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55 Cards in this Set
- Front
- Back
How can viruses indirectly cause cancer?
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- Chronic infection (e.g., Hepatitis B and C) cause cirrhosis, inflammation, tissue damage, high levels of cell division
- Cycle vastly increases probability that hepatocytes develop mutations and chromosomal aberrations that derail their "growth control" |
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How can viruses directly cause cancer?
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- E.g., Papillomavirus
- Upon infection, some DNA viruses stimulate cells to enter S phase of cell cycle and ready themselves for DNA synthesis - Virus needs this for replication - If virus does not complete lifecycle and kill infected cell then the same viral proteins can continue to direct cell to override normal controls on cell growth - Inappropriate division |
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What kind of cancer are Hepatitis B and C associated with? What kind of viruses are they?
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- Hepatocellular Carcinoma
- Hep B = hepadnavirus - Hep C = flavivirus |
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What kind of cancer are herpesvirus associated with? What viruses specifically?
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- Lymphoma; nasopharyngeal carcinoma (EBV)
- Kaposi's sarcoma KSHV (HHV8) |
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What kind of cancer is lentivirus associated with? What virus specifically?
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- Adult T cell leukemia
- HTLV1 |
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What kind of cancer are papillomavirus associated with? What viruses specifically?
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- Cervical cancer
- Head and neck cancer - HPV |
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What kind of cancer is Merkel cell polyoma virus (MCPyV) associated with?
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Merkel Cell Carcinoma - aggressive skin cancer (in elderly and immunosuppressed patients)
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How was it discovered that viruses were associated with cancer?
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Observation that a particular cancer is more common in immunosuppressed individuals
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Human Papillomavirus (HPV) is a member of what viral family?
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Papovavirus
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What do Papillomaviruses infect?
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- Cutaneous and mucosal epithelia
- Hands, feet (warts) - Anogenital tract |
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What is the genome of Papillomaviruses?
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Small, circular, dsDNA
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How many subtypes of Papillomaviruses are there? Notable group of subtypes?
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~100
1/3 infect genital tract - sexually transmitted |
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What genes do the Papillomaviruses encode? Functions?
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- Early (E) and Late (L) genes:
- E1 and E2 - mediate replication and transcription of viral DNA - E4 - disrupts cytokeratins to facilitate virus exit - E5 - stimulates constitutive growth factor receptor signaling - E6 and E7 - neutralize major "brakes" that regulate cell cycle (p53 and Rb), uncoupling cell division from regulatory controls - L1 and L2 - capsid proteins |
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Which Papillomavirus genes mediate replication and transcription of viral DNA?
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E1 and E2
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Which Papillomavirus gene disrupts cytokeratins to facilitate virus exit?
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E4
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Which Papillomavirus gene stimulates constitutive growth factor receptor signaling?
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E5
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Which Papillomavirus genes neutralize major "brakes" that regulate cell cycle (p53 and Rb), uncoupling cell division from regulatory controls?
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E6 and E7
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Which Papillomavirus genes form capsid proteins?
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L1 and L2
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Which Papillomavirus genes intersect with key elements of cellular growth control, and are associated with oncogenesis?
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E5, E6, and E7
- E5 - stimulates constitutive growth factor receptor signaling - E6 and E7 - neutralize major "brakes" that regulate cell cycle (p53 and Rb), uncoupling cell division from regulatory controls |
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What is the course of a Papillomavirus infection?
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Papillomavirus -->
inoculation of epithelium (hand, foot, throat, or cervix) --> local multiplication --> wart --> resolution (latency) or cell transformation |
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How does Papillomavirus inoculate the epithelium?
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Enters through a microabrasion / break in the skin
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What is the life cycle of Papillomavirus tied to?
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Differentiation state of the keratinocytes
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How does the gene expression / lifecycle of Papillomavirus relate to the keratinocytes?
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- Virus enters through break in skin to level of Dermis
- Begins early gene expression (E1, E2, E6, E7) in Stratum Basale and Spinosum - Late gene expression and viral genome amplification in Stratum Spinosum and Granulosum - Virion assembly and release in Stratum Granulosum and Corneum |
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What does Human Papillomavirus (HPV) stimulate? Where? How does this differ from normal?
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- Stimulation of cell cycle
- Causes cells in statrum spinosum to replicate - Normally only stratum basale cells replicate |
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What are the stages of the cell cycle?
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- G1
- S (DNA replication) - G2 - M |
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What controls the movement through the stages of the cell cycle?
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- Cyclin dependent kinases (CDKs)
- Move cell cycle ahead by phosphorylating key substrates |
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What regulates the cyclin dependent kinases (CDKs)?
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- Temporally regulated synthesis
- Proteasome-mediated degradation of cyclin subunits - Stimulatory and inhibitory phosphorylation events - Stoichiometric inhibitors |
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What is the "brake" that blocks progression into S phase? How is it regulated?
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- Rb protein (Retinoblastoma)
- When sufficient Cdk/cyclin has accumulated in G1, Rb becomes phosphorylated and inactivated, cell can move into S phase |
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What protein from Papillomavirus affects the Rb protein? How?
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E7 protein binds to Rb and prevents it from blocking the progression to S phase (removes a key regulator of cell cycle progression)
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When there is inappropriate entry into the cell cycle, what should happen?
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Activation of the p53 protein - "guardian of the genome"
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What is the role of p53?
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- Activated by inappropriate entry into the cell cycle
- "Guardian of the genome" - Induces production of Cdk/cyclin inhibitors to stop cell cycle - Major inducer of apoptosis - Stops and weeds out cells that are dividing inappropriately |
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What protein from Papillomavirus affects the p53 protein? How?
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E6 protein recruits a ubiquitin ligase that targets p53 for degradation, thereby preventing it from blocking the progression to S phase or inducing apoptosis; E6 removes a key regulator of cell "accuracy"
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What protein from Papillomavirus affects the telomeres? How?
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E6 protein induces the expression of telomerase, which enables cells to maintain their chromosomal telomeres and avoid senescence; E6 therefore induces a key component of cellular immortality
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What data supports the hypothesis that HPV causes cervical cancer?
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- Sexually active populations have a higher risk of cervical cancer
- Sexually inactive populations have an extremely low risk of cervical cancer - Greater than 99% of all cervical cancer specimens show evidence of infection with "high risk" strains of HPV (16, 18, 6, and 11) - Low risk strains are associated with warts - Correlation between "high risk" strains and activity of E6 and E7 proteins --> immortalize keratinocytes |
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What kind of proteins are p53 and Rb?
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"Tumor suppressor genes" - their loss or inactivation causes a predisposition to cancer formation
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What percentage of human cancers have a mutated p53?
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>50%
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What happens to the viral DNA from Papillomavirus in the earlier stages of acute and persistent infection?
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Maintained as an episome (genetic element that can replicate independently of the host and also in association with a chromosome with which it becomes integrated)
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What happens to the viral DNA from Papillomavirus during the development of carcionma?
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- Associated with the integration of the DNA into the host chromosome; E6 and E7 always retained in cancer cells
- Integration disrupts expression of E2 gene, which is a transcriptional repressor and allows increased levels of E6 and E7 expression - Replication of integrated DNA triggers DNA amplifications and chromosomal abnormalities |
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What is a key step towards oncogenesis of HPV infection?
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Genome integration
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What is the cytological progression of HPV-induced lesions?
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- Normal <-->
- Infection <--> - LSIL (Low grade Squamous Intraepithelial Lesion) <--> - HSIL (High grade Squamous Intraepithelial Lesion) --> - Cervical Cancer (doesn't always progress) |
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What is the histological progression of HPV-induced lesions?
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CIN-1 --> CIN-2 --> CIN-3
(CIN = Cervical Intraepithelial Neoplasia) |
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What kind of lesion occurs during a productive infection?
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LSIL - Low grade squamous intraepithelial lesion
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What kind of lesion occurs during cellular gene deregulation?
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HSIL - High grade squamous intraepithelial lesion
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What kind of lesion occurs with DNA integration and breaks in basal membrane?
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Cervical Cancer
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What immune, environmental, genetic, and life-style choices impact the outcome of HPV infection?
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- Host immune response involved in initial infection of HPV
- Smoking, Oral contraceptive use, viral-load, and coinfections determine conversion from Low grade to High grade squamous intraepithelial lesion - Viral integration and methylation determines conversion from HSIL to cervical cancer |
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What are some markers of the progression from a normal cervix --> HPV infection --> LGIL --> HGIL --> cervical cancer?
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- Pap test: (-) for HPV infection; (+) for LSIL, HSIL, and CC
- E6/E7 mRNA: (-) for HPV infection; (+) for LSIL, HSIL, and CC - L1 protein: (+) for HPV infection and LSIL; (-) for HSIL and CC |
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What diagnostic tests are used for CIN1, CIN2, and cervical cancer?
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- Pap Smear
- Hybrid Capture Assay for HPV DNA |
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What are you looking for on a pap smear?
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- Cytological evidence of displasia or neoplasia; detection of koilocytotic cells (vacuolated cytoplasm) which are rounded and appear in clumps
- Odd looking cells (easy to miss and easy to get false positive) |
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What is done if there is an abnormal pap smear?
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Hybrid Capture Assay - for detection, strain analysis, and quantification of HPV DNA
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What are the steps of the Hybrid Capture Assay for detection, strain analysis, and quantification of HPV DNA
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1. Release nucleic acids - by combination w/ base solution (releases target DNA)
2. Hybridize RNA probe w/ target DNA - creates RNA:DNA hybrids 3. Capture hybrids - onto solid phase coated w/ universal capture antibodies specific for RNA:DNA hybrids 4. Label for detection - conjugated to alkaline phosphatase; signal can be amplified >3000-fold 5. Detect, read, and interpret results - substrate produces light that is measured on luminometer in Relative Light Units (RLUs) |
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What are the issues with making an effective vaccine that would prevent genital infection with high-risk strains of HPV?
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- Need for mucosal infection due to route of infection
- Need to recognize multiple high risk strains - Administration of a vaccine that included "oncogenes" not possible - Societal issues - is this to prevent cancer or STD? |
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What protein from HPV is utilized in vaccines? How does it work?
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- Capsid protein L1 induces productive humoral immunity
- Recombinant L1 can be produced in culture (insect cells or yeast) - L1 self-assembles into "VLPs - virus like particles" that resemble virions and induce appropriate immunological response |
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What is the effect of the HPV vaccine that contains purified "VLPs - virus like proteins"?
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- Induces protective, humoral immunity
- Antibodies present at mucosal surface prevent incoming HPV from establishing infection |
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When was HPV discovered? When was HPV proposed as a necessary cause of cervical cancer? When was the vaccine licensed?
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- Discovered in 1982
- HPV --> cervical cancer in 1999 - Vaccine (Gardasil) licensed in 1008 |
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What strains of HPV cause cervical cancer?
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Types 6, 11, 16, and 18
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