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what do alkylating agents do?
- alkyl radicals, fuck with DNA
- dacarbazine (purine)
- cisplatin: sulfur groups
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what do antimetabolites do?
- mimic metabolites of nucleic acids effect S phase
- inhibit enzymes or produce incorrect code
- methotrexate: DHF reductase inhibitor
- mercatopurine: purine mimic
- 5-fluoruracil: pyrimidine analouge
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How does B12 deficiency present w/neuro symptoms?
abberrant fatty acid synthesis incorporated to cell membranes
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What do antitumor antibiotics do?
- streptomyces cytotoxin bind DNA inhibit cell division
- dactinomycin: G-C intercalater
- doxorubicine: inhibit replication, topoisomerase
- bleomycin: DNA scission & fragmentation (G2 and M phases)
- mitomycin: cross-link DNA
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Whatdo vinca alkaloids do?
- antimicrotubule agent, arrest metaphase
- vinblastine
- vincristine
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What do taxanes do?
- disrupt tubulin (tubules) normal dynamic reoganization of microtuble network
- paclitaxel & docetaxel
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What are key features of combination therapies?
- synergy
- intermittent
- alternating non-cross resistant regamin
- bone marrow transplantation or peripheral stem cell reinfusion.
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What are risk factors for oral cancer?
- alcohol, tobacco, HPV, radiation
- chewing quids of betel
- non-fitting dentures
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What are tx of oral cancer?
- surgery, radiation
- chemo: cisplatin, 5-flurouracil, carboplatin, paclitaxel
- tumor growth factors: EGFR
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EGFR pathway?
- tyrosine kinase dimerize to activate overexpression in many HNSCC
- EGFR Abs & tyrosine kinase inhibitors
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What are the recombinant chemotherapeutic agents?
- Gleevec (imantinib) bcr:abl, gastrointestinal stromaltumors
- Iressa: getitinib: non-small cell lung
- Tarceva (erlontinib): non small cell lung and pancreatic cancer
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what are the oral cancer dental implications?
- oral mucositis
- xerostomia
- taste dysfunction
- TMJ dysfunction
- dental and skeletal growth or dev anomalies
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Innate v adaptive immunity
- innate: non-spec, no memory, fast, granulocytes-monocytes, invariant, Non-MHC
- adaptive: specific, memmory, delayed, lymphocytes, variant, MHC restricted
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What are the 3 APCs?
dendritic, monocyte/macrophage, B cells
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What are the 3 steps of interactions of T cells and APCs?
- 1. binding T Cell receptor in context of MHC I or II
- 2. Co stimulation (CD28 T, B7 APC)
- 3. activation through secreted cytokines
- activate, survive, differentiate
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What specific enzyme or gene is important for adaptive immunity for rearrangement of T and B cells?
RAG1 RAG2 recombinase (only adaptive)
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What are the MHC specifics?
- MHC I: CD8 T cells, 9AA peptides
- MHC II: CD4 T cells, 13-14 peptides
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What are the different thypes of CD4 T cells?
- TH1: IF-gamma, IL-2 activate macrophages
- TH2: IL 4,5,6,10, activate B cells
- TH17: IL-17, oral cavity, stim & recruit PMN
- Treg: TGF-beta regulate/anti-inflammatory
- can recruit & stim PMNs
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Features of clonal selection.
- select good cells
- delete auto cells
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3 functions of Antibodies?
- 1. neutralization
- 2. opsonization
- 3. activation of complement
-
Steps of cancer progression?
- genetically altered
- hyperplasia
- dysplasioa
- in situ
- metastasis
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What type of cancer affects epithelial?
carcinoma
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what type of cancer affects connective tisue/mesenchymal cells?
sarcoma
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CNS and PNS neuroectodermal cancers?
-blastomas
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What is polymorphism?
DNA seq variation, can be responsible for individual variability
-
What happens to germline mutations?
transmitted to every cell
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What happens to somatic mutations?
clonal descendents only affected.
-
What are the characteristics of cancer cells?
- evade apoptosis
- self-sufficient growth signals (oncogenes)
- insensitive to anti-growth (tumor suppressor)
- angiogenesis
- limitless replication: (telomerase activation)
- tissue invasion (metastasis)
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What are proto-oncogenes?
- proliferation genes normally regulated by growth signals, cell-cell or extracellular matrix interactions
- growth factors: PDGF, FGF, EGF
- signal transducers: ras, src, abl
- signal effectors: myc, fos, jun
- oncogene: mutant allele of proto-oncogene (self sufficient)
- dominant gain of function
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What are the 4 mucosal division?
respiratiory, urogentital, GI, glands(lacrimal, salivary, mammary)
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What is K-ras?
protooncogene that has a point mutation to be constitutively active (pancreas 100%, colon 50%, lung, AML (30%))
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What is BCR-ABL?
- tranlocation of 9 to 22 overactive tyrosine kinase
- philadelphia (CML)
- FISH diagnosis
- treat w/ gleevec (binds to BCR/ABL)
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What is HER2/neu?
- human epithelial growth factor 2 (tyrosine kinase) breast cancer
- treat w/ herceptin
- FISH diagnosis
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What are tumor suppressor genes?
- brakes on cell growth, protect inappropriate cell division
- recessive loss of function-> cancer (usually both copies to be deleterious)
- deletion (loss of heterozygosity) most common
- missense(1 bp), nonsense(premature stop), frameshifts(insertions or microdeletions)
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What is hypermethylation?
epigenetic, lead to inactivation of gene, occurs nearly every neoplasm
-
What is UPD?
uniparental disomy, normal allele deleted, mutated duplicated
-
What is the Rb gene?
- inhibits cell cycle until ready
- binds E2F (prevents G1 to S) until phosphorylated
- mutations prevents binding
-
What is p53?
DNA damage/stress detector
-
What are BRCA1, BRCA2?
DNA repair genes, lead to breast or ovarian cancers
-
What genes repair mismatches?
MLH1, MSCH2, MSH6
-
What is the surface area of mucosa?
400m2 vs 2.5 for skin
-
Where are M cells found?
- microfold specialized lymphoid follicle-associated dever adntgens across
- found in GI tract(adenoids, tonsils, small intestin, colon, rectum)
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What are the extrinsic barrierfunctions?
- exlude antigens
- tight junctions, air or fluid flow, mucus (glycocalyx), pH, microvillae
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What are the intrinsic barriers?
- collectins: prevent colonization & entry
- defensins: antimicrobial
- TLR & NODs: ID microbes as foreign, activate NFkB which signal epithelial to secrete cyto and chemokines
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What are pulmonary collectins?
- c-type lectins SP-A, SP-D (surfactant proteins)
- complement mannose binding
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What are typical mammalian sugars?
Surfactant proteins recognize sialic acid and galactose
-
What cells secrete defensins?
- PMNs
- paneth cells (intestinal crypts)
- eptithelial (UG & respiratory tract)
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what is waldeyer's ring?
tonsils and adenoids ring of lymphoid tissues around entrance of gut and airway
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What is peyer's patch?
lymph node analogue of B cells not as many T cells in GALT
-
What is the process of GALT T cell trafficking
- enter peyers patches via CCR7 and L-selectin
- activate
- drain to lymph nodes
- activated T cells w/ CCR9 go to lamina propria of small intestine
-
What Ig is found in mucosal secretions?
IgA-bind and neutralize (all over, from laminal propria, endosomes or lumen)
-
Which Ig is most abundant in serum?
IgG>>IgM
-
What is the process of IgA secretion?
- IgA dimerize via J chain
- attach to poly-Ig receptor to be trancytosed to lumen
-
Which chemokines are important in M cells of gut?
CCL20 and CCL9 (direct dendritic to microbe) (DCs can reach trough tight junctions
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