what do alkylating agents do?
- alkyl radicals, fuck with DNA
- dacarbazine (purine)
- cisplatin: sulfur groups
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
How does B12 deficiency present w/neuro symptoms?
abberrant fatty acid synthesis incorporated to cell membranes
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
Whatdo vinca alkaloids do?
- antimicrotubule agent, arrest metaphase
What do taxanes do?
- disrupt tubulin (tubules) normal dynamic reoganization of microtuble network
- paclitaxel & docetaxel
What are key features of combination therapies?
- alternating non-cross resistant regamin
- bone marrow transplantation or peripheral stem cell reinfusion.
What are risk factors for oral cancer?
- alcohol, tobacco, HPV, radiation
- chewing quids of betel
- non-fitting dentures
What are tx of oral cancer?
- surgery, radiation
- chemo: cisplatin, 5-flurouracil, carboplatin, paclitaxel
- tumor growth factors: EGFR
- tyrosine kinase dimerize to activate overexpression in many HNSCC
- EGFR Abs & tyrosine kinase inhibitors
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
what are the oral cancer dental implications?
- oral mucositis
- taste dysfunction
- TMJ dysfunction
- dental and skeletal growth or dev anomalies
Innate v adaptive immunity
- innate: non-spec, no memory, fast, granulocytes-monocytes, invariant, Non-MHC
- adaptive: specific, memmory, delayed, lymphocytes, variant, MHC restricted
What are the 3 APCs?
dendritic, monocyte/macrophage, B cells
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
What specific enzyme or gene is important for adaptive immunity for rearrangement of T and B cells?
RAG1 RAG2 recombinase (only adaptive)
What are the MHC specifics?
- MHC I: CD8 T cells, 9AA peptides
- MHC II: CD4 T cells, 13-14 peptides
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
Features of clonal selection.
- select good cells
- delete auto cells
3 functions of Antibodies?
- 1. neutralization
- 2. opsonization
- 3. activation of complement
Steps of cancer progression?
- genetically altered
- in situ
What type of cancer affects epithelial?
what type of cancer affects connective tisue/mesenchymal cells?
CNS and PNS neuroectodermal cancers?
What is polymorphism?
DNA seq variation, can be responsible for individual variability
What happens to germline mutations?
transmitted to every cell
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)
- limitless replication: (telomerase activation)
- tissue invasion (metastasis)
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
What are the 4 mucosal division?
respiratiory, urogentital, GI, glands(lacrimal, salivary, mammary)
What is K-ras?
protooncogene that has a point mutation to be constitutively active (pancreas 100%, colon 50%, lung, AML (30%))
What is BCR-ABL?
- tranlocation of 9 to 22 overactive tyrosine kinase
- philadelphia (CML)
- FISH diagnosis
- treat w/ gleevec (binds to BCR/ABL)
What is HER2/neu?
- human epithelial growth factor 2 (tyrosine kinase) breast cancer
- treat w/ herceptin
- FISH diagnosis
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)
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)
What are the extrinsic barrierfunctions?
- exlude antigens
- tight junctions, air or fluid flow, mucus (glycocalyx), pH, microvillae
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
What are pulmonary collectins?
- c-type lectins SP-A, SP-D (surfactant proteins)
- complement mannose binding
What are typical mammalian sugars?
Surfactant proteins recognize sialic acid and galactose
What cells secrete defensins?
- paneth cells (intestinal crypts)
- eptithelial (UG & respiratory tract)
what is waldeyer's ring?
tonsils and adenoids ring of lymphoid tissues around entrance of gut and airway
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
- 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?
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