone for inflammatory conditions. peak absorption is in 30-60 min, related to gastric emptying. metabolized in large doses=liver toxic (depletes glutathione stores). hepatotoxicity is biggest and most common concern. limit to less than 4000 mg in 24hrs.

Question 249

how do cox 2 selective inhibitors work? (aspirin in particular)

Answer 249

inhibits COX1 and 2. reduces mild to moderate pain of inflammatory origin. less effective in visceral pain. initial RA therapy and other inflammatory conditions, reduces elevated body temp, inhibits platelet aggregation. rapid absorption from small intestine. GI irritation minimized if pH >3.5. high plasma protein binding-may lead to displacement. avoids in: ulcers, alcoholics, older NSAIDs (warfarin), pregnancy, chronic renal insufficiency, asthma.

Question 250

aspirin poisoning

Answer 250

once frequent in children. mild is headache, dizzy, tinnitus, visual disturbances, mental confusion, drowsiness, sweating, thirst, hyperventilation, diarrhea. acute is: vomiting, fever, sweating, respiratory alkalosis, metabolic acidosis, death

Question 251

cyclooxygenase

Answer 251

critical enzyme in path for production of prostaglandins and thromboxanes from arachidonic acid. PGG/PGH synthase. no drugs currently inhibit isomerases/synthases.

Question 252

COX2 induced by?

Answer 252

cytokines, shear stress, GF, or up regulated as needed or for specialized functions. located inflamed/activated tissues.

Question 253

areas of pain/inflammation (PGE2/PGI2)

Answer 253

enhance edema formation, leukocyte infiltration via vasodilation

Question 254

hypothalmus/fever (PGE2)

Answer 254

increase heat generation and decrease in heat loss

Question 255

kidneys (PGE2/PGI2)

Answer 255

renal adaptation to stresses via maintenance of renal blood flow. most critical in elderly

Question 256

NSAIDS that inhibit COX1 result in:

Answer 256

potential side effects: GI ulceration, prolonged bleeding time, acute renal failure

Question 257

NSAIDS that inhibit COX2 would result in:

Answer 257

therapeutic actions (relief pain, fever reduction, inflammation reduction), potential side effects (acute renal failure, thrombotic events, prolonged gestation

Question 258

5-lipoxygenase

Answer 258

enzyme in path for production of leukotrienes from AA. LTB4—> mast cells, eonsinophils, basophils, macrophages—> becomes CysLTs LTC4, LTD4, LTE4—>mediated by receptors.

Question 259

LTB4 stimulates what?

Answer 259

neutrophil chemotaxis, aggregation, transmigration through endothelium

Question 260

LTC4/LTD4/LTE4 stimulate what?

Answer 260

increased vascular permeability, bronchoconstriciton, vasoconstritction. role in asthma, psoriasis, arthritic process.

Question 261

glucocorticoids

Answer 261

involved in carb and protein metabolism and anti-inflammatory response. cortisol is prototype hormone. only glucocorticoids have anti-inflammatory activity

Question 262

mineralocorticoids

Answer 262

involved sodium retention. aldosterone is prototype hormone

Question 263

adrenal androgens

Answer 263

increased release occurs in concert with cortisol, but not aldosterone. DHEA and androstenedione have weak androgen activity, some is converted to testosterone and estradiol outside of adrenals

Question 264

regulation of secretion and synthesis of adrenal corticosteroids

Answer 264

ACTH release controlled by corticotropin-releasingg factor from hypothalmus. glucocorticoids and androgens are controlled by AcTH action last adrenal cortex.

Question 265

diurnal rhythm of basal steroidogenesis

Answer 265

entrained by higher neuronal centers that release CRH from hypothalmus in response to sleep wake cycles

Question 266

negative feedback regulation via circulating corticosteroids

Answer 266

endogenous hormones and exogenous agents used in therapy. hypothalmus and pituitary decrease ACTH release and steroidogenesis.

Question 267

what can suppress HPA axis and result in adrenal crisis?

Answer 267

chronic use of pharmacologic doses of glucocorticoids

Question 268

glucocorticoid path is a ______limited system with synthetic enzymes in excess that provide for rapid responsiveness.

Answer 268

substrate. rate limiting is cholesterol—>pregnelonone. ACTH stimulates this in zone fasted and reticularis. inhibited by metyrpone and mitotane

Question 269

mineralocorticoid path in ______ has 18-OH-steroid dehydrogenase enzyme that converts corticosterone to aldosterone.

Answer 269

zona glomerulosa. | renin angiotensin system stimulates conversion of cholesterol to pregnenolone and cortiosterone to aldosterone.

Question 270

what is the mechanism of action of glucocorticoids?

Answer 270

most actions are mediated by widely distributed glucocorticoid receptors. cortisol as CBG enters cell—> binds to systolic receptor to release Hsp90 for dimerization of S-R complex (transcription regulated)—> effects on protein synthesis result in delayed onset

Question 271

does secretion of glucocorticoids change circadian rhythm?

Answer 271

YES! ACTH pulses govern cortisol changes (peak post mea and in AM)

Question 272

how is glucocorticoid removed from circulation?

Answer 272

via the liver.

Question 273

Describe the regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal gland axis, especially as it relates to the mechanism of glucocorticoid drug-induced suppression of adrenal gland function

Answer 273

• Diurnal rhythm of basal steroidogenesis, entrained by higher neuronal centers that release CRH from hypothalamus in response to sleep-wake cycles —>ACTH release —>cortisol release • Negative feedback regulation by circulating corticosteroids (both endogenous hormones and exogenous agents used in therapy) at the hypothalamus and pituitary decreases ACTH release and steroidogenesis. NOTE: Chronic use of pharmacologic doses of glucocorticoids can suppress the HPA axis and result in adrenal atrophy and insufficient adrenal response to environmental stressors —> adrenal crisis. • Stress (injury, hemorrhage, severe infection, surgery, hypoglycemia, cold, pain, fear) can override negative feedback and produce marked increases in steroidogenesis.

Question 274

Describe the metabolic and mineralocorticoid effects of associated with glucocorticoids and explain how these effects can result in serious adverse effects when they are used as pharmacotherapeutic agents.

Answer 274

structural changes can be made to produce glucocorticoid drugs with altered protein binding, prolonged half life, separation of mineralocorticoid and glucocorticoid activity. Carbohydrate stimulate gluconeogenesis—> increased blood glucose (increased insulin release)—> gluconeogenesis—> liver glycogen deposition. protein increased aa uptake into liver/kidney—> decreased protein synthesis—> net aa transfer from muscle to liver (muscle wasting). lipid inhibit uptake glucose by fat—> lipolysis—> lipogenic effect in central tissue. net physiologic result: maintenance of glucose supply to brain. anti inflammatory effects (decreased synthesis of inflammatory and immune mediators), immunosuppressive effects (suppress t cell activation, decreased healing/immunity), reduced vasodilation, reduced accumulation of activation of cells (decreased leukocytes in acute inflammation, decreased monocytes/lymphocytes in chronic inflammation, decreased clonal expansion T/B cells.

Question 275

Hydrocortisone (Solu-Cortef®) describe • Mechanism of anti-inflammatory and immunosuppressive actions • Metabolic pathways – activating vs inactivating • General clinical uses • Dosing considerations / formulations • Toxicities (distinguish acute vs chronic vs withdrawal)

Answer 275

Common use in physiologic doses for replacement therapy and emergencies; glucocorticoid and mineralocorticoid actions [1:1]; administered orally and parenterally

Question 276

Prednisone —> Prednisolone describe • Mechanism of anti-inflammatory and immunosuppressive actions • Metabolic pathways – activating vs inactivating • General clinical uses • Dosing considerations / formulations • Toxicities (distinguish acute vs chronic vs withdrawal)

Answer 276

Most commonly used oral agent when steroid burst therapy desired; glucocorticoid and mineralocorticoid actions [13:1]; activated to prednisolone in liver. NO topical activity, not activated until first pass hepatic metabolism.

Question 277

Methylprednisolone (Solu-Medrol®) describe • Mechanism of anti-inflammatory and immunosuppressive actions • Metabolic pathways – activating vs inactivating • General clinical uses • Dosing considerations / formulations • Toxicities (distinguish acute vs chronic vs withdrawal)

Answer 277

Used if parenteral administration desired for steroid burst (no better than oral prednisone in acute exacerbations of asthma); minimal mineralocorticoid action. Oral (Medrol) and parenteral (Solu-Medrol)

Question 278

Dexamethasone (Decadron®) describe • Mechanism of anti-inflammatory and immunosuppressive actions • Metabolic pathways – activating vs inactivating • General clinical uses • Dosing considerations / formulations • Toxicities (distinguish acute vs chronic vs withdrawal)

Answer 278

Most potent anti-inflammatory agent, used in cerebral edema, chemotherapy-induced vomiting; no mineralocorticoid action, greatest suppression of ACTH secretion at pituitary.

Question 279

Triamcinolone (Kenalog®) describe • Mechanism of anti-inflammatory and immunosuppressive actions • Metabolic pathways – activating vs inactivating • General clinical uses • Dosing considerations / formulations • Toxicities (distinguish acute vs chronic vs withdrawal)

Answer 279

Potent systemic agent - excellent topical activity; no mineralocorticoid action

Question 280

Explain the rationale for alternate day therapy and tapered withdrawal following chronic therapy with glucocorticoids

Answer 280

Consider seriousness of disease, minimal amount for desired effect, duration of therapy. Always reduce dosage as soon as therapeutic objectives are obtained. If using large doses, advisable to use shorter-acting agent with little mineralocorticoid effect. Alternate day schedule can minimize adverse effects (lessens growth-suppressive effects because anti-inflammatory actions apparently outlast suppressive effect on HPA axis); make gradual transition to alternate day schedule after control of disease achieved. Terminate administration gradually if taken longer than 7-10 to 28 days, otherwise may cause severe rebound of disease or symptoms of adrenal insufficiency (adrenal crisis).

Question 281

physiologic actions of mineralocorticoids

Answer 281

aldosterone binds to cystolic receptor, migrates to nucleus to induce mRNA formation to synthesize proteins. insertion of protein into membrane increases sodium reabsorption, increased secretion of H and K.

Question 282

mineralocorticoid activity vs glucocorticoid activity

Answer 282

mineralocorticoid=salt retaining action at kidney. glucocorticoid=metabolic effects.

Question 283

metabolism of glucocorticoids

Answer 283

liver: 11beta-HSD1 converts cortisone to cortisol (activating. also prednisone to prednisolone). kidney 11beta-HSD2 converts cortisol to cortisone (inactivating). fetus placental 11beta-HSD2 is active but not HSD1 (liver isn’t functional), so use agent that is poor substrate for 11betaHSD2

Question 284

rheumatoid arthritis is managed with what 3 categories of drugs?

Answer 284

nonsteroidal anti inflammatory drugs, glucocorticoids, disease modifying antirheumatic drugs (DMARDs)

Question 285

early RA is controlled with what?

Answer 285

NSAIDS. then DMARDS are added when the diagnosis is certain

Question 286

what is used as a “bridge” to reduce disease activity in slower acting DMARDS when treating RA?

Answer 286

low dose glucocorticoids. also used as adjunctive therapy when active disease persists through DMARDS

Question 287

mineralocorticoid toxicities effects (acute, short course, high dose)

Answer 287

na and h20 retention—>edema—> increased BP, hypokalemia

Question 288

glucocorticoid toxicities effects (acute, short course, high dose)

Answer 288

glucose intolerance, mood changes, insomnia, GI upset

Question 289

glucocorticoid effects high dose sustained therapy side effects (more than 2 weeks)

Answer 289

iatrogenic cushings syndrome, hypothalmic-pituitary-adrenal axis suppression, mood disturbance, impaired wound healing, increased susceptibility to infection

Question 290

possible effects with large, cumulative doses of glucocorticoids

Answer 290

osteoporosis, posterior capsular cataracts, skin atrophy or loss of collagen support, growth retardation, peptic ulceration

Question 291

hemodynamics

Answer 291

hydrostatic and osmotic forces are nearly balanced. want a controlled movement of fluid from tissues into the body cavities. eg: if high capillary hydrostatic pressure fluid and salts into the interstitial space. venous area has concentration of proteins to pull back in. usually fairly equal pressure, only a small amount of fluid is leftover and collected by the lymph

Question 292

problems with hemodynamics

Answer 292

extravasation (buildup of fluid in tissues—>edema, and natural spaces—>effusion). due to decreases in plasma oncotic pressure, increased permeability, lymph drainage exceeded.

Question 293

transudate

Answer 293

vascular wall=intact. increased hydrostatic pressure, reduced oncotic pressure. usually just fluid without extra proteins and such

Question 294

exudate

Answer 294

increased permeability of vascular wall. inflammation—> endothelial cells contract to make small gaps. direct damage to endothelial cells. proteins move across into interstitial space. can cause damage b/c things moving across that shouldn’t be

Question 295

transudate: etiology, specific gravity, protein concentration, protein fluid/serum ratio, LDH fluid/serum ratio, glucose fluid/serum ratio, WBC

Answer 295

ultrafiltrate of plasma (increased hydrostatic pressure and/or reduced oncotic pressure). less than 1, less than 3, less than 0.5, less than .6, greater than 0.5, few WBC. essentially: less (except glucose)

Question 296

exudate: etiology, specific gravity, protein concentration, protein fluid/serum ratio, LDH fluid/serum ratio, glucose fluid/serum ratio, WBC

Answer 296

increased vessel permeability due to inflammation. greater than 1, greater than 3, greater than .5, greater than .6, less than .5, many WBC. essentially: more (except glucose)

Question 297

which should have a higher specific gravity, exudate or transudate?

Answer 297

exudate

Question 298

increased blood volume

Answer 298

too much blood volume systemically or in a specific area.

Question 299

hyperemia

Answer 299

physiologic: active! (inflammation, exercise, etc.). arteriolar dilation, oxygenated blood: red

Question 300

congestion

Answer 300

pathologic: passive. impaired venous outflow (obstruction causes backup into capillaries/arterioles). deoxygenated blood: pale or red/blue. low nutrient/oxygen blood that can’t move. get ischemia of adjacent tissue since not getting enough oxygen

Question 301

what are the 3 organs that cause issues if fluid problems in body?

Answer 301

heart, kidney, liver

Question 302

L heart failure

Answer 302

mostly due to scar tissue. not good output=peripheral tissue is not perfused well. fluid buildup in lungs. Kidney hates this, not enough fluid in vasculature so it holds onto fluid, dilutes out proteins and decreases oncotic pressure. fluid gets stuck in legs and move up the body from there. Lungs and Legs and Kidney

Question 303

R heart failure

Answer 303

backs up into venous system. liver/portal circulation backs up you get portal congestion/liver congestion. oral system from gut goes to liver/spleen. fluid backs up into spleen. GI tract varies-dilated veins. then lots of fluid in organs, moves out of serosal surfaces—>acites. venous to liver to spleen to gut to organs to acites

Question 304

hemorrhage

Answer 304

blood outside of the vasculature into surrounding tissue. due to vessel damage (platelets and coag. factors can’t fix it). commonly due to trauma. impaired integrity of vessel walls, can be fixed if small but otherwise not. can’t keep up with constant capillary damage. Concern is WHERE damage is occuring. low level function of platelets, low level function of coagulation factors

Question 305

petichia

Answer 305

small, pinpoint hemorrhages. tiny capillary breaks

Question 306

purpura

Answer 306

>3mm.

Question 307

ecchymoses

Answer 307

bruise 1-2 cm

Question 308

hematoma

Answer 308

within tissue. placental abruption is example

Question 309

thrombosis

Answer 309

builds up in flowing blood occurs in layers (tell if pre/post mortem). out of control is when layers keep building up and up. layers=lines of Zahn (platelet, red cells, platelet, red cells, etc.) can be driven by Factor 5 leiden.

Question 310

Virchow triad

Answer 310

used for thrombosis. Endothelial injury, abnormal blood flow, hypercoagulability

Question 311

thromboembolus

Answer 311

most common type of embolus. largely driven by stasis. DVT (immobility: recent surgery, estrogen, pregnancy/post partum, previous/current cancer, coagulation abnormalities, limb trauma/orthopedic procedures, obesity).

Question 312

embolis

Answer 312

fluid/gas/solid mass floating in blood that shouldn’t be! pro-coagulant states push this. travels through big vessels to small ones of the pulmonary vessels. severity depends on what is blocked and how large the block is

Question 313

do you get thrombi in arterial flow areas?

Answer 313

not typically since flow is really fast

Question 314

can thrombosis and hemorrhage occur simultaneously?

Answer 314

yes! initially starts with too much clotting, something in vessels floats around in bloodstream damaging vessels. continued vessel damage can lead to lack of sufficient platelets/clotting factors, so you bleed. otherwise issues can lead to thrombosis.

Question 315

disseminated intravascular coagulation (DIC)

Answer 315

lots of little clots. symptoms from multiple organ systems (respiratory insufficiency, MSC, convulsions, acute renal failure, peticiae/purpura, GI, oral hemorrhage). shock. hemolytic anemia, thrmobocytopenia, low fibrinogen, elevated D-dimer and other fibrin degradation products

Question 316

infarction

Answer 316

tissue death (necrosis) caused by vessel occlusion. typically coagulative necrosis caused. liquefactive necrosis is caused in the brain. damaged tissue gets replaced by scar tissue (generally), doesn’t work so well anymore…

Question 317

white infarction

Answer 317

dense tissue where you block off an artery. single blood supply. no reperfusion. dense tissue.

Question 318

red infarction

Answer 318

involved blood flow. temporarily block off, it comes back and you get hemorrhage. dual blood supply. reperfusion. loose tissue.

Question 319

shock

Answer 319

not enough blood, heart isn’t pumping enough blood to tissues. circulating blood volume is inadequate to perfuse tissues (can lead to multigrain dysfunction/damage).

Question 320

cardiogenic shock

Answer 320

myocardial pump failure. myocardial damage, extrinsic compression, outflow obstruction

Question 321

hypovolemic shock

Answer 321

low blood volume. severe dehydration, hemorrhage, burns

Question 322

can you have hypovolemic and cariogenic shock?

Answer 322

YES! low cardiac output+low BP=vasoconstriction, increased heart rate, recall conservation of fluid. skin is cool and pale, tachycardia, low urine output

Question 323

SIRS (systemic inflammatory response syndrome)

Answer 323

type of shock we go into due to significant inflammatory shock. eg: septic shock (microbial infection, subset of SIRS). often not responsive to IV fluids. arterial vasodilation, vascular leakage, venous blood pooling

Question 324

development from organism perspective

Answer 324

early on=highly orchestrated, dynamic program. results in formation of specialized tissues, organs, systems. very dynamic state

Question 325

development from cellular perspective

Answer 325

dramatic change in: proliferation (1 to billions), death (apoptosis), differentiation (totipotent—>organs/tissues), programmed cell death creates spaces, cell migration, cell-cell interactions

Question 326

adult organism homeostasis

Answer 326

highly orchestrated, static program that provides optimal function of specialized tissues/organs/organ system. once you have adult, goal is to NOT proliferate, resulting in functional organs

Question 327

continuously dividing tissues

Answer 327

constant turnover (benign and malignant neoplasm). skin, gut, epithelia, hematopoietic system

Question 328

quiescent tissue

Answer 328

normally little/no turnover. capacity to turnover if needed. hepatocytes, liver

Question 329

non dividing tissues

Answer 329

little to no proliferative capacity. brain development = post mitotic. CNS neurons, cardiac muscle

Question 330

mechanisms of maintenance: external environment interactions

Answer 330

physical environment, infectious agents, inhaled/ingested substances

Question 331

mechanisms of maintenance: cell extrinsic; macroenvironment

Answer 331

circulating factors, hormones, cytokines

Question 332

mechanisms of maintenance: cell extrinsic; microenvironment

Answer 332

extracellular matrix, stroma, growth factor, inflammatory mile

Question 333

mechanisms of maintenance: cell intrinsic

Answer 333

differentiation program. age of cell

Question 334

mechanisms of maintenance-pathology

Answer 334

when homeostatic balance is disturbed, pathology results.

Question 335

list the 3 disorders of cell growth

Answer 335

hypertrophy, hyperplasia, neoplasia

Question 336

neoplasia

Answer 336

new formation. progressive, unchecked increase in cell number. non invasive, non metastatic=benign. clonal process. pathologic and irreversible. “tumor”. disruption of normal homeostatic mechanisms

Question 337

neoplasia-global mechanistic hallmarks

Answer 337

altered cell-autonomous mechanisms (activate oncogenes, inactivate tumor suppressor), cell non autonomous mechanisms (altered microenvironment: contribution of immune system can be important driving force. altered macroenvironment: breast cancer is example, hormonal force if counteracted impacts tumor growth)

Question 338

bengin neoplasms

Answer 338

don’t invade/metastasize. caused injury via compression/interference. treatment is surgical in most cases. tumor in essential spot, nowhere for organs to go (brainstem) can be fatal even though not invading. circumscribed/encapsulated. necrosis uncommon

Question 339

malignant neoplasms

Answer 339

invade and METASTASIZE. cancer. cause injury with local tissue destruction and distant dissemination and tissue destruction. clinically very significant. how most cancers kill you. invasive, necrosis common

Question 340

microscopic pathologic features benign neoplasia

Answer 340

relatively well differentiated. low rate cell turnover. cytologic uniformity. boundary btw. tumor and adjacent tissue maintained

Question 341

microscopic pathologic features malignant neoplasia

Answer 341

variable differentiation. high rate of cell turnover. cytologic pleomorphism (cells differ markedly). loss of boundary btw tumor and tissue

Question 342

classifications by tissue of origin: benign neoplasia

Answer 342

epithelial, mesenchymal

Question 343

classifications by tissue of origin: malignant neoplasia

Answer 343

epithelial (carcinoma, subset adenocarcinoma), mesnchymal (sarcoma), hematopoietic (lymphoma, lukemia)

Question 344

clinical correlates benign neoplasia

Answer 344

treated by surgical resection alone. may recur. do not progress to malignancy except for benign, premalignant neoplasms (colonic adenoma)

Question 345

overview cancer pathology for me:

Answer 345

cancer cells change over time (neoplasm/tumors). heterogeneous population of cells, makes targeted therapies difficult. ongoing genetic alterations+selection=clonal evolution

Question 346

what’s the most common cancer?

Answer 346

carcionomas (cancers of epithelia)

Question 347

dysplasia

Answer 347

disordered growth. applied to epithelia, hallmark of early premalignant neoplasia. lose cytologic uniformity, lose normal histologic maturation, loss of architectural orientation. usually given a grade (low grade=less abnormal)

Question 348

what is carcinoma in situ?

Answer 348

looks like cancer but can’t yet demonstrate invasiveness

Question 349

histologic grades

Answer 349

degree of histologic differentiation. low grade-more differentiation, greater resemblance to normal. higher grade-less differentiation and resemblance to normal. grading scheme varies by tumor. low mitotic activity-low grade. can be predictive of biologic behavior, overall less reliable than disease stage

Question 350

what does tumor stage and clinical outcome risk/threat go up with?

Answer 350

N and M involvement of the TNM stage scale. lowest T stage is non-invasive. the deeper the tumor invades, the worse the prognosis, so higher T stage is worse prognosis. goes up with lymph involvement

Question 351

pediatric neoplasms

Answer 351

childhood neoplasms arise out of developing tissue-so they are different. origin n developmental (proliferative/migratory) precursors. recapitulate aspects of developmental program of tissue of origin. short latency and early metastasis. fewer mutations, prominent role for oncogenic fusions and epigenetic dysregulation. relative chemosensitivity

Question 352

what are the 2 characteristics of malignant tumors?

Answer 352

invasion and metastasis.

Question 353

invasion

Answer 353

infiltration of adjacent tissues by malignant cells

Question 354

metastasis

Answer 354

transfer of malignant cells from primary site to non -connected/secondary site. discontinuous with primary tumor

Question 355

carcinoma in situ

Answer 355

pre invasive stage. stays above basement membrane. common in skin, breast, other sites. precursor to cancer

Question 356

malignant tumors are ______ demarcated from surrounding tissue.

Answer 356

poorly. why it got name cancer (crab). invasive and can penetrate organ walls. surgical resection is difficult/impossible

Question 357

methods of cancer dissemination

Answer 357

1) direct seeding of body cavities/surfaces; 2) lymphatic spread; 3) hematogenous spread.

Question 358

list the steps of the metastatic cascade

Answer 358

invasion (through basement memb./ECM), intravasation (get into blood/lymph), extravasation (exit vessel at new site), colonization (grow in new site)

Question 359

why do cancers leave their original area of formation?

Answer 359

when conditions are crowded/harsh/ there is waste buildup.

Question 360

what are some additional hallmarks of cancer?

Answer 360

it has the capacity to modify cellular metabolism, it can evade immunological destruction (EMERGING hallmarks). It also has genomic instability and inflammation from immune cells can become tumor promoting (ENABLING CHARACTERISTICS).

Question 361

in the metastatic cascade, how do cancer cells interact with the ECM?

Answer 361

carcinoma cells must breach the basement membrane, traverse the connective tissue, intravasaste.

Question 362

_______ of ECM is an active process that involves several steps.

Answer 362

Invasion! loosens up E-cadherin, degrades ECM, attaches ECM components, the cells migrate

Question 363

how do cancers dissociate cells from each other?

Answer 363

they alter molecular adhesions. Ecadherin is down regulated, which facilitates detachment.

Question 364

how is the basement membrane and interstitial tissue degraded by cancer cells for invasion?

Answer 364

proteolytic enzymes are secreted or stromal cells are induced to make them. Matrix Metallo Proteases (MMPs) remodel insoluble components, and release ECM sequestered growth factors. when collagen is cleaved, proteoglycans have chemotactic, angiogenic, and growth promoters that get released

Question 365

how do cancer cells move

Answer 365

ameboid migraion or by cutting basement with proteases

Question 366

how do cancer cells change their attachment to ECM and the proteins there?

Answer 366

tumor cells are resistant to apoptosis. cleavage of basement membrane allows for new binding sites that stimulate migration. receptors are not as important in cancer cells as in normal cells for maintaining the cells in a resting state

Question 367

cancer cell motitlity

Answer 367

cleavage products of matrix components and IGF have chemotactic tumor activity. movement can be potentiated by tumor cell derived cytokines like autocrine motility factors. move collectively, mesenchymally, ameboid

Question 368

when you lose Ecadherin, what does it mean about your cancer phenotype?

Answer 368

it’s invasive! E cadherin is lost through: LOH, inactivation mutation, silencing, repression

Question 369

what transcription factors promote epithelial to cell mesenchymal transition by repressing Ecadherin?

Answer 369

SNAIL, TWIST, ZEB 1/2

Question 370

list the steps of epithelial to mesenchymal transition that is used inappropriately by cancer cells.

Answer 370

palatogenesis, neural crest formation and movement, cardiac valve formation, myogenesis

Question 371

do cancer cells self destruct when not attached to a basement membrane?

Answer 371

No!

Question 372

what changes are associated with EMT (epithelial to Mesenchymal Transition)?

Answer 372

downregulation epithelia proteins (ecadherin, cytokeratins). upregulation mesenchymal proteins (vimentin, fibronectin, n-cadherin, motility/invasiveness, increased protease secretion, fibroblast-like morphology

Question 373

What does EMT help cancer cells resist?

Answer 373

chemo

Question 374

tumor microenvironment

Answer 374

ECM+growth facors+ fibroblasts + immune cells. cross talk between these. not a static barrier, an area instead where reciprocal signaling can affect tumor suppression, promotion, progression

Question 375

what are tumor cells vulnerable to when they are in circulation?

Answer 375

destruction!!!! by: mechanical shear stress, apoptosis by adhesion loss (can resist), immune system defenses. Typically they bind/aggregate to enhance survival/implantability. can bind and activate coagulation factors.

Question 376

how do tumor emboli extravasate?

Answer 376

adhere to endothelium, egress through basement membrane via adhesion molecules

Question 377

what are/where are tumor associated macrophages found?

Answer 377

found in tumor margin. they help tumors intravasate into their new tissue home

Question 378

do natural pathways of drainage explain distribution of cancer metastases?

Answer 378

nope.

Question 379

what are the 2 theories about why metastasis is preferential to certain areas?

Answer 379

seed and soil theory (needs of cancer cell for specific environment), and the mechanical arrest theory (cells arrest in first capillary bed encountered). these theories are not mutually exclusive.

Question 380

breast cancer cells express chemokine receptors such as ____ sense chemical gradients and lead cancers to favorable sites.

Answer 380

CXCR4

Question 381

are tumor cells efficient at colonizing distant organs?

Answer 381

no….tumor cells shed each day can be detected in the bloodstream. to compensate they can lie dormant. it seems that tumor cells secrete cytokines, growth factors, ECM molecules that act on stream cels that make a metastatic site habitable for cancer cells

Question 382

direct metastases

Answer 382

invasive masses which interfere with normal function

Question 383

indirect metastases

Answer 383

“paraneoplastic syndrome” paracrine/endocrine effects. occur in 7-15% of patients

Question 384

paraneoplastic syndrome

Answer 384

consequence of cancer presence, but not due to local present of cancer cells. neither direct or indirect cuase. thought to be the result of hormones/cytokines secreted by tumor cells and or immune responses the tumor triggers. can trigger: ectopic hormone production, cutaneous lesions, arthropathies, myopathies, myopathies, neuropatheis, thromboses, nephrosis, cachexia, DIC

Question 385

what are the main causes of death in cancer (non-lukemic)

Answer 385

in order: infection, organ failure, thromboembolism, hemorrhage, emaciation

Question 386

_____% of all malignant neoplasms are caused by environmental factors.

Answer 386

80%. this is shown by regional differences in cancer rates, worldwide differences in cancer rates, and especially shown when migration to a new country happens (within a few generations you switch to being at risk for THAT countries cancers)

Question 387

what causes the environmental risk factors for most types of cancer?

Answer 387

that is unknown. Tobacco causes 30% of all cancer deaths (with 85% of lung carcinoma related to tobacco use).

Question 388

tobacco has been implicated as a risk factor for what cancers?

Answer 388

cancer of oral pharynx, larynx, pancreas, bladder, esophagus.

Question 389

what cancers are highest death rates for men and women in US?

Answer 389

men=lung cancer (34% of cancer deaths) then prostate (12%) then colo/rectal (11%). women=lung (21%), then breast (18%), and colon (13%)

Question 390

what is the cumulative lifetime risk of cancer for men and women in Colorado?

Answer 390

1/2 for men and 2/5 for women

Question 391

when are you most likely to get cancer?

Answer 391

in the 7th/8th decades

Question 392

is Colorado lower or higher cancer incidence that US?

Answer 392

2-5% lower than US rates recently. in the last decade, its 10-13% lower

Question 393

what's the most common cancer diagnosed in men and women?

Answer 393

breast in women, prostate in men.

Question 394

who identified polycyclic aromatic hydrocarbons as active carcinogens in tar?

Answer 394

Kenneway and Heiger.

Question 395

who found that croton oil promotes but doesn’t initiate skin tumors?

Answer 395

Berenblum

Question 396

environmental carcinogens (4)

Answer 396

1) polycyclic aromatic hydrocarbons; 2) aromatic amines; 3) nitrosamines; 4) aflatoxins. all must be activated to a carcinogenic form by microsomal enzymes (cytochrome P450). “PAANA-cotta is delicious, but may be a carcinogen!”

Question 397

how do polycyclic aromatic hydrocarbons form?

Answer 397

from incomplete combustion of fossil fuels. they become the diol epoxide

Question 398

how do aromatic amines form?

Answer 398

industrial and consumer products. N-hydroxylation and sulfating are required.

Question 399

how do nitrosamines form?

Answer 399

when 2 amines in food react with nitrous acid in stomach. hydroxylation leads to carbonium intermediate.

Question 400

how does aflatoxin form?

Answer 400

moldy grains and ground nuts, particularly when no refrigeration. produced by aspergillum flavus. microsomal expoxidation required

Question 401

what is the general theory on chemical carcinogenesis? (3 things)

Answer 401

chemical carcinogens are usually metabolized by microsomal enzymes to be active. the metabolite is an electrophile. the electrophilic species can modify protein, RNA, and DNA

Question 402

what are the direct acting carcinogenic compounds?

Answer 402

alkylating agents (n-mustards, chemotherapeutic agents). acylating agents (dimethylcarbamyl chloride)

Question 403

if adducts created by electrophilic attack are not excised from DNA, what happens

Answer 403

these bulky adducts cause mutations (eg: mispairing, frameshift)

Question 404

what are some other carcinogens that account for a small percentage of known cancers?

Answer 404

metal vapors, arsenic, thorotrast (liver cancer from radiology), exposure to vinyl chloride, asbestos, benzene exposure (ML), radon gas

Question 405

ames test

Answer 405

measures the ability of things to mutagenize a set of strains of salmonela typhimurium

Question 406

principles of cancer established by administration of suspected carcinogens (8):

Answer 406

1) effect of chemical is dose dependent, 2) specific carcinogen=specific cancer, 3) time is required, 4) cell proliferation is required (rapid turnover is more risk), 5) changes transmit to daughter cells, 6) malignant risk is in stem cells, 7) malignant cells are incorrectly differentiated stem cells, 8) cancers develop through initiation and promotion

Question 407

is promotion due to carcinogens?

Answer 407

no it is the effect of a non-carcinogen.

Question 408

what are promoters of cancer?

Answer 408

mutagens or carcinogens. often irritants but not all irritants are promoters. often cause inflammation, Phorbol ester is best experimental example-activates kinase which activates cell proliferation

Question 409

what are some types of inflammation that promote cancer? (6)

Answer 409

``` ulcerative colitis, atrophic gastritis, cholecystis, chosteomyelitis (may cause scams cancer), schistosomiasis of urinary bladder, chronic hepatitis ```

Question 410

how do chemicals cause cancer?

Answer 410

they cause mutations that accumulate in DNA! all carcinogens are mutagens, human cancers have lots of mutations, DNA repair mutations can lead to cancer, chromosomal aberrations and aneuploidy can affect/activate genes, loss of growth suppression causes

Question 411

epigenetic effects of chemicals

Answer 411

chemicals cause perterbuations in cell cell interactions and communication. carcinogens can modify protein and RNA, resulting in things like activation. many chemical carcinogens are toxic to cells, they may therefore promote improper cell growth.

Question 412

what are the four major forms of cancer seen frequently and are often fatal?

Answer 412

lung, pancreas, colon, prostate. they are carcinomas (malignant tumors) derived from organ’s epithelium.

Question 413

“invasion” means what with cancer?

Answer 413

somewhere along the edge of the growth of the carcinoma in the epithelium, small groups of tumor cells broke through the basement membrane to invade connective tissue storm

Question 414

what must you do before planning any type of cancer treatment?

Answer 414

do a biopsy! to identify as carcinoma or something else

Question 415

what are 2 features that need to be determined about a carcinoma?

Answer 415

grade and stage. both contribute to a prognosis and treatment planning

Question 416

stage

Answer 416

extent of tumor spread at diagnosis time. strongest predictor of prognosis. Now we use a TNM classification. T (1-4)=size of tumor, N (1-4) is lymph node involvement, M is presence of metastasis (Mo or M1)

Question 417

what does Tis mean

Answer 417

tumor in situ

Question 418

grade

Answer 418

state of differentiation of tumor cells seen in histological sections. low grade-well differentiated. high grade-don’t resemble normal epithelia

Question 419

low grade tumors produce what?

Answer 419

squamous carcinoma= spindle shaped, produce keratin, have desmosomal connections. adenocarcinomas= form primitive glands and produce mucin.

Question 420

signs and symptoms stem from _____ effects of the cancer at the site where it developed, or ______ effects from metastasis.

Answer 420

local, distant. advanced stage=weight loss, fatigue, extreme cachexia, infection (usually acute bronchopneumonia)

Question 421

lung carcinoma

Answer 421

present with cough, difficulty breathing, secondary pneumonia, chest pain, facial swelling, wight loss, distant mets. diagnose with imaging, biopsy, VATS (video assisted thoroscopic biopsy), cytology, meidastioscopy. 124,000 deaths from cancer from smoking each year. risk is age, duration of smoking and level, occupational history, air pollutant exposure, family history.

Question 422

squamous cell carcinoma lung cancer

Answer 422

25-40% of cases. linked to cigarette smoking. arise from squamous metaplasia and dysplasia in bronchial tree. epithelium replaced with squamous epithelia over time. often large, necrotic, hemorrhagic near center of lesion. cancer cells are moderately-well differentiated. keratin pearls, P53 mutations, loss of Rb, p16 inactivation

Question 423

adenocarcinoma lung cancer

Answer 423

25-40% of cases. most common type in women, nonsmokers. many are smokers. arise centrally. form primitive gland-like structures, positive for mucin. K-Ras mutations common. has bronchioloalveolar carcinoma (best prognosis, not linked to smoking)-cells grow along alveolar septa and airspace w/ little storm. Treat with surgery and radiation

Question 424

large cell carcinoma lung cancer

Answer 424

10-15% of cases. undifferentiated high grade cancer where anapestic cancer cells may not produce keratin or mucin.

Question 425

small cell carcinoma lung cancer

Answer 425

20-25% of cases. linked to smoking. arises anywhere in lung. only chemo. no differentiation. small, dark cell clusters that metastasize widely in the body. Bad news bears.

Question 426

lung cancer is associated with _______ syndromes.

Answer 426

paraneoplastic. (1-5% of cases). hormones and hormone like production by cancer cells.

Question 427

pancreatic cancer

Answer 427

back pain, jaundice (due to bile duct block), cachexia, migratory thrombophlebitis. arises in all stages, mostly in cola areas of pancreatic ducts/ductules (intraepithelial neoplasias). cancer grows silently so diagnosed too late-already metastasized widely. diagnose with imaging, biopsy. treat with surgery (rare), radiation and chemo. most are differentiated adenocarcinomas. K-ras mutations. synthesize prominent connective tissue storm. Stent sometimes to prevent ascending cholangitis (leads to septic, infection, shock)

Question 428

colorectal carcinoma

Answer 428

second leading cause of death in men and women. moderately well differentiated adenocarcinomas arising in mucosal layer of bowel wall. arise in pre-existing adenomatous polyps. spread via lymph/blood. 2 major types: (neoplastic colonic polyps), tubular adenoma and villous adenoma=risk for cancer. size of polyp correlates to risk. found a lot on the R side (large growths protruding into lumen), and some on L (apple core lesion, creates constipation). often metastasizes to liver. over 50, colonoscopy.

Question 429

prostate carcionoma

Answer 429

leading cause of cancer in men, second leading cause of cancer death. arise in periphery, can be felt on exam. firm mass, produce difficulties voiding urine. most common in African Americans, least common in Asians. androgens may play a role, cause is largely unknown. diagnose with ultrasound/biopsies. PSA can be elevated. progresses via loss of tumor suppressor genes. often treated by radical prostatectomy. advanced stage=anti-androgen therapy. Gleason system grading, subordinate pattern and predominant pattern are added. 8-10 is aggressive cancer.

Question 430

BPH, benign prostatic hypertrophy

Answer 430

enlarges central, peri-urethral region of gland. produces problems with voiding

Question 431

primary induction chemotherapy

Answer 431

drug treatment= primary treatment strategy, no surgery radiation. may be curative in some cases (germ cell cancers, Wilms tumor, etc.). used also for patients who present with advanced/metastatic disease with no other effective treatment. goal is to palliate tumor related symptoms, improve quality of life, prolong time btw. progression, improve survival

Question 432

neoadjuvant chemotherapy

Answer 432

used in patients with localized cancer when localized therapies (surgery/radiation) may not be completely effective. used BEFORE surgery/radiation, can help spare vital organs (may shrink tumor to make surgery more effective, etc). may kill micrometastatic disease. goal is to increase effectiveness of the surgery/radiation, maximize tumor destruction, minimize normal tissue damage. used to treat anal, bladder, breast, esophageal, head and neck, gastric rectal cancers, osteogenic, soft tissue sarcomas

Question 433

adjuvant chemotherapy

Answer 433

used in patients AFTER local treatment modalities (surgery/radiation). goal is to reduce incidence of localized/systemic recurrence-kill metastatic tumor cells. can increase effectiveness, improve survival rate. used to treat breast, colorectal, gastric, non small cell lung, melanoma. primary tumor removal makes it difficult to measure response to drug-relapse free survival

Question 434

does conventional cancer chemotherapy have a small or large window?

Answer 434

small. smallest in therapeutic medicine. variable pharmacokinetics mean differences in treatment with same agent (efficacy and toxicity), small changes can have large effect

Question 435

polymorphisms in what region/gene are associated with toxicity by irinotecan treatment?

Answer 435

UGT1A1, phase 2 enzyme is responsible for inactivating the active metabolite

Question 436

is more or less better for combining chemotherapy drugs?

Answer 436

more is probably better. single drugs rarely cure cancer. mutations can cause drug resistance, which makes them harder to kill with 1 drug.

Question 437

what are some general principles for combining chemotherapy drugs?

Answer 437

drugs that are partially effective against same tumor alone should be combined! when several members of a class of drug are available, choose ones that have toxicities that don’t overlap with other agents (more side effects but less lethal interactions). use drugs in optimal doses and schedules. use intervals as short as possible. avoid removal or dose reduction from combination since this may allow resistant cells to grow

Question 438

how do you treat with cancer chemotherapy?

Answer 438

try to find a cytotoxic agent that can kill tumor cells (death via apoptosis). identify the maximally tolerated dose (MTD) and treat as close to this as possible. hope you kill all tumor cells with as few side effects as possible. choose drug based on tumor site

Question 439

BH3 profiling

Answer 439

BCL domains are mediated by BH3. this helps to determine if cells are near or far to death threshold. mitochondria are exposed to titrated doses of BH3 peptides to make mitochondrial outer membrane permeabilization (MOMP). primed=low dose and lots of MOMP. unprimed=high dose and little to no MOMP

Question 440

why does chemo work?

Answer 440

despite the fact that disruption of apoptosis/cell death is a hallmark of cancer, tumor cells are closer to apoptosis threshold than most normal cells. BH3 profiling measures this proximity where death will occur

Question 441

in AML, how doe BH3 profiling work?

Answer 441

pretreatment BH3 predicts a clinical response to chemo in AML. This is done by testing how easily tumors cells undergo apoptosis

Question 442

what are some problems with current chemo therapeutics?

Answer 442

kill normal cells along with tumor ones. window is small. affects dividing cells, we aren’t often targeting defect that caused the tumor

Question 443

how do we hope to treat with cancer chemotherapy in the future?

Answer 443

identify particular defect that cause patient’s cancer, predict what to go after. use drug that targets that/causes death or growth arrest in tumor with the defect. determine Optimal Biological Dose (OBD) for inhibiting biological target. combine agents based on understanding how they work.

Question 444

what are some common mechanisms of chemoresistance?

Answer 444

reduced uptake of drug into tumor cells/increased efflux pumps. leads to MDR (multiple drug resistance). reduced apoptosis machinery. mutations alter cellular targets. repair of cellular damage. tumor stem cells regenerate. Cancer cells are unstable and evolve to resist treatment. Inactivate the drug. Some of these processes work for one drug, but a different drug may also be needed for different resistance mechanisms (single or multiple drugs).

Question 445

alkylating agents that react with DNA:

Answer 445

form covalent chemical adducts and inter strand crosslinks. if they don’t repair, no replication. apoptosis

Question 446

cyclophsophamide

Answer 446

nitrogen mustard. alkylating agent. most frequently used. used for breast cancer and lymphomas, child tumors, solid tumors. inactive, must be metabolized. metabolite is ALDH substrate. cells with high levels ALDH are resistant. *think about how drug metabolized to understand how it works. *

Question 447

alkylating agents: resistance mechanisms

Answer 447

reactions with cellular molecules. GSH tripeptide with free cysteine sulphydryl reacts with inactive alkylating agents. DNA repair removes alkyl group from guanine. cross link repair-high levels NER to remove crosslinks

Question 448

alkylating agents: toxicity

Answer 448

hematopoeitic toxicity. dose limiting. nausea, vomiting, gonadal toxicity, alopecia, carcinogenesis. increased risk of cancer.

Question 449

cisplatin and analogues

Answer 449

anti cancer drug. derivatives are less toxic. crosslink DNA making replication impossible-apoptotic response. effective testicular and ovarian, head and neck, lung, bladder cancer

Question 450

platinum compounds: resistance

Answer 450

reduced accumulation (decreased uptake, increased efflux), inactivation, increased NER repair, more repair proteins, increased tolerance DNA damage. inhibition of aopoptotic response.

Question 451

platinum compounds: toxicity

Answer 451

cisplantin-nephrotoxic (aggressive hydration helpful). nausea, vomiting, ototoxicity. damage inner ear. neurotoxicity. carboplatin (myelosuppression, platelet toxic), oxliplatin (sensory neuropathy). different toxicities with different PK.

Question 452

antimetabolites: 5-fluorouracil

Answer 452

pyrimidine analogue. activates intracellular FdUMP by Thymidine kinase. (causes dTTP deletion and inhibits DNA synthesis). Inhibits DNA synthesis and activates apoptotic response because of DNA damage. GI, breast, head/neck, ovarian

Question 453

5-FU: resistance mechanisms

Answer 453

target enzyme is altered. point mutations=reduced affinity FdUMP. regulation of translation, TS suppresses mRNA translation. inactivation of normal feedback TS level mechanism

Question 454

5-FU: toxicity

Answer 454

primarily on rapidly growing normal cells. myelosuppression, gastrointestinal toxicitgy. alopecia, derm problems

Question 455

topoisomerase interacting agents

Answer 455

topoisomerases help package chromatin. form temp. single/double strand breaks in DNA and religation. derived from natural products.

Question 456

topoisomerase interacting agents: mechanism of action

Answer 456

stabilize cleavable complex btw. topoisomerase and DNA, inhibiting relegation to leave the breaks. damage=apoptosis. used in breast, ALL, AML, lymphoma, sarcoma, other.

Question 457

topoisomerase interacting agents: resistance

Answer 457

increased drug efflux. important for etoposide, doxorubicin. mutations confer resistance don’t alter enzyme activity

Question 458

topoisomerase interacting agents: toxicity

Answer 458

myelosuppression. can result cardiotoxicity and acute and chronic effects. associated with chelating ability, damage due to levels of ant-oxidant enzymes (catalse) lower in heart. iron chelators may protect. can cause secondary malignancies (esp. in AML)

Question 459

antimicrotubule agents

Answer 459

polymers of alpha and beta tubulin. stabilizes or destabilizes microtubule dynamics to activate apoptosis

Question 460

antimicrotubule agents: vinca alkaloids

Answer 460

naturally occurring (vinblastine, vincristine). used pediatric malignancies, hematopoietic tumors, solid tumors. bind tubulin and cause depolymerization

Question 461

vinca alkaloids-resistance

Answer 461

increased drug efflux. MDR transporters (MDR1). cross resistance other drugs. mutations in tubulin and alter binding

Question 462

vinca alkaloids: toxicity

Answer 462

neurotoxicity, damage to nerve cells (esp. wi/vincristine). myelosuppression, neutropenia

Question 463

microtuble targeted agents: taxanes

Answer 463

paclitaxol, docetaxel. occurring compounds from pacific yew tree bark. used breast, ovarian, lung, solid. bind interior of microtubule and stabilize against depolymerization by altering dissociation rates. blocks mitosis

Question 464

taxanes: resistance

Answer 464

drug efflux: MDR family ABC transporters. cross resistance other drugs. mutations in tubular prevent binding. inhibition apoptosis

Question 465

taxanes: toxicity

Answer 465

myelosuppression-neutropenia. peripheral neuropathy. alopecia

Question 466

hormonal agents cancer treatment

Answer 466

treat hormonally responsive cancers (breast, prostate, endometrial)

Question 467

tamoxifen

Answer 467

estrogen receptor inhibitor

Question 468

antiandrogens

Answer 468

bind androgen receptor and inhibit transcription factor

Question 469

aromatase inhibitors

Answer 469

catalyze synthesis of estrogen from androgens. inhibits this

Question 470

gonadotrophin releasing hormone (GNRH)

Answer 470

inhibit testosterone production

Question 471

hormonal agents: toxicities

Answer 471

side effects are associated altered steroid hormone signaling. hot flash, bone density change, gynecomastia

Question 472

antibodies in cancer treatment

Answer 472

rituximab (anti CD20, B cell tumor treatment), perception (anti-her2 breast cancer), avastin (anti-VEGF colon cancer), inhibit function of target. some deliver toxins, chemotherapeutic drugs, radioisotopes

Question 473

retuximab

Answer 473

antibody recognizes antigen displayed on B cell tumors derived from progenitor cells at different stages of differentiation

Question 474

kinase inhibitors

Answer 474

targeted to defects that cause tumor development. less toxic. may be highly effective. we have few examples were they cure alone. resistance is almost always guaranteed.

Question 475

chronic myelogenous lukemia

Answer 475

caused by single oncogenic event (fusion of Bcr-Abl), translocation makes active tyrosine kinase Bcr-Abl. Imantinib inhibits the active site of the enzyme. majority of resistance is appearance of resistant alleles. Most Imatinib resistant patients have mutations that alter drug binding. Dasatinib works in CML patients with mutated Bcr-Abl (resistant to Imatinib)

Question 476

how do immune checkpoint inhibitors circumvent tumor strategies to avoid immune system?

Answer 476

CTLA-4 reduces T cell activation to maintain self-tolerance (negative signals sent in response to dendritic activation). if you block this you enhance T cell activation. PDL-1 mechanism inhibits T cell effector function, if tumors have unregulated PDL-1 they can avoid immune destruction

Question 477

Contrast and compare differences and purposes of different kinds of chemotherapy- adjuvant, neoadjuvant and primary chemotherapy.

Answer 477

Adjuvant- after local treatment, trying to kill micrometastases. Neoadjuvant- before localized treatment such as surgery, trying to make that treatment more effective and less damaging. Primary- on its own with no other therapy in a few cases curative, more often for palliation of symptoms in patients with advanced disease.

Question 478

Describe major differences between “targeted therapies” and conventional cytotoxics.

Answer 478

Conventional agents damage normal cells as well as tumor cells- therapeutic window is largely based on tumor cells being closer to their apoptotic threshold, MTD relevant for conventional agents less so for targeted agents, which are usually less toxic, resistance mechanisms different. Remember: conventional cytotoxics hit specific targets (e.g. Topoisomerase/DNA) just like “targeted” agents do- difference is that with the newer “targeted” agents we aim to hit a target that is different/faulty in tumor cells but not normal cells.

Question 479

Discuss the basis for combining anti-tumor agents.

Answer 479

Combine agents that work to at least some extent on their own, avoid overlapping toxicities, use drugs at optimal doses, keep treatment-free schedules as short as possible. Works because of the heterogeneity in the tumor cell population- some tumor cells respond to drug A some to drug B.

Question 480

Describe the mechanism of action, major toxicities and resistance mechanisms of prototypical drugs for each class of anti-tumor agent.

Answer 480

DNA damaging agents, toposiomerase interacting agents, microtubule interacting agents, hormonal agents, antibodies, kinase inhibitors. Some resistance mechanisms generally applicable- e.g. drug efflux through transporters, resistance to apoptosis. Some resistance mechanisms specific to agent- e.g. mutations in drug target, activation of repair mechanisms, other ways to activate steroid receptors. Many drugs have similar toxicities- usually associated with damage to fast growing cells- GI toxicity, myelosuppression. Specific toxicities depend upon mechanism of action- e.g. neurotoxicity associated with microtubule-interacting agents.

Question 481

drug tailoring is important for anti cancer drugs. describe how pharmacogenetics is important for this?

Answer 481

small differences in drug handling can have major effects. polymorphisms can can affect toxicity and activation dramatically.

Question 482

examples of cancer chemo

Answer 482

DNA damaging agents, topoisomerase interacting agents, antimetabolites, microtubule interacting agents, hormonal agents antibodies, kinase inhibitors, immune checkpont inhibitors