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Onco boards 2024 > Chemo Flash Cards - SS/AB > Flashcards

Chemo Flash Cards - SS/AB

1
Q

Drugs metabolized by non-enzymatic hydrolysis?

A

BCNU
Mustargen
Melphalan

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2
Q

Drugs metabolized by ubiquitous enzymes?

A

Cytarabine
Gemcitabine
6 mercaptopurine?

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3
Q

Which chemo undergo HEPATIC metabolic? Via cyp450 vs conjugation?

A

CYP450: bisulfan, chloarmbucil, cytoxan, ifosfamide, paclitaxel, vinca alkaloids

Conjugation: etopisde

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4
Q

Which drugs are excreted really?

A

bleomycin
carbo, cisplatin
etoposide
hydroxyurea
methotrexate
topotecan?

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5
Q

Drugs eliminated by biliary excretion?

A

doxo
vinca alkaloids

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6
Q

How do lymphs die from RT?

A

apoptosis (interphase death)

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7
Q

Why is cytoxan platelet sparing?

A

megakaryocytes have increased ALDH (break down of phosphoramide mustard)

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8
Q

L-MOPP with T-cell LSA (Brodsky 2009)?

A

CR 78%

CR 1 (achieved and maintained through 28d cycle) 56%

CR 2 (lost during cycle but subsequent CR at next MOPP) 22%

PFS 189d

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9
Q

Respond of dogs to single agent doxo?

A

B: 100% (86% CR, 13% PR)
T: 50%

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10
Q

Hodgkins LSA in cats?

A
  • Head, neck (can be other regions e.g. inguinal)
  • cats >6, all FIV/FeLV-

Histo: mostly non-neoplastic T cells with REED-STERNGERG cells scattered throughout
- tumor cells are B-CELL (CD79a+, BLA36+)
- RS cells are CD79-, BLA36, CO3, Mac38+

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11
Q

MST dogs with splenic MZL?

A

~380d (12 mo) if symptomatic

> 1,100d (36 mo, 3 yr) if asymptomatic

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12
Q

DLBCL subtype

A
  • centroblastic (multiple central nucleolus)
  • immunoblastic (single nucleolus)
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13
Q

What is the agreement of IHC with Flow? PARR?

A

Flow: 94%

PARR: 69%

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14
Q

T-zone LSA flow?

A

CD45-
CD3, CD21, CD25 +
High MHC class II
variable CD4/8

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15
Q

Most common Tcell LSA immunophenotype?

A

CD4+

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16
Q

Most common CLL immunophenotpye?

A

Tcell CD8+

<30k/uL cells prognosis 1,098d (36 mo, 3 yr) vs >30k (131d)

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17
Q

Thymoma Flow?

A

> /= % CD4+/CD8+

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18
Q

Large granular LSA dog

A
  • few cytoplasmic granules
  • 100% CD8+, most CD3+
  • most common TCR alpha, beta 60%
  • 8% CD3-
  • 92% + for alphadb2 integrin found in spleen/BM
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19
Q

Which cells express CD4?

A
  • neutrophil: CD4/18
  • activated dendritic cell
  • T help lymph
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20
Q

Two means of T-regs decreased immune response?

A
  1. Direct interaction
  2. alpha interferon cytokines; TGFb, IL10
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21
Q

What are the Treg markers?

A
  • subset of CD4+ (10-15%)
  • FOXP3 + TF
  • CD25+ IL2 receptor
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22
Q

What is the role of NK?

A

kill cells that down regulate MHC class I missing “self recognition”

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23
Q

Which immune cells posses MCH I? MCH II?

A

MHC I: all cells
MHC II: dendritic, macrophages, B lymphs

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24
Q

Which immune cell is principle to mediate tumor immunity?

A

CD8

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25
Q

How do CTLs kill targets via apoptosis?

A
  1. cytotoxic granules
    - granzymes - some proteases
    - perforin

2, FasL expression -> cas8

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26
Q

Which portion of Ab is responsible for Ag binding?

A

Primarily hypervariable region of Vh and VL CDRs

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27
Q

Palladia targets

A

PDGFR
EGFR
KIT

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28
Q

Cat carbo dose?

A

240 mg/m2 q 3 week

OR

Dose = AUC x 2.6 GFR x BW (kg)

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29
Q

Doxo MOA?

A
  • inhibition of RNA and DNA polymerase
  • Topo II inhibition
  • DNA alkylation
  • ROS generation
  • Perturb Ca2+ homeostasis
  • Change plasma membrane
  • inhibition of thioredoxin reductase
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30
Q

What is terminal half life?

A

how long it takes a drug to decay in the bosy

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31
Q

Weird rxn in people with DTIC?

A
  • Flu syndrome
  • photosensitivity
  • eosinophilia
  • depresses Ab responses
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32
Q

anti tumor activity of DTIC?

A
  • Methylation of O6 guanine
  • originally developed as a purine alpha metabolite but not cell cycle dependent nor AIC portion needed for activity
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33
Q

Procarbazine metabolism?

A
  • extensive hepatic microsomal metabolism
  • monoamine oxidase inhibitor
  • MANY DRUG INTERACTIONS d/t this
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34
Q

Cytotoxic mechanism of procarbazine?

A

methylation at O6 guanine –> increased in AGT, MGMT deficient cells

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35
Q

What is the MOA of Mesna?

A
  • 2-mercaptoethane sulfonate
  • dimerizes (inactive in plasma) in urine –> hydrolysis –> conjugates with alkylators

disulfide detoxifier

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36
Q

Why is cytoxan particularly applying for metronomic chemotherapy?

A

selective inhibition of Tregs

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37
Q

What effect do alkylating agents have on immunity?

A

suppress humoral and cellular immunity

especially cytoxan (B+T)

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38
Q

Why does cytoxan spare BM cells?

A

high levels of ALDH –> detox

  • aldophosphamide –> inactive carboxycyclophosphamide
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39
Q

Predominant metabolites of cytoxan?

A

-nornitorgen mustard
-phosphoramide mustard

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40
Q

Alkylating agent metabolism?

A
  1. Spontaneous hydrolysis by H2O
  2. Enzymatic (important for PK of phosphor amide mustard and nistrosureas)
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41
Q

What is a major difference in MOA and efficacy of oxaliplatin?

A
  1. DNA polymerase alpha cannot pass over adduct
  2. decreased thymidylate synthase
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42
Q

Which other organs may be affected by platinums?

A
  1. Neuro: peripheral neuropathy
  2. ototoxicity
  3. Hypersensitivity IgE mediated in 10-15%
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43
Q

What can ameliorate platinum induced neuropathies?

A

amifostine & B6 (pyridoxine)

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44
Q

How do platinum agents affect the immune system?

A

JUN/Jnk increase after cisplatin may cause increased FaS

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45
Q

Pulmonary reactions with vinca?

A
  1. acute bronchospasm
  2. interstitial infiltrates w/in 1 hour

most common with mitomycin

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46
Q

How do platinum drugs enter the cell?

A
  • Cisplatin: diffusion at pH 7.4, Cl- replaced by -OH

also transmembrane transporters: CTR1, ATP7A, ATP7B, Cu transport

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47
Q

What happens to platinum agents inside the cell?

A
  1. exported from cell by active transport proteins
  2. become reactive by displacement of Cl- (cis) or carboxylic groups –> covalent binding with sulthyonyl groups
  3. React with nucleophiles (e- on protein, RNA, DNA)

Affinity for RNA»»DNA

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48
Q

How do platinum drugs kill cells?

A

primarily via DNA adduct formation (must be CIS)

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49
Q

Cell with what mutation are most sensitive to platinums?

A

BRCA mutants

(decreased dsDNA break repair)

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50
Q

Mechanisms of resistance (increase drug target)

A

DHFR (dihydrofolate reductase) - methotrexate
RNR (ribonucleotide reductase) - hydroxyurea, gemcitabine
TS (thymidylate synthase) - 5FU

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51
Q

Mechanisms of resistance (decrease drug target)

A

Topo I: topotecan, irinotecan
Topo II: etoposide, anthracylines

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52
Q

MRP1 substrates?

A
  • many PGP substrates
  • methotrexate
  • conjugated metabolites
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53
Q

What is the ABCB1-1delta mutation?

A

4 base pair deletion = frameshift = several premature stops

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54
Q

What happens when MDR1 mutants are treated with substrate drugs?

A
  • severe GI upset
  • 3x higher exposure
  • 20-25% decrease with mut/norm, 50% decrease in mut/mut
  • Doxo decrease to 10.7 mg/m2 in mut/mut
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55
Q

Taxane MOA

A

-disruption of microtubule function
- Microtubules are essential to cell division
- taxanes stabilize GDP-bound tubulin in the microtubule inhibiting the process of cell division
- depolymerization is prevented
- B tubulin
- Cannon dissolve but can assemble

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56
Q

How are taxanes different from other microtubule inhibitors?

A

Vinca alkaloids prevent mitotic spindle formation while taxanes prevent function

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57
Q

Taxane resistance?

A
  1. MDR
  2. delta binary sites, tubulin dynamics
  3. signaling activation (PI3k) –> increase threshold for apoptosis
  4. increase MAP–> MAP4 increase Paclitaxel sensitivity
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58
Q

What drugs can reverse MDR phenotype?

A
  • Ca2+ channel blockers
  • tamoxifen
  • alpha arrhythmic
  • cremophor/polysorbate
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59
Q

How is 5-azacytidne activated?

A

conversion to monophosphate by uridine-cytidine kinase

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60
Q

How does 5-aza enter cells?

A

facilitated nucleoside transport shared with uridine and cytidine

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61
Q

5-aza MOA?

A
  • does not require deoxycitidine activation
    1. inhibits methylation
    2. competed with CTP for incorporation into RNA
    3. incorporates into DNA
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62
Q

How does 5-aza structure differ form cytidine?

A
  • S1 Nk of heterocyclic ring unstable –> spontaneous decomposition
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63
Q

What is the first strategy for correction of a miscopied nucleotide?

A

polymerase 8 proof reading and 3’-5’ exonuclease activity

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64
Q

When is mismatch repair used?

A
  • used during DNA repair
  • singe base mistmatch
  • MSH/MLH proteins
  • MMR deficiency = microsatellite instability
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65
Q

How are inter strand crosslinks repaired?

A
  1. problem when replication fork is stalled
  2. Fanconi protein recruited with ATR
  3. Incision to enable bypass –> broken strand = HR (homologous repair), adduct = NER (nucleotide excision repair)
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66
Q

How is ssDNA/ss breaks repaired?

A

PARP activation

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67
Q

How does homologous recombination occur?

A
  1. ds break
  2. mRNA complex recruitment (endonuclease) and ATM
  3. RPA recruited –> DNA resection (BRCA1 dept)
  4. Rad protein loading DNA (BRCA2 controlled)
  5. dsDNA invasion
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68
Q

Non-homologous end joining (NHEJ) - how does it occur?

A
  1. Break recruits Ku70/80
  2. Ku80 interacts with DNA-PKcS –> autophosphorylates
  3. DNA polymerase recruitment and strand ligate

Targets of PKcs:
- KU70/80
-XRCC4
- DNApKcs
+/- ATM

*Pic include HR repair

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69
Q

G2 DNA damage checkpoint

A

ATM (chk2), ATR (chk1) –> CDC25C –> Cyclin B/CDK1 (wee1 inhibitory) –> Stop B2

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70
Q

What protein is needed for replication checkpoint?

A

ATR

  1. Fork stabilization
  2. Origin firing
  3. S-m checkpoint
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71
Q

G1 DNA damage checkpoint

A
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72
Q

When in the cell cycle are ATM and ATR active?

A
  • ATM: all checkpoints
  • ATR: ONLY when sDNA template available (S + G2)
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73
Q

What are the major proteins for ssDNA repair?

A

RPA, RAD1, RAD9, TOPBP1 –> ATR, ATRIIP

also for base alkylation adducts –> MUTs, MUTc (MMR proteins)

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74
Q

Via what mechanism does p53 halt the cell cycle?

A

up regulation of p21

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75
Q

Beclin-1

A
  • autophagy promoting protein
  • autophagy activated when cells suffer nutrient starvation and digest own intracellular organelles
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76
Q

BID function?

A
  • activated (cleaved) by caspase 8 in cytosol –> mitochondrial channel opening

*see figure 8-15 in T&H

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77
Q

What are the death receptor ligands?

A

TNF proteins (TNFalpha, TRIAL, FasL)

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78
Q

What are executioner caspases?

A

3,6,7

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79
Q

What is the role of smac/diablo?

A

protein released rom the mitochondria with cytochrome C –> inactivated proteins (alpha-apoptotic IAPS[inhbitiors of apoptosis]) –> increase apoptosis

  • IAPs normally block caspase reaction:
    1. bind directly –> block proteolysis
    2. mark caspases for ubiquitination
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80
Q

What are the components of the apoptosome?

A
  • heptameric protein complex of the intrinsic apoptotic pathway

pro-caspase 9 + apaf1 + cytochrome C (activated caspase 9) –> pro-caspases 3,6,7 –> caspases 3,6,7 –> cleavage of death substrate

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81
Q

How does the AKT/PKB kinase act to inhibit apoptosis?

A

phosphorylation of BAD by AKT/PKB –> decreased ability to keep mitochondrial channel open –> decreased apoptosis

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82
Q

What is TSP1?

A

-thrombospondin-1
- blocks blood vessel development

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83
Q

What are the majority of p53 mutations?

A

-AA substitutions in DNA binding domain

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84
Q

ARF function?

A
  • AKA p14
  • growth inhibitory - depends on functional p53
  • ARF binds MDM2 –> sequesters in nucleus –> p53 increases d/t decreased levels of destroyer
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85
Q

PI3k pathway connection to p53?

A

anti-apoptotic pathways

PI3K–> AKT/PKB kinase–> MDM2 phosphorylation –> MDM2 translocation to nucleous

RAS–> RAF–> MAPk –> ETS –> API (Fas+Jun) –> increased MDM2

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86
Q

How is p53 protected from ubiquitination?

A
  • phosphorylation (n-terminus) blocks MDM2s ability to bind and ubiquitinate
  • ATM, chk1/2

*ATM kinases can also phosphorylate mdm2 –> functional inactivation

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87
Q

Role of MDM2?

A

*function in nucleus

  • ubiquitination of p52 as it is synthesized
  • mdm2 expression is induced by p53
  • mdm2 bind p53 and blocks transcription activity –> directs ubiquitin attachments and export from nucleus –> polyubiquinated in cytoplasm
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88
Q

3 pathways to p53 activation?

A
  1. ds breaks –> ATM –> p53 phosphorylation
  2. DNA damaging agents: ATR –>chk2–> p53 phosphorylation
  3. deregulation of pRb-E2f
89
Q

What is the role of ATM?

A

damage –> atm kinase (chk2) –> air kinase –> p53 phosphorylation = protection from destruction

90
Q

UV radiation

A
  • causes pyrimidine dimers
  • CC-TT transition characteristic of misrepair or lack of repair
91
Q

What happens in the cell after DNA damage has occurred?

A
  1. DNA repair: most likely
  2. No DNA repair: mutation
    - error prone replication = base substitution
    - frame-shift mutations occur when an adduct is bound to a nucleoside base (usually base deletion)
    - DNA breaks from incomplete excision repair or alkylation and cleavage of backbone
92
Q

What bases have amine groups?

A

-NH2

Purines & cytosine

93
Q

Which base is most commonly incorporated with error prone repair?

A

adenine

94
Q

Which is the most prevalent oxidized base?

A

8-oxo-deoxyguanosine = marker of overall oxidative DNA damage

95
Q

How do genotoxic chemicals damage DNA?

A
  • either add carcinogen adduct or oxidative damage
  • strong electrophiles –> bind wide array of weak bases –> must bind strong nucleophiles
  • may also be oxidized by hydrocylanine of nucleotide bases
96
Q

What is the first step in metabolic activation of chemical carcinogens?

A

oxidative metabolism often mediated by CYP enzyme (change in carbon, nitrogen, sulfur)

97
Q

3 most extensively studied carcinogens requiring bio activation?

A
  1. PAHS
  2. aromatic amines
  3. nitrosamines
98
Q

What properties do all genotoxic carcinogens share?

A
  • electrophilic or capable of being converted to electrophiles –> interact with nucleophilic groups on DNA/protein
  • most require enzymatic bio activation typically by drug-metabolizing enzymes
99
Q

When is relative risk equal to odds ratio?

A

If disease prevalence is LOW (<10^210)?

100
Q

Information bias

A

due to errors in obtaining bias (aka misclassification)

101
Q

What is selection bias?

A

systematic differences between those in study vs those eligible

102
Q

3 criteria for confounder

A
  1. risk factor of disease of interest
  2. must be associated with EXPOSURE under the study but not a result of it
  3. Should NOT be intermediate factor on the causal pathway between exposure and disease
103
Q

Tumor progression

A

benign lesions acquire ability to grow, invade tissues, and establish metastasis

104
Q

Tumor promotion

A
  • clonal expansion of initiated cell d/t changes in altering gene expression
  • agents ten to be NON-genotoxic and cause division w/o death/differentiation
105
Q

What is tumor initiation?

A
  • creation of DNA damage that must be corrected or mutation will become integrated
  • irreversible!!
  • may die via apoptosis
106
Q

Ionizing radiation mechanisms of genetic instability?

A
  • mutation of genes involves in control of DNA synthesis/repair
  • chromosome instability
  • aberrant production of oxygen radicals–> DNA damage
107
Q

Fluctuation of cyclins during cell cycle

A
108
Q

What CDK/cyclin is responsible for each phase of the cell cycle?

A
  • G1 = D, CDK 4,6
  • S = cyclin E, CDK2
  • G2 = cyclin A, CDK2
  • m = cyclin B, CDK 1 (CDC2)
109
Q

What are CDKs?

A
  • serine/threonine kinases
  • associated with cyclins to activate CKD catalytic activity
110
Q

What is the neurotoxic metabolite of ifosfamide?

A
  • d/t dechloroethylifosfamide
  • Chloroacetyl aldehyde
111
Q

What is the most important methyltransferase? What drugs target this?

A

-DNMT1
- 5-azacytidine
- 5-cita-deocycitidine

  • incorporate into DNA and inhibit DNMT while allowing replication to proceed
112
Q

What are the most prominent cancer stem cell subpopulation in BCL and TCL?

A

BCL = CD34, CD90, CD117, OCT 3/4
TCL = OCT 3/4

Tx with CHOP enriched for CSC (increase CSC markers, increase ALDH)

Hartley et al 2018

113
Q

How does leptin contribute to tumorigenesis?

A

leptin (from adipocytes) –> proliferation of BC cells (breast cancer I think) via increased aromatase

114
Q

TGFb signaling pathway

A

*receptor is a heterodimer

TGFb binds type II receptor –> dimerization with type I and phosphorylation of type I –> SMAD 2/3 recruitment –> phosphorylation –> associated of SMAD4 + 2/3 –> nucleus

115
Q

Patched Pathway

A

Hedgehog –> patch receptor –> release of SMO = activation –> cytoplasmic GLI stabilization

  • ON: normally cleaved into 2 fragments; 1 nuclear repressor of transcription
  • SMO protect GLI from cleavage –> trans ACTIVATION
116
Q

Notch Pathway

A

Delta/jagged –> NOTCH = surface receptor –> 2x cleavage

1) ectodomain
2) transmemebrane

–> nucleus

117
Q

What is the REL gene?

A

NFKB subunit amplified in 1/4 DLBCL in people

118
Q

WNT signaling pathway

A

WNT binds frizzled –> disheveled activated –> blocks GKS3B–> B-catenin accumulation in cytoplasm and nucleus

119
Q

Normal B-catenin cytosolic complex?

A

B-cateninc + APC + axin } GSK3b executioner

120
Q

NFkb pathway

A
121
Q

What does B catenin associate with in the nucleus?

A

TCF/LEF transcription factor

122
Q

Important targets of RAS –> RAF –> MEK–> ERK pathway?

A
  • promoters of Fos + Jun
  • Fos + Jun associate –> API –> transcription factor hyper activated in cancer
123
Q

MAPk pathway

A

RAS –> RAF (MAPKKK) –> MEK (MAPKK) –> ERK (MAPK) –> targets

124
Q

PI3k pathway

A

PI3k –> PIP3 –> AKT/PKb –>

  • Bad inhibition of apoptosis
    -mTOR stim
  • GSK3b stem of cell proliferation
125
Q

Dual specificity kinase?

A
  • can phosphorylate serine/threonine residues and tyrosine

ex. MEK

126
Q

GRB2 + SHC bridging proteins

A
127
Q

GRB2 protein structure?

A

2 SH3 groups –> SOS
1 SH2 –> ligand receptor

128
Q

What is the difference in the SRC domains?

A

SH1 = catalytic domain

SH2 = enables association with partner protein displaying specific phosphotyrosine + AA
- may or may not have catalytic activity

SH3 = binds purine rich sequence domaines in partner proteins –> ligands of SHC domain

129
Q

Phosphatidyl pathways

A

PI –> kinases –> PIP2 –>

1) PI3k –> PIP3 –> attracts proteins with PH domain

2) phospholipase C –> DAG –> PKC + IP3 –> Ca2+ reduces

130
Q

Most important PH domain protein?

A
  • AKT
  • PI3k –> IP3 attracts AKT/PKI3 via pH domain
  • PD1,2 activated kinases
131
Q

Anti-apoptotic substrates of AKT/PKB?

A

Bad (pro)
Cas 9 (pro)
IKB kinase (alpha)
FOXO TF (pro)
MDM2 (alpha)

132
Q

Proliferative substrates of AKT/PKB?

A
  • GSK3b (alpha)
  • FOXO4 (alpha)
  • p21 (alpha)
133
Q

Growth substrates of AKT/PKB?

A

TSC2 (alpha)

134
Q

Ral A/B

A
  • 1/3 major effector pathways of RAS
  • Ral A/B gene 58% identity with RAS
135
Q

SOS function?

A

To induce RAS to shed GDP

136
Q

Ral pathway

A

RAS –> Ral-GEF –>

RalA
RalB

–> RCLBp –> Cdc42 –> proliferation

137
Q

Examples of JAK/STAt receptor

A

EPO, TPO

138
Q

JAK/STAT pathway

A
139
Q

Integrin signaling

A
  • alpha and beta heterodimers
  • link cytoskeleton to ECM + signaling
  • signaling via SOS–> RAS–> ERK
140
Q

Wnt- B- catenin

A
  • signals via frizzled receptors - GSK3b
  • GSK3b normally phosphorylates B catenin –> ubiquinated
141
Q

B-catenin states

A
  1. bound cytoplasmic domain of cell-cell adhesion receptors
  2. soluble cytosol
  3. transcription factor
142
Q

What are promoters of the cyclin D genes?

A

D1 - API, TCF/Lef, NFkb, TFs
D2 - myc, increased camp
D3 - Stat 3/5, E2A

143
Q

What is the exception to fluctuating cyclin levels?

A

Cyclin D
- controlled by extracellular signals (tyrosine kinase receptors)
- others controlled by rapid degradation via ubiquitination

144
Q

What is CD25?

A

part of IL2 receptor

145
Q

T-zone LSA flow?

A

Cd3+, Cd5+
CD45-

High CD21
High MHC II

146
Q

PARR sensitivity?

A

neoplastic 1/100 cells

147
Q

Factors that may affect PARR?

A
  • DNA quality (e.g. formula increases fragmentation)
  • Taq inhibitors
  • Primer choice
148
Q

Terminal deoxynucleotidyl transferase (TDT) enzyme

A

Adds nucleotides between V+D, and J.

149
Q

Where does Ig rearrangement occur?

A

Bone Marrow

  • acute leukemia may not have yet, may be -
150
Q

Ig formation

A

V 80
D 6
J 6

151
Q

T cell markers

A

Surface: CD3 (TCR), CD5, CD4, CD8

Cytoplasmic: CD3c

152
Q

Where do T cells acquire markers?

A

CD3 –> BM
CD 4/8 –> thymus

153
Q

B cell markers for flow and IHC?-

A

Flow: CD21, CD22, CD20

IHC: CD79a (BCR), Pax5 (TF), CD20c, Mum1, IRF4

154
Q

BRCA in canine mammary tumors?

A
  • no association between polymorphisms and development
  • several SNPs identified
  • CMT have decreased nuclear and increased cytoplasmic BRCA but this is likely not significant
155
Q

1) What is AgNOR?
2) Where is it located?
3)When are levels highest?

A
  • Crucial for formation of nucleolus
    1) chromosome segments involved in ribosome biogenesis composed of agrophylic proteins that localize with DNA loops of nucleolus, decondensation of DNA loops during high transcription –> segregation of associated proteins

2) nucleus, nucleolus

3) interphase –> give an indication of duplication role

156
Q

1) what is ki67?

2) where is it located?

3) when are levels highest?

4) half life?

A

1) proliferation associated protein

2) nucleus

3) peak in M, low in G1/S

4) <1hr –> rare detection if cells aren’t cycling

*Ab - MIb1

157
Q

1) what is PCNA?

2) where is it normally located?

3) when is expression highest?

A

1) cofactor of DNA polymerase delta –> increased DNA replication
- also plays a role in RAD6 dependent DNA repair and inhibitory apoptosis via negative regulation of abl stability

2) nucleus

3) high in G1/S but also M because of half life (8-20 hours)

158
Q

Feline MI cut offs: cutaneous & intestinal MCT?

A

Cutaneous: 5 (same as dog)

Intestine: >2

159
Q

Feline MCT IHC markers?

A

+ vimentin
alpha 1 alpha trypsin
KIT

160
Q

What’s the difference between metric and proportional approach for MCT margins?

A
  • metric: 1 cm for low and 2 cm intermediate
  • proportional: lateral proportional to maximum MCT dimension
161
Q

What % of dogs with MCT have BM involvement?

A
  • 2.8% on FNA
  • if visceral, 37% Buffy coat + and 56% BM+
162
Q

MCT IHC markers?

A

Vimentin +
Typtase + (skin only)
+/- Chymase (GI and skin)
CD117/KIT +
IL8

163
Q

SQ MCT MI prognosis?

A

> 4
- also if infiltrative +/- multinucleate cells

164
Q

Kueppel grading criteria

A

1) MI >/= 7
2) 3 bizarre nuclei /10 hpf
3) 3 multinucleate cells/10 hpf
4) karyomegaly

  • if any of these = high grade
165
Q

Cutaneous MCT MI prognosis?

A

MI > 5 –> 3 mo MST
MI <5 –> 80 mo MST

166
Q

Which molecules control extent of R6 phosphorylation?

A

Cyclin d + e

167
Q

What is the difference in cyclin D control vs others?

A

cyclin D = extracellular signals

others = gradual accumulation and rapid destruction

168
Q

What type of kinases are the CDKs?

A

serine 1 threonine

169
Q

Most critical CDKI in cancer? How is it controlled?

A
  • p27 = cyclone E , CDk2

cell enter G0 –> increased p27
enter G1 –> decreased p27, fall during late G1 by cyclin E/CDk

*p27 decreased by SKP2 protein - acts with cul1 to recognize p27 and ubiquitance –> tagged for destruction = decrease skp2 at G0 = increased p27

170
Q

How does TGFb guarantee cells do not proliferate?

A
  • must ensure p21 is not inhibited
  • in normal cells –> TGFb keeps Mac away from promoters by decreasing Mac expression via smad3 promoter sequence
171
Q

TGFb basics

A
  • uses serine/threonine kinases
  • targets mad 2/3 –> smad4 association –> heterodimer moves to nucleus –> TF
  • most important targets: CDKs, p21, each has CAGAC seq in promoter
172
Q

Number 1 target of Mac for cell cycle progression?

A

cyclin D2 –> R of Rb

  • myc also increased expression of e2f1/2/3
173
Q

Cul1

A
  • protein increased by myc
  • plays central role in p27 degradation (CDKI) via ubiquitination
174
Q

myc function

A
  • transcription factor
  • creates homo-heterodimers
  • dimers associated with regulatory sequences termed “e boxes” of promoters “CACGTG”
  • phosphorylation of myc regulates activity
175
Q

How do mitogenic signals reduce CC progression?

A

mitogen signals –> RAS (–> Jun/fas –> cyclin D1 transcription) –> PI3k –> AKT/PKb–> GSK3b –> increase b cat

  • cyclin D is not deposited on EaF
  • cyclins D+e inactivat E2f –> S phase entrance
176
Q

What is the most important target gene of ear for cell cycle progression?

A

-cyclin e
- responsible for complete hyperphosphorylation of pRB

177
Q

How does Rb inhibit E2F?

A
  • E2F sits on promoters
  • when hypO phosphorylated Rb bound, transactivation domain is blocked, which is needed for transcription
  • pRb recruits other proteins that decrease transcription
  • E2F1/2/3 –> binds Rb
  • E2f 4 + 5 –> gene repression via p107/130 to attract repressors
  • E2F6–> doesn’t interact with proteins –> acts exclusively as a repressor
178
Q

What controls Rb phosphorylation?

A
  • D type cyclins with CDK 4/6 (controlled by extracellular signals)
  • cyclin e +CDK2 increased at R and drives pRB phosphorylation to completion
179
Q

Importance of pRB phosphorylation status?

A
  • unphosphated in G0
  • weak in G1
  • hyper on ser/thre residues to advance through R
  • remains hyper throughout cell cycle
  • once cells exit mitosis, phosphorylation stripped of by PP1
180
Q

How can PI3K activation increase proliferation?

A
  • TGFb can stimulate
  • stimulation of RTK
  • AKT/PKB –> p21 in nucleus
181
Q

Role of TGFb in cell cycle progression?

A
  • increase levels of p15 –> blocks cyclin D/CDK4/6 complex and inhibits those already formed
  • without active complex cannot proceed through G1-R
182
Q

Cyclin-CDK inhibition

A
  • CDKIs
  • INK4 proteins –> CDK 416 (p16, p18, p19)
  • p21, p 27, pS7 –> inhibit all others
183
Q

Extrinsic apoptosis pathway

A

FAS/FADD interaction –> DED-containined procaspase 8 (8 = ex) –> DISC formation –> (+ procasp 8) –> active casp 8 –> Cas 3,6,7, BID

184
Q

What is the function of survivin?

A

inhibits of apoptosis protein

185
Q

What is the primary means of DNA repair during G1?

A

non-homologous end joining

186
Q

What triggers DNA replication?

A

increased cyclin A2-CDK2 at G1/S transition

*cyclin E may also contribute

187
Q

What activates ADP ribosylation factor (ARF)?

A

excessive activity of E2F

188
Q

2 roles of cyclin d CDK4/6 at G1/S?

A

1) non-catalytic binding to p27 and prevention of p27 inhibition of cyclin E-CDK2

2) cyclin D-CDK 4/6 phosphorylation 2 pocket proteins:
- Rb
- p107
- p130
All release from E2f

189
Q

How do cells ensure each origin of replication fires only once per cycle?

A
  • pre-RC complexes in early G1
  • replication only occurs when DNA polymerase is recruited in S phase
  • temporal separate = safe
190
Q

Which protein cleaves notch?

A

ADAM

191
Q

WNT pathway ON

A

WNT –> FX + LPR 5/6 (coreceptor) –> DSH recruitment –> GSK3B/APC/AXN–>Bcatenin to nucleus –> increase myc, cyclin D, mmp7

192
Q

WNT pathway OFF

A

LRP5/6 + Fz –X DSH –> GSK3B/axin+APC –X bcatenin –> ubiquination

193
Q

Types of transcription factors (4)

A
  1. Homeodomain - 60AA, DNA binding domain called a homeobox
  2. Zn finger - 20-30AA with 2 cysteine on histidine residues with zn ion
  3. Leucine zipper - helices region of lutein every 7th AA which protrude from some side of helix
  4. Helix-loop-helix - similar to leucine but have loop regions separate alpha helexis
194
Q

What is mTOR and what are its targets?

A

-serine/threonine kinase that complexes to form TORC1 (proliferation, inhibits autophagy) and TORC2 (activation of AKT, change cytoskeletal dynamics)

195
Q

What happens following PIP3 degeneration?

A
  • recruitment of PH-domain containing serine/threonine kinases PDK/AKT
  • full AKT activation requires phosphorylation at second site by TORC2
  • regulator of cell survival (phosphorylation of FOXO)
  • regulator for cell proliferation (mTOR)
196
Q

What 3 distinct MAPk pathways have been characterized in mammalian cells?

A

1) ERK 1/2
2) C-JUN
3) p38

197
Q

Which protein serves as SH2 linker in the PI3k pathways?

A

p85 subunit of PI3k

198
Q

What do SH3 motifs bind?

A

proline of target proteins

199
Q

What is the function of BRCA1/2?

A
  • Tumor suppressor
  • BRCA1 = critical to DNA reapir, CC checkpoint and chromatin remodeling, ubiquitination
    -BRCA2 = binds rad51 –> ssDNA repair by HR
200
Q

What is the function of SMURF 1 + 2?

A

regulation of SMAD –> ubiquitination

201
Q

TGFb signaling

A

binding –> association of type I + 2 (type 2 phosphorylates I) –> SMAD –> SMURF 1/2

202
Q

PI3k

A

signal (phosphorylates)–> 3’ hydroxyl of PIs–> activation –> PI3k (p110 and p85 subunit) –> PIP2 –>PIP3 –> PH domain proteins –>PKB/AKT

203
Q

Lead time vs length time bias?

A

types of selection bias
- lead: appearance of longer survival d/t diagnosis earlier in the course of disease = longer knowledge of disease vs tx response

  • length: screened subjects with better prognosis detected by screening ( detected a disproportionate number of slowly growing)
204
Q

polyaromatic hydrocarbons

A
  • in tobacco
  • methylated CpGs target of attack
205
Q

What is the most commonly methylated sequence/base?

A
  • CpG islands - cytosine bases
  • only when 5’ to guansine
206
Q

Deamination of 5-methyl cytosine

A

= thymine –> normal DNA base may not be repaired

207
Q

Deamination

A

Removal of amine groups from guanine, adenine, cytosine –> xanthine, hypoxanthine, uracil (respectively) –> causes TRANSITION mutation

208
Q

Why are areas of DNA repeat likely to have more error?

A
  • increased strand slippage = higher/lower copy number of repeat in to daughter strand
  • insertions/deletion of repeat may evade polymerase proof reading
209
Q

Proof reading

A
  • 3’-5’ exonuclease activity of DNA polymerase
210
Q

E1A

A
  • deregulation of pRB
  • effective at induing apoptosis
  • binds effectively sequesters pRb
211
Q

How is p53 targets fine tuned?

A

C terminus covalent modification

(acetylation, glycosylation, phos, ribosylation, simulation) –> targets protein to specific intracellular site

212
Q

MYC

A
  • induced apoptosis but also has mitogenic functions
  • when p53 decreases mitogenic signal more prominent
213
Q

How do cells protect telomeres?

A

1) Telomerase (hTERT)
2) ALT (telomerase independent) exchange of sequences between telomeres = copy choice mechanism

214
Q

What is the T-loop?

A
  • G rich strand of telomere in hundreds of nucleotides longer - long 3’
  • helps protect DNA
215
Q

Telomeric sequence

A

5’ TTAAGGG 3’

216
Q

When does p16 affect the cell cycle?

A

G1 –> blocks phosphorylation of Rb by cyclin D/CDK 4/6 –> hypophosphorylates of Rb - halt cell cycle progression

217
Q

When does p21 affect the cell cycle?

A

can halt cell cycle progression via blocking all CDKs involved in G1, S, G2, M

218
Q

miz-1

A

when no myc present miz1 associates with smad 3/4 –> increase p15/p21 expression

if myc associates decreased expression of p15/p21 CKDI –> increase action of CDK 4/6 and 2

= way to confer resistance to TGFb alpha growth signals

Onco boards 2024 (17 decks)

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