principles of cancer biology 22% LC Flashcards

Question

Relationship of β-catenin and GSK-3β

Answer 1

GSK-3β degrades β-cat and prevents nuclear transcription | a part of the destruction complex that degrades b catenin

Answer 2

transcription factor that is activated by TGF b - regulate growth and proliferaiton ## Footnote cna be tumor supressor or tumor promoting ( smad blocks c-myc)

Answer 3

Increased transcription by preventing histone deacetylation and gene silencing; Ex. valproic acid, vorinostat induce apoptosis, dna damage, cell cycle arrest, inhibit angiogenesis, generate ROS

Answer 4

Valproic acid

Answer 5

increased apoptosis in a dose dependant manner hyperacetylation

Answer 6

heritable change that impact dna template processes that are not encoded in the primary linear dna sequence

Answer 7

attachments of methyl or acetyl groups to DNA associated proteins, histones, and chromatin

Answer 8

covalent addition of methyl group at position 5 of cytosine nucleotide mediated by DNA methytransferase DNMT

Answer 9

occurs in CpG island - 70% of promotor regions of genes CpG islands associated with tumor suppressor genes are unmethylated in normal tissues but often become hypermethylated during tumor formation

Answer 10

hyperMethylation in promoters (CpG) = silencing Methylation in gene bodies = typifies transcribed genes gen body = region of the gene past the first exon because methylation of the first exon, like promoter methylation, leads to gene silencing

Answer 11

neutralizes positive charge of lysine on histone tails - weakens the interaction with DNA. increases availability for gene transcription - active promotors and enhancers

Answer 12

Writers: add modifications to histones Readers: recognize modified histones Erasers: mediate removal of histone modifications

Answer 13

not cell cycle specific contribute to control of transcription early signalling of dsDNA break repair

Answer 14

Cancer cells globally are hypOmethylated and locally hypERmethylated at promoters

Answer 15

Promoter methylation correlates w/ reduced gene expression. Therefore, hypERmethylation results in silencing tumor suppressor genes → carcinogenesis

Answer 16

CTCFL/BORIS (promoter normally limited to testis) is associated with overexpression in cancer development

Answer 17

→ tumor progression and metastasis Increased expression of urokinase plasminogen activator (uPA) has been reported in various malignancies including prostate cancer

Answer 18

enhancer variants that are either lost or gained in cancer cells compared to normal tissue

Answer 19

enzymes responsible for removing acetyl groups from histone leading to decreased transcrption and inhibits gene expression will silence tumor supressor genes ## Footnote tightening the histone coils

Answer 20

EZH2 inhibitor enhancer of zeste homolog 2 - methyltransferase enzyme - methylates = gene silencing inhibitors promote the reexpression of silenced genes

Answer 21

Removing inhibitory methylation of p53’s promoter with decitabine DNMT inhibitors - can reactivate methylated tumor suppressor genes

Answer 22

treats myelodysplastic syndrome Antimetabolite antineoplastic agent inhibits DNMT

Answer 23

global hypomethylation leading to genomic instability and demethylation could trigger reactivation of gene promoting more aggressive or metastatic phenotype

Answer 24

The uPA/uPAR interaction can promote the expression of oncogenes and cell proliferation, eventually leading to the development of tumors, invasion or metastasis

Answer 25

5-azacitidine shown to increase expression of uPA

Answer 26

G0 : cyclin C + CDK3 G1: cyclin D and E + CDK2,4,&6 S: cyclin A and E + CDK2 G2: cyclin A + CDK2 & CDK1 M: cyclin B + CDK1

Answer 27

INK 4 binds to CDK4 and D type cyclins - regulate the g1 phase CIP/KIP proteins bind to cdk/cyclin 1/B, 2/a, 2/E - regulate at any check point

Answer 28

DNA synthesis

Answer 29

growth and prep for mitosis

Answer 30

mitosis - cell division prophase anaphase metaphase telophase

Answer 31

resting phase

Answer 32

looking for: cell size nutrients DNA damage growth factors

Answer 33

nonhomologous end joining - NHEJ

Answer 34

use NHEJ and homologous recombination - use the replicated sister chromatid as a template for repair Homologous recombination is considered error free

Answer 35

cell enters G0

Answer 36

Restriction point is lost in most cancers allowing proliferation without requirement for extracellular mitogenic signals

Answer 37

DNA damage DNA replication

Answer 38

cell size DNA replication ## Footnote HR and NHEJ

Answer 39

spindle assembly

Answer 40

mediated by Natural Killer (NK) lymphocytes or CD8-positive Cytotoxic T lymphocytes (CTLs) ligand binding on the cell surface receptors (FAS, TNFa, TRAIL) bind to death receptor activate caspase 8 and (maybe 10) then cleave and activate executioner caspase 3, 6, 7

Answer 41

caspase 3 controls DNA fragmentation caspase 7 control cell viability (such as DNA repair, genomic stability, and programmed cell death) by cleaving PARP

Answer 42

mitochondrial pathway cell stress or damage to dna - activates p53 (Bax, BAK) and then transcription of proapoptotic proteins (Bcl -> BID) . leading to increased mitochondrial permeability and leakage of cytochrome c. this binds to apaf1 forming the 7 spoke apoptosome and cleave procaspase 9 - caspase 9 to activate executionaer caspases 3,6,7

Answer 43

1. mutagenic event 2. leads to repair, apoptosis or failed repair 3. failed repair leads to perpetuation of genomic defect in daughter cells 4. progression = clonal expansion of mutated cell. premalignant 5. promotion = acquisition of additional genetic mutations to support growth and survival

Answer 44

control cell growth through cell cycle regulation and programed cell death loss of function leads to cancer

Answer 45

protect the genome through regulation of dna repair loss of function leads to cancer

Answer 46

code for normal cell machinery involved in cell growth and differentiation gain of function mutations lead to cancer - point mutation, gene amplification, chromosomal translocation, viral insertions

Answer 47

- tumor suppressor - cell adhesion and signal transduction and cell division - a part of wnt destruction complex - colorectal cancer

Answer 48

- tumor suppressor - transcriptional elongation regualtion - angiogenesis - schwannoma, meningioma, etc

Answer 49

- tumor suppressor - phosphatase that covert PIP3 back to PIP2 stopping PDK1 -mtor- cell survivial - hamartoma, glioma, etc

Answer 50

- tumor suppressor - cell cycle control - when bound to E2F prevents cell cycle progression when phosphorylated (cancer) allow progression through cell cycle by releasing E2F - OSA others

Answer 51

- tumor supressor - cell cycle control ( activates p21 (cip) which blocks CDk2/cyclinE and p27 (KIP) which blocks other cyclins/cdks) , apoptosis via activation of caspase 9 - sarcoma, leukemia, etc

Answer 52

- Tumor supressor - blocks Ras ( similar to PTEN - converts RAS GTP to RAS GDP) - neurofibroma, sarcoma , etc

Answer 53

- tumor supressor - cell cycle control ( encode p16 or INK ie blocking CDK4/6 CyclinD whihc then cannot phosphorylate Rb1) - melanoma, pancreatic cancer

Answer 54

- tumor supressor and oncogene - transcription factor of p53 - activates p21, and degrades b catenin. or blocks apoptosis and promotes cell EMT via blocking e cadherin - nephroblastoma ( in embyro helps develop kidneys and testes) also on lymphoblastic leukemias

Answer 55

- tumor supressor - DNA repair (HR) , cycle checkpoint control (p21 ie CIP block CDK/Cylins) - Breast and ovarian cancer

Answer 56

- tumor supressor - dna repair and apoptosis via AKT and p53 - lymphoma

Answer 57

- tumor supressor - dna rapair of intrastrand crosslinks - Fanconi anemia (FA) pathway - complex of proteins that rec and activate NHEJ and HR and NER - acute myeloid leukemia

Answer 58

- tumro supressor - dna mismatch repair microsattelite - lymphoma, sarcoma

Answer 59

- tumor supressor - nucleotide excision repair - skin cancer

Answer 60

- oncogene - receptor tyrosine kinase - constituatively activates jak,pi3k,ras, nfkb, etc - lymphoma

Answer 61

- oncogene - anti-apoptotic protein - lymphoma leukemia

Answer 62

- oncogene - transcription of both apoptotic proteins and cell proliferation and cell cycle progression - leukemia, carcinoma, etc

Answer 63

- oncogene - cell surface receptor - binds TNFa or EGF to start PI3k or RAS - survival - SCC

Answer 64

- oncogene - transcription factor - HH path and ras - > repair, metastasis, and theapeutic resistance - glioblastoma, basal cell carcinoma, panc carcinoma, medulloblastoma

Answer 65

- oncogene - receptor tyrosine kinase - sarcoma gi stromal tumor mct

Answer 66

- oncogene with FOS - transcription factor self renewal and differentiation - sarcom

Answer 67

- oncogene - g protein signal transduction - carcinoma

Answer 68

- oncogene - receptor tyrosine kinase protein- binding domains and fusion proteins - thryoid carcinoma, endocrine neoplasia

Answer 69

- oncogene - encode growth factor PDGF - glioma, fibrosarcoma

Answer 70

- oncogene - encodes non-receptor tyrosine kinase protein c-srs which phosphorylates tyrosine residues - sarcoma

Answer 71

- oncogene - receptor tyrosine kinase - Neurotrophic tyrosine receptor kinase - colon, thyroid cancer

Answer 72

G2 S phase requires homology between broken DNA strand and template - usually newly replicated chromatid

Answer 73

CHK2 at G1-S - dsDNA break -> ATM phosphorylates CHK 2 CHK 2 phosphorylates CDC25 to prevent activation of CDKS and E2F to inhibit cell cycle progression ## Footnote chk 2 = serine/threonine kinase

Answer 74

deregulating cellular energetics and avoiding immune destruction

Answer 75

genome instability and mutation tumor promoting inflammation

Answer 76

senescent cells ar elarger and more morphologically diverse

Answer 77

Cdk-activating kinase (CAK)

Answer 78

1. cyclin and cdk1 bind - inactive 2. CAK phosphorylates threonine 160 on CDK - inactive 3. other active cyclin/cdk can phosphorylate CDC25 which in turn activates the inactive cyclin/cdk complex (positive feedback) 4. active CDK/cyclin can also activate Wee1 - whcih is an inhibitory CDK kinase that inhibits CAK phosphorylation

Answer 79

p15, p16, p18, p19 inhibit CDK4/6 to block Cyclin D interaction ** cannot progress through G1**

Answer 80

p21, p27, p 57 inhibit Cyclin E-CDK2 and Cycklin A-CDK2 preventing entry into S phase inhibit Cyclin A/CDK1 and Cyclin B/CDK1 for progression through G2 and M phase

Answer 81

inactivate all 3 CDC25 and activate Wee1 kinase prevents removal of the inhibitory phosphate group preventing activation of Cycline B and CDK1 p21 and p27 inhibit Cyclin A/CDK1 and Cyclin B/CDK1 for progression through G2 and M phase

Answer 82

Dominant negative CDK2 should halt cell cycle in late G1

Answer 83

in G1 phase Sequential phosphorylation by kinase complexes Cyclin D:Cdk 4/6 and Cyclin E:Cdk 2, causes conformational changes to the Rb structure and release of E2F. The release of E2F is necessary for the expression of S-phases genes

Answer 84

regulation of cell cycle and DNA replication, such as cyclins E and A

Answer 85

Hypophosphorylated Rb is active and binds to E2F, thereby silencing E2F-dependent activity therefore play a central role in maintaining cells in a resting or quiescent state. Phosphorylation of Rb promotes its dissociation from E2F, allowing transcriptional activation of E2F targets such as cyclin E. represents the transition from mitogen-dependent to mitogen-independent cell cycle progression (or passage through the restriction point)

Answer 86

ATM activate CHK which stabilizes/phosp p53 when DNA DSB, p53 activates CIP/KIP (p21) stops G1/S checkpoint and less G2/M

Answer 87

Inhibits PIP3 so no PI3k, stabilize p27 which inhibits G2/M

Answer 88

colorectal cancer, gastric cancer, endometrial cancer mammary gland tumors and OMM, HCC in dogs

Answer 89

short tandem repeats that are prone to mutations. located in inherited genes when you have mismatch repair deficiency (MSI) host cannot see the errors

Answer 90

tumors that have mismatch repair deficiency - cant recognize errors - have insertions and deletions. leads to carcinogenesis very responsive to immunotherapy

Answer 91

Mismatch repair; Proteins MLH1, MSH2

Answer 92

proof reading failure either insertions or deletions or polymerase creates helical distortions 1. recognition 2. excision 3. synthesis by polymerase ligation

Answer 93

Enzymatic removal of the damaged DNA base by DNA glycosylases - Cleave glycosidic bonds - Specific to DNA base lesions

Answer 94

major pathway - single nucleotide replacement Minor pathway is long patch base excision repair which enable repair of 2-13 damaged nucleotides

Answer 95

MUTYH - glycolase

Answer 96

P53 can stimulate BER by direct interaction with APE1 and DNA polymerase BER defective in cells with p53 mutations

Answer 97

BER ## Footnote ionizing radiation ds break repaired via hr and nhej

Answer 98

Required at an intermediate step preceding DNA synthesis during BER or when ssDNA region are recognized

Answer 99

leads to ss gaps that result in dna collapse or repair via other mechanisms

Answer 100

Can be repaired by Homologous recombination When HR is altered as in BRCA1/2 mut, PARP inhibitors can cause cell death via Synthetic lethality

Answer 101

mismatch repair MLH1, MSH2 microsatellite instability

Answer 102

nucleotide excision repair XP, CS - point mutations

Answer 103

DNA DSB - non homologous end joining ATM - chromosome aberration

Answer 104

VHL Von Hippel-Lindau Disease

Answer 105

p53 DNA DSB response - DNA checkpoint damage

Answer 106

APC -adenomatous polyposis coli (APC) gene inherited point mutation APC is a tumour suppressor gene that controls beta-catenin turnover in the Wnt pathway

Answer 107

dna crosslink repair FANC - chromosome abberation

Answer 108

homologous recombination BRCA1/2

Answer 109

Synthetic lethality BRCA mutations = HR defect, dependent on BER PARP inhibitor impairs BER → cell death

Answer 110

UV damage due to nucleotide excision repair failure

Answer 111

involves 30 genes 1. Recognition of damaged dna 2. Dual incision of damaged dna strand on each side of the lesion leading to excision of an oligonucleotide of 24-32 residues 3. Filling in of the gap by dna polymerase 4. Ligation of the nick

Answer 112

· Transcription coupled repair - stalled RNA polymerase induces the recognition of the DNA lesions on the transcribed strands - efficient - facilitated by CSA and CSB proteins

Answer 113

· Global genome repair - transcription independent and surveys the entire genome for DNA lesions - slow

Answer 114

Decreased DNA repair - inhibit NER

Answer 115

homologous recombination

Answer 116

G2 & S phase *Requires homology between broken DNA strand and template - typically newly replicated sister chromatid*

Answer 117

If compromised dsDNA repair (ex. BRCA1/2 or RAD51 loss) PARPi blocks ssDNA repair

Answer 118

nucleotide excision repair

Answer 119

homologous recombination

Answer 120

homologous recombination and non homologous end joining

Answer 121

E7 protein is a transforming protein that binds to Rb

Answer 122

Genomic hybridization in situ FISH mitosis

Answer 123

- Requires homology between broken DNA strand and the template strand used in repair - Typically provided by a newly replicated sister chromatid - Restricted to S and G2 phases - Error free repair

Answer 124

RAD proteins, MRE11, and BRCA1

Answer 125

heterodimer recognizes the DNA ends and recruits the DNA dependent protein kinase catalytic subunit which autophosphorylates and forms the active DNA-PK complex while downstream a ligase dimer associates with the proteins and joins the DNA ends together

Answer 126

end are repaired by ATM kinase and may require chromatin modification for repair then follow fast pathway - Used when DSB ends are unligatable by fast pathway

Answer 127

DNA dependent protein kinase (DNA-PK) MRE11-RAD50-NBS1 (MRN) protein complex

Answer 128

sensitivity to ionizing radiation and reduced ability to repair radiation-induced DNA DSBs

Answer 129

various human diseases that can lead to increased incidence of lymphoid tumors and death

Answer 130

specialized pathway for repair of interstrand crosslinks (ICLs) People with deficiencies of any of the proteins in this pathway have a predisposition to cancer Increased protein of FAP found in metastasizing canine OMM

Answer 131

highly toxic lesions that prevent DNA strand separation interfering with transcription and replication

Answer 132

ATM, ATR, DNA Pk act upstream of cell signaling cascades and detect damaged chromosomes and block cell cycle progression

Answer 133

ensure that microtubules are assembled into a functional mitotic spindle that connects sister kinetochores to opposite centrosomes prior to division

Answer 134

delay progression through the cell cycle in response to DNA damage or replication defects

Answer 135

“Sensor” proteins (ATM, DNA-PK) activated→ phosphorylation of histone proteins → assembly of “mediator” proteins (mediator of DNA checkpoint [MDC1]) around DSB → concentration of “effector” proteins (p53) to facilitate enactment of downstream processes like DNA repair & checkpoints

Answer 136

P53 stabilization activates cyclin D/E kinase complex inhibitor which leads to hypophosphorylation of Rb protein to effect G1 cell cycle arrest Second G1 checkpoint pathway activated that targets CDC25A phosphatase that is essential for G1/S transition → inactive CDC25 is incapable of removing inhibitory phosphate group which prevents entry into mitosis

Answer 137

MAD2, BUBR1, BUB1, and BUB3

Answer 138

regulate mitotic progression by direct interaction and inhibition of the APC machinery

Answer 139

mediate mitotic arrest after disruption of microtubules

Answer 140

do not undergo mitotic arrest when treated with spindle-disrupting agents such as docetaxel or vinblastine

Answer 141

central regulator of the tension checkpoint If activated by lack of tension will result in removal of improper attachments and activation of spindle assembly checkpoint pathway

Answer 142

Detects telomerase activity using primer and amplification

Answer 143

DNA fragmentation or strand breaks - tells you if cells are apoptotic

Answer 144

NFKB and Pi3K, Jak Stat (N-ras, p53, Rb, p16 CDK, telomerase)

Answer 145

Wnt and β-catenin; Wnt/β-cat activity regulates telomerases by increasing TERT (telomerase reverse transcriptase), involved in apoptotic resistance . Without β-cat you get shorter telomeres. Cancer and CSCs can upregulate β-cat promotes cell survival

Answer 146

alternate lengthening of telomeres (Alt) -alternate route for telomerase so will always be resistant

Answer 147

Tumors, germline/embryo, testicles/ovary

Answer 148

Mice 40-60 bps, Dogs 20 bps, Men 10-15 bps Mouse telomeres are 5-10x longer compared to dogs and humans

Answer 149

proteins on the ends of chromosomes to protect them from being inappropriately recognized as DNA damage

Answer 150

Cancer cells most often protect their telomeres through the activation of an enzyme called Telomerase that adds new telomere DNA onto chromosome ends Those that do not express telomerase maintain cells with ALT mechanisms Several telomerase chemotherapeutic targets have been proposed but with limited efficacy bc of ALT - will always be resistant

Answer 151

Loss of telomeres led to fusion or loss of chromosomes and an ensuing cycle of chromosome breakage, chromosome fusion, and anaphase bridges during cell division BFB cycles are a major source of genome instability could be cause of heterogeneity in tumors

Answer 152

DNA damage foci at uncapped telomeres Coincides with activation of checkpoint kinases and lead to p53 and p21 dependent apoptosis or cell cycle arrest

Answer 153

directs new telomere DNA synthesis

Answer 154

In normal cells, levels of TERT is undetectable due to transcriptional repression and therefore cells undergo telomere shortening with each cell division Cellular senescence - eventual loss of replicative potential

Answer 155

Shelterin “shelters” the chromosome ends and protects telomeric DNA from degradation and end-to-end fusion events Telomeres are bound by protein complexes called Shelterins

Answer 156

Antiapoptotic, proliferation, angiogenesis

Answer 157

Activates PUMA, NOX, Bak/Bim -> Apaf1, cytochrome-c ->caspase9 - caspase 3,6,7

Answer 158

Inhibits PIP3 so no PI3k, stabilize p27

Answer 159

Hypophos blocks cyclinD/cdk4/6, HyperphosRb, release E2F, cell cycle progression (wont produce cyclin e /a), Halt cells at G1/S checkpoint if hypophos

Answer 160

Apoptosis; Necrosis causes inflammation

Answer 161

Death receptor (Fas/FADD, TRAIL, TNFa) - extrinsic mitochondrial - intrinsic

Answer 162

PI3K, BcL2

Answer 163

Activated in cytoplasm after released from IkB (phos->ubiquinated),Travels to nucleus; Produces cytokines

Answer 164

Retrovirus transduction, amplification, translocation, proviral insertion MYC can be directly genetically activated through chromosomal translocation, genomic amplification, retroviral integration, and mutation, as well as activated through increased gene expression and/or protein stability by the activation of other oncogenes, including RAS, SRC, NOTCH, or the inactivation of tumor suppressor genes such as APC.

Answer 165

Attachment/communication with ECM, Tumor suppressor ; Activate FAK/Src->Ras, ERK, Rho

Answer 166

Regulated cycle, survival, cytoskeleton; Works through RTK and Gcoupled

Answer 167

Point mutation

Answer 168

Raf, Ral, PI3K

Answer 169

PI3K, Stat, MAPK, HER2/neu

Answer 170

VEGF, IGF1, TGFb, PDGF, kit, Ret, Met, Erb2

Answer 171

Wnt->receptor Frizzled-> disheveled ->GSK3b, APC/Axin - DSH blocks GSK3b so B catenin released to promote survival noncanonical wnt not bound so gsk3b apc complex bound to b catenin

Answer 172

FAP Familial adenomatous polyposis and colon cancer - APC point mutation

Answer 173

Mitotic recombination, chromosomal nondysjunction, gene conversion

Answer 174

Gate-direct against proliferation, promote tumor death, ex. Rb, p53,PTEN, BRCA1/2, APC, VHL Care-Gene encodes protein that helps with genomic integrity, sensitive to DNA damage, inherited diseases, ex. ATM, XP, MSH2/MLH1

Answer 175

Point mutation cause dominate negative effect

Answer 176

MDM2 ubiquinate p53 for degredation, p53 makes MDM2; Arf moves MDM2 to nucleolus where it cant bind p53; E2f makes Arf

Answer 177

o Aka DIABLO, pro-apoptotic o Inhibits IAP (inhibitor of apoptosis) o Promotes caspase activation in cytochrome c/Apaf-1/caspase 9 pathway o Promotes caspase 9 activation by binding to inhibitor of apoptosis proteins and removing their inhibitor activity o Normal mitochondrial protein – release into cytosol when undergo apoptosis o Mitochondrial import and cleavage of its signal peptide are required for SMAC o Overexpression of SMAC increases cells’ sensitivity to apoptotic stimuli

Answer 178

o DR5 (TRAIL - death receptor 5) o FAS o TNFR o Also: granzyme via caspase 3 and 8 cleavage

Answer 179

o Caspase-mediated apoptosis o Caspase 3/7

Answer 180

Condensed chromatin - cell shrinkage no inflammatory response phagocytes versus necrosis - inflammation - swelling of ER and mitochondria

Answer 181

anti apoptosis - Bcl2, Bcl XL, Bcl w, Mcl 1, A1 pro apoptosis - Bax Bad Bid Bck Bak Bak

Answer 182

o Effector/executioner: caspase 3, 6, 7 o Initiators: 1. Extrinsic: 8, 10 2. Intrinsic: 9

Answer 183

Bid via Caspase-8

Answer 184

o Binds CD36 o Blocks proliferation o Activates FasL→ apoptosis

Answer 185

Prevents release of Cyt-C from mitochondria

Answer 186

Beclin-1, p62

Answer 187

o Propidium iodide (PI) is widely used in conjunction with Annexin V to determine if cells are viable, apoptotic, or necrotic through differences in plasma membrane integrity and permeability o One of the first steps in apoptosis is flipping the cell membrane so that phosphatidylserine (PS) is exposed on the outside. Annexin V binds PS with high specificity, making it a good indicator of early apoptosis o PI will penetrate the membrane and bind nucleic acids in late apoptosis and necrosis o Flow gated cells = viable (Annexin V– PI– ), early (Annexin V+PI– ), and late (Annexin V+ PI+ ) apoptosis/ necrosis

Answer 188

4N (S/G2/mitosis peak)

Answer 189

Beclin 1 regulates autophagy (the ability to remove and degrade these otherwise toxic cellular components is thought to provide a tumor-suppressor function in some instances during early tumorigenesis)

Answer 190

Elsamitrucin, the most potent topoisomerase II inhibitor available, is unique in that it does not cause neutropenia or cardiotoxicosis (Fiocchi 2011 JVIM)

Answer 191

Camptothecin (also irinotecan)

Answer 192

Delivery of a gene enzyme directly into tumor followed by delivery of a prodrug that is normally non-toxic but converted to active compound in tumor to kill Cytokine-enhanced vaccine and IFN-beta plus suicide gene for canine sarcomas - administered IFN-beta and HSVtk-carrying lipoplexes and ganciclovir Combination of suicide and cytokine gene therapies as surgery adjuvant for canine mammary carcinomas.

Answer 193

DNA absorbed onto gold particles and fired into tissues under high pressure

Answer 194

lysosome mediated degradation of membrane bound vesicles called autophagosomes cell response to stress Beclin 1 is key protein

Answer 195

Chemotherapy can induce a type I interferon response through production of DAMPs that are sensed by pattern-recognition receptors (PRRs) on innate and adaptive immune cells initiates an immune response towards antigens expressed by the dying cells

Answer 196

an intracellular iron-dependent form of cell death that is distinct from apoptosis, necrosis, and autophagy ferroptosis is initialized through GSH depletion or inactivation of GPX4 activity leads to iron-dependent accumulation of lipid peroxidation products ( ROS) leading to cell death

Answer 197

lipophilic antioxidants (e.g., ferrostatin-1 and α-tocopherol) and iron chelators (e.g., deferoxamine) can prevent ferroptotic cell death

Answer 198

Triggered by internal cellular signals such as DNA damage, oxidative stress, or lack of growth factors. Key regulators include members of the Bcl-2 protein family, which control mitochondrial membrane permeability. When activated, pro-apoptotic Bcl-2 proteins such as Bax and Bak induce mitochondrial outer membrane permeabilization (MOMP). MOMP leads to the release of cytochrome c and other pro-apoptotic proteins from the mitochondria into the cytoplasm. Cytochrome c, along with apoptotic protease activating factor 1 (Apaf-1) and procaspase-9, forms the apoptosome, initiating the caspase cascade. The caspase cascade leads to the activation of executioner caspases (caspase-3, -6, and -7), which dismantle the cell by cleaving specific substrates.

Answer 199

Initiated by external signals such as binding of death ligands (e.g., Fas ligand, TNF-alpha, TRAil (DR5)) to death receptors (e.g., Fas, TNFR1). Binding of death ligands induces clustering of death receptors, leading to the formation of the death-inducing signaling complex (DISC). The DISC recruits and activates procaspase-8. Activated caspase-8 can directly cleave and activate executioner caspases (e.g., caspase-3), initiating the caspase cascade. In some cases, caspase-8 cleaves and activates the pro-apoptotic Bcl-2 family member Bid. Activated Bid triggers the intrinsic pathway by inducing mitochondrial outer membrane permeabilization.

Answer 200

Process: Hormones released into the bloodstream, hormones travel to distant target cells, where they bind to receptors on the cell surface or inside the cell, initiating cellular responses.

Answer 201

occurs when a cell releases signaling molecules that bind to receptors on its own surface or neighboring cells of the same type. In other words, the signaling molecule acts on the same cell or cell type that secreted it. regulate cell proliferation, differentiation, and other cellular functions.

Answer 202

involves the release of signaling molecules by one cell that act on neighboring cells in the immediate vicinity. The signaling molecules (paracrine factors) are released into the extracellular space and affect nearby target cells.

Answer 203

molecular mechanisms that cells utilize to promote their survival and prevent programmed cell death (apoptosis). Wnt/β-catenin Pathway NF-κB Pathway PI3K-Akt Pathway MAPK/ERK Pathway JAK-STAT Pathway

Answer 204

The pathway is typically initiated by the binding of growth factors (e.g., insulin, insulin-like growth factor 1, epidermal growth factor) to their respective receptor tyrosine kinases (RTKs) on the cell surface. This leads to receptor dimerization and autophosphorylation of tyrosine residues in the receptor's cytoplasmic domain Activated RTKs recruit and activate phosphoinositide 3-kinase (PI3K), which phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) Akt (also known as protein kinase B) is recruited to the plasma membrane by binding to PIP3 through its pleckstrin homology PH domain. Once localized to the membrane, Akt is phosphorylated and activated by phosphoinositide-dependent kinase 1 (PDK1) at threonine 308. Akt is further activated by phosphorylation at serine 473, primarily by the mammalian target of rapamycin complex 2 (mTORC2). Akt phosphorylates and inhibits pro-apoptotic proteins such as Bad and caspase-9, while activating anti-apoptotic proteins such as Bcl-2 and Mdm2.

Answer 205

**cell proliferation** Activation of RTKs or G protein-coupled receptors by growth factors (e.g., EGF, FGF, PDGF) leads to receptor dimerization and autophosphorylation of tyrosine residues in the receptor's cytoplasmic domain -> recruit and activate the small GTPase Ras (Rat sarcoma protein) by facilitating the exchange of GDP for GTP. Ras-GTP activates a cascade of protein kinases. First, it activates a MAP3K (Mitogen-Activated Protein Kinase Kinase Kinase), such as Raf (Rapidly Accelerated Fibrosarcoma), through direct interaction. Raf phosphorylates and activates MAP2K (Mitogen-Activated Protein Kinase Kinase or MEK). Activated MAP2K/MEK phosphorylates and activates MAPK/ERK (Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase) by phosphorylating specific threonine and tyrosine residues within the activation loop Activated ERK then phosphorylates various cytoplasmic and nuclear targets, including transcription factors (e.g., Elk-1, c-Myc, c-Fos), protein kinases, and other signaling proteins. Phosphorylation of these targets leads to changes in gene expression, cytoskeletal rearrangements, and modulation of various cellular proliferation

Answer 206

Cell Proliferation: ERK activation promotes cell cycle progression by upregulating cyclins and cyclin-dependent kinases (CDKs) and downregulating CDK inhibitors. Cell Differentiation: ERK signaling induces differentiation in various cell types by activating specific transcription factors. Cell Survival: ERK activation promotes cell survival by phosphorylating and inactivating pro-apoptotic proteins such as Bad. Cell Migration: ERK signaling regulates cell migration by controlling cytoskeletal dynamics and cell adhesion.

Answer 207

PIP3 serves as a second messenger that recruits proteins containing pleckstrin homology (PH) domains, such as Akt, to the plasma membrane. Akt is phosphorylated and activated by phosphoinositide-dependent kinase 1 (PDK1) at threonine 308. and by mtor2 on serine

Answer 208

Cell Growth and Protein Synthesis: Akt activates mTORC1 (mammalian target of rapamycin complex 1) by phosphorylating and inhibiting the tuberous sclerosis complex 2 (TSC2), leading to increased protein synthesis and cell growth. Cell Survival: Akt promotes cell survival by phosphorylating and inactivating pro-apoptotic proteins such as Bad, caspase-9, and Forkhead box O (FoxO) transcription factors. Glucose Metabolism: Akt stimulates glucose uptake and glycolysis by promoting translocation of glucose transporter proteins (GLUT4) to the cell membrane and activating glycolytic enzymes. Cell Proliferation and Cell Cycle Progression: Akt promotes cell proliferation by phosphorylating and activating various proteins involved in cell cycle progression, including cyclin-dependent kinases (CDKs) and the mTORC1 substrate p70S6 kinase (p70S6K).

Answer 209

NF-κB proteins are transcription factors that exist in the cytoplasm as inactive complexes bound to inhibitory proteins called IκBs (inhibitors of κB). The NF-κB family includes various dimers, most commonly p50/p65 (RelA), p52/RelB, and c-Rel

Answer 210

activated in response to various extracellular signals, such as pro-inflammatory cytokines (e.g., TNF-α, IL-1β), microbial products (e.g., lipopolysaccharide, LPS), and stress signals. Activation of the pathway typically involves the phosphorylation and degradation of IκB proteins, allowing NF-κB to translocate into the nucleus and regulate gene expression 2 pathways - canonical and non canonical

Answer 211

In the canonical NF-κB pathway, activation is initiated by the engagement of cell surface receptors, such as TNF receptor (TNFR) or Toll-like receptors (TLRs), by their ligands. This triggers the recruitment of adaptor proteins such as TNF receptor-associated factors (TRAFs) and TGF-β-activated kinase 1 (TAK1), leading to the activation of the IκB kinase (IKK) complex. The IKK complex consists of two catalytic subunits (IKKα and IKKβ) and a regulatory subunit (IKKγ or NEMO). IKK phosphorylates IκB proteins, marking them for ubiquitination and proteasomal degradation. Degradation of IκB proteins frees NF-κB dimers, allowing them to translocate into the nucleus. In the nucleus, NF-κB binds to specific DNA sequences called κB sites and regulates the transcription of target genes.

Answer 212

Inflammation: Pro-inflammatory cytokines (e.g., IL-6, IL-8, TNF-α), chemokines, adhesion molecules (e.g., ICAM-1, VCAM-1). Immune Response: Genes encoding immune receptors, antimicrobial peptides, and immunoregulatory molecules. Cell Survival: Anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL), cell cycle regulators, and growth factors.

Answer 213

The non-canonical NF-κB pathway is initiated primarily by members of the TNF receptor superfamily, such as lymphotoxin β receptor (LTβR), CD40, B-cell activating factor receptor (BAFF-R), and receptor activator of NF-κB (RANK). Activation of these receptors leads to the recruitment of TRAF3 (TNF receptor-associated factor 3) and subsequent activation of the NF-κB-inducing kinase (NIK). TRAF3, in its unbound state, mediates the degradation of NIK through the proteasomal pathway. However, upon receptor activation, TRAF3 is degraded, leading to the stabilization and accumulation of NIK. Accumulated NIK then phosphorylates and activates IKKα, also known as IKK1, but not IKKβ. Activated IKKα phosphorylates p100, a precursor protein that binds to RelB to form an inactive complex in the cytoplasm. Phosphorylation of p100 targets it for partial proteasomal degradation, resulting in the generation of p52, the active form of NF-κB. This processing allows the release of RelB/p52 dimers from p100 and their translocation into the nucleus. In the nucleus, RelB/p52 dimers regulate the expression of specific target genes. The non-canonical pathway's target genes often include those involved in lymphoid organogenesis, B-cell maturation, bone metabolism, and immune responses, distinct from those regulated by the canonical NF-κB pathway.

Answer 214

The pathway is initiated by the binding of cytokines or growth factors to their respective cell surface receptors, such as cytokine receptors or receptor tyrosine kinases (RTKs). Binding of the ligand induces dimerization of the receptor subunits, leading to activation of associated Janus kinases (JAKs) that are constitutively associated with the receptor cytoplasmic domains. Activated receptors induce conformational changes in the associated JAKs, leading to their transphosphorylation and activation. Once activated, JAKs phosphorylate tyrosine residues on the cytoplasmic tails of the receptor (receptor-associated tyrosine residues) Phosphorylated tyrosine residues on the receptor serve as docking sites for signal transducer and activator of transcription (STAT) proteins. they are phosphorylated by activated JAKs on a conserved tyrosine residue near their C-terminus Phosphorylated STAT proteins undergo a conformational change that promotes their dimerization through reciprocal interactions between phosphorylated tyrosine residues. Dimerized STATs then dissociate from the receptor complex and translocate to the nucleus as transcriptionally active dimers STAT dimers bind to specific DNA sequences known as gamma-activated sites (GAS) or interferon-stimulated response elements (ISRE), located within the promoters of target genes. Binding of STATs to these DNA elements leads to the recruitment of co-activators and chromatin-modifying enzymes, resulting in transcriptional activation or repression of target genes. Negative regulators, such as protein tyrosine phosphatases (PTPs) and suppressor of cytokine signaling (SOCS) proteins, inhibit JAK activity and dephosphorylate activated receptors or STATs. Additionally, unphosphorylated STAT proteins are actively exported out of the nucleus by exportins, limiting their transcriptional activity.

Answer 215

Immune Responses: JAK-STAT signaling is crucial for the regulation of immune responses, including the development, differentiation, and activation of immune cells such as lymphocytes (T cells, B cells), natural killer (NK) cells, and myeloid cells. Cytokines such as interleukins (ILs), interferons (IFNs), and colony-stimulating factors (CSFs) activate the JAK-STAT pathway to modulate immune cell proliferation, differentiation, and function. Inflammation: Cytokines such as IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α) activate the JAK-STAT pathway to induce the expression of inflammatory mediators and adhesion molecules, promoting inflammation. Dysregulation of JAK-STAT signaling can lead to chronic inflammation and autoimmune diseases. Cell Growth and Proliferation: JAK-STAT pathway regulates cell growth, proliferation, and survival by controlling the expression of genes involved in these processes. Growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) activate the JAK-STAT pathway to promote cell proliferation and survival. Hematopoiesis: Cytokines such as erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), and thrombopoietin (TPO) activate the JAK-STAT pathway to stimulate the production of red blood cells, granulocytes, and platelets, respectively. Development and Differentiation: JAK-STAT signaling is involved in the development and differentiation of various tissues and organs during embryogenesis and tissue regeneration. Antiviral Responses: The JAK-STAT pathway is a critical component of the innate antiviral immune response.

Answer 216

promoting T cell proliferation and differentiation

Answer 217

particularly STAT3 and STAT5, is associated with cell cycle progression and inhibition of apoptosis.

Answer 218

activate STAT3 to promote stem cell pluripotency and self-renewal

Answer 219

The pathway is initiated by secreted glycoprotein ligands called Wnts. Wnts bind to Frizzled (Fzd) family receptors on the cell surface, in conjunction with co-receptors LRP5/6 (low-density lipoprotein receptor-related protein 5/6). leads to the recruitment and activation of Dishevelled (Dsh) Activated Dsh inhibits a the destruction complex consisting of Axin, APC (adenomatous polyposis coli), GSK-3β (glycogen synthase kinase-3β), and CK1 (casein kinase 1). Inhibition of the Axin complex prevents the phosphorylation and subsequent degradation of β-catenin and it accumulates in the cytoplasm. Stabilized β-catenin then translocates to the nucleus. In the nucleus, β-catenin associates with transcription factors of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family. This complex activates the transcription of target genes by binding to specific DNA sequences known as Wnt response elements (WREs) in the promoters of target genes. Target genes include those involved in cell proliferation (e.g., c-Myc, cyclin D1), cell fate determination (e.g., Axin2, CD44), and stem cell maintenance (e.g., Lgr5, Sox9).

Answer 220

colorectal cancer, hepatocellular carcinoma, and breast cancer.

Answer 221

Active TGF-β ligands bind to TGF-β type II receptor (TβRII) on the cell surface. Upon ligand binding, TβRII phosphorylates and activates TGF-β type I receptor (TβRI or ALK5), a serine/threonine kinase. Activated TβRI phosphorylates receptor-regulated Smads (R-Smads), primarily Smad2 and Smad3. Phosphorylated R-Smads form complexes with the common Smad (Co-Smad), Smad4. The R-Smad/Co-Smad complexes translocate into the nucleus. In the nucleus, Smad complexes regulate the transcription - can act as transcriptional activators or repressors - cmyc Target genes include those involved in extracellular matrix production, cell cycle regulation, apoptosis, and differentiation.

Answer 222

Regulation of Target Gene Expression: TGF-β regulates the expression of a wide range of target genes, including: Extracellular matrix proteins (e.g., collagen, fibronectin) and proteases (e.g., MMPs) involved in tissue remodeling. Cell cycle inhibitors (e.g., p21, p15) and pro-apoptotic factors (e.g., Bim) that inhibit cell proliferation and induce apoptosis. Transcription factors (e.g., Snail, Slug) involved in epithelial-mesenchymal transition (EMT) and cell differentiation. Cytokines and growth factors (e.g., TGF-β itself, IL-6) that modulate immune responses and inflammation. Cross-talk with Other Signaling Pathways: The TGF-β pathway interacts with other signaling pathways, including the MAPK/ERK, PI3K-Akt, and Wnt/β-catenin pathways, to regulate cellular responses.

Answer 223

Negative regulators include inhibitory Smads (Smad6 and Smad7), which inhibit TGF-β receptor activation, and various phosphatases and ubiquitin ligases that target components of the pathway for degradation.

Answer 224

The HER2/neu receptor, also known as ErbB2 or HER2 (human epidermal growth factor receptor 2), is a member of the epidermal growth factor receptor (EGFR) family. HER2 is a transmembrane receptor tyrosine kinase that lacks a ligand-binding domain. Instead, it is activated through heterodimerization with other EGFR family members, particularly EGFR (ErbB1), HER3 (ErbB3), or HER4 (ErbB4). Heterodimerization leads to activation of the intracellular kinase domain of HER2, resulting in autophosphorylation of tyrosine residues. Activation of HER2 leads to the activation of several signaling pathways, including the PI3K-Akt pathway, the MAPK/ERK pathway, and the PLC-γ (phospholipase C-gamma) pathway. These pathways regulate cellular processes such as cell proliferation, survival, differentiation, and migration. In normal cells, HER2 signaling is tightly regulated and plays a role in tissue development and homeostasis. Dysregulation of the HER2 pathway, often due to HER2 gene amplification or overexpression, is associated with various cancers, particularly breast cancer and gastric cancer.

Answer 225

HER2 overexpression is a hallmark of a subset of breast cancers known as HER2-positive breast cancers. Therapies targeting HER2, such as monoclonal antibodies (e.g., trastuzumab, pertuzumab) and small molecule inhibitors (e.g., lapatinib), have revolutionized the treatment of HER2-positive breast cancer,

Answer 226

MDM2 (Mouse double minute 2) is an E3 ubiquitin ligase that plays a key role in the negative regulation of p53. Under normal conditions, MDM2 binds to p53 and promotes its ubiquitination, targeting it for proteasomal degradation. This interaction forms an auto-regulatory feedback loop, as p53 can induce the transcription of the MDM2 gene, leading to increased MDM2 levels and subsequent inhibition of p53 activity. ARF (Alternative Reading Frame) is a tumor suppressor protein encoded by the INK4a/ARF locus, also known as CDKN2A. ARF is activated in response to oncogenic stress, such as hyperproliferative signals or DNA damage. In normal cells, ARF acts as a nucleolar stress sensor, detecting abnormalities in ribosome biogenesis or other cellular stresses. Upon activation, ARF binds to MDM2 and inhibits its E3 ubiquitin ligase activity, preventing the ubiquitination and degradation of p53 When ARF binds to MDM2, it disrupts the MDM2-p53 interaction, leading to the stabilization and activation of p53. Stabilized p53 accumulates in the nucleus and functions as a transcription factor, activating the expression of genes involved in cell cycle arrest, apoptosis, and senescence.

Answer 227

Dysregulation of the MDM2/ARF pathway is common in cancer and contributes to tumorigenesis. Loss of ARF function or overexpression of MDM2 can lead to the inactivation of p53 and promote tumor formation. Mutations in the p53 gene itself are also common in cancer and can disrupt its function independently of the MDM2/ARF pathway. Small molecule inhibitors of MDM2, such as Nutlin-3a, disrupt the MDM2-p53 interaction, leading to p53 stabilization and activation. These inhibitors are being investigated as potential cancer therapeutics, particularly in tumors with wild-type p53. Additionally, strategies to restore ARF function or reactivate mutant p53 are also under investigation.

Answer 228

PCNA, Ki67, AgNOR

Answer 229

TGFβ-immunosupressive/inhibit dendritic cells up regs tregs tams, increase fibrin, expressed in tumors

Answer 230

Antiapoptotic, cell proliferation

Answer 231

cytokines; (ILs), (IFNs), (CSFs) Inflammation: IL-6, IL-1β, (TNF-α) a Cell Growth and Proliferation: (EGF), (PDGF) Hematopoiesis: (EPO), (G-CSF), (TPO)

Answer 232

Antiapoptotic, proliferation, angiogenesis

Answer 233

Southern-dna, Northern-mRNA, Western-proteins

Answer 234

Cell Transformation Assays (CTAs) The assay uses histidine-dependent strains of Salmonella typhimurium that are unable to synthesize histidine due to mutations in genes Bacterial strains with specific mutations (usually his- or rfa-) are exposed to the test chremical or compound in the presence or absence of a metabolic activation system, If the test compound induces reverse mutations in the bacterial strains, resulting in the reversion of the his- or rfa- mutation, colonies of revertant bacteria will grow on the agar plates. An increase in the number of revertant colonies compared to the negative control indicates a positive result for mutagenicity. Positive results suggest that the compound has the potential to cause mutations in DNA, which could lead to carcinogenesis. Negative results suggest that the compound is not mutagenic under the conditions tested. dose-response relationship

Answer 235

FISH is used for detecting specific chromosomal abnormalities and gene mapping - you know the abnormality you are looking for - use of fluorescently labeled DNA probes that bind to specific target sequences on chromosomes CGH provides a genome-wide view of DNA copy number changes - dont know the abnormality you are searching for one - compares the relative DNA copy number between a test sample and a reference sample - bets combined wiht micro array

Answer 236

PI3K, mTOR

Answer 237

Link between inflammation & cancer

Answer 238

High mobility group/box that regulate transcription binding, HMGB enables NfKB and both elevated in dogs with LSA compared to normal

Answer 239

Humanized monoclonal Ab against Her2/neu (Erb2 growth factor); Trastuzumab

Answer 240

Overexpression-Her2/neu, fusion-Bcr-Abl, (CML) autocrine loops-MET/HGF

Answer 241

sensitive to rapamycin. bound to RAPTOR Activation of mTORC1 occurs in response to growth factors (e.g., insulin, insulin-like growth factor 1), amino acids (particularly leucine), and cellular energy status (e.g., AMP:ATP ratio). Key regulators of mTORC1 include: Rheb (Ras homolog enriched in brain), a small GTPase that activates mTORC1 when in the GTP-bound state. TSC1 (tuberous sclerosis complex 1) and TSC2, form a complex that inhibits Rheb when activated by upstream signals. Akt (protein kinase B), phosphorylates and inhibits TSC2, leading to activation of mTORC1.

Answer 242

bound to RICTCHER Akt is phosphorylated and activated by mTORC2 at a serine residue (Ser473) mTORC2 regulates various downstream targets, including Akt, SGK1 (serum- and glucocorticoid-regulated kinase 1), and PKC (protein kinase C

Answer 243

Protein synthesis: promoting ribosome biogenesis and translation initiation. Cell growth and proliferation mTORC1 inhibits autophagy, mTORC1 regulates cellular metabolism by modulating nutrient uptake, glycolysis, lipid metabolism, and mitochondrial function. Both mTORC1 and mTORC2 regulate cell survival pathways through their downstream effectors.

Answer 244

 MEK inhibitor  Upstream: 1. Farneysl transferase inhibitor 2. Gerangylgeranyl transferase inhibitor

Answer 245

PIP2 to PIP3 PIP3 attracts AKT to cell membrane where PDK1 phosph threonine and mtor phosphorylates serine

Answer 246

Patched is TSG; without → Gli cleaved to active TF, stimulating proliferation

Answer 247

o Proliferation o Invasion o Metastasis o Also: embryogenesis, angiogenesis, and activation of CSCs

Answer 248

The Hedgehog family includes three ligands in mammals: Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh) primary receptor for Hedgehog ligands is the transmembrane protein Patched (Ptch) When Hedgehog ligands bind to Ptch, it relieves the inhibition on Smo. Once activated, Smo initiates downstream signaling by modulating the activity of the Gli (Glioma-associated oncogene) transcription factors - cyclin D, cmyc, Bcl, nanog

Answer 249

In the absence of Hedgehog ligands, Ptch inhibits another transmembrane protein called Smoothened (Smo) - therefore GLI2 and GLI3 are phosphorylated by PKA, CK1 and GSK3β, which create binding sites for the E3 ubiquitin ligase β-TrCP. GLI3 and GLI2 undergo partial proteasome degradation, leading to the formation of repressor forms (GLI3/2R), that translocate into the nucleus where they inhibit the transcription of HH target genes. When Hedgehog ligands bind to Ptch, it relieves the inhibition on Smo. | non canoniucal pathway

Answer 250

in the absence of Hedgehog ligands, Ptch inhibits Smo, preventing Gli activation. When Hedgehog ligands bind to Ptch, it relieves the inhibition on Smo, allowing Smo to accumulate and activate Gli proteins. Activated Gli proteins translocate into the nucleus, where they regulate the transcription of target genes. GliA promotes the expression of Hedgehog target genes, such as Ptch1, Gli1, and Hhip (Hedgehog-interacting protein), while GliR inhibits their expression. Target Genes: cell proliferation (e.g., Cyclin D1), survival (e.g., Bcl-2), differentiation (e.g., Ptch1, Gli1), and tissue patterning (e.g., Hox genes).

Answer 251

basal cell carcinoma, medulloblastoma, and pancreatic cancer

Answer 252

Notch receptors are single-pass transmembrane proteins. In mammals, there are four Notch receptors: Notch1, Notch2, Notch3, and Notch4. Notch ligands are transmembrane proteins expressed on neighboring cells. In mammals, there are five Notch ligands: Jagged1, Jagged2, Delta-like 1 (Dll1), Delta-like 3 (Dll3), and Delta-like 4 (Dll4). Intracellular Domain: Upon ligand binding, Notch receptors undergo proteolytic cleavage, releasing the intracellular domain of Notch (NICD), which translocates to the nucleus to regulate gene expression.

Answer 253

Notch ligands (e.g., Jagged or Delta-like) on one cell bind to Notch receptors on neighboring cells. Ligand binding induces conformational changes in Notch receptors, leading to proteolytic cleavage by γ-secretase. The NICD is released from the cell membrane and translocates to the nucleus. In the nucleus, NICD binds to the DNA-binding protein CSL (CBF1/RBPJκ in mammals), converting it from a transcriptional repressor to an activator. The NICD-CSL complex recruits coactivators, target genes such as Hes (Hairy and enhancer of split) and Hey (Hes-related with YRPW motif), which regulate cell fate decisions.

Answer 254

influences the choice between different cell lineages (e.g., neuronal vs. glial cells in the nervous system, secretory vs. absorptive cells in the intestine). Notch signaling regulates cell proliferation, differentiation, and stem cell maintenance in various tissues and organs. In certain contexts, Notch signaling can inhibit apoptosis and promote cell survival. Notch signaling is involved in the development and function of the immune system, including T cell development and activation.

Answer 255

the inability to inhibit Smo, resulting in constitutive activation of Smo even in the absence of Hedgehog ligands cell proliferation, survival, and differentiation Dysregulated HH Patched function is associated with the development of various cancers, particularly basal cell carcinoma (BCC) and medulloblastoma.

Answer 256

FDG taken up by hypermetabolic cells via GLUT1 Phosphorylated by hexokinase → traps metabolically active cells

Answer 257

o Metabolism of cancer cells (Warburg effect) o Proliferation, hypoxia, etc. vs. anatomic localization only (with CT)

Answer 258

karyotype chromosomal microarray SNP array Comparative genomic hybridization microsatelitte array FISH

Answer 259

visual assessment of metaphase chromosomes using microscopy = size shape and number combines with FISH or pcr it could be a molecular test - should detect balanced chromocomal abnormalities

Answer 260

high resolution method for detecting copy number changes - gains or losses accross the entire genome in a singe assay and is sometimes called molecular karyotypes can detect aneuploidies as well as smaller deletions and duplications (microdeletions/microduplications) in chromosomes. CMA can be performed using array comparative genomic hybridization (aCGH) or single nucleotide polymorphism (SNP) arrays.

Answer 261

assay measures LDH activity in cell lysates, reflecting lactate production. It can be used to assess cell viability and glycolytic activity.

Answer 262

qPCR can be used to quantify the copy number of specific chromosomal regions by measuring the relative abundance of target DNA sequences By comparing the amount of target DNA to reference DNA (e.g., a housekeeping gene), qPCR can detect aneuploidies Multiplex qPCR assays are available for detecting aneuploidies in specific chromosomes, such as chromosomes 13, 18, 21, X, and Y

Answer 263

SNPs are variations in a single nucleotide base at specific positions in the DNA sequence, representing the most common type of genetic variation in humans

Answer 264

SNP arrays consist of thousands to millions of DNA probes, each designed to hybridize to a specific SNP locus. SNP arrays are used for large-scale genotyping studies to identify genetic variations associated with diseases, traits, and drug responses. SNP arrays can detect chromosomal gains and losses (CNVs) by analyzing changes in signal intensity across adjacent SNP loci. SNP arrays are used in family-based linkage studies and case-control association studies to identify genetic variants linked to complex diseases. SNP arrays are used to study population genetics, ancestry, and evolutionary relationships

Answer 265

Reverse Transcription PCR (RT-PCR): Used to amplify RNA by first converting it to complementary DNA (cDNA) using reverse transcriptase enzyme. Quantitative PCR (qPCR): Used to measure the amount of DNA or RNA present in a sample by monitoring the PCR amplification in real-time using fluorescent dyes or probes. Multiplex PCR: Amplifies multiple target DNA sequences in a single reaction using multiple primer sets. Nested PCR: Utilizes two sets of primers to increase the specificity and sensitivity of amplification.

Answer 266

Denaturation: The PCR reaction starts with heating the reaction mixture to around 94-98°C to denature the double-stranded DNA into single strands, separating the two DNA strands. Annealing: The reaction temperature is lowered to around 50-65°C to allow the primers to anneal (bind) to their complementary sequences on the single-stranded DNA template. Extension (Elongation): The temperature is raised to around 72°C, the optimal temperature for DNA polymerase activity. The DNA polymerase synthesizes new DNA strands by extending from the primers, using the template DNA and incorporating dNTPs. Cycle Repeats: These three steps (denaturation, annealing, extension) are repeated for multiple cycles (usually 20-40 cycles), with each cycle doubling the amount of DNA produced. PCR Product: After each cycle, the target DNA sequence is amplified exponentially, resulting in a large amount of DNA product. The PCR product is typically analyzed by gel electrophoresis, DNA sequencing, or other downstream applications to confirm the presence and size of the amplified DNA fragment.

Answer 267

also known as short tandem repeat (STR), arrays are used to analyze microsatellite loci throughout the genome Microsatellites are repetitive DNA sequences consisting of short (1-6 base pair) tandem repeats (e.g., CA, AGAT). Microsatellite arrays use fluorescently labeled probes to detect variations in the number of repeats at specific microsatellite loci following PCR amplificaiton

Answer 268

Genotyping: Microsatellite arrays are used for genotyping in research and forensic applications. Linkage Mapping: Microsatellite markers are used in linkage analysis to identify regions of the genome associated with inherited traits or diseases . Population Genetics: Microsatellite arrays are used to study genetic diversity and population structure in various species. Cancer Research: Microsatellite instability (MSI) analysis using microsatellite arrays is used to detect genetic instability in cancer cells, which can be indicative of certain types of cancer or response to treatment.

Answer 269

Detects apoptotic cells using techniques like TUNEL assay, Annexin V staining, or caspase activity assays

Answer 270

differentiation of hematopoietic stem cells (HSCs) into common lymphoid progenitors (CLPs) in the bone marrow which express specific transcription factors and surface markers, committing them to the B cell lineage. Rearrangement occurs in the Ig heavy (IgH) and light (IgL) chain gene loci, leading to the assembly of variable (V), diversity (D), and joining (J) gene segments. Recombination-activating genes (RAG1 and RAG2) mediate the DNA rearrangement process. Successful rearrangement of IgH genes results in the production of μ (mu) heavy chains, which combine with surrogate light chains (VpreB and λ5) to form the pre-B cell receptor. Pre-B cells that express functional pre-B cell receptors undergo positive selection, leading to further differentiation into immature B cells. Immature B cells undergo negative selection Immature B cells exit the bone marrow and migrate to secondary lymphoid organs, such as the spleen and lymph nodes. In secondary lymphoid organs, mature B cells encounter antigens and receive signals from helper T cells, leading to activation, proliferation, and differentiation into antibody-secreting plasma cells or memory B cells.

Answer 271

Thymic Seeding: T cell development begins with the migration of bone marrow-derived lymphoid progenitors to the thymus. Progenitors enter the thymus through the bloodstream and settle in the thymic cortex. T cell development involves the rearrangement of T cell receptor (TCR) genes, which encode the TCRα and TCRβ chains. TCR gene rearrangement occurs through V(D)J recombination Developing thymocytes express both TCRα and TCRβ chains on their surface, forming the pre-TCR complex. Pre-TCR-expressing cells undergo positive selection in the thymic cortex, where cells with functional receptors that interact with self-major histocompatibility complex (MHC) molecules survive. Positively selected thymocytes migrate to the thymic medulla, where they undergo negative selection to eliminate self-reactive T cells through apoptosis or regulatory T cell differentiation. Thymocytes that successfully pass positive and negative selection differentiate into mature CD4+ or CD8+ T cells. Mature T cells migrate to secondary lymphoid organs, where they circulate in search of antigens presented by antigen-presenting cells (APCs). Interaction with APCs and recognition of antigen-MHC complexes lead to T cell activation, proliferation, and differentiation into effector or memory T cells.

Answer 272

Innate cytotoxic cell o CD56+ Cytotoxicity: 1. Perforin/granzyme 2. Fas-FasL 3. Cytokines (MAFs, IFNɣ, GM-CSF, TNF-ɑ)

Answer 273

CD16 KARs (KIRS are inhibitory) C-type lectins Target recognition: 1. FcyRII (CD16) - ADCC 2. Absence of MHC I

Answer 274

TLR 4 - LPS, RSV-F protein (Recognition of LPS is aided by CD14 and MD-2) TLR 2, 6, 1 work together - peptidoglycan, lipoprotein, mycobacterium, LPS of letup, porphyromonas, Glycophosphoinositol on trypanosome Cruzi, yeast zymosan TL3 - dsDNA TL5 - bacterial flagellin TLR9 - unmethylated CpG DNA

Answer 275

- inherited defect are rare - acquired defects are common - rapid onset - recognition of DAMPs and PAMPs - no memory - PMN control pathogens by phagocytosis, cytokines, ROS, apoptotic vs necrotic cell death and inflammation - macrophages are separate lineage - endogenous and self renewing specific to each organ - TLRs, NLRs, PIG-I pathways

Answer 276

monocytes respond rapidly, fxn determined by the environment, immune suppression in chronic inflammation

Answer 277

NK cell generate rapid anti-viral and antitumor activity key early producers of IFNy

Answer 278

dendritic cells are the link between the innate and adaptive immunity antigen processing and presentation to TCells

Answer 279

classical MB lectin alternative

Answer 280

Innate: immediate, no memory 1. IgM > IgG 2. Lower affinity, non-Sp Adaptive: delayed response, memory 1. Increase in Igs (IgG) 2. Higher affinity, more Sp 3. IL-17**, IL-15

Answer 281

CD40L (T cell) = CD40 (APC)

Answer 282

CD28:B7 family CD2 4-1BB OX40 Also* 1. GITR 2. ICOS 3. CD27 4. CD40L 5. CD122

Answer 283

o Melanoma o OSA o Mammary o Prostatic adenocarcinoma o TCC o HSA

Answer 284

o Dendritic cells o (CD11b drives CD4+) o Interdigitating DC (CD8+): LN/spleen o Interstitial DC (CD103): perivascular **costimulation necessary for activation of naive T cells

Answer 285

Th1 - produce IFNy, IL2 and TNF - stimulate cell mediated immunity - trigger production of certain IgG isotypes that fix complement Th-2 - produce IL-4, IL-5, IL-13 - trigger production of high levels of IgG and IgE - associated with helminth responses and allergy

Answer 286

IL-2 (from Th1)→ proliferation of T, NK and B cells IL-4 (from Th2)→ more Th2 cells, B cell isotype switch to IgE, inhibition of IFN-ɣ

Answer 287

* IFNy - Key Th1 cytokine produced by activated T cells and NK cells; promotes the differentiation of naïve CD4+ T cells to Th1 phenotype; activates macro- phages, increases MHC Class I/II expression.

Answer 288

IFN a and b - Induce apoptosis of tumor cells; enhances CTL effector function, activates NK cells, modulates MHC Class I/II expression, inhibits tumor angiogenesis

Answer 289

IL10, TGFb, TNFa

Answer 290

- Activate NK and CTLs - Directly causes B cells to produce Abs - stimulates synthesis of IFN-γ and TNF-α - dec angiogenesis - stimulates differentiation of naïve CD4+ T cells to T cells with the Th1 phenotype.

Answer 291

- Pro-inflammatory, anti-angiogenic = IFN-ɑ, -β, -ɣ - Activation of macrophages = IFN-ɣ - Direct tumor effects = IFN-ɑ - Anti-angiogenic, induces TSGs, downregulates OGs, inhibits tumor cell proliferation

Answer 292

MHC II = CD4+ MHC I = CD8+ MHC I on all nucleated cells MHC II on professional APCs NK cells attack cells that do not express MHC I

Answer 293

produce IL 17 which stimulate neutrophil recruitment and inflammation

Answer 294

native T cells in lymph nodes and spleen effector t cell sin tissues

Answer 295

binding fluorescent antibodies to CD4 or CD8 or CD3 on surface of T cells passing as fluid stream past lasers whihc excite fluorescent dyes and number of positive events are counted electronically

Answer 296

low IgG recurrent bacterial infections with intracellular pathogens

Answer 297

give plasma transfusion, non specific immune stiumulation recombinant IFN (cats(

Answer 298

TCR recognize peptides presented by MHC - Ag INSIDE of cell Vs. B cell recognize naive Ag OUTSIDE of cell B cell receptor is a membrane-bound soluble Ab. B cells recognize Ag in native form. TCR recognize Ab as peptides presented by MHCs

Answer 299

Undergo Ag-independent maturation

Answer 300

Fc/constant region (determines immune response)

Answer 301

T cell cytokine and B cell CD40

Answer 302

more rapid response higher titer and higher affinity antibodies

Answer 303

antigen concentration and antibody cross linking efficiency

Answer 304

IL 4, 5, 13

Answer 305

measure IgA IgM and IgG concentrations detemrine b cell numbers measure vaccine titres

Answer 306

hypogammaglobulinemia

Answer 307

IgA in the Gi tract and lung

Answer 308

complement binds to Fc molecules on certain isotope of antibodies

Answer 309

recurrent bacterial infections esp Gi urinary lung anf skin

Answer 310

activation of complement C5a release which functions as a chemoattractant for PMN

Answer 311

o Membrane: CD4, CD25 o Intracellular: FoxP3

Answer 312

Inhibits activation of effectors cells by binding to PD-L1

Answer 313

o Downregulation of MHC class 1 o Induction of immune cell tolerance o Activate PD-L1 o Loss of tumor antigen expression o T cell exclusion from TME o Masking of tumor antigens

Answer 314

Tumors can upregulate immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), to inhibit T cell activation and function. Interaction between PD-L1 on tumor cells and PD-1 on T cells leads to T cell exhaustion and dysfunction, inhibiting anti-tumor immune responses.

Answer 315

Tumors recruit immunosuppressive cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), to the tumor microenvironment. Tregs suppress effector T cell responses and promote immune tolerance, while MDSCs inhibit T cell activation and proliferation. TAMs exhibit an M2-like phenotype and promote immunosuppression, angiogenesis, and tissue remodeling.

Answer 316

Tumors secrete immunosuppressive cytokines, such as interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF), to suppress anti-tumor immune responses. IL-10 and TGF-β inhibit effector T cell function and promote Treg differentiation, while VEGF contributes to the formation of an immunosuppressive tumor microenvironment.

Answer 317

Tumors can induce T cell anergy and exhaustion through chronic antigen exposure and signaling. Anergic T cells lose their ability to respond to antigen stimulation, while exhausted T cells display reduced cytokine production and cytotoxicity.

Answer 318

Tumors may downregulate or lose expression of tumor antigens, making them less recognizable by the immune system. Loss of tumor antigens reduces T cell recognition and targeting of tumor cells.

Answer 319

Tumors undergo metabolic reprogramming, change from kreb cycle to glycolysis to use glucose to make pyruvate and lactate due to hypoxia. Tumors can consume nutrients such as glucose and amino acids, limiting the availability of these nutrients for immune cells. Metabolites produced by tumors, such as lactate and adenosine, inhibit T cell function and promote immunosuppression.

Answer 320

Dense ECM structures and increased collagen deposition limit T cell migration and function within the tumor microenvironment.

Answer 321

Tumors promote immune tolerance by inducing the expression of immune regulatory molecules, such as indoleamine 2,3-dioxygenase (IDO) and arginase-1 (Arg-1). These molecules inhibit T cell activation and promote the generation of regulatory T cells.

Answer 322

Tumors downregulate the expression of ligands for natural killer (NK) cell activating receptors, such as NKG2D ligands. Decreased expression of NKG2D ligands prevents NK cell-mediated killing of tumor cells.

Answer 323

Dysregulation of apoptosis pathways, such as increased expression of anti-apoptotic proteins (e.g., Bcl-2) and decreased expression of pro-apoptotic proteins, contributes to tumor survival.

Answer 324

The ECM is a complex network of proteins, glycoproteins, and polysaccharides that provides structural support to tissues and organs. Cells interact with the ECM through cell surface receptors, such as integrins, which bind to ECM components like collagen, fibronectin, and laminin. ECM receptors transmit signals bidirectionally, regulating cell adhesion, migration, proliferation, differentiation, and survival. Cells within tissues exhibit polarity, with distinct apical and basal surfaces and specialized junctions for cell-cell adhesion. Stem cell niches provide microenvironments that support self-renewal and differentiation of stem cells.

Answer 325

cell - cell: CAMs mediate cell-cell adhesion and form specialized junctions between adjacent cells. Cadherins, including E-cadherin, N-cadherin, and P-cadherin, are calcium-dependent CAMs that form adherens junctions and maintain tissue integrity. Adherens junctions provide mechanical strength to tissues, regulate cell polarity, and facilitate cell signaling. Cell-ECM Adhesion: CAMs mediate cell-ECM adhesion by binding to ECM components such as collagen, fibronectin, and laminin. Cell adhesion to the ECM activates intracellular signaling pathways, including focal adhesion kinase (FAK), Src, and Rho GTPases, which regulate cytoskeletal dynamics, cell motility, and gene expression. Integrins are the primary CAMs involved in cell-ECM adhesion and signaling. cell signaling: CAMs transmit signals bidirectionally across cell membranes, activating downstream signaling pathways involved in cell growth, differentiation, and survival. Tissue Morphogenesis and Development: CAMs regulate cell sorting, tissue patterning, and organogenesis during embryonic development.

Answer 326

* TGF b - immune suppressive, produced by macrophages, DC and T regs, inhibits B cells

Answer 327

* TNFa - Produced by Th1 T cells, Cytotoxic T cells, activated DCs and macrophages; induces NO production by macrophages, induces tumor apoptosis; important pro-inflammatory cytokine

Answer 328

* IL-2, 7 - T cell growth, proliferation and survival. induces B cell proliferation. approved by FDA for animals

Answer 329

* IL 3 - multi colony stimulating factor- production and differentiation of macrophages, monocytes, granulocyts, and DC

Answer 330

* IL 4, 5, - produced by Th2 CD4 T cells. promote IgG and IgE. inhibits macrophage activation, induces B cell growth and differentiation,

Answer 331

* IL 6 - Supports B-cell proliferation and differentiation to plasma cells; proinflammatory, antiapoptotic cytokine that may contribute to tumor development associated with chronic inflammation. Causes upregulation of PD-1 on monocytes that are triggered to produce IL-10

Answer 332

* IL 8 - Chemotactic/activation factor for neutrophils and T cells; induces matrix metalloproteinase-2 activity; plays a role in inflammation and tumor metas- tasis.

Answer 333

* IL 10 - Immunosuppressive cytokine produced by activated DCs, macrophages, and T cells; induces regulatory T cell function; also overexpressed by some tumors and tumor-associated leukocytes

Answer 334

* IL 11 - Stimulates proliferation of hematopoietic stem cells; induces megakaryocyte maturation resulting in increased platelet production.

Answer 335

* IL 13 - Th2 promoting cytokine, tumor immune surveillance

Answer 336

* IL 15 - T cell growth factor; supports survival of memory CD8+ T cells; promotes NK cell activation and survival and triggers cytotoxic activity.

Answer 337

* IL 17 - Induces proinflammatory response. Role in cancer is currently controversial

Answer 338

* IL 19 - Promotes T-cell differentiation toward the Th2 phenotype.

Answer 339

* IL 21 - Member of IL-2 cytokine family; enhances cytotoxicity and proliferation of CTL and NK cells

Answer 340

* GM-CSF - Promotes growth and differentiation of pleuripotent progenitor cells; stimulates growth of cells of the granulocyte, macrophage, and eosinophil lineage.

Answer 341

Suppression of T cells by: 1. Arginase deprivation 2. NOS 3. ROS Also: 1. Cysteine deprivation 2. Produce TGF-β and IL-10

Answer 342

Can bind extracellular site to block or trigger cell signaling cascade → cell lysis via complement or antibody-dependent cell-mediated cytotoxicity

Answer 343

o Gene conversion o Translocation o Mitotic recombination

Answer 344

Mutations in TSGs (ex. p53) PTCH, BRAF (human melanoma), loss of INK4a (familial cut melanoma)

Answer 345

depletion/inhibit proliferation promote maturation inhibit recruitment block interactions block function

Answer 346

Loss of E-Cadherin and Adherens Junctions: - epithelial-mesenchymal transition (EMT) in cancer - leading to loss of cell-cell adhesion and increased cell motility and invasion. - associated with increased tumor aggressiveness, invasion, and metastasis. Upregulation of N-Cadherin (Cadherin Switch): - N-cadherin-mediated adhesion promotes cell migration, invasion, and metastasis. Integrin Dysregulation: - Upregulation of specific integrin subunits promotes cancer cell adhesion to the ECM and facilitates tumor cell dissemination and metastasis. - Dysregulated integrin signaling promotes tumor angiogenesis, survival in the circulation, and colonization of distant organs. CAM-Mediated Signaling Pathways: - Aberrant CAM signaling activates downstream pathways involved in cell proliferation, survival, migration, and invasion. CAM-mediated signaling promotes cancer cell survival under stress conditions and resistance to apoptosis and cytotoxic therapies. CAMs as Therapeutic Targets: CAMs and their associated signaling pathways represent potential targets for cancer therapy.

Answer 347

1. Migration begins with the polarization of the cell, establishing a leading edge (front) and a trailing edge (rear). - At the leading edge, the cell forms dynamic protrusions called lamellipodia and filopodia. 2. The leading edge of the migrating cell establishes transient adhesions with the extracellular matrix (ECM) or neighboring cells. Integrins, a family of cell surface receptors, mediate adhesion to the ECM by binding to specific ECM proteins such as fibronectin, collagen, and laminin. 3. As the leading edge adheres to the ECM, the cell generates traction forces by contracting its cytoskeleton, pulling itself forward. 4. Actin polymerization drives the extension of lamellipodia and filopodia at the leading edge. The Arp2/3 complex nucleates actin polymerization, generating a branched actin network in lamellipodia. 5. Myosin motor proteins, particularly myosin II, generate contractile forces that retract the trailing edge of the cell. 6. As the leading edge advances, the cell body moves forward by a process known as cytoplasmic streaming. Cytoplasmic streaming involves the flow of cytoplasmic contents toward the leading edge, driven by actin polymerization and myosin II-mediated contraction. 7. Integrin-mediated adhesions are dynamic and undergo turnover, allowing the cell to detach from the substrate at the trailing edge and move forward. Cell-cell adhesions, such as cadherin-mediated adherens junctions, stabilize cell-cell contacts and coordinate collective migration of groups of cells. 8. Polarity proteins, such as Par complex and Rho GTPases, regulate the distribution of signaling molecules and cytoskeletal components within the cell. Directional sensing mechanisms, including chemotaxis, haptotaxis, and durotaxis, guide cells toward specific cues in the microenvironment, such as chemical gradients, ECM stiffness, or topographical features. 9. At the trailing edge, integrin-mediated adhesions disassemble, allowing the cell to detach from the substrate. Myosin II-mediated contraction generates contractile forces that retract the rear of the cell, completing the migration cycle.