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Flashcards in 1st Exam Deck (451)
1

Mediators of vasodilation:

Protoglandins, NO, Histamine, and C3a and C5a

2

mediators of increased vascular permeability:

histamine, sreotonin, C3a and C5a, Bradykinin, Leukotrienes C4, D4, E4, PAF, Substance P, prostaglandin

3

mediators of chemotaxis:

C3a and C5a, Cytokines TNF, IL-1, Leukotrienes B4 (LTB4), Bacterial Products, chemokines, IL-8

4

mediators of fever:

prostoglandins, cytokines TNF, IL-1

5

mediators of pain:

prostoglandins, bradykinin, substance P

6

mediators of tissue damage:

NO, Lysosomal enzyes, ROS Chemokines

7

Effects of prostoglandin:

fever, pain, vasodilaiton, increased vascular permeability (at least PGD2 and PGE2)

8

Effects of NO:

Tissue damage, vasodilation

9

Effects of histamine:

Vasodilation, increased vascular permeability

10

Effects of serotonin:

increased vascular permeability, vasod, and vasoc (if injury to bv, primary hemostasis, clotting)

11

Effectes of C3a, C5a:

vasodilation, increased vascular permeability, chemotaxis

12

Effects of bradykinin:

increased vascular permeability, pain, (vasod and bronchial sm contraction?)

13

Effects of Leukotrienes C4, D4, and E4:

Increased vascular permeability

14

effects of PAF:

Increased vascular permeability, aggregate platelets, degranulation (release of pre-formed mediators), bonchoconstriction, vasod (1000 X more than histamine), chemotaxis of inflammatory cells

15

Effects of Substance P

Increased (LL says modulate), vascular permeability, pain, regulate vessel tone, stimulate cytokine P and R

16

Effects of cytokines TNF, IL-1:

chemotaxis, fever

17

Effects of Leukotrienes B4:

chemotaxis:

18

Effects of Bacterial products:

chemotaxis

19

Effects of lysosomal enzymes:

Tissue damage

20

Effects of ROS:

Tissue damage

21

Effects of chemokines:

chemotaxis and tissue damage

22

Paraneoplastic syndrome(s) assoc w lung small cell anaplastic (oat cell) carcinoma:

Cushing Syndrome, Hyponatremia

23

Paraneoplastic syndrome(s) assoc w various carcinomas:

Troussea Syndrome, hypoglycemia

24

Paraneoplastic syndrome assoc w Lung ssc:

hypercalcemia

25

Paraneoplastic syndrome assoc w renal cell carcinoma:

polycythemia (increased concentration of hemoglobin)

26

Paraneoplastic syndrome assoc w metastatic malignant carcinoid tumors;

Carcinoid syndrome

27

Mechanism of Cushing Syndrome (cortisol levels too high cause CS):

ACTH-like substnace

28

Mechanism of hypercalcemia:

PTH-like hormone

29

Mechanism of hyponatremia:

innappropriate ADH secretion

30

Mechanism of polycythemia:

erythropoeitin-lke substance

31

Mechanism of Trousseau syndrome:

hypercoagulable state

32

Mechanism of hypoglycemia:

insulin-like substance

33

Mechanism of carcinoid syndroe

5-hydroxy-indoleacetic acid

34

15% of ppl w dermatomyositis get:

carcinoma of lung, ovary, breast

35

Tumor assoc w migratory venous thrombosis:

pancreatic carcinoma

36

Tumor assoc w Myasthenia gravis:

thymoma, thymus tumor

37

dermatomyositis:

heliotropic (directs toward the sun) rash on malar (cheek) surface of face, ai disease, inflammatory, affects bv, m atrophy

38

PSA is a marker for:

Prostate cancer

39

AFP is a marker for:

Hepatocellular carinoma

40

CEA is a marker for:

colon carcinoma

41

hCG is a marker for:

choriocarcinoma, tumor of uterus, originates from chorion of fetus (human chorionic gonadotropin)

42

PLAP is a marker for:

Seminoma, malignant tumor of testis (balls fFLAP) (from primordial germ cells of sexually undifferentiated embryonic gonad. (I thought -'oma' 's were benign?)

43

Health issues that cause chronic inflammation:

persistent infections/toxins, ai disorders

44

4 pw acute inflammation can go down:

CHAR: Chronic, Healing, Abscess, Resolution

45

Histamine is released by:

mast, basophils, and platelets

46

2 main descriptors of inflammatory mediators:

pleiotropic and redundant

47

Why do we need so many mediators with overlapping effects?

they are all short lived, leads to amplification

48

From where are mediator derived?

cell or plasma

49

7 cell derived mediators:

VAN PELCC: Vasoactive amines, neuropeptides, prostaglandins, enzymes, leukotrienes, cytokines, chemokines,

50

3 plasma-derived mediators of inflammation:

complement, coagulation, and kinin systems (3 'C' sounds) mp

51

2 vasoactive amines:

histamine and serotonin

52

Preformed mediators:

Vasoactive amines (histamine, serotonin) and leukocyte lysosomal enzyme

53

3 neutral proteases:

elastase, collagenase, cathepsin (endopeptidase found in most cells, autolysis and self-digestion of tissues)

54

Major sources of newly formed mediators:

leukocytes, mast cells, endothelial cells, platelets (LMEndoP)

55

How are newly formed mediators removed from body?

enzymes or spontaneous decay

56

This liberates AA from the cell if there is cell injury (cell membrane I think):

phospholipase

57

2 pathways for AA metabolism:

cyclooxygenase and 5-Lipoxygenase

58

cyclooxygenase pw to metabolize AA:

Thromboxane A2: vasoc, platelet agg/ Prostacyclin: vasod, inhibit platelet agg/ PGD2 and PGE2: vasod, inc perm/ pain and fever

59

5-Hete:

Part of 5-Lipoxygenase pw to breakdown AA, recruits inflammatory cells via chemotaxis

60

5-Lipoxygenase pw of AA metabolism:

5-Hete: recruits inflammatory cells, leukotrienes A4-E4: asthma and increased vascular permeability, Lipoxin A4, B4: inhibits neutrophil adhesion and chemotaxis

61

Acids besides AA being metabolized via this pw:

Omega 3 and 6 fatty acids

62

Group of natural antiinflammatory mediators:

resolvins, natural antagonists to prostaglandins

63

Why do steroids decerase inflammation?

prevent liberation of AA

64

2 cyclooxygenase inhibitor (Cox-1, Cox-2):

aspirin (NSAIDS), indometacin

65

Newly synthesized mediators of inflammation:

AA, PAF, cytokines, chemokines, neuropeptides, ROS, NO (CNNCRAP)

66

PAG is aka:

AGEPC

67

PAF is derived from:

phospholipid

68

Sources of PAF:

platelets, PMN, mast cells, macros, endothelium (PPEMM)

69

What liberates PAF?

activation of phospholipase A2

70

Families of cytokines:

lymphokines, monokines, chemokines, interleukins, interferons (3 kines and 2 I's)

71

4 major cytokines in acute inflammation:

TNF, IL-1, IL-6, and chemokines

72

Major cytokines of acute inflammation are produced by (3):

macros, mast cells, endo cells

73

Major cytokines in chronic inflammation:

IL-12, INF-gamma

74

Effect of IL-1 and 6 on liver:

production of acute phase proteins

75

Effect of IL-1 and 6 on brain:

fever

76

Effect of IL-1 and 6 on bone marroe:

Wbc production

77

3 Systemic protective effects of acute inflammation (IL-1 and 6):

fever, wbc production, and acute phase protein production (TNF also promotes fever and wbc prod)

78

5 Pathological systemic effects of TNF:

low heart output, hypertension, shock, thrombus formation, insulin resistance of skeletal muscle (IL-1 also causes insulin resistance)

79

5 Systemic mani of inflammation:

fever, leukocytosis, inc acute-phase proteins, decrease apetite, inc sleep (FLAPPAS)

80

4 Fxn of chemokines:

wbc recruitement, cellular organization, active (sic?) leukocytes, regulate cell trafficking

81

How do chemokines interact with cells?

receptors

82

2 newly synthesized neuropeptides:

sub P and calcitonin gene related protein (CGRP)

83

Neurogenic inflammation occurs when these are activated:

neuropeptides (transmit pain)

84

Effect of CGRP

(Calcitonin gene related protein) vasod, pain

85

Sources of ROS:

activated PMN's and macros

86

How are ROSs synthesized?

NADPH oxidase pw

87

Effect of low level secretion of ROS:

inc chemokine, cytokine, adhesion molecule expression

88

Effect of high level secretion of ROS:

endothelial damage, inc perm, protease activation, antiprotease inactivation

89

What limits the toxicity of secreted ROS?

endogenous antioxidant mechanisms

90

NO is found in:

endo cells, macros

91

System(s) activated by Hageman factor:

Complement, Kinin-Bradykinin, Coagulation (all 3 plasma mediators of inflammation)

92

Fxn of plasma-protein derived mediators of inflammation:

inc perm, vasoactive

93

This activates fibrinogen:

thrombin

94

2 ways to activate the complement cascade:

plasmin or kallikrein (not hageman factor?)

95

Endogenous antimediators that "stop" inflammation:

antioxidnats, lipoxins, protease inhibitors (PAL)

96

This interleukin inhibtis TNF:

IL-10

97

These interleukins promote repair:

IL-2, IL-4

98

WHat do NSAID's do?

block COX-1 and Cox-2 (from making PG's)

99

What do steroids do?

prevent AA release by PLA2

100

What do Etanercept and Infiximab do?

block TNF (RA and Crohn's)

101

Causes of infection (inflammation?)

physical, chemical, infection, immune reaction, ischemia

102

Type of inflammation depends on:

chronology and pathology

103

Vasoactive mediators that cause gaps due to endothelial contraction:

histamine, leukotrienes, etc.

104

4 mechanisms of inflammation permeability:

endothelial gaps, necrosis/apoptosis, leukocyte-dependent injury, transcytosis

105

Selectins are involved in these cellular events:

rolling, activation (P, E, and L selectins_)

106

Integrins/Immunoglobulins are involved in these cellular events:

activation, adhesion

107

PECAM-1 is involved in this cellular event:

transmigration (synonymous with transcytosis?)

108

List of integrins/Immunoglobulins involved in cellular events:

MAC 1, ICAM 1, VCAM-1, LFA 1, VLA-4

109

These recognize sialylated carbohydrate groups:

selectins

110

This selectin is stored in Weibel–Palade bodies of endothelial cells:

P selectin

111

This selectin is not produced under normal conditions:

E selectin

112

These are the ligands to the homing receptors of lymphocytes and determine which tissues the lymphos will enter next:

addressins

113

Plays a key role in removing aged neutrophils from body:

PECAM-1 (involved in transmigration)

114

4 major groups of adhesion molecules:

selectins, addressins, integrins, immunoglobulin superfamily

115

Mechanism of acute inflammation molecule adhesion:

P and E selectin (ELAM-1), then ICAM-1 bind Lewis X (CD15) on WBC's (check, I think ICAM-1 bonds something else)

116

What cause P seletins to be expressed on endothelial cell surface?

thrombin (or histamine?) act on W-P (Wiebel-Palade) bodies on the bvs, leads to inflammation (vWF is also store in W-P bodies, homeostasis)

117

Where is L selectin expressed?

lymphocyte

118

Mechanism of chronic adhesion molecules:

CD34 (w Lewis X on it) binds L-selectin (on lymphos), ICAM-1 binds CD18 (lyphos and monos), and some acute adhesion molecules

119

PECAM is involved in:

transmigration (diapadesis)

120

PECAM is aka:

CD31, on both endo and lymphos

121

How does PECAM pierce the basement membrane to allow diapadesis of the WBC?

collegenase

122

How does a cell relocate during chemotaxis?

by binding ecm

123

Chemotactic pw:

C5a binds G-protein CR, phospholipase C which activates both phosphatidyl-inositol bisphosphate and inositol 3-phosphate, I3P then increases Ca2+, actin and myosin build and aide in motility, inc number and affinity of adhesion molecules

124

Bradykinin is broken down via:

kininases

125

Where are the mediators for the cascading enzyme systems synthesized?

liver

126

How is fibrin broken down?

plasminogen cascade

127

How to determine if there is a clot somewhere in he body via blood draw?

look for fibrin split products

128

Activators of Hageman factor(4):

platelets, necrosis, collagen, bm

129

Increased intracellular Ca+ concentration can lead to:

Inc expression of endonuclease (DNA), ATPase (energy), protease (protein) , phospholipase (membrane)

130

Trigger formation of the inflamasome:

bacterial endotoxins, necrosis, cytokines

131

Function of the inflamasome:

activate proteases

132

Function of pyrin:

antiinflammatory

133

Function of corticosteroids:

block AA synthesis (blocking inflammation) (and steroid prevent the release from the lipid membrane...?)

134

4 major groups of antiinflammatory drugs:

antihistamines, corticosteroids, NSAIDS, Leukotriene drugs

135

Function of Leukotriene drugs:

5-lipoxygenase inhibitors (zileuton), LT receptor antagonist (Accolate)

136

Cells of acute and chronic inflammation:

acute: polys, chronic: lymphos, macros, and plasma

137

Sub-acute inflammation is characterised by:

polymorphous granulation tissue

138

Specific causes of granulomatous inflammation:

TB, fungus, sutures, syphilis

139

Contributes to the formation of granulomas:

IL-4 (Th2 cells)

140

water + mucus, nasal discharge:

catarrhal

141

Pus + polys:

purulent

142

pseudomembranous:

dead cells + polys

143

governs the increased production and release of neutrophils from the marrow during inflammation:

IL-1 and TNF

144

Normal WBC count:

4,500-11,000 cells/mm^3

145

Blood test for inflammation or leukocytosis:

WBC differential count

146

Causes of neutrophilic leukocytosis:

infection, inflammation, necrosis

147

Shift to the left:

BM cells release immature forms of polys

148

Lymphocytic leukocytosis:

polys aren't increased, chronic inflammatory process, ie TB, viral diseaese

149

This type of leukocytosis is common with allergic reactions, parasitic infections:

eosinophilic leukocytosis

150

3 types of leukocytosis:

neutrophilic lymphocytic, eosinophilic

151

4 ex of acute phase reactants:

Fibrinogen, globulins, CRP, protein SAA (transport cholesterol to liver for secretion into bile, recruit immune cells to inflammatory sites, induce enzymes that degrade ECM)

152

How to test for bacterial inflammation:

Blood PCT level (procalcitonin)

153

Is CRP elevated in acute or chronic inflammation?

Both

154

When would blood ESR level be high?

Infection and systemic inflammatory disease (erythrocyte sedimentation rate, nonspecific test for inflammation)

155

ESR results that indicate inflammation:

RBC travel further than 20mm

156

Prime stimulant of CRP:

IL-6

157

CRP is produced here:

liver

158

Elevated blood SAA levels indicate:

chronic infammatory disease

159

Protein SAA is stimulated by:

IL-1 and TNF (if these are mediators of acute, do they decrease in numbers once protein SAA identification initiated? I would have thought they would need to be present for continued expression of P SAA)

160

Protein SAA has a tendency to form:

fibrils (amyloidosis), diagnose with congophilic dyes

161

Calcitonin is made by these cells:

C cells of thyroid gland

162

When does granulation tissue form?

as inflammation subsides

163

Granulation tissue is composed of:

proliferating capillaries, fibroblast, and myofibroblasts, amorphous ECM, and macros

164

Sitmulate angiogenesis:

VEGF and betaFGF (made by macros, betafibroblast growth factor)

165

Activates the transcription of VEGF and B-FGF

hypoxia-induced factors (HIF)

166

These are responsible for wound contraction:

myofibroblasts derived from pericytes

167

Amorphous ECM is made by, and contains lots of:

fibroblasts, glucosamines looks acellular

168

Function of HIF:

induce VEGF and BFGF

169

Effects of VEGF and BFGF:

proteolysis of ECM, migration, chemotaxis, proliferation of endo cells, lumen formation, maturation and inhibition of growth, and increased permeability (gaps and transcytosis)

170

Antagonist of Angiopoietin 1:

Angiopoietin 2, tube regression

171

How does granulation tissue become scar tissue?

Organization of fibroblasts and collagen fibrils in tissue

172

Scars form through:

the remodelling of granulation tissue

173

How is granulation tissue broken down?

matrix metalloproteinases

174

2 inhibitors of angiogenesis:

angiopoietin 2 adn angiostatin

175

Wound contraction starts at day __ and usually ends by day__:

3, 30

176

Granulation tissue starts to form at day __ and usually ends by day__:

0.3, 10

177

How long does it take for inflammation to start?

about 0.1 days: 2.4 hrs

178

Early wound collagen is Type __ and late wound collagen is converted to type __

III, I

179

Which type of collagen is stronger, Type I or Type III?

I

180

dehiscence:

Reopening of wound, esp. scar tissue

181

Stages of skin wound healing:

blood clot, dries, scab, polys, macs, granulation tissue, scar (dermis forms),

182

These would be present around a wound 3-7 days after injury:

granulation tissue, macs, fibroblasts, new caps

183

How much faster do oral wounds heal than other wounds?

2-3 times faster

184

This, found in saliva, speeds mucosal redeneration:

histatin

185

Special types of wound healing:

fibrosis wo granulation tissue, tumor encapsulation, liver cirrhosis, hyalinized granuloma

186

What is cirrhosis?

fibrotic processes bw columns of liver cells

187

Complications of normal wound healing:

excessive granulation tissue, excess scar, defective scar, dystrophic calcification

188

Ex of excessive granulation tissue formation:

pyogenic granuloma

189

Hypertrophic scar:

keloid

190

Stimulus for dystrophic calcification (calcium where you don't want it)

atherosclerosis, aging heart valve, granulomas, tumors

191

Local causes of delayed wound healing:

Infection, poor blood supply, foreign material, type/ size/ location of wound

192

Which heals slower, heart or skin?

heart

193

Systemic causes of delayed wound healing:

age, diabetes, diet (DAD)

194

Antimicrobial, painted on wound, retards bacterial growth:

silvadene (silver)

195

bandage with growth factors to stimulate healing:

smart dressing

196

Take this from a pt to speed their healing of a wound:

PRP (platelet-rich plasma)

197

How can oxygen and pressure be used to speed healing?

negative pressure, hyperoxygenated

198

When to order a liver function test:

surgical procedures

199

Normal CK levels:

38-174 (creatinine kinase)

200

Where in the body is CK present?

heart, brain, muscle (run marathon, creatinine kinase elevated)

201

How long does it take for CK levels to peak and return to normal?

24h, 5 days

202

Results win __ standard deviations are considered 'normal.'

2 SD's, 5% will be abnormal (check, I thought 5% would come back as abnormal, despite being normal)

203

TF? Mutations in one gene will always cause the same type of cancer.

F. Cancer is gene specific, mutations in one gene can cause many different types of cancer.

204

Most common cancers:

breast, uterine, lung, colon (BULC, the bulk of cancers are...)

205

What type of skin cancer is on the highest incidence list?

melonama

206

Japan has a high incidence of __ cancer.

stomach

207

Cancer is most likely do to:

environmental influence, esp. food, no pollutants

208

Fraction of cancer we get that is random and unpredictable:

2/3

209

Tobacco is a major player in these cancers:

lung, kidney, bladder

210

These food increase risk for bowel, pancreas, breast, and prostate cancers:

high fat, low fiber, fried, broiled

211

3 ex of inherited cancers:

breast (Brc1, Brc2, prevelant in Ash Jew), colon/ rectal cancer, skin cancer (XP), retinoblastoma (Rb)

212

Diff bw carcinogen and mutagen:

Car: anything that causes, mutagen: chemical that causes, so a mutagen is a carcinogen

213

Cancer begins as:

a single cell clone, mutation in a specific gene in a specific cell

214

TF? Proto-oncogenes are abnormal genes that will eventually lead to cancer.

F. Normal genes

215

Do oncogenes gain or loose activity.

Gain (check)

216

Define lose activity:

can not supress gene expression

217

This is a test for mutagens:

Ames test

218

As long as these are working, you will not get severe cancer:

tumor suppressor genes

219

When we first turn on cell growth and cell division we activate

cyclin D, activates CDK

220

This stops division if anything is going wrong in G1 phase:

p53

221

What occurs during S phase:

DNA and histone synthesis

222

The cell cycle is regulated by:

cyclins and CDK's

223

When are cyclins made and destroyed in cell cycle?

Destroyed: end of phase they were used in, Made: End of previous phase

224

The longest phase of the cell cycle:

G1, protein synthesis/ cell growth

225

Where is the first major checkpoint in the cell cycle?

end of G1 phase, if cancerous, tsg would stop the cycle

226

What turns on the cell cycle?

D-CDK

227

What turn on the synthesis of DNA?

E-CDK

228

TF? Most cells can divide.

F.

229

What cells normally do not divide?

organ cells: brain, liver, kidney

230

How do pathologist diagnose cancer?

less differentiated or undifferentiated

231

How do growth factors stimulate growth?

by activating multistep pws

232

What stops cell growth and activate cellular differentiation?

differentiation factors

233

Do stem cell precursors normally divide quickly or slowly?

slowly

234

Why does the incidence of cancer increase with age?

You need many mutations

235

All prokaryotes are:

bacteria

236

how do we turn off expression of a gene?

tightly wrap it around a nucleosome

237

Nucleosome:

octamers of a specific histone that look like beads on a slide

238

Fxn of writers:

modify lysines and other residues

239

Readers:

proteins that bind to modified lysines (turn gene exp on or off)

240

Levels of this are elevated in metastatic breast and prostate cancer

Ez

241

1 type of leukemia is due to:

an enzyme that methylates H3K4

242

When are Ez levels markedly increased?

worst cases of metastatic breast and prostate cancer

243

Page turners:

proteins that loosen DNA around a histone, increasing accessibility

244

Enzymes that remove histone modifications:

erasers

245

Trimethylation of __ is very important in gene activation.

lysine at position 4 of Histone 3 (H3K4)

246

How do euk's turn gene expression on and off?

wrap or unwrap DNA around a nucleosome, accessibility regulated by a 'histone' code

247

How many nucleosomes does it take to wrap around one gene?

about 10

248

Enzymes that modify residues:

writers

249

Effect of Ez adding 3 methyl groups to H3K27:

Turn off adjacent gene

250

Levels of this are increased in the worst types of metastatic breast and prostate cancer:

Ez

251

A mutation in an enzyme that methylates H3K4 causes:

a type of leukemia

252

A mutation of an enzyme that adds only one methyl groups to H3K4 bound to an enhancer of DNA expression is related to this type of cancer:

breast

253

What is Ez?

Histone code writer

254

Normal function of Ez

adds 3 m groups to H3K27, silencing adjacent genes responsible for early development proteins

255

TF? epigenetics is usually a part of cancer.

T

256

Epigenetics:

changes passed on from daughter cell to daughter cell

257

How are heterotrimeric G proteins activated?

hormone binding

258

What happens when heteromeric G protein is activated?

GDP dissociates from G Protein, GTP then binds, a-GTP subunit dissociates and activates an enzyme that makes 2nd msgs, they activate protein kinases that activate hormones

259

How are g proteins turned off?

inherent GTpase activity, converting GTP to GDP.

260

How are small G proteins activated?

GDP dis and GTP binding

261

How do heteromeric G Protein and small G proteins differ?

Small: have GTPase activity for automatic self-inactivation, hetero: can not fully activate GTPase activity wo hormone

262

Quintessential G protein:

Ras

263

This G protein is a major player in the pws that either lead to growth or to differentiation (depends on cell type).

Ras

264

TF? Ras works through the 2nd msg system.

F. directly activates PK's

265

Inactive, small G proteins are bound to:

GDP

266

TF? Small G proteins have GTPase activity.

T, for self inactivation

267

What is the multi-hit theory?

multiple gene mutations (9-11) are required to initiate cancer

268

TF? Not all cancers affect the cell cycle or decrease TSG function.

F.

269

Cancer always involves:

cell cycle, TSG, epigenetics, mutant proto-oncogenes

270

How many auxiliary proteins are required to activate and inactivate Ras?

3

271

Major players of the growth and differentiation pathways:

growth/ differentiation factor, RTK, Small G protein, 3 auxiliary proteins, kinases, phosphatases,

272

What kind of pathways are growth and differentiation pathways:

signal transduction pathways

273

All differentiation factors make cells:

stop dividing

274

How are growth and differentiation pathways turned off?

protein phosphatases

275

What is the first signal in the signal transduction pw of growth and differentiation?

a growth factor binding to RTK

276

Fxn of auxiliary proteins:

activate and deactivate Ras

277

What happens to the primary signal in signal transduction pwy?

transduced to factors that lead to growth

278

What makes the receptor tyrosine kinases come toward each other?

growth factor binds the RTK

279

how is the RTK activated

auto Phosphorylation

280

How does autophosphorylation of the RTK lead to growth?

after A-p, proteins bind to specific sites which leads to growth

281

RTK pw:

RTK - auto phosphorylation - GRB2 binds P group - Ras - SOS (binds both) - (GDP off, GTP on) - Raf - Mek - Mapk - in nucleus, P myc, fos, june - activate growth

282

What turns on Ras?

SOS, gdp comes off, GTP binds (auxiliary proteins too)

283

What binds bw the 2 receptor tyrosine kinases?

growth factor (a protein/ hormone)

284

More than __ tyrosines are normally phopshoylated in the RTK.

2

285

TF? Additional, complementary pws are needed for growth to occur besides the RTK pw.

T

286

SOS binds:

Grb2 and Ras

287

When is GDP released from Ras?

when SOS binds Ras

288

Ras recruits Raf to:

the membrane

289

a factor that stimulates growth (mitosis)

mitogen

290

When does MAPK enter the nucleus?

after phosphorylation (by Mek)

291

3 TF's heavily implicated in cancer:

myc, fos, jun (too much of any of these = cancer)

292

TF? Ras has inherent GTPase activity.

T, w help from a GTPase Activating Protein (then why do we have audxillary proteins to turn off?)

293

Growth activity of the entire pathway is regulated by:

Ras GTPase activity, by inactivation of Ras (w the help of GAP) (not regulated by initial growth hormone binding to RTK?)

294

How is Ras inactivated?

Inherently losing its GTPase activity, binds GDP, wo this we would have tons of cancer

295

How can the RTK that EGF binds be permanently turned on (cancer)?

mutation/deletion removes part of EC domain, mutated receptors dimerize and activate pw wo growth factor

296

Ras is mutated in _ % of cancers

20

297

Mutations in Ras lead to loss of what activity?

GTPase to activity, Ras always active, can't turn itself off anymore

298

This mutation is found in 60% of pt w melanoma:

Raf

299

What would a mutation in Myc, Fos, or Jun lead to?

cancer

300

What is SARK?

a cytoplasmic tyrosine kinase.

301

pw that is initiated by binding phosphotyrosine when a RTK is activated by a growth factor and involved in cancer:

Src, causes cancer bc its mitogenic pw is always active

302

How are PI3 kinases acitvated?

by many RTK's (binding Phosphotyrosine on an activated RTK)

303

Fxn of Akt:

promote growth and survival, inhibit apoptosis, stimulate mTOR which stimulates protein synthesis

304

What is mTOR?

a kinase

305

Most commonly mutated part of the RTK pw:

Ras

306

What stops the PI3 pw when needed?

PTEN, phosphatase of PI3

307

What would happen if PTEN is mutated?

cancer

308

PTEN is a:

tumor suppressor, decreases the motor system

309

TF? Certain steps in the pw give you cancer.

F. any step that is altered

310

p53, major checkpoint:

end of g1

311

3rd checkpoint:

G2/M pahse boundary

312

Mitogen:

causes mitosis in cell cycle

313

RB protein binds this normally:

E2f proteins

314

How to get Rb off of E2f protein?

phosphorylation of Rb protein via Myc, enter cell cycle

315

Myc makes

d cyclin, then its kinase that p's the Rb protein, comes off, E2f proteins activated and the cell cycle turns on

316

Ex of a mitogen:

Myc,activates cell cycle (anything that promotes growth, cell division)

317

How do mitogens regulate the rate of cell division?

by their effects during G1

318

how does normal Myc work?

stimulation of gene expression of cyclin D (turns on the cell cycle)

319

What happens if Myc is always active?

cancer

320

How to regulate the rate of cell cycle?

E2f proteins are bound to genes poised to be expressed but nothing is happening because Rb protein is bound

321

What makes the turning on of the cell cycle so rapid?

E2f proteins are there, ready to be actvated to turn on the genes in the cell cycle

322

This can cause cancer of the retina:

Mutation in Rb that prevents binding to E2f, retinoblastoma

323

3 ways p53 works:

stimulate transcription of p21 protein (can stop cell cycle in G1 or S if there is damage),

324

What happens to p53 if DNA is damaged?

it is phosphoryated, preventing its degradation adn the progression to M phase

325

TF? p53 is always active.

F. only active when we need it

326

p53 must do this to prevent cancer:

bind to DNA

327

oncogenes that lead to a gain of action:

mutated Ras or Myc

328

2nd most important ts after p53:

p16

329

How is Rb-protein normally phosphorylated?

cyclin D-G1 cyclin dependent kinase complex

330

What prevent the formation of the cyclin D complex in stressed or overly-rapidly dividing cells?

p16, methylation will silence p16

331

at what stage of cancer ore p16 mutations common?

early stages (epigenetic mechanism)

332

Why might drugs that target p53 stop working?

if p53 is mutated

333

Does phosphorylation of Rb lead to activation or deactivation?

activation

334

Epigenetic change vs. genetic change

change in expression (daughter to daughter) vs. change in DNA sequence

335

This can cause gene silencing in cancer cells an prevent the formation of proteins that inhibit growth

DNA methylation

336

Methylation of what can lead to permanent gene silencing?

H3 and Lys9 (removes ts's)

337

Is heterochromatin active or inactive?

inactive

338

How are developmental genes related to cancer?

many of these are turned on AFTER development, causing cancer

339

Ez is active in what cancers?

metastatic breast and prostate

340

How does Gleevac work?

binds Phile chromo. CML, binds specific mutant protein

341

Marjor factor in whether or not cancer forms

how fast stem cells are dividing in a articular organ

342

PAP smears can test for:

uterine and cervical

343

Cancer:

GROUP of neoplasms, invading tissue

344

Histological groupings of neoplasm:

epi, mesnchymal, neuroectoderml, hematopoietic, lymphioid, germ cell

345

Types of epi cancers:

squaous or glandular

346

benign growth characteristics:

slow, expansile (capable of expansion) gowth, local, encapsulated, push on surrounding structure, small, well differentiated

347

Metastasis:

non-adjacent organ

348

Parenchyma:

tumor cells

349

supporting cells of tumor:

stroma

350

Malignant epi tumor:

Carcinoma

351

Malignant mesenchymal tumor:

Sarcoma

352

Benign squamous epithelium cancer:

squamous papilloma

353

Malignant squamous epithelium:

SSC

354

Benign glandular epi:

ademoa

355

Malignant glandular epi:

adenocarcinoma

356

Benign melanocyte:

nevus

357

Malignant melanocyt:

malignant melanoma

358

Prefix :adeno":

gland

359

Benign fibrous tumor:

fibroma

360

Benign sm tumore:

leiomyoma

361

Benign striated muscle tumor:

rhabdomyoma

362

Benign cartilage tumor:

chndroma

363

exothitic:

rising above and growing above the normal epithelium

364

papillary:

irregular finger-like growth:

365

scirrhous

carcinoma, hard to the touch

366

desmoplastic:

Causing fibrosis in the vascular stroma of a neoplasm.

367

What is the mucinous component normally made by?

glandular epithelium

368

Ewing's sarcoma:

supporting cell tumor, mostly arises in bone, treated and responds like sarcomas

369

Hodgkin's disease:

Lymphoma, malignant neoplasm of lymphoid cells

370

4 phases of malignant growth:

Mutation/ change, growth, invasion, metastasis (not just the ability to invade blood vessels and lymphatics)

371

Are pre-neoplastic morphological changes reversible?

some

372

Difference bw hyperplasia and hypertrophy

plasia: more cells, trophy: larger cells, same number

373

Ex of when cells atrophy:

menophause

374

Dysplasia:

proliferation of abnormal cells, disordered development, increased mitosis, varying numbers of cells, tends to disorder in cellular arrangement

375

These can cause metaplasia:

toxin, physical stimulus, or gf (change from one epithelium type to another)

376

Ex of metaplasia in smokers:

glandular to squamous, don't secrete mucus

377

loss of normal arrangment of cells:

atypia

378

Why do cancerous cells have a darker nuleus?

more chromatin

379

Carcinoma in situ is a type of:

Intra-epithelial neoplasm

380

Carcinoma in situ is confined to what tissue type?

epithelium (full thickness)

381

Invasion :

malignant EPI tumor

382

Is carcinoma in situ invasive or non-invasive?

non-invasive (pre-malignant)

383

Low-grade dysplasia:

confined to lower half of epi, high grade includes outer half

384

When is a cell capable of invasion?

When it can express cell surface adhesion molecules

385

epithelial tumors invade:

the lymphatics rather than blood vessels

386

sarcomas tend to invade:

blood vessels rather than lymphatics

387

osteosarcoma metasizes here:

typically to lungs via blood

388

breast cancer metastasizes here:

lymphatic, lymph nodes, bone, and lungs

389

How do tumors disrupt the ECM?

proteolytic enzymes

390

Tumor cell that lacks differentiation:

anaplastic (pleiomorphism, variation in size/shape, abnormal nuclear shape, quickly dividing, numerous mitoses)

391

Tumors are graded by:

mitotic activity, nuclear size and shape, presence of nucleoli or architecture

392

Local effects of neoplasms:

swelling, irritation, pain, thrombosis, hemorrhage, necrosis, obstruction or perforation of hollow viscera, infection, involvement of adjacent structures

393

Colon might spread to:

bladder, pelvic side wall, other loops of bowel

394

Systemic tumor effects:

inc or dec hormonal expression, hypercoagulable state, myopathies, neuropathes

395

generalized wasting:

cachexia

396

paraneoplastic symptoms:

can't be explained by distant or local tumor growth or indigenous tissue hormones

397

Ex (?) of hypercogulable state;

migrating intravascular thrombophlebitis, non bacterial intravascular coagulation, disseminated intravascular coagulation

398

Cancer assoc w inc hemoglobin levels:

Renal Cell Carcinoma

399

Cancer assoc w dec Na levels:

Lung small cell anaplastic carcinoma

400

Cancer assoc w inc Ca2+ levels:

Lung SCC

401

TF? Dermatomyositis is a hormonally related.

F. not hormonal, rheumatic or skin disease

402

Serum protein markers are useful for:

dx, follow-up

403

Serum protein markers:

monoclonal Ab's against sp antigen produced by tumor cell, not perfect in either specificity or senstivity

404

In what way is staging more reliable than grading?

prognosis

405

hidden tumor:

occult tumor

406

3 parameters of staging:

Size, lymph node metastasis, distant non-lymphoid metastasis

407

Haber's Law

Time/ dose relationship of toxicity, high dose/ brief duration acute disease

408

Threshold dose

min dose needed to have an effect, doesn't apply to all toxins

409

Chloracne

acne-like rash, folliculitis, due to PCB exposure

410

iniator;

carcinogen makes permanent DAN damage

411

promoter:

induce tumors in primed cells (not carcinogens)

412

pnemoconiois

lung disease due to dust inhalation: chronic, progressive, dyspnea, cough, disability

413

Basic principles of carcinogenesis:

causes: chemicals, radiation, viruses/ nonlethal DNA damage, multistep process, initiators and promoters

414

Farming disease

pesticides, herbicides

415

Disease from Lead

gingivitis (lead lines on bones and teeth), anemia (rbc stippling), not cancer

416

Disease from Asbestos:

Pulmonary cancer: 15-20yrs after exposure, asbestos fibers, highly malignant, Mesothelioma: highly anaplastic, most die in less than a year, in leura and surround the lung parenchyma

417

Most proven human disease is due to:

occupation or massive exposure

418

Theshold dosein mainly based on:

animal models

419

4 modes of direct toxic effect:

tissue vulnerability, mode of action (enz inh), metabolism (procarcinogens), excretion (toxic conc)

420

Rsxns to injury are due to:

direct toxic effect, allergic mechs, idiosyncratic factors (genetic or host)

421

formaldehyde causes:

throat cancer

422

Sources of formaldehyde:

insulation, fixation of tissues

423

Miners are exposed to:

arsenic, nickel, asbestos

424

Is DNA damage due to carcinogenesis reversible?

No

425

Carcinogenesis causes damage to what types of genes?

proto-oncogenes, suppressor genes, genes regulating apoptosis, DNA repair genes

426

Most chemical carcinogens are:

indirect acting

427

How do electrophiles react with DNA?

covalent bonds

428

What do electrophiles form with DNA?

adducts with nucleotides

429

Ex of direct acting carcinogens;

alkylating anti-neoplastic drugs

430

Procarciniogens requrie:

metabolic conversion, often P-450 dependent mono-oxygenase system in liver

431

3 types of chemical carcinogens:

Electrophiles, direct and indirect acting

432

Ex of direct acting carcinogen:

alkylating anti-neoplastic drugs

433

benzo(a)pyrene is a:

procarcinogen, polycyclic aromatic hydrocarbon

434

benzo(a)pyrene is converted by this and tend to form this:

cytochrome P-450 system, epoxides (3 member rings with one O2, active metabolites)

435

What do epoxides react with/

covalently bind DNA

436

Determinants of pneumoconiioses:

density in air, duration of exposure, particle size (usually les than 2-3um), chemical nature of dust

437

Type of asbestos fiber that is more pathogenic:

straight (curved, not very)

438

Asbestos fibers are:

hydrated silicates (silica, Fe, Mg, Na)

439

2 examples of curved asbestos fibers:

crosidolite, amosite

440

What part of asbestos enters the lung?

Amphiboles

441

Number of toxic dump sites in USA:

5,000

442

Sources of PCB's:

(polychlorinated biphenyl molecules) insulation, lubricants, caulking, paints, fish, poultry

443

PCB's:

water stable, resist biodegradation, build up in fat tissue, generate free radicals, form xenoestrogens (leads to malignant change in breast epi)

444

PCB exposure can lead to:

liver failure, carcinoma of breast

445

Gross morphology of cirrhotic liver:

nodular and fibrotic (firm)

446

Pathogenesis of lead poisoning:

inhibits ALA dehydrase (heme)

447

Benefit of nano particles in new materials:

greater strength and durabiilty, temp resistant, water proof

448

Why are we suspicious of the health effects of nano particles?

unusual physical, chemical, biological properties, migrate undetected to various tissues, cancer-causing effects in animal models

449

Cancer-causing effects in animal models from nanoparticle exposure:

cross intact membranes, generate free radicals, break DNA strands in mice given water with titanium (tio2)

450

Where is titanium used?

coat building windows, sunscreen

451

Shapes of nanoparticles:

spherical or fiber-like