Flashcards in Foundations Deck (281):
How is the cell cycles regulated?
3. Cyclin-CDK complexes
4. Tumor suppressors
What is the shortest phase of the cell cycle
What are CDKs
they are constitutive and inactive
What are cyclins
regulatory proteins that control cell cycle. They are phase specific and activate CDKs
What is the importance of cyclin-CDK complexes
must be activated and and inactivated for cell cycle to progress. Inactivated by p21, p27, and p57.
What controls p21 activation
What tumor suppressors inhibit G1 to S progression
p53 and hypophosphorylated Rb
What are the different type of cells
What are examples of permanent cell
Neurons, skeletal/cardiac muscle, RBCs. - remain in Go, regenerate from stem cells
What are examples of stable cells
Hepatocytes, lymphocytes. - enter G1 from Go when stimulated
What are examples of labile cells
bone marrow, gut epithelium, skin, hair follicles, germ cells. - NEVER go to Go, divide rapidly w/ a short G1
What is the role of the Rough ER
1. synthesis of secretory proteins and N-linked oligosaccharide addition to proteins
Where in the body are RER found in excess
mucus-secreting goblet cells of small intestine and Ab secreting plasma cells
What are Nissl bodies
RER in neurons. They make enzymes and peptide neurotransmitters
What is the role of free ribosomes
site of synthesis of cytosolic and organellar proteins
What is the role of the SER
steroid synthesis and detoxification of drugs and proteins
What cells are rich in SER
liver hepatocytes and steroid hormone producing cells of the adrenal cortex
How do proteins get into the nucleus
need to have a nuclear localization signal : 4-8 AA sequence rich in L, R, and Proline
What regulates G1 to S phase
1. Cyclin D -- activated CDK4 --> phosphorylates Rb protein which releases it from the TF E2F which transcribes and synthesizes components needed to progress thru S phase
2. Cyclin E - activates CDK2
What regulates G2 to M phase
1. Cyclin A - CDK2 complex --> mitotic prophase
2. Cyclin B - CDK1 complex activated by cdc25 = allows breakdown of nuclear envelope and initiation of mitoses
What is the role of the Golgi Appartus
1. distribution center for proteins and lipids from the ER to vesicles and plasma membrane
2. Modifies N-oliogosaccharides on asparagine
3. Adds O-oligosaccharides on serine and threonine
4. Adds mannose6-phosphate for trafficking to lyososomes
5. glycosylation of proteins
6. sulfation of sugars and tyrosines
What are endosomes
sorting centers for material from outside the cell of from the Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi for further use
What is I cell disease
1. inherited lysosomal storage disease due to failure of addition of mannose 6-phosphate to lysosome proteins.
What are the clinical manifestations of I cell disease
1. coarse facial features
2. clouded cornea
3. restricted joint movement
4. high plasma levels of lysosomal enzymes
often fatal in childhood
What are the vesicular trafficking proteins?
1. COP I - retrograde
2. COP II - antegrade
3. Clathrin : from trans-Golgi to lysosomes or plasma membrane to endosome (receptor mediated endocytosis)
What other proteins are needed for receptor mediated endocytosis
Clathrin, adaptin, and dynamin (plays a role in pinching off the membrane)
What is the role of peroxisome?
membrane enclosed organelle invovled in catabolism of very long fatty acids and amino acids.
What are the 3 ways protein can be degraded?
2. lysosomal degradation
3. Ca dependent enzymes
What is a proteasome
barrel-shaped protein complex that degrades damaged or unnecessary proteins tagged for destruction w/ ubiqutin
What is are microtubules
cyclindrical structure composed of a helical array of polymerized dimers of alpha and beta subunits. They grow slowly and collapse quickly.
How many GTP are bound to each dimer
What uses microtubules
flagella, cilia, mitotic spindles. They also are involved in slow axoplasmic transport in neurons
What helps microtubles w/ transported cellular cargo
Molecular motor proteins.
1. Dynenin - retrograde to microtubule
2. Kinesin - anterograde to microtubule
What drugs have an effect on microtubules
2. griseofulvin (antifungal)
What is Chediak-Higashi Syndrome
mutation in lysosomal trafficking regulator gene whose product is required for the microtubule-dependent sorting of endosomal proteins into late multivesicular endosomes.
What are clinical presentations of Chediak-Higashi Syndrome
recurrent pyogenic infections, partial albinism, and peripheral neuropathy
Describe the structure of cilia
1. 9+2 arrangement of microtubules.
2. Axonemal dynenin - ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets
3. gap junctions allows cilia to communicated w/ each other
What is Kartagener's syndrome
aka Primary Ciliary dyskinesia
1. immotile cilia due to a dynenin arm defect
- male infertility, decreased female fertility, bronchiectasis, recurrent sinusitis, associated w/ situ inversus
What are other components of the cytoskeleon
1. actin and mysoin - microvilli, muscle contraction, cytokinesis, adherens junctions
2. intermediate filaments -
What is the composition of the plasma membrane
asymmetric lipid bilary. Contains cholesterol and phospholipids As well as sphingolipids, glycolipids, and proteins.
What does a high cholesterol content due to the plamsa membrane
decreased fludity, and increases melting temperature
What are the various immunohistochemical stains for?
7. Nuclear lamins
1. connective tissue - found in sarcomas
2. muscle - rhadomyosarcoma
3. epithelial cells (desmosomes and hemidesmosomes) - carcinomas
4. neuroglia (astrocytes, Schwann cells)
7. nuclear envelope and DNA
Tell me about the Na-K ATPase pump
3 Na out and 2 K in. During cycle, pump is phosphorylated.
What drug can inhibit the NaKATPase
cardiac glycosides (digoxin and digitoxin)
- inhibition of the pump leads to an indirect inhibition of Na/Ca exchange so Ca increases inside the cell --> increasing cardiac contractility
What is the most abundant protein in the human body
Where is type 1 collagen found
BONE, skin, tendon, dentin, fascia, cornea, late wound repair
Where is type 2 collagen found
Cartilage (including hyaline), vitreous body, nucleus pulposus
Where is type 3 collagen found
Reticulin - skin, blood vessels, uterus, fetal tissue, granulation tissue
What is the type 4 collagen found
What cells do collagen synthesis take place in?
What are the steps of collagen synthesis?
1. RER - translation of collagen alpha chains (preprocollagen) -- usually Gly-X-Y (prolin and lysines)
2. Hydroxylation in ER - requires Vit C
3. Glycosylation in ER of hydroxylysine and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen alpha chain)
4. exocytosis into extracellular space
5. Cleavage of disulfide rich terminal regions = insoluble tropocollagen
6. Covalent lysine-hydroxylysine cross linkage making collagen fibrils via Cu containing lysyl oxidase
What is osteogenesis imperfecta
genetic bone disorder. Most common form is AD w/ abnormal type I collagen. Type II OI - fatal in utero
What are the features of the common OI form
1. multiple fractures w/ minimal trauma; may occur during the birth process
2. blue sclerae due to translucency of connective tissue over the choroidal veins
3. hearing loss
4. dental imperfections due to lack of dentin
What is Ehlers-Danlos
faulty collagen synthesis during the cross-linking process
What are features of Ehlers-Danlos
hyperextensible skin, tendency to bleed, hypermobile joints, berry anuerysms, organ rupture.
What are the collagen types affects
1. Type III
2. Type 1 and 5 most frequently in sever classic syndrome
What is Alport syndrome
due to a variety of gene defects resulting in abnormal type 4 collagen.
- x-Linked recessive
What are the features of Alport syndrome
progressive hereditary nephritis and deafness. may be associated w/ ocular disturbances
What is elastin
a stretchy protein w/in skins, lungs, large arteries, elastic ligaments, vocal cords, ligamenta glava.
What is the component of elastin
1. rich in proline and glycine - the nonhydroxylated forms
2. topoelastine w/ Fibrillin scaffolding
How is elastin degraded
elastase which is normally inhibited by alpha1-antitrypsin. A defect in antitrypsin will lead to excess elastase and panacinar emphysema or liver problems
What is Marfan's syndrome
-defect in Fibrillin. Heart problems, tall, long fingers
What is apoptosis
programmed cell death, requires ATP. there are two pathways but both ends up activated cytosolic caspases that mediate cellular breakdown. No inflammation is involved with this.
what are the histology features of apoptosis
1. cell shrinkage
2. nuclear shrinkage
4. membrane blebbing
5. nuclear fragmentation (karyorrhexis)
6. formation of apoptotic bodies which are then phagocytosed
What can trigger apoptosis
p53, cytokines, cytotoxic T cells, cell stress, absence of GFs
What is the intrisinc pathway for apoptosis involved in?
involved in tissue remodeling in embryogenesis, occurs when a GF is withdrawn from a proliferating cell population, also occurs after exposure to injurious stimuli
What are the steps for the intrinsic pathway for apoptosis?
1. increase in pro-apoptotic signals : Bax, bak, bcl-x
2. decrease in anti-apptotic signals: Bcl2
3. they increase mitochondrial permeability and cytochrome C is released
4. binds to cytosolic Apaf-1 which activates caspase 9
What are the steps for the extrinsic pathway for apoptosis?
1. Ligand receptor interactions: Fas ligands binds to CD95 --> FADD activates caspase 8
2. Immune cells such as killer T cells release perforn and granzyme B
What is necrosis?
enzymatic degradation and protein denaturation of a cell resulting from exogenous injury. Intracellular components extravasate and there is an inflammatory process.
What are the various types of necrosis?
1. coagulative - heart, liver, kidney
2. liquefactive - brain, bacterial abscess, pleural effusions
3. caseous - TB, systemic fungi
4. Fatty - peripancreatic fat
5. Fibrinoid - blood vessels
6. Gangrenous - dry or wet; common in limbs and in the GIT
What type of cell injury is reversible w/ O2?
1. decreased ATP synthesis
2. cellular swelling
3. nuclear chromatin clumping
4. decreased glycogen
5. fatty change
6. ribosomal detachment
What type of cell injury is irreversible?
1. nuclear pyknosis, karyolysis, and karyorrhexis
2. Ca influx --> caspase activation
3. plasma membrane damage
4. lysosomal rupture
5. mitochondrial permeability
What areas of the following organs are susceptible to ischemia/infarction?
1. subendocardium (LV)
2. ACA/MCA/PCA boundary areas
3. straight segment of the PT (medulla), thick ascending limb (medulla)
4. areas around the central vein (zone 3)
5. splenic flexture, rectum
Where do red infarcts occur?
loose tissue w/ collaterals such as liver, lungs, or intestines or following reperfusion
where do white infarcts occur
solid tissues w/ single blood supply such as heart, kidney, and spleen
What are the cell injury byproducts of the following organs?
2. skeletal muscle
4. salivary glands
1. CK, LDH, troponin
2. CK, aldolase, LDK
3. AST, ALT, alk phos, GGT
5. amylase and lipase
6. LDH, haptoglobin, bilirubin
What are the various types of shock?
What happens w/ hypovolemic/cardiogenic shock?1
1. low output failure
2. increased TPR
3. low cardiac output
4. cold, clammy patient due to vasoconstriction
What happens w/ septic shock?
1. high output failure
2. decreased TPR
3. dilated arterioles and high venous return
4. hot patient due to vasodilation
What is atrophy?
reduction in size or number of cells. Decreased metabolic activity b/c of decrease proteins, autophagy, increased protein degradation.
What are causes of atrophy?
1. decreased hormones - menopause
2. decreased innervation - motor neuron damage
3. decreased blood flow
4. decreased nutrients
5. increased pressure (nephrolithiasis)
5. occlusion of secretory ducts (CF)
What are charactersitics of inflammation?
5. loss of function
What happens to the vasculature during inflammation?
increased vascular permeability, vasodilation, and endothelial injury
What happens to the cellular component during inflammation?
PMNs extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation, and inflammatory mediator release
What are components of acute inflammation?
1. PMNs, eosinophils, Ab mediated
2. Rapid onset, lasts minutes to days
3. outcome = complete resolution, abscess formation, and progression to chronic inflammation
4. IL 1/6/TNFalpha
what are components of chronic inflammation?
1. mononuclear cell mediated
2. persistent destruction and repair
3. blood vessel proliferation, fibrosis
5. outcomes = scarring and amyloidosis
what are granulomas?
nodular collections of epithelioid macrophages and giants cells. Mediated by TNFalpha
What are patterns of inflammations?
1. serous - transudate
2. fibrinous - exudate
What causes cell aging?
1. there is a fixed number of times a cell can divide
2. telomeres - shortened by each round of division
3. telomerases elongate the telomeres. germs cells have a lot of this E. Cancer cells figured out how to activate telomerase
4. restricting caloric intake increases lifespan
What is leukocyte extravasation?
neutrophils exit from blood vessels at sites of tissue injury and inflammations
What are the steps of leukocyte extravasation?
1. Rolling - mediated by selectins which are increased due to inflammatory cytokines. Sialyl-Lewis on leukocytes bind to selectine
2. Tight Binding - LFA-1 (integrin) on leukocytes bind to ICAM1
3. Diapedesis: leukocytes travel b/w endothelial cells and exits blood vessels. PECAM-1
4. MIgration - cells travel through interstitium to site of injury guided by chemotactic signals.
What are some chemotactic signals?
C5a, IL8, LTB4, and Kallikrein
What are the various ways that free radicals can damage cells?
1. membrane lipid peroxidation
2. protein modification
3. DNA breakage
How is free radical injury initiated?
radiation exposure, metabolism of drugs, redox reaction, NO, transition metals, leukocyte oxidative burst
How can free radicals be eliminated?
1. by enzymes - catalase, superoxide dismutase, GSH peroxidase
2. spontaneous decay
3. antioxidants - vitamins A, C, E
What pathologies are included w/ free radical injury?
1. retinopathy of prematurity
2. bronchopulmonary dysplasia
3. CCl4, leading to liver necrosis ( fatty change)
4. Acetaminophen overdose (fulminant hepatitis)
5. Fe overload (hemochromatosis)
6. Reperfusion after anoxia especially after thromblytic therapy
During wound healing, angiogenesis takes places. What are the 2 ways that angiogenesis can take place?
1. growth of new vessel from preexisting vessel. VEGF, endothelium grows, MMPs modify and create new endothelium and basement membrane
2. VEGF can recruit endothelial progenitor cells to connect up to existing vessel
What are the various steps of wound healing?
1. Immediate (0-3 hrs) : clot formation and increased vessel permeability
2. w/in 2 days - neutrophil migration
3. 2-3 days after wound : deposition of granulation tissue and collagen; angiogenesis; epithelial cell proliferation; dissolution of clot; wound contraction mediated by fibroblasts
4. 3-5 days : granulation tissue w/ Type 3 collagen
5. Remodeling: 1 week after wound. Type 3 collagen is replaced by type 1 collagen. Increased tensile strength of tissue. Vit C and Zinc needed for new collagen.
What are common granulomatous disease?
1. TB - caseating
2. fungal infxns
3. syphilis - T. pallidum
4. Leprosy - M. Leprae
5. Cat scratch disease - Bartonella Henselae
7. Crohn's Disease
9. Churg- Strauss
10. Berylliosis, silicosis
11. foreign bodies
What can happen w/ anti TNF drugs in an granulomatous diease?
TNF-alpha from macrophages induce and maintain granuloma formation. W/ this drugs a side effect can cause sequestering granulomas to breakdown leading to disseminated disease
What are the characteristics of a transduate?
1. hypocellular, protein poor
2. low specific gravity < 1.012
3. due to increased hydrostatic pressure, decreased oncotic pressure, and Na retention
What are the characteristics of an exudate?
1. cellular, protein rich
2. specific gravity > 1.020
3. Due to lymphatic obstruction and inflammation
Where is CRP made?
it's an acute phase reactant made in the liver
What is the role of CRP
part of the innate immune system - opsonizes bacteria and activates complement
- can be secreted from atherosclerotic plaques to activate local endothelial cells to induce prothrombotic state to increase adhesions of endothelium leukocytes
When is CRP elevated and what can decrease it?
-elevations are strong indicators for MI, stroke, PAD
- lowered by smoking cessation, wt loss, statins, and exercise
What is ESR?`
product of inflammation that coats RBCs and causes aggregation. When aggregated the RBCs call at a faster rate within the test tube
When do you see increased ESR
1. infections - osteomyelitis
2. inflammation (temporal arteritis)
When do you see decreased ESR
1. sickle cell
2. polycythemia vera
What are some important genes of embryogenesis?
1. Sonic hedgehog gene
2. Wnt7 gene
3. FGF gene
4. Homeobox Gene (hox)
Tell me about sonic hedgehog gene
1. produced at base of limbs in zone of polarizing activity
2. anterior to posterior axis
3. CNS development
4. mutation can cause holoprosencephaly
Tell me about Wnt-7 gene
1. produced at apical ectodermal ridge
2. necessary for proper organziation along dorsal ventral axis
Tell me about FGF gene
1. produced at apical ectodermal ridge
2. stimulates mitosis of underlying mesoderm, providing for lengthening of limbs
3. mutation = short limbs
Tell me about Homebox genes
1. segmental organziation of embryo in craniocaudal direction
2. Hox mutations -- appendages in wrong location
3. Vit A - high levels can later Hox gene expression
4. HoxD13 mutation = synpolydactyl
What happens w/in wk 1 of fetal development
Day 0 - fertilization
Day 2- zygote
Day 3 - morula at proximal end of fallopian tube
Day 5- Blastocyst.
Day 6- implantation
- hCG secretion begins after implantation of blastocyst
What happens w/in wk 2 of fetal developmentb
Hypoblast - becomes endodermal yolk sac
What happens w/in wk 3 of fetal development
Trilaminar disc - gastrulation
epiblasts becomes the 3 layers
- primitive streak, notochord, mesoderm and its organization, and neural plate begin to form
What happens b/w wks 3-8
neural tube forms neuroectoderm and closes by week 4.
- extremely susceptible to teratogens
What happens during wk 4 of fetal development
- heart begins to beat
- upper and lower limbs begin to form
What happens at wk 8 of fetal development
- fetal movement, fetus looks like a baby
What happens to wk 10 of fetal development
- genitalia have male/female characteristics
What is gastrulation
process that forms the trilaminar disc. establishes the ectoderm, mesoderm, and endoderm germ layers. Starts w/ epiblast invaginating to form the primitive streak
What comes from the surface ectoderm?
1. adenohypophysis (ant pituitary)
2. lens of eyes
3. epithelial lining of oral cavity, sensory organs of ear, and olfactory epithelium
5. anal canal below the pectinate line
6. parotid, sweat, and mammary glands
What is a crangiopharyngioma?
benign Rathke's pouch tumor w/ cholesterol crystals, calcification
What comes from the neuroectoderm?
1. Brain - neurohypophysis, CNS neurons, oligodendrocytes, astrocytes, ependymal cells, pineal gland
2. retina and optic nerve
3. spinal cord
What comes from the neural crest cells?
1. PNS - DRG, cranial nerves, celiac ganglion, Schwann cells, ANS
3. chromaggin cells of adrenal medulla
4. parafollicular C cells of thyroid
5. pia and arachnoid mater
6. skull of bones and ear
8. aorticopulmonary septum
9. Eye - anterior chambe, cornea, sclera, ciliary muscle, iris pigment cells
10. GI - ENS, enterochromaffin cells
What comes from the Mesoderm
muscle, bone, CT, serous lining of body cavities, spleen, CV structures, lymphatics, blood, wall of gut tube, wall of bladder, urethra, vagina, kidneys, adrenal cortex, dermis, testes, ovaries
What comes from endoderm?
gut tube epithelium - including anal canal above the pectinate line
- luminal epithelial derivatives ( lungs, liver, gallbladder, pancreas, eustachian tube, thymus, parathyroid, thyroid follicular cells)
What is agenesis?
absent organ due to absent primordial tissue
What is aplasia?
absent organ despite present primordial tissue
What is deformation
extrinsic disruption; occurs after the embryonic period
What is hypoplasia
incomplete organ development; primordial tissue present
What is malformation
intrinsic disruption; occurs during the embryonic period
What are common teratogens and what effect due they have?`
1. ACE inhibitors - renal damage
2. Alkylating agents - absence of digits, other problems
3. Aminoglycosides - CN 8 toxicity
4. Carbamazepine - neural tube defects, craniofacial defects, finger nail hypoplasia, developmental delay, IUGR
5. DES - vaginal clear cell adenocarcinoma; congenital Mullerian anomalies
6. Folate antagonists - neural tube defects
7. Lithium - Ebsteins' anomaly - atrialized RV
8. Phenytoin - fetan hydantoin syndrome, microcephaly, dysmorphic craniofacial features, hypoplastic nails and distal phalanges, cardiac defects, IUGR, mental retardation
9. Tetracyclines - discolored teeth
10. Thalidomide - limb defects
11. Valproate - inhibition of maternal folate absorption --> neural tube defects
12. Warfarin - bone deformities, fetal hemorrhage, abortion, ophthalmologic abnormalities
What are examples of substance abuse affected fetal development?
1. Alcohol - leading cause of birth defects and mental retardation
2. Cocaine - abnormal fetal development and fetal addiction, placental abruption
3. Smoking - preterm labor, placental problems, IUGR, ADHD
What are some other causes of fetal developmental problems?
1. Iodide (lack of excess) - congenital goiter or hypothyroidism (cretinism)
2. Maternal diabetes - caudal regression syndrome (anal atresia to sirenomelia), congenital heart defects, neural tube defects
3. Vit A excess - extremely high risk for spontaneous abortions and birth defects (cleft palate, cardia problems)
4. X-rays : microcephaly, mental retardation
What is fetal alcohol syndrome?
1. congenital abnormalities- cleft lip/palate
2. mental retardation
3. pre and postnatal developmental retardation
6. facial abnormalities
7. limb dislocation
8. heart and lung fistulas
What makes up the fetal component of the placenta?
1. cytotrophoblasts - inner layer of chorionic villi
2. syncytiotrophoblast - outer layer of chorionic villi, secretes hCG, stimualtes corpus luteum to secrete progesterone during first trimester to maintain endometrium
What makes up the maternal component of the placenta?
Decidua basalis - derived from endometrium, Materal blood is in the lacunae.
What are all the aortic arch derivatives?
1st Arch - part of maxillary artery (branch of external carotid)
2nd Arch - stapedial artery and hyoid artery
3rd Arch - common carotid artery and proximal part of internal carotid artery
4th Arch - on left (aortic arch); on right (proximal part of right subclavian artery)
6th Arch - proximal part of the pulmonary arteries and ductus arteriosus
Where is the right recurrent laryngeal nerve going to loop around?
b/w 3rd and 4th arch
Where does the left recurrent laryngeal nerve get caught?
btw 4th and 6th arch due to the ligamentum arteriosum
What is the branchial apparatus?
- also called pharyngeal appartus
- made up of branchial clefts, arches, and pouches
What are the branchial clefts derived from?
What are the branchial arches derived from?
mesoderm (muscles, arteries) and neural cresst (bones, cartilage)
What are the branchial pouches derived from?
What are the branchial cleft derivatives?
1st cleft = external auditory meatus
2nd through 4th = temporary cervical sinuses, which are obliterated by proliferation of 2nd arch mesenchyme
- persistent cervical sinus --> branchial cleft cyst w/in lateral neck -- DOES NOT move w/ swallowing
What comes from the 1st branchial arch? think M and T structures
1. Meckel's cartilage: Mandible, Malleus, incus,
2. Muscles of Mastication (Temporalis, masseter, lateral and medial pterygoid)
3. Mylohyoid anterior belly of digastric, tensor tympani, tensor veli palatini
What nerves innervate the 1st branchial arch?
CN V2 and V3 - to help w/ chewing
What is the Treacher Colins Syndrome?
1st arch neural crest fails to migrate --> mandibular hypoplasia, facial abnormalities
What comes from the 2nd branchial arch? think S structures
1. Reichert's cartilage: staphes, styloid process, lesser horn of hyoid, stylohyoid ligament
2. Muscles of facial expression, stapedius, stylohyoid posterior belly of digastric
What nerve innervates the 2nd branchial arch/
CN 7 - facial-- think smile
What comes from the 3rd branchial arch?
1. Cartilage: greater horn of hyoid
What nerve innervates the 3rd branchial arch?
CN 9 - GP - think swallow stylishly
What is a congenital pharyngocutaneous fistula?
persistence of cleft and pouch - fistula btw tonsillar area, cleft in lateral neck
What comes from the 4 and 6th arches?
1. Cartilage - thyroid, cricoid, arytenoids, corniculate, cuneiform
2. 4th: most pharygneal constrictors, cricothyroid, levator veli palatini
3. 6th : all intrinsic muscles of larynx except cricothyroid
What nerves innervate the 4th and 6th arch?
4th: CN 10 - superior laryngeal branch to help w/ swallow
6th: CN 10 - recurrent laryngeal branch to help w/ speaking
What branchial arches helps make the posterior 1/3 of tongue?
3 and 4
What does the 1st branchial pouch form?
middle ear cavity, eustahcian tube, mastoid air cells
- endodermal lined structures of ear
What does the 2nd branchial pouch form?
develops into epithelial lining of palantine tonsil
What does the 3rd branchial pouch form?
1. Dorsal wings - inferior parathyroids
2. Ventral wings - thymus
What does the 4th branchial pouch form?
Dorsal wings- superior parathyroids
What is Digeorge Syndrome?
aberrant development of 3rd and 4th pouches -- T cell deficiency (thymic aplasia) and hypocalcemia (failure of parathyroid to develop)
What mutation is associated w/ Digeorge syndrome?
Ch 22 q11
When does a cleft lip form?
failure of fusion of maxillary and medial nasal processes (formation of primary palate)
When does a cleft palate form?
failure of fusion of lateral palatine process, the nasal septum, and/or the median palatine process (formation of secondary palate)
What is one of the leading causes of fatality from toxicologic agents in kids?
- Fe poisoning
What is the mechanism of damage w/ iron poisoning?
cell death due to perodixation of membrane lipids
What are the symptoms of iron poisoning?
acute - gastric bleeding
chronic - metabolic acidosis, scarring leading to GI obstruction
What is amyloidosis?
abnormal aggregation of proteins or their fragments into Beta-pleated sheet structures leading to cell damage and apoptosis
- affected tissue have a waxy appearance
What causes primary amyloidosis?
- AL: deposition of proteins from Ig Light chains
- can occur as plasma cell disorder or associated w/ multiple myeloma
What parts of the body are affected w/ primary amyloidosis?
many organs: renal (nephrotic syndrome); cardiac (heart failure, arrhythmia); hematologic (easy bruising); hepatomegaly, and neuropathy
What causes secondary amyloidosis?
- seen w/ chronic diseases like RA, IBD, spondyloarthropathy, chronic infxns
- fibrils composed of Serum Amyloid A
What amyloid is seen w/ Dialysis-related amyloidosis?
- Beta2 microglobulins in pts w/ ESRD and long term dialysis
- often present as carpal tunnel syndrome and other joint tissues
What amyloid is seen w/ heritable amyloidosis?
- heteogeneous group of disorders
- ex: ATTR neurologic/cardia amyloidosis due to transthyretin gene mutation
What is seen w/ age-related (senile) systemic amyloidosis?
- deposition of normal (WT) TTR in myocardium and other sites
- slower progression of cardiac dysfunction vs. AL amyloidosis
What type of amyloid is seen w/ Alzheimers?
amyloid Beta protein cleaved from amyloid precursor protein (APP)
What are the hallmarks of cancer?
1. evasion of apoptosis
2. self-sufficiency in growth signals
3. insensitivity to anti-growth signals
4. sustained angiogenesis
5. limitless replicative potential
6. tissue invasion
What is seen w/ hyperplasia?
- increased number of cells
ex: hormone Estrogen causes breasts to enlarge
What is seen w/ dysplasia?
abnormal growth w/ loss of cellular orientation, shape, and size in comparison to normal tissue maturation. Commonly preneoplastic
What is seen w/ metaplasia?
one adult cell type is replaced by another
- often secondary to irritation and/or environmental exposure
ex: squamous metaplasia in trachea and bronchii of smokers or intestinal metaplasia in Barrett's esophagus
What is seen w/ hypertrophy?
increase in size
What are examples of hypertrophy?
1. uterine muscle during pregnancy
2. Chronic HTN - cardiac cells get bigger but makes ventricle stiffer (maladaptive)
3. organelles can hypertrophy as well--> phenobarbitol causes liver SER hypertrophy
What is anaplasia?
abnormal cells lacking differentiation, resemble primitive cells of same tissue
- often equated w/ undifferentiated malignant neoplasms. Little or no resemblance to tissue of origin.
What -plasia are reversible?
hyperplasia, metaplasia, dysplasia
What -plasias are irreversible?
anaplasia, neoplasia, desmoplasia
What is neoplasia?
clonal proliferation of cells that is uncontrolled and excessive. May be benign of malignant
What is desmoplasia?
fibrous tissue formation in response to neoplasm
What is carcinoma in situ?
- neoplastic cells have not invaded basement membrane
- high nuclear/cytoplasmic ratio and clumped chromatin
- neoplastic cells encompass entire thickness
How do neoplastic cells invade and metastasize?
- use collagenases and hydrolases (metalloproteinases)
- can metastasize if they reach blood vessel of lymphatics
What is grade of a tumor determined by?
degree of cellular differentiation based on histologic appearance
1 = well differentiated, low grade
4 = anaplastic, high grade
What is stage of tumor determined by?
- degree of localization/spread based on site and size of primary lesion
- spread to regional lymph nodes
-presence of metastases
- spread of tumor in a specific pt: based on TNM
What is an adenoma or papilloma?
benign epithelium neoplasm
What do you call a malignant epithelium neoplasm?
adenocarcinoma, papillary carcinoma
What is a malignant neoplasm of blood cells?
leukemia and lymphoma
What is a benign neoplasm of blood vessels?
What is a malignant neoplasm of blood vessels?
What is a benign neoplasm of smooth muscle?
What is a malignant neoplasm of smooth muscle?
What is a benign neoplasm of striated muscle? Malignant?
What is a benign neoplasm of connective tissue? malignant?
What is a benign neoplasm of bone? Malignant?
What is a benign neoplasm of fat? Malignant?
What are proangiongenic cytokines?
bFGF and VEGF
What does benign neoplasm mean?
usually well differentiated, slow growing, well demarcated, no mets
What does malignant neoplasm mean?
may be poorly differentiated, erratic growth, locally invasive/diffuse, may mets
What is cachexia?
wt loss, muscle atrophy, and fatigue that occur in chronic dz (cancer, AIDS, heart failure, TB)
What cytokines mediate cachexia?
- TNF alpha, IFN gamma, IL6
What disease condition is associated w/ ALL and AML?
What neoplasms are associated w/ xeroderma pigmentosum and albinism?
melanoma, Basal cell carcinoma, SCC of skin
What disease condition is associated w/ gastric adenocarcinoma?
- chronic atrophic gastritis, pernicious anemia, postsurgical gastric remnants
What disease condition is associated w/ SCC of skin?
What neoplasms are associated w/ tuberous sclerosis (facial angiofibroma, seizures, and mental retardation)?
Giant cell astrocytoma, renal angiomyolipoma, and cardiac rhabdomyosarcoma(!!!)
What disease condition is associated esophageal adenocarcinoma?
Barrett's esophagus (GERD)
What disease condition is associated w/ SCC of esophagus?
Plummer-Vinson syndrome (decreased iron) and Achalasia
What disease condition is associated w/ HCC?
Cirrhosis due to Hep B and C and alcoholic
What disease condition is associated w/ colonic adenocarcinoma?
What disease condition is associated w/ malignant lymphomas?
What neoplasms is Paget's dz of bone associated w/?
Secondary osteosarcoma and fibrosarcoma
What disease condition is associated w/ lymphoma?
Autoimmune diseases (Hashimoto's thyroiditis, myasthenia gravis)
What neoplasms are associated w/ AIDS?
- aggressive malignant lymphomas and Kaposi's sarcoma
What disease condition is associated w/ visceral malignancy (stomach, lung, uterus)?
acanthosis nigricans (hyperpigmentation and epidermal thickening)
What disease condition is associated w/ malignant melanoma?
What neoplasms is radiation associated w?
leukemia, sarcoma, papillary thyroid cancer, and breast cancer
What disease condition is associated w/ B cell lymphoma?
How can tumors arise due to oncogene and TSG dysfunction?
1. Oncogenes - gain of function, only need 1 mutations
2. TSG - loss of function, both alleles must be lost for expression of dz
What oncogene is linked w/ CML?
abl - think t9;22 for Y kinase
What oncogene is linked w/ Burkitt's lymphoma?
c-myc: transcription factor
What oncogene is linked w/ follicular and undifferentiated lymphomas?
bcl-2: anti-apoptotic molecule
What oncogene is linked w? breast, ovarian and gastric carcinomas?
HER2/neu (c-erbB2) : Y kinase
What oncogene is linked w/ colon carcinoma?
ras - GTPase always on
What oncogene is linked w/ lung tumor?
L-myc : transcription factor
What oncogene is linked w/ neuroblastoma?
N-myc: transcription factor
What oncogene is linked w/ MEN type 2A and 2B?
ret - Y kinase
What oncogene is linked w/ GIST?
c-kit: cytokine receptor
What TSG is linked w/ Retinoblastoma and osteosarcoma?
Rb : inhibits E2F normally and blocks G1 to S phase
What TSG is linked w/ most human cancers and Li-Fraumeni syndrome?
p53: normally a transcription factor for P21 and blcoks G1 to 2 phase as well as G2 to M phase
What TSG is linked w/ beast and ovarian canceer?
BRAC1 and 2 - DNA repair proteins
What TSG is linked w/ melanoma?
p16 and BRAF
What TSG is linked w/ CRC?
What TSG is linked w/ Wilm's Tumor?
What TSG is linked w/ Neurofibromatosis type 1? what chromosome?
NF1 on Ch17 - RAS GTPase activating protein
What TSG is linked w/ Neurofibromatosis type 2? what chromosome?
NF2 on Ch22 - Merlin (schwannomin) protein
What TSG is linked w/ pancreatic cancer?
What TSG is linked w/ colon cancer?
What is the PSA tumor marker used for?
- follow prostate carcinoma
- can also be elevated in BPH and prostatitis
What can also be looked for in prostatic carcinoma besides PSA?
prostatic acid phosphatase
What causes increases in CEA levels?
- very nonspecific
- CRC and pancreatic cancers
- gastric, breast, and medullary thyroid carcinomas
What causes increases in AFP?
HCC and nonseminomatous germ cell tumors (testis and ovaries)
What causes increases in beta-HCG?
- hydatidiform moles and choriocarcinomas
What is the marker for ovarian cancer?
What is S-100 increased in?
melanoma, neural tumors, schwannomas, astrocytomas
What is alk phosphatase increased in?
Mets to bones and liver.
- Paget's dz of bone
- Gallstone stuff
What is bombesin increased in?
neurblastoma, lung and gastric cancer
What is increased in hairy cell leukemia?
What is increased in pancreatic adenocarcinoma?
What is increased in medullary thyroid carcinoma?
calcitonin - may even cause amyloid deposits
What neoplasm is HTLV-1 associated w?
adult T cell leukemia and lymphoma
What neoplasm is HBV and HCV associated w?
What neoplasm is EBV associated w?
Burkitt's; Hodgkin's lymphoma; nasopharyngeal carcinoma; CNS lymphoma
What neoplasm is HPV associated w?
- cervical carcinoma (16 and 18)
- penile/anal carcinoma
- upper respiratory SCC
What neoplasm is HHV-8 associated w?
- body cavity fluid B cell lymphoma
What neoplasm is H pylori associated w?
- gastric adenocarcinoma and lymphoma (MALToma)
What neoplasm if Schistosoma haematobium associated w?
- SCC of bladder
What neoplasm is liver fluke (Clonorchis sinensis) associated w?
What neoplasm is Strep bovis associated w?
- colon cancer
What neoplasms do the following chemical carcinogens cause?
2. Vinyl chloride
3. Carbon tertrachloride
4. Nitrosamines (smoked foods, hot dogs, bologne)
1. liver - HCC
2. Liver - angiosarcoma
3. liver - centrilobular necrosis, fatty change
4. stomach - gastric cancer
5. lung - bronchogenic carcinoma and mesohelioma
What neoplasms do the following chemical carcinogens causes?
2. Naphthalene (aniline) dye - moth balls
3. alkylating agents
1. Skin - SCC; Liver- angiosarcoma
2. Bladder- transitional cell carcinoma
3. Blood - leukemia
4. Blood - leukemia and Hodgkin's lymphoma
5. Hodgkin's lymphoma
What neoplasms do the following chemical carcinogens causes?
3. Smoking cigs
1. prostate/lung cancer
2. lung cancer
3. Larynx - SCC; Lung - SCC and small cell carcinoma; Kidney - RCC; Bladder- transitional cell carcinoma; Pancreas - adenocarincoma
What paraneoplastic syndromes cause hypercalcemia?
- PTHrP due to lung SCC, renal cell carcinoma and breast cancer
- D3 due to Hodgkin's lymphoma and some non-Hogdkin's lymphoma
What paraneoplastic syndrome causes SIADH?
ADH from small cell lung carcinoma and intracranial neoplasms
What paraneoplastic syndrome causes Cushing's syndrome?
- ACTH or ACTH like peptide from small cell lung carcinoma
What paraneoplastic syndromes cause polycythemia?
- EPO from renal cell carcinoma, hemangioblastoma, HCC, and pheochromocytoma
What paraneoplastic syndromes cause Lambert-Eaton syndrome?
Abs against presynaptic Ca channels at NMJ due to small cell lung carcinoma
What are psammoma bodies?
- laminated concentric calcific spherules
What neoplams are psammoma bodies seen in?
- Papillary adenocarcinoma of thyroid
- Serous papillary cystadenocarcinoma of ovary
- malignant mesothelioma
What is the cancer epidemiology in men and women?
Men: prostate > lung > colon
Women: breast > lung > colon
What is the cancer mortality in men and women?
Men: lung > prostate >colon >pancreas
W: lung > breast > colon > pancreas
What neoplasms usually met to the brain?
What are the symptoms of mets to brain?
headache, seizures, personality changes
- typically see well circumscribed tumors at gray/white matter junction
What neoplasms usually met to liver?