general Flashcards
end pathway of apoptosis?
activation of cytostolic caspases –> cellular breakdown
** ATP required
histologic features of apoptosis?
eosinophilic cytoplasm cell and nuclear shrinkage (pyknosis) basophilia membrane blebbing nuclear fragmentation (karyorrhexis) apoptotic body formation
what is DNA laddering?
sensitive indicator of apoptosis
endonucleases cleave DNA during karyorrhexis –> fragments in multiples of 180bp
radiation therapy effects on tumor cells?
apoptosis of tumors and surroudning tissue
free radical formation
dsDNA breakage
intrinsic pathway of apoptosis?
when regulating factor is withdrawn
increase in BAX and BAK (proapoptotic), decrease in Bcl-2 (antiapoptotic)
increased mito permeability and cytochrome c release
Bcl-2 function?
binds and inhibits Apaf-1 –> prevent cytochrome c release
Apaf-1 normally induces caspase activation
what happens with overexpression of Bcl-2?
Apaf-1 overly inhibited
decreased caspase activation
tumorigenesis
** e.g. follicular lymphoma
extrinsic pathway of apoptosis?
1) FasL binds Fas (CD95) –> multiple Fas molecules coalesce –> binding site for FADD –> binds/activates caspases
2) cytotoxic T cell –> perforin and granzyme B
defects in Fas-FasL cause what?
autoimmune disorders (needed for thymic medullary negative selection)
cell outlines preserved, increased cytoplasmic acidophilia?
coagulative necrosis
ischemia/infarcts in most tissues
** proteins denature –> enzymatic degradation
cellular debris and macrophages –> cystic spaces and cavitation?
liquefactive necrosis
bacterial abscesses, brain infarcts
** enzymatic degradation (lysosomal enzyme from neutrophils) –> proteins denature
fragmented cells and debris surrounded by lymphocytes and macrophages?
caseous necrosis
TB, systemic fungi
** macrophages wall off –> granular debris
outlines of dead fat cells without peripheral nuclei, dark blue on H&E?
fat necrosis
enzymatic (pancreatitis), nonenzymatic (breast trauma)
** cells –> lipase –> FAs in cell membranes broken down
thick and pink vessel walls?
fibrinoid necrosis
immune rxns in vessels
** immune complexes + fibrin –> vessell wall damage
types of gangrene?
ischemia –> dry gangrene – coagulative
superinfection –> wet – liquefactive
irreversible types of cell injury?
nuclear pyknosis, karyorrhexis, karyolysis
plasma membrane damage
lysosomal rupture
mitochondrial permeability/vacuolization
reversible types of cell injury?
cellular/mitochondrial swelling nuclear chromatin clumping decreased glycogen fatty change ribosomal/polysomal detachment membrane blebbing
area of brain susceptible to ischemia?
ACA/MCA/PCA boundary - watershed
area of heart susceptible to ischemia?
subendocardium (LV)
areas of kidney susceptible to ischemia?
straight segment of prox tubule
thick ascending limb
area of liver susceptible to ischemia?
zone III - around central vein
area of colon susceptible to ischemia?
splenic flexure, rectum - watershed
vascular component of inflammation?
increased vascular permeability
vasodilation
endothelial injury
cellular component of acute inflammation?
neutrophil
eosinophil
antibody
cellular component of chronic inflammation?
mononuclear cell
fibroblast
- assoc with blood vessel prolif, fibrosis
- can lead to scarring or amyloidosis
what is chromatolysis?
what happens to neuronal cell body following axonal injury
increased protein synthesis
findings: round cellular swelling, nuclear peripheralization, Nissl dispersal throughout cytoplasm
what is dystrophic calcification?
Ca deposition in abnormal tissues 2/2 injury/necrosis
usually localized
** TB, chronic abscesses, fat necrosis, infarcts, thrombi, schistosomiasis, Monckeberg arteriolosclerosis, congenital infx, psammoma bodies
what is metastatic calcification?
Ca deposition in normal tissues 2/2 hypercalcemia or high Ca-Ph levels
mostly in interstitial tissues of kidney, lung, gastric mucosa - lose acid quickly, increased pH favors deposition
** hyperparathyroidism, sarcoid, hypervitaminD, renal failure, dialysis
what signaling molecules mediate leukocyte margination/rolling?
on stroma/vasculature: E-selectin, P-selectin, GlyCAM1, CD34
on leukocyte: Sialyl-Lewis, L-selectin
what signaling molecules mediate leukocyte tight-binding?
on stroma/vasculature: ICAM1 (CD54), VCAM1 (CD106)
on leukocyte: CD11/18 (LFA1, Mac1), VLA4
what signaling molecules mediate leukocyte diapedesis?
PEDCAM1 (CD31) on vasculature/stroma AND on leukocytes
what signaling molecules mediate leukocyte migration?
vasculature/stroma: release C5a, IL-8, LTB4, kallikrein, platelet activating factor
what step of leukocyte extravasation is deficient in LAD2?
decreased Sialyl Lewis –> defective margination and rolling
what step of leukocyte extravasation is deficient in LAD1?
decreased CD18 subunit –> defective tight-binding
how do free radicals damage cells?
membrane lipid peroxidation
protein modification
DNA breakage
what can eliminate free radicals?
scavenging enzymes (catalase, superoxide dismutase, glutathione peroxidase)
spontaneous decay
antioxidants (vit A,C,E)
metal carrier proteins (ceruloplasmin, transferrin)
by when has a scar regained 70-80% of tensile strength?
3 months
doesn’t regain much additional after that
secreted by platelets and macrophages, induces vascular remodeling and smooth mm cell migration, stimulates fibroblast growth?
PDGF
stimulates angiogenesis?
FGF
VEGF
stimulates cell growth via tyrosine kinases?
EGF
** e.g. EGFR
stimulates angiogenesis, fibrosis, cell cycle arrest?
TGF-beta
stimulates tissue remodeling?
metalloproteinases
inflammatory phase of wound healing?
up to 3 days after injury
clot formation, increased vessel permeability, neutrophil migration
macrophages clear debris 2 days later
** platelets, neutrophils, macrophages
proliferative phase of wound healing?
day 3-weeks after injury
granulation tissue and collagen, angiogenesis, epithelial cell proliferation, clot dissolution, wound contraction (myofibroblasts)
** fibrolbasts, myofibroblasts, endothelial cells, keratinovytes, macrophages
remodeling phase of wound healing?
1 week - 6 months after injury
type III collagen –> type I collagen
tensile strength of tissue increases
** fibroblasts
mechanism of granuloma formation?
TH1 cells –> IFN-gamma –> macrophage activation
macrophages –> TNF-alpha –> induces and maintains granuloma formation
what things cause decreased ESR?
sickle cell polycythemia HF microcytosis hypofibrinogenemia
what things cause increased ESR?
anemia infection inflammation cancer preg autoimmune
deposition of proteins from Ig light chains?
AL (primary amyloidosis)
can be plasma cell disorder orassociated with multiple myeloma
** cardiac, renal, hematologic, GI, neurologic involvement
deposition of fibrils composed of serum amyloid A?
AA (secondary amyloidosis)
seen with chronic inflammatory conditions - RA, IBD, spondyloarthropathy, infx
beta-2 microglobulin fibril deposition?
dialysis-related amyloidosis
** may present as carpal tunnel syndrome
transthyretin gene mutation?
heritable amyloidosis
deposition of normal transthyretin in myocardium (and elsewhere)?
age-related systemic amyloidosis
** slower progression of cardiac dysfunction relative to AL
islet amyloid polypeptide?
(IAPP)
commonly seen in DM2
deposition of amylin in pancreatic islets
yellow-brown wear-and-tear pigment?
associated with normal aging
formed by oxidation and polymerization of autophagocytosed organellar membranes
cellular mechanism of invasive carcinoma?
collagenases and hydrolases (metalloproteinases) –> basement membrane invasion
inactivation of E-cadherin –> loss of cell-cell contacts
pumps out toxins, including chemo agents?
MDR1 = P-glycoprotein
classically in adrenal cell carcinoma
what factors mediate cachexia?
TNF-alpha
IFN-gamma
IL-1
IL-6
what do dermato/polymyositis predispose to?
visceral malignancies
esp genitourinary
what do xeroderma pigmentosum and albinism predispose to?
squamous cell carcinoma
basal cell carcinoma
melanoma
bcr-abl?
tyr kinase
assoc with CML and ALL
bcl-2?
anti-apoptotic
assoc with follicular and undifferentiated lymphomas
braf?
serine/threonine kinase
assoc with melanoma and NHL
c-kit?
cytokine receptor
assoc with GIST
c-myc?
transcription factor
assoc with Burkitt lymphoma
her2neu?
tyrosine kinase
assoc with breast, ovarian, gastric a
l-myc?
transcription factor
assoc with lung tumors
n-myc?
transcription factor
assoc with neuroblastoma
ras?
GTPase
assoc with colon, lung, pancreatic ca
ret?
tyrosine kinase
assoc with MEN2A/2B, medullary thyroid ca
apc?
colorectal cancer, assoc with FAP
dcc?
dcc - deleted in colon cancer
dpc4/smad4?
dpc - deleted in pancreatic cancer
men1?
menin - MEN1
nf1?
Ras GTPase activating protein - neurofibromin
nf2?
merlin (schwannomin) protein
p16?
cyclin-dependent kinase inhibitor 2a
assoc with melanoma
p53?
TF for p21 - blocks G1–>S
assoc with Li-Fraumeni
pten?
breast ca
prostate ca
endo ca
rb?
inhibits E2F, blocks G1–>S
assoc with retinoblastoma, osteosarcoma
TSC1/TSC2?
hamartin/tuberin protein
assoc with tuberous sclerosis
vhl?
inhibits hypoxia inducible factor 1a
assoc with VHL, renal cell carcinoma
alpha-fetoprotein is marker for?
HCC
hepatoblastoma
yolk sac tumor
mixed germ cell tumor
Ca 15-3, CA 27-29 is marker for?
breast cancer
CA 19-9 is marker for?
pancreatic adenocarcinoma
CA 125 is marker for?
ovarian cancer
calcitonin is marker for?
medullary thyroid carcinoma
CEA is marker for?
carcinoembryonic antigen - produced by 70% CRC and pancreatic ca; gastric, breast, medullary thyroid carcinomas
chromogranin is marker for?
neuroendocrine tumors, carcinoid
psammoma bodies?
papillary carcinoma of thyroid
serous papillary cystadenocarcinoma of ovary
meningioma
malignant mesothelioma
cancer incidence in male/female?
male: prostate > lung > colon
female: breast > lung > colon
cancer mortality in male/female?
male: lung > prostate > colon
female: lung > breast > colon
MC source of mets in brain?
lung > breast > prostate > melanoma > GI
** commonly at gray/white matter junction
MC source of mets in liver?
colon»_space; stomach > pancreas
MC source of mets in bone?
prostate, breast > lung, thyroid, kidney
