1st Exam Flashcards
1
Q
Mediators of vasodilation:
A
Protoglandins, NO, Histamine, and C3a and C5a
2
Q
mediators of increased vascular permeability:
A
histamine, sreotonin, C3a and C5a, Bradykinin, Leukotrienes C4, D4, E4, PAF, Substance P, prostaglandin
3
Q
mediators of chemotaxis:
A
C3a and C5a, Cytokines TNF, IL-1, Leukotrienes B4 (LTB4), Bacterial Products, chemokines, IL-8
4
Q
mediators of fever:
A
prostoglandins, cytokines TNF, IL-1
5
Q
mediators of pain:
A
prostoglandins, bradykinin, substance P
6
Q
mediators of tissue damage:
A
NO, Lysosomal enzyes, ROS Chemokines
7
Q
Effects of prostoglandin:
A
fever, pain, vasodilaiton, increased vascular permeability (at least PGD2 and PGE2)
8
Q
Effects of NO:
A
Tissue damage, vasodilation
9
Q
Effects of histamine:
A
Vasodilation, increased vascular permeability
10
Q
Effects of serotonin:
A
increased vascular permeability, vasod, and vasoc (if injury to bv, primary hemostasis, clotting)
11
Q
Effectes of C3a, C5a:
A
vasodilation, increased vascular permeability, chemotaxis
12
Q
Effects of bradykinin:
A
increased vascular permeability, pain, (vasod and bronchial sm contraction?)
13
Q
Effects of Leukotrienes C4, D4, and E4:
A
Increased vascular permeability
14
Q
effects of PAF:
A
Increased vascular permeability, aggregate platelets, degranulation (release of pre-formed mediators), bonchoconstriction, vasod (1000 X more than histamine), chemotaxis of inflammatory cells
15
Q
Effects of Substance P
A
Increased (LL says modulate), vascular permeability, pain, regulate vessel tone, stimulate cytokine P and R
16
Q
Effects of cytokines TNF, IL-1:
A
chemotaxis, fever
17
Q
Effects of Leukotrienes B4:
A
chemotaxis:
18
Q
Effects of Bacterial products:
A
chemotaxis
19
Q
Effects of lysosomal enzymes:
A
Tissue damage
20
Q
Effects of ROS:
A
Tissue damage
21
Q
Effects of chemokines:
A
chemotaxis and tissue damage
22
Q
Paraneoplastic syndrome(s) assoc w lung small cell anaplastic (oat cell) carcinoma:
A
Cushing Syndrome, Hyponatremia
23
Q
Paraneoplastic syndrome(s) assoc w various carcinomas:
A
Troussea Syndrome, hypoglycemia
24
Q
Paraneoplastic syndrome assoc w Lung ssc:
A
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
