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68 Cards in this Set
- Front
- Back
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reasons why cancer rates are declining:
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earlier diagnosis of uterine/cervical cancer: PAP smears
decrease in dietary carcinogens: decreased stomach cancer |
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what it takes to transform non-immortalized cells
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more than a single oncogene
combination of oncogenes and the loss of tumor suppressor genes |
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accelerator for cellular proliferation
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oncogenes
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brakes for cellular proliferation
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tumor suppressor genes
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gatekeeper genes
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oncogenes and tumor suppressor genes
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caretaker genes
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genes that do not directly control tumor growth but affect genomic stability
includes mismatch repair genes and other DNA repair genes damage to caretaker gene-> increased mutation of all genes |
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which is more severe damage to a gatekeeper or caretaker gene?
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gatekeeper genes: with one defective copy of the gatekeeper gene, only 1 more somatic event is required for cancer initiation
caretaker gene damage: requires subsequent mutations |
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signs of increasing malignancy
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accelerated growth
invasiveness ability to form distant metastases |
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How do tumor cells progress
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monoclonal in origin but they become extremely heterogenous by the time they are clinically evident
transformed cells are genetically unstable- some mutations are lethal, some are destroyed by host defenses, and some survive |
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chemical carcinogenesis process
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1. initiation (exposure of cells to carcinogenic agent)
2. permanent damage occurs- rapid and irreversible 3. promotors can induce tumors in initiated cells 4. the damaged DNA template must be replicated |
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2 categories of chemical carcinogens
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1. direct acting: do not require chemical transformation
2. indirect acting or procardinogens: require metabolic conversion to produce carcinogens |
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common property of direct acting carcinogens
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they are highly reactive electrophiles (electron deficient atoms) that react with nucleophilic (electron rich) sites in cell
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major chemical carcingogens
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alkylating agents
acylating agents aromatic hydrocarbons aromatic amines, amides, Azo dyes natural plant and microbial products |
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carcinogenic potency of an indirect carcinogen is determined by
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1. inherent reactivity of its electrophilic derivative
2. the balance between metabolic activation and inactivation |
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enzymes that metabolize most carcinogens
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cytochrome P450 dependent mono-oxygenases
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cancer risk factors
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genetics
age sex nutrition status |
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specific enzyme deficiency in 50% of whites that is involved in the detoxification of polycyclic aromatic hydrocarbons
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glutathione-S-transferase
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mutagenic potential studied with
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Ames test
ability of a chemical to induce mutations in the bacterium salmonella typhimurium |
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Radiation carcinogenesis
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UV
ionizing electromagnetic and particualate transform all cell types skin cancer medical/occupational exposure nuclear plant accidents atomic bombs radiation |
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UV rays cancer risk
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squamous cell carcinoma, basal cell carcinoma, malignant melanoma
depend on type of UV rays, intensity of exposure, and quantity of light absorbing "protective mantle" melanin of skin |
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UV wavelengths
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UVA 320-400
UVB 280-320 UVC 200-280 UVB: cutaneous cancers UVC: potent mutagen, but filtered out by ozone shield |
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mechanism of UVB damage
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formation of pyrimidine dimers in DNA
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How is DNA damage repaired?
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nucleotide excision repair
5 steps: 1. recognition of DNA lesion 2. incision of damaged strand on both sites of the lesion 3. removal of the damaged nucleotide 4. synthesis of a nucleotide patch 5. ligation |
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ionizing radiation
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x-rays
radioactive elements |
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radiation carcinogenesis examples
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atomic bombs
hydrogen bomb containing thyroid seeking radioactive iodines |
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microbial carcinogenesis examples
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DNA and RNA viruses
Helicobacter pylori-> gastric tumors Human papilloma virus epstein-Barr virus hepatitis B virus kaposi sarcoma herpesvirus Hep C virus (not a DNA virus)- associated with liver cancer |
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transformation by DNA viruses:
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1. oncogenic DNA viruses integrate into host cell genome. Virus is not able to replicate because viral genes are interrupted- can remain latent for years
2. viral genes transcribed in early viral life cycle- important for transformation |
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cancers caused by human papilloma virus
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squamous cell carcinoma of cervix and anogenital region
oral and laryngeal cancers |
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strains of HPV that cause benign squamous papillomas
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1, 2, 4, 7
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strains of HPV that cause cervical cancer
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16, 18, (less commonly 31, 33, 35, 51)
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genital warts with low malignant potential HPV strains
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6, 11
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What is the difference in the DNA between benign and cancer caused by HPV
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benign/preneoplastic: episomal (nonintegrated) into DNA
cancer: viral DNA is integrated into host cell genome |
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epstein-Barr virus
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member of herpes family
involved in 4 types of tumors: 1. african form of burkitt lymphoma 2. B cell lymphomas in immunosuppressed individuals 3. Hodgkin lymphoma 4. nasopharyngeal carcinomas |
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Burkitt lymphoma
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neoplasm of B lymphocytes
most common childhood tumor in central africa and new guinea 90% of African tumors carry EBV genome 100% have elevated antibody titers |
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Nasopharyngeal carcinoma
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associated with EBV infection
100% of nasopharyneal carcinomas are associated with EBV DNA viral integration in the host cells is clonal antibody titers and IgA antibodies develop before tumor |
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cancer associated with Hep B virus
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liver cancer
highest incidence of hepatocellular carcinoma in countries where HBV is endemic the role of HBV in the causation of human liver cancer is unclear - no consistent pattern of integration near the known protooncogenes |
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how Hepatitis B is thought to cause liver cancer
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HBV effect is thought to be indirect and multifactorial
1. by causing liver cell injury and regenerative hyperplasia, HBV expands pool of cycling cells at risk - in mitochondrially active liver cells: mutations arise spontaneously or are caused by environmental agents like dietary aflatoxins 2. HBV encodes a regulatory element called HBx protein which disrupts normal growth control of infected liver cells by transcriptional activation of growth promoting genes (like insulin like GF) -HBx binds p53 and interferes with growth suppressing activities |
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oncogenic RNA virus
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human T cell leukemia virus type 1
retrovirus |
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human T-cell leukemia virus type 1
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RNA retrovirus
tropism for CD4 T-cells transmission: by sex, blood products, breast feeding Leukemia after 40-60 year latent period associated with a demyelinating neurologic disorder called tropical spastic paraparesis and uveitis and arthritis |
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Helicobacter pylori induced cancer
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gastric carcinomas and gastric lymphomas
treatment with antibiotics causes regression of the lymphoma H. pylori is present in 90% of chronic gastritis 20-30% of people infected with H. pylori develop gastric carcinomas/lymphomas the disease causing strains have "pathogenicity islands" containing Cytotoxin associated gene A gene (CagA) and a secretory system which injects CagA protein into the host cells |
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location of gastric lymphomas caused by H. pylori
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mucosa associated lymphoid tissue (MALT)
the B cells that give rise to the tumors reside in the marginal zones (marginal zone lymphoma) it is thought that chronic H. pylori infection leads to formation of lymphoid infiltrates in which B cells proliferate and acquire genetic abnormalities tumor growth is dependent on immune stimulation by H. pylori (at least initially) |
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host defenses against tumors
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immune surveillance- immune recognition of autologous tumor cells
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cancer immunoediting
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the effects of the immune system in preventing tumor formation and in sculpting the immunogenic properties of tumors to select tumors that escape immune elimination
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evidence of tumor immunity
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lymphocytic infiltrates around tumors and in lymph nodes draining sites of cancer
experiments with transplanted tumors increased incidence of certain cancers in immunodeficient individuals demonstration of tumor-specific T cells and antibodies in patients |
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tumor antigens
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2 classes:
tumor specific: present only on tumor cells tumor associated: present on tumor and normal cells |
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studies on tumor antigens
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early studies: monoclonal antibodies specific for tumor cells
techniques for identifying tumor antigens based on recognition by cytotoxic T lymphocytes |
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principle antitumor effector mechanism
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killing of tumor cells by CD8 CTLs
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cellular effectors that mediate immunity
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cytotoxic T lymphocytes
NK cells macrophages antibodies |
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strongest argument for the existence of immune surveillance
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increased frequency of cancers in immunodeficient hosts
most are lymphomas, often immunoblastic B cell lymphomas |
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ways tumor cells evade the immune system of immunocompetent hosts
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1. selective outgrowth of antigen negative variants
2. loss or reduced expression of MHC molecules 3. lack of costimulation 4. immunosuppression 5. antigen masking 6. apoptosis of cytotoxic T cells |
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factors to consider in tumors
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effects on host
grading and clinical staging lab diagnosis of neoplasm |
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neoplasia may cause problems due to:
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1. location and impingement on adjacent structures
2. functional activity such as hormonal synthesis 3. bleeding and secondary infections 4. initiation of acute symptoms caused by rupture or infarction |
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paraneoplastic syndromes
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symptom complexes in patients with cancers that cannot be readily explained by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue
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Why is recognizing paraneoplastic syndromes important?
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1. may represent the earliest manifestation of an occult neoplasm
2. may represent clinical problems 3. may mimic metastatic disease and confound treatment |
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prognosis of a cancer is based on
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the efficacy of cancer treatment for a particular type of cancer
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Grading of cancer
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based on degree of differentiation of the tumor cells and the number of mitoses
presumed to correlate with neoplasm's aggressiveness grade 1-4 with increasing anaplasia |
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staging of cancers
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based on:
-the size of the primary lesion -the extend of spread to regional lymph nodes -and the presence or absense of blood-borne metastases |
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2 major staging systems
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union internationale contre cancer
american joint committee on cancer staging |
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Union internationale conre cancer staging system
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T: primary tumor (T0: in situ lesion)
N: regional lymph node involvement (No: no nodal involvement, N1-N3 increasing) M: metastases (Mo: no distant metastases, M1-M3 blood borne metastases) |
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american joint committee staging of cancer
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stages 0-4
based on: size of primary lesion presence of nodal spread and distant metastases |
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importance of staging
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select the best form of therapy
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staging or grading which is better?
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staging
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laboratory diagnosis of cancer using histologic and cytologic methods:
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excision or biopsy
needle aspiration cytologic smears remember that in a large mass the margins may not be representative and the center may be necrotic |
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"quick frozen section"
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used to evaluate margins to be sure entire neoplasm has been removed
evaluate within minutes |
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fine needle aspiration of tumors
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aspirate cells and examine stained smear
used in assessment of readily palpable lesions (breast, thyroid, lymph nodes) faster and less invasive than needle biopsies |
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immunohistochemistry
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use of monocolonal antibodies to ID cell products and surface markers
used to: categorize undifferentiated malignant tumors, leukemias, lymphomas determine site of origin of metastatic tumors detect molecules with prognostic or therapeutic significance |
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Flow cytometry
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used to rapidly and quantitatively measure individual cell characteristics (like DNA content)
ID surface antigens |
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tumor markers
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biochemical indicators of the presence of a tumor
include: cell surface antigens, cytoplasmic proteins, enzymes, hormones definition clinically: a molecule that can be detected in plasma or other body fluids used to support the diagnosis used to determine the response to therapy and in indicating relapse |
