Flashcards in 1st Exam Deck (451)
Mediators of vasodilation:
Protoglandins, NO, Histamine, and C3a and C5a
mediators of increased vascular permeability:
histamine, sreotonin, C3a and C5a, Bradykinin, Leukotrienes C4, D4, E4, PAF, Substance P, prostaglandin
mediators of chemotaxis:
C3a and C5a, Cytokines TNF, IL-1, Leukotrienes B4 (LTB4), Bacterial Products, chemokines, IL-8
mediators of fever:
prostoglandins, cytokines TNF, IL-1
mediators of pain:
prostoglandins, bradykinin, substance P
mediators of tissue damage:
NO, Lysosomal enzyes, ROS Chemokines
Effects of prostoglandin:
fever, pain, vasodilaiton, increased vascular permeability (at least PGD2 and PGE2)
Effects of NO:
Tissue damage, vasodilation
Effects of histamine:
Vasodilation, increased vascular permeability
Effects of serotonin:
increased vascular permeability, vasod, and vasoc (if injury to bv, primary hemostasis, clotting)
Effectes of C3a, C5a:
vasodilation, increased vascular permeability, chemotaxis
Effects of bradykinin:
increased vascular permeability, pain, (vasod and bronchial sm contraction?)
Effects of Leukotrienes C4, D4, and E4:
Increased vascular permeability
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
Effects of Substance P
Increased (LL says modulate), vascular permeability, pain, regulate vessel tone, stimulate cytokine P and R
Effects of cytokines TNF, IL-1:
Effects of Leukotrienes B4:
Effects of Bacterial products:
Effects of lysosomal enzymes:
Effects of ROS:
Effects of chemokines:
chemotaxis and tissue damage
Paraneoplastic syndrome(s) assoc w lung small cell anaplastic (oat cell) carcinoma:
Cushing Syndrome, Hyponatremia
Paraneoplastic syndrome(s) assoc w various carcinomas:
Troussea Syndrome, hypoglycemia
Paraneoplastic syndrome assoc w Lung ssc:
Paraneoplastic syndrome assoc w renal cell carcinoma:
polycythemia (increased concentration of hemoglobin)
Paraneoplastic syndrome assoc w metastatic malignant carcinoid tumors;
Mechanism of Cushing Syndrome (cortisol levels too high cause CS):
Mechanism of hypercalcemia:
Mechanism of hyponatremia:
innappropriate ADH secretion
Mechanism of polycythemia:
Mechanism of Trousseau syndrome:
Mechanism of hypoglycemia:
Mechanism of carcinoid syndroe
15% of ppl w dermatomyositis get:
carcinoma of lung, ovary, breast
Tumor assoc w migratory venous thrombosis:
Tumor assoc w Myasthenia gravis:
thymoma, thymus tumor
heliotropic (directs toward the sun) rash on malar (cheek) surface of face, ai disease, inflammatory, affects bv, m atrophy
PSA is a marker for:
AFP is a marker for:
CEA is a marker for:
hCG is a marker for:
choriocarcinoma, tumor of uterus, originates from chorion of fetus (human chorionic gonadotropin)
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?)
Health issues that cause chronic inflammation:
persistent infections/toxins, ai disorders
4 pw acute inflammation can go down:
CHAR: Chronic, Healing, Abscess, Resolution
Histamine is released by:
mast, basophils, and platelets
2 main descriptors of inflammatory mediators:
pleiotropic and redundant
Why do we need so many mediators with overlapping effects?
they are all short lived, leads to amplification
From where are mediator derived?
cell or plasma
7 cell derived mediators:
VAN PELCC: Vasoactive amines, neuropeptides, prostaglandins, enzymes, leukotrienes, cytokines, chemokines,
3 plasma-derived mediators of inflammation:
complement, coagulation, and kinin systems (3 'C' sounds) mp
2 vasoactive amines:
histamine and serotonin
Vasoactive amines (histamine, serotonin) and leukocyte lysosomal enzyme
3 neutral proteases:
elastase, collagenase, cathepsin (endopeptidase found in most cells, autolysis and self-digestion of tissues)
Major sources of newly formed mediators:
leukocytes, mast cells, endothelial cells, platelets (LMEndoP)
How are newly formed mediators removed from body?
enzymes or spontaneous decay
This liberates AA from the cell if there is cell injury (cell membrane I think):
2 pathways for AA metabolism:
cyclooxygenase and 5-Lipoxygenase
cyclooxygenase pw to metabolize AA:
Thromboxane A2: vasoc, platelet agg/ Prostacyclin: vasod, inhibit platelet agg/ PGD2 and PGE2: vasod, inc perm/ pain and fever
Part of 5-Lipoxygenase pw to breakdown AA, recruits inflammatory cells via chemotaxis
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
Acids besides AA being metabolized via this pw:
Omega 3 and 6 fatty acids
Group of natural antiinflammatory mediators:
resolvins, natural antagonists to prostaglandins
Why do steroids decerase inflammation?
prevent liberation of AA
2 cyclooxygenase inhibitor (Cox-1, Cox-2):
aspirin (NSAIDS), indometacin
Newly synthesized mediators of inflammation:
AA, PAF, cytokines, chemokines, neuropeptides, ROS, NO (CNNCRAP)
PAG is aka:
PAF is derived from:
Sources of PAF:
platelets, PMN, mast cells, macros, endothelium (PPEMM)
What liberates PAF?
activation of phospholipase A2
Families of cytokines:
lymphokines, monokines, chemokines, interleukins, interferons (3 kines and 2 I's)
4 major cytokines in acute inflammation:
TNF, IL-1, IL-6, and chemokines
Major cytokines of acute inflammation are produced by (3):
macros, mast cells, endo cells
Major cytokines in chronic inflammation:
Effect of IL-1 and 6 on liver:
production of acute phase proteins
Effect of IL-1 and 6 on brain:
Effect of IL-1 and 6 on bone marroe:
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)
5 Pathological systemic effects of TNF:
low heart output, hypertension, shock, thrombus formation, insulin resistance of skeletal muscle (IL-1 also causes insulin resistance)
5 Systemic mani of inflammation:
fever, leukocytosis, inc acute-phase proteins, decrease apetite, inc sleep (FLAPPAS)
4 Fxn of chemokines:
wbc recruitement, cellular organization, active (sic?) leukocytes, regulate cell trafficking
How do chemokines interact with cells?
2 newly synthesized neuropeptides:
sub P and calcitonin gene related protein (CGRP)
Neurogenic inflammation occurs when these are activated:
neuropeptides (transmit pain)
Effect of CGRP
(Calcitonin gene related protein) vasod, pain
Sources of ROS:
activated PMN's and macros
How are ROSs synthesized?
NADPH oxidase pw
Effect of low level secretion of ROS:
inc chemokine, cytokine, adhesion molecule expression
Effect of high level secretion of ROS:
endothelial damage, inc perm, protease activation, antiprotease inactivation
What limits the toxicity of secreted ROS?
endogenous antioxidant mechanisms
NO is found in:
endo cells, macros
System(s) activated by Hageman factor:
Complement, Kinin-Bradykinin, Coagulation (all 3 plasma mediators of inflammation)
Fxn of plasma-protein derived mediators of inflammation:
inc perm, vasoactive
This activates fibrinogen:
2 ways to activate the complement cascade:
plasmin or kallikrein (not hageman factor?)
Endogenous antimediators that "stop" inflammation:
antioxidnats, lipoxins, protease inhibitors (PAL)
This interleukin inhibtis TNF:
These interleukins promote repair:
WHat do NSAID's do?
block COX-1 and Cox-2 (from making PG's)
What do steroids do?
prevent AA release by PLA2
What do Etanercept and Infiximab do?
block TNF (RA and Crohn's)
Causes of infection (inflammation?)
physical, chemical, infection, immune reaction, ischemia
Type of inflammation depends on:
chronology and pathology
Vasoactive mediators that cause gaps due to endothelial contraction:
histamine, leukotrienes, etc.
4 mechanisms of inflammation permeability:
endothelial gaps, necrosis/apoptosis, leukocyte-dependent injury, transcytosis
Selectins are involved in these cellular events:
rolling, activation (P, E, and L selectins_)
Integrins/Immunoglobulins are involved in these cellular events:
PECAM-1 is involved in this cellular event:
transmigration (synonymous with transcytosis?)
List of integrins/Immunoglobulins involved in cellular events:
MAC 1, ICAM 1, VCAM-1, LFA 1, VLA-4
These recognize sialylated carbohydrate groups:
This selectin is stored in Weibel–Palade bodies of endothelial cells:
This selectin is not produced under normal conditions:
These are the ligands to the homing receptors of lymphocytes and determine which tissues the lymphos will enter next:
Plays a key role in removing aged neutrophils from body:
PECAM-1 (involved in transmigration)
4 major groups of adhesion molecules:
selectins, addressins, integrins, immunoglobulin superfamily
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)
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)
Where is L selectin expressed?
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
PECAM is involved in:
PECAM is aka:
CD31, on both endo and lymphos
How does PECAM pierce the basement membrane to allow diapadesis of the WBC?
How does a cell relocate during chemotaxis?
by binding ecm
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
Bradykinin is broken down via:
Where are the mediators for the cascading enzyme systems synthesized?
How is fibrin broken down?
How to determine if there is a clot somewhere in he body via blood draw?
look for fibrin split products
Activators of Hageman factor(4):
platelets, necrosis, collagen, bm
Increased intracellular Ca+ concentration can lead to:
Inc expression of endonuclease (DNA), ATPase (energy), protease (protein) , phospholipase (membrane)
Trigger formation of the inflamasome:
bacterial endotoxins, necrosis, cytokines
Function of the inflamasome:
Function of pyrin:
Function of corticosteroids:
block AA synthesis (blocking inflammation) (and steroid prevent the release from the lipid membrane...?)
4 major groups of antiinflammatory drugs:
antihistamines, corticosteroids, NSAIDS, Leukotriene drugs
Function of Leukotriene drugs:
5-lipoxygenase inhibitors (zileuton), LT receptor antagonist (Accolate)
Cells of acute and chronic inflammation:
acute: polys, chronic: lymphos, macros, and plasma
Sub-acute inflammation is characterised by:
polymorphous granulation tissue
Specific causes of granulomatous inflammation:
TB, fungus, sutures, syphilis
Contributes to the formation of granulomas:
IL-4 (Th2 cells)
water + mucus, nasal discharge:
Pus + polys:
dead cells + polys
governs the increased production and release of neutrophils from the marrow during inflammation:
IL-1 and TNF
Normal WBC count:
Blood test for inflammation or leukocytosis:
WBC differential count
Causes of neutrophilic leukocytosis:
infection, inflammation, necrosis
Shift to the left:
BM cells release immature forms of polys
polys aren't increased, chronic inflammatory process, ie TB, viral diseaese
This type of leukocytosis is common with allergic reactions, parasitic infections:
3 types of leukocytosis:
neutrophilic lymphocytic, eosinophilic
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)
How to test for bacterial inflammation:
Blood PCT level (procalcitonin)
Is CRP elevated in acute or chronic inflammation?
When would blood ESR level be high?
Infection and systemic inflammatory disease (erythrocyte sedimentation rate, nonspecific test for inflammation)
ESR results that indicate inflammation:
RBC travel further than 20mm
Prime stimulant of CRP:
CRP is produced here:
Elevated blood SAA levels indicate:
chronic infammatory disease
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)
Protein SAA has a tendency to form:
fibrils (amyloidosis), diagnose with congophilic dyes
Calcitonin is made by these cells:
C cells of thyroid gland
When does granulation tissue form?
as inflammation subsides
Granulation tissue is composed of:
proliferating capillaries, fibroblast, and myofibroblasts, amorphous ECM, and macros
VEGF and betaFGF (made by macros, betafibroblast growth factor)
Activates the transcription of VEGF and B-FGF
hypoxia-induced factors (HIF)
These are responsible for wound contraction:
myofibroblasts derived from pericytes
Amorphous ECM is made by, and contains lots of:
fibroblasts, glucosamines looks acellular
Function of HIF:
induce VEGF and BFGF
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)
Antagonist of Angiopoietin 1:
Angiopoietin 2, tube regression
How does granulation tissue become scar tissue?
Organization of fibroblasts and collagen fibrils in tissue
Scars form through:
the remodelling of granulation tissue
How is granulation tissue broken down?
2 inhibitors of angiogenesis:
angiopoietin 2 adn angiostatin
Wound contraction starts at day __ and usually ends by day__:
Granulation tissue starts to form at day __ and usually ends by day__:
How long does it take for inflammation to start?
about 0.1 days: 2.4 hrs
Early wound collagen is Type __ and late wound collagen is converted to type __
Which type of collagen is stronger, Type I or Type III?
Reopening of wound, esp. scar tissue
Stages of skin wound healing:
blood clot, dries, scab, polys, macs, granulation tissue, scar (dermis forms),
These would be present around a wound 3-7 days after injury:
granulation tissue, macs, fibroblasts, new caps
How much faster do oral wounds heal than other wounds?
2-3 times faster
This, found in saliva, speeds mucosal redeneration:
Special types of wound healing:
fibrosis wo granulation tissue, tumor encapsulation, liver cirrhosis, hyalinized granuloma
What is cirrhosis?
fibrotic processes bw columns of liver cells
Complications of normal wound healing:
excessive granulation tissue, excess scar, defective scar, dystrophic calcification
Ex of excessive granulation tissue formation:
Stimulus for dystrophic calcification (calcium where you don't want it)
atherosclerosis, aging heart valve, granulomas, tumors
Local causes of delayed wound healing:
Infection, poor blood supply, foreign material, type/ size/ location of wound
Which heals slower, heart or skin?
Systemic causes of delayed wound healing:
age, diabetes, diet (DAD)
Antimicrobial, painted on wound, retards bacterial growth:
bandage with growth factors to stimulate healing:
Take this from a pt to speed their healing of a wound:
PRP (platelet-rich plasma)
How can oxygen and pressure be used to speed healing?
negative pressure, hyperoxygenated
When to order a liver function test:
Normal CK levels:
38-174 (creatinine kinase)
Where in the body is CK present?
heart, brain, muscle (run marathon, creatinine kinase elevated)
How long does it take for CK levels to peak and return to normal?
24h, 5 days
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)
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.
Most common cancers:
breast, uterine, lung, colon (BULC, the bulk of cancers are...)
What type of skin cancer is on the highest incidence list?
Japan has a high incidence of __ cancer.
Cancer is most likely do to:
environmental influence, esp. food, no pollutants
Fraction of cancer we get that is random and unpredictable:
Tobacco is a major player in these cancers:
lung, kidney, bladder
These food increase risk for bowel, pancreas, breast, and prostate cancers:
high fat, low fiber, fried, broiled
3 ex of inherited cancers:
breast (Brc1, Brc2, prevelant in Ash Jew), colon/ rectal cancer, skin cancer (XP), retinoblastoma (Rb)
Diff bw carcinogen and mutagen:
Car: anything that causes, mutagen: chemical that causes, so a mutagen is a carcinogen
Cancer begins as:
a single cell clone, mutation in a specific gene in a specific cell
TF? Proto-oncogenes are abnormal genes that will eventually lead to cancer.
F. Normal genes
Do oncogenes gain or loose activity.
Define lose activity:
can not supress gene expression
This is a test for mutagens:
As long as these are working, you will not get severe cancer:
tumor suppressor genes
When we first turn on cell growth and cell division we activate
cyclin D, activates CDK
This stops division if anything is going wrong in G1 phase:
What occurs during S phase:
DNA and histone synthesis
The cell cycle is regulated by:
cyclins and CDK's
When are cyclins made and destroyed in cell cycle?
Destroyed: end of phase they were used in, Made: End of previous phase
The longest phase of the cell cycle:
G1, protein synthesis/ cell growth
Where is the first major checkpoint in the cell cycle?
end of G1 phase, if cancerous, tsg would stop the cycle
What turns on the cell cycle?
What turn on the synthesis of DNA?
TF? Most cells can divide.
What cells normally do not divide?
organ cells: brain, liver, kidney
How do pathologist diagnose cancer?
less differentiated or undifferentiated
How do growth factors stimulate growth?
by activating multistep pws
What stops cell growth and activate cellular differentiation?
Do stem cell precursors normally divide quickly or slowly?
Why does the incidence of cancer increase with age?
You need many mutations
All prokaryotes are:
how do we turn off expression of a gene?
tightly wrap it around a nucleosome
octamers of a specific histone that look like beads on a slide
Fxn of writers:
modify lysines and other residues
proteins that bind to modified lysines (turn gene exp on or off)
Levels of this are elevated in metastatic breast and prostate cancer
1 type of leukemia is due to:
an enzyme that methylates H3K4
When are Ez levels markedly increased?
worst cases of metastatic breast and prostate cancer
proteins that loosen DNA around a histone, increasing accessibility
Enzymes that remove histone modifications:
Trimethylation of __ is very important in gene activation.
lysine at position 4 of Histone 3 (H3K4)
How do euk's turn gene expression on and off?
wrap or unwrap DNA around a nucleosome, accessibility regulated by a 'histone' code
How many nucleosomes does it take to wrap around one gene?
Enzymes that modify residues:
Effect of Ez adding 3 methyl groups to H3K27:
Turn off adjacent gene
Levels of this are increased in the worst types of metastatic breast and prostate cancer:
A mutation in an enzyme that methylates H3K4 causes:
a type of leukemia
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:
What is Ez?
Histone code writer
Normal function of Ez
adds 3 m groups to H3K27, silencing adjacent genes responsible for early development proteins
TF? epigenetics is usually a part of cancer.
changes passed on from daughter cell to daughter cell
How are heterotrimeric G proteins activated?
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
How are g proteins turned off?
inherent GTpase activity, converting GTP to GDP.
How are small G proteins activated?
GDP dis and GTP binding
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
Quintessential G protein:
This G protein is a major player in the pws that either lead to growth or to differentiation (depends on cell type).
TF? Ras works through the 2nd msg system.
F. directly activates PK's
Inactive, small G proteins are bound to:
TF? Small G proteins have GTPase activity.
T, for self inactivation
What is the multi-hit theory?
multiple gene mutations (9-11) are required to initiate cancer
TF? Not all cancers affect the cell cycle or decrease TSG function.
Cancer always involves:
cell cycle, TSG, epigenetics, mutant proto-oncogenes
How many auxiliary proteins are required to activate and inactivate Ras?
Major players of the growth and differentiation pathways:
growth/ differentiation factor, RTK, Small G protein, 3 auxiliary proteins, kinases, phosphatases,
What kind of pathways are growth and differentiation pathways:
signal transduction pathways
All differentiation factors make cells:
How are growth and differentiation pathways turned off?
What is the first signal in the signal transduction pw of growth and differentiation?
a growth factor binding to RTK
Fxn of auxiliary proteins:
activate and deactivate Ras
What happens to the primary signal in signal transduction pwy?
transduced to factors that lead to growth
What makes the receptor tyrosine kinases come toward each other?
growth factor binds the RTK
how is the RTK activated
How does autophosphorylation of the RTK lead to growth?
after A-p, proteins bind to specific sites which leads to growth
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
What turns on Ras?
SOS, gdp comes off, GTP binds (auxiliary proteins too)
What binds bw the 2 receptor tyrosine kinases?
growth factor (a protein/ hormone)
More than __ tyrosines are normally phopshoylated in the RTK.
TF? Additional, complementary pws are needed for growth to occur besides the RTK pw.
Grb2 and Ras
When is GDP released from Ras?
when SOS binds Ras
Ras recruits Raf to:
a factor that stimulates growth (mitosis)
When does MAPK enter the nucleus?
after phosphorylation (by Mek)
3 TF's heavily implicated in cancer:
myc, fos, jun (too much of any of these = cancer)
TF? Ras has inherent GTPase activity.
T, w help from a GTPase Activating Protein (then why do we have audxillary proteins to turn off?)
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?)
How is Ras inactivated?
Inherently losing its GTPase activity, binds GDP, wo this we would have tons of cancer
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
Ras is mutated in _ % of cancers
Mutations in Ras lead to loss of what activity?
GTPase to activity, Ras always active, can't turn itself off anymore
This mutation is found in 60% of pt w melanoma:
What would a mutation in Myc, Fos, or Jun lead to?
What is SARK?
a cytoplasmic tyrosine kinase.
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
How are PI3 kinases acitvated?
by many RTK's (binding Phosphotyrosine on an activated RTK)
Fxn of Akt:
promote growth and survival, inhibit apoptosis, stimulate mTOR which stimulates protein synthesis
What is mTOR?
Most commonly mutated part of the RTK pw:
What stops the PI3 pw when needed?
PTEN, phosphatase of PI3
What would happen if PTEN is mutated?
PTEN is a:
tumor suppressor, decreases the motor system
TF? Certain steps in the pw give you cancer.
F. any step that is altered
p53, major checkpoint:
end of g1
G2/M pahse boundary
causes mitosis in cell cycle
RB protein binds this normally:
How to get Rb off of E2f protein?
phosphorylation of Rb protein via Myc, enter cell cycle
d cyclin, then its kinase that p's the Rb protein, comes off, E2f proteins activated and the cell cycle turns on
Ex of a mitogen:
Myc,activates cell cycle (anything that promotes growth, cell division)
How do mitogens regulate the rate of cell division?
by their effects during G1
how does normal Myc work?
stimulation of gene expression of cyclin D (turns on the cell cycle)
What happens if Myc is always active?
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
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
This can cause cancer of the retina:
Mutation in Rb that prevents binding to E2f, retinoblastoma
3 ways p53 works:
stimulate transcription of p21 protein (can stop cell cycle in G1 or S if there is damage),
What happens to p53 if DNA is damaged?
it is phosphoryated, preventing its degradation adn the progression to M phase
TF? p53 is always active.
F. only active when we need it
p53 must do this to prevent cancer:
bind to DNA
oncogenes that lead to a gain of action:
mutated Ras or Myc
2nd most important ts after p53:
How is Rb-protein normally phosphorylated?
cyclin D-G1 cyclin dependent kinase complex
What prevent the formation of the cyclin D complex in stressed or overly-rapidly dividing cells?
p16, methylation will silence p16
at what stage of cancer ore p16 mutations common?
early stages (epigenetic mechanism)
Why might drugs that target p53 stop working?
if p53 is mutated
Does phosphorylation of Rb lead to activation or deactivation?
Epigenetic change vs. genetic change
change in expression (daughter to daughter) vs. change in DNA sequence
This can cause gene silencing in cancer cells an prevent the formation of proteins that inhibit growth
Methylation of what can lead to permanent gene silencing?
H3 and Lys9 (removes ts's)
Is heterochromatin active or inactive?
How are developmental genes related to cancer?
many of these are turned on AFTER development, causing cancer
Ez is active in what cancers?
metastatic breast and prostate
How does Gleevac work?
binds Phile chromo. CML, binds specific mutant protein
Marjor factor in whether or not cancer forms
how fast stem cells are dividing in a articular organ
PAP smears can test for:
uterine and cervical
GROUP of neoplasms, invading tissue
Histological groupings of neoplasm:
epi, mesnchymal, neuroectoderml, hematopoietic, lymphioid, germ cell
Types of epi cancers:
squaous or glandular
benign growth characteristics:
slow, expansile (capable of expansion) gowth, local, encapsulated, push on surrounding structure, small, well differentiated
supporting cells of tumor:
Malignant epi tumor:
Malignant mesenchymal tumor:
Benign squamous epithelium cancer:
Malignant squamous epithelium:
Benign glandular epi:
Malignant glandular epi:
Benign fibrous tumor:
Benign sm tumore:
Benign striated muscle tumor:
Benign cartilage tumor:
rising above and growing above the normal epithelium
irregular finger-like growth:
carcinoma, hard to the touch
Causing fibrosis in the vascular stroma of a neoplasm.
What is the mucinous component normally made by?
supporting cell tumor, mostly arises in bone, treated and responds like sarcomas
Lymphoma, malignant neoplasm of lymphoid cells
4 phases of malignant growth:
Mutation/ change, growth, invasion, metastasis (not just the ability to invade blood vessels and lymphatics)
Are pre-neoplastic morphological changes reversible?
Difference bw hyperplasia and hypertrophy
plasia: more cells, trophy: larger cells, same number
Ex of when cells atrophy:
proliferation of abnormal cells, disordered development, increased mitosis, varying numbers of cells, tends to disorder in cellular arrangement
These can cause metaplasia:
toxin, physical stimulus, or gf (change from one epithelium type to another)
Ex of metaplasia in smokers:
glandular to squamous, don't secrete mucus
loss of normal arrangment of cells:
Why do cancerous cells have a darker nuleus?
Carcinoma in situ is a type of:
Carcinoma in situ is confined to what tissue type?
epithelium (full thickness)
malignant EPI tumor
Is carcinoma in situ invasive or non-invasive?
confined to lower half of epi, high grade includes outer half
When is a cell capable of invasion?
When it can express cell surface adhesion molecules
epithelial tumors invade:
the lymphatics rather than blood vessels
sarcomas tend to invade:
blood vessels rather than lymphatics
osteosarcoma metasizes here:
typically to lungs via blood
breast cancer metastasizes here:
lymphatic, lymph nodes, bone, and lungs
How do tumors disrupt the ECM?
Tumor cell that lacks differentiation:
anaplastic (pleiomorphism, variation in size/shape, abnormal nuclear shape, quickly dividing, numerous mitoses)
Tumors are graded by:
mitotic activity, nuclear size and shape, presence of nucleoli or architecture
Local effects of neoplasms:
swelling, irritation, pain, thrombosis, hemorrhage, necrosis, obstruction or perforation of hollow viscera, infection, involvement of adjacent structures
Colon might spread to:
bladder, pelvic side wall, other loops of bowel
Systemic tumor effects:
inc or dec hormonal expression, hypercoagulable state, myopathies, neuropathes
can't be explained by distant or local tumor growth or indigenous tissue hormones
Ex (?) of hypercogulable state;
migrating intravascular thrombophlebitis, non bacterial intravascular coagulation, disseminated intravascular coagulation
Cancer assoc w inc hemoglobin levels:
Renal Cell Carcinoma
Cancer assoc w dec Na levels:
Lung small cell anaplastic carcinoma
Cancer assoc w inc Ca2+ levels:
TF? Dermatomyositis is a hormonally related.
F. not hormonal, rheumatic or skin disease
Serum protein markers are useful for:
Serum protein markers:
monoclonal Ab's against sp antigen produced by tumor cell, not perfect in either specificity or senstivity
In what way is staging more reliable than grading?
3 parameters of staging:
Size, lymph node metastasis, distant non-lymphoid metastasis
Time/ dose relationship of toxicity, high dose/ brief duration acute disease
min dose needed to have an effect, doesn't apply to all toxins
acne-like rash, folliculitis, due to PCB exposure
carcinogen makes permanent DAN damage
induce tumors in primed cells (not carcinogens)
lung disease due to dust inhalation: chronic, progressive, dyspnea, cough, disability
Basic principles of carcinogenesis:
causes: chemicals, radiation, viruses/ nonlethal DNA damage, multistep process, initiators and promoters
Disease from Lead
gingivitis (lead lines on bones and teeth), anemia (rbc stippling), not cancer
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
Most proven human disease is due to:
occupation or massive exposure
Theshold dosein mainly based on:
4 modes of direct toxic effect:
tissue vulnerability, mode of action (enz inh), metabolism (procarcinogens), excretion (toxic conc)
Rsxns to injury are due to:
direct toxic effect, allergic mechs, idiosyncratic factors (genetic or host)
Sources of formaldehyde:
insulation, fixation of tissues
Miners are exposed to:
arsenic, nickel, asbestos
Is DNA damage due to carcinogenesis reversible?
Carcinogenesis causes damage to what types of genes?
proto-oncogenes, suppressor genes, genes regulating apoptosis, DNA repair genes
Most chemical carcinogens are:
How do electrophiles react with DNA?
What do electrophiles form with DNA?
adducts with nucleotides
Ex of direct acting carcinogens;
alkylating anti-neoplastic drugs
metabolic conversion, often P-450 dependent mono-oxygenase system in liver
3 types of chemical carcinogens:
Electrophiles, direct and indirect acting
Ex of direct acting carcinogen:
alkylating anti-neoplastic drugs
benzo(a)pyrene is a:
procarcinogen, polycyclic aromatic hydrocarbon
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)
What do epoxides react with/
covalently bind DNA
Determinants of pneumoconiioses:
density in air, duration of exposure, particle size (usually les than 2-3um), chemical nature of dust
Type of asbestos fiber that is more pathogenic:
straight (curved, not very)
Asbestos fibers are:
hydrated silicates (silica, Fe, Mg, Na)
2 examples of curved asbestos fibers:
What part of asbestos enters the lung?
Number of toxic dump sites in USA:
Sources of PCB's:
(polychlorinated biphenyl molecules) insulation, lubricants, caulking, paints, fish, poultry
water stable, resist biodegradation, build up in fat tissue, generate free radicals, form xenoestrogens (leads to malignant change in breast epi)
PCB exposure can lead to:
liver failure, carcinoma of breast
Gross morphology of cirrhotic liver:
nodular and fibrotic (firm)
Pathogenesis of lead poisoning:
inhibits ALA dehydrase (heme)
Benefit of nano particles in new materials:
greater strength and durabiilty, temp resistant, water proof
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
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)
Where is titanium used?
coat building windows, sunscreen