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237 Cards in this Set
- Front
- Back
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What demographic of people leads the cancer mortality rates in the US as well as in WV?
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black males
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What is the average cancer mortality rate in WV?
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152-159.5 per 100,000 people
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What 3 cities were found with the highest cancer mortality rate in the US by city for men?
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beckley, wv : 16th
huntington, WV : 29th Martinsburg, WV: 48th |
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What were the 3 cities out of the top 50 in female cancer mortality rates in WV?
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wheeling, WV: 14th
martinsburg, WV: 38 Beckley, WV: 43 |
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What is a really high cancer mortality found specifically in appalachia?
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cerival cancer
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What can contribute to the high rates of lung cancer in WV?
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high rates of smoking:
youth: -use overall: 28.% in WV, 4th highest -Female: 31.4%, 2nd highest -Males: 25.6% 9th highest Adults: -Overall: 27.4 %: 2nd highest -Females: 27.3 % 2nd highest -Males: 27.6% 13th highest |
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carcinoma -
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epithelial cells: organs, skin: renal, breast, lung
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sarcoma -
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derived from mesenchymal cells: CT, muscles, hematopoietic, vasculature
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Teratoma -
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derived from germ cells
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What are the 4 molecular markers of cancer?
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-molecular, biochemical and cellular changes associated with cancer
-call shapes -changes in gene signatures or chromosomal changes -changes in the expression pattern of proteins |
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What are the laboratory diagnosis options for malignancy?
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surgical removal - then testing
fine needle aspirates IHC, cytology, morphology/phenotype, electron microscopy |
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Where does endometrial stromal sarcoma metastisize to and how can you diagnose this?
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to lung from uterus, neoplastic cells are oval, high nucleocytoplasmic ratio and have nuclei with a moderate amout of heterochromatin and prominent nucleoli. Mitochondia are the main cytoplasmic organelle in some cells, so you can diagonose this via electron microscopy
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How can you tissue type of cancer be determined based on differentiation?
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well differentiated tumors resemble identifiable tissue types
poorly differentiatied tumors may only be identificable by the expression of cell markers or by extremely focal and subtle histologic and/or cytologic findings |
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What information does the differentiation state of the cancer give you?
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-helps determine origin of the disease
-prognosis: well differentiated often has better prognosis than poorly differentiated tumors -treatment specific |
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anaplasia -
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loss of differentiation
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immunocytochemisty -
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antibodies directed against antigens found in specific tumors types can be used to help diagnose poorly differentiated tumors
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What are used as serum tumor markers? and list 3 specific one:
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cell surface antigens, cytoplasmic proteins, enzymes and hormones which indicate the presence of tumor. A tumor marker is measured in serum or other body fluid in the clinical laboratory, often utilizing immunoassays.
prostate specific antigen: PSA Carcinoembryonic antigen (CEA) Ca-125 |
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What is PSA and how is it used?
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a serine protease produced by normal as well as neoplastic prostate epithelium. In normal men, only small amounts circulate in the serum. Elevated blood levels are associated with prostatic cancer. Benign conditions such as prostatic hyperplasia can also raise the serum PSA level, but to a lesser degree.
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What is carcinoembryonic antigen? and how is it used?
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a complex glycoprotein that is normally produced in embryonic tissue of the gut, pancreas, and liver. It is elevated in some colorectal and pancreatic neoplasms. Increased serum levels can also sometimes be present in patients with gastric and breast cancer. Non neoplastic causes of increased serum CEA include smoking, alcoholic cirrhosis, and ulcerative colitis
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What is Ca-125 and how is it used?
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a glycoprotein expressed by coelomic opithelium during fetal development. Increased serum levels can be presetn in patients with ovarian cancer. Other malignancies such as pancreatic carcinoma may also have increased leveles. Non malignant causes of high serum Ca125 include pregnancy, endometriosis, and liver failure.
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What all can flow cytometry tell us about malignancy? (3 specific examples)
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the classification of leukemias and lymphomas is based on cell surface antigens which can be easily identified by flow cytometry
DNA ploidy appears to correlate with prognosis in a variety of tumors In general, aneuploidy seems to be associated with a poorer prognosis in early-stage breast cancer, bladder, lung, colorectal, and prostate cancer |
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What is a terminal end bud and how does it relate to breast cancer?
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TEB's are sites of rapid elongation, normal cell proliferation with, cap cells differentiating into myoepithelial cells which serve as a barrier, and body cells will differentiate into epithelial cells in the lumen
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What are the breast cancer progression steps?
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normal breast --> atypical hyperplasia (lobular or ductal) --> carcinoma In Situ (DCIS or LCIS): stage 1-4- Comedo --> invasive breast cancer --> metastatic breast cancer
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What are the unusual hyperplasia's seen in breast cancer?
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mitotic activity decreases as the cells move away form the basal lamina, cells show an aligned polarity. Myoepithelial cells are present
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What is benign hyperplasia?
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there is no net increase in ductur cells compared to the other cell types of their environment, but myoepithelial cells are slightly active and there is a 2x risk for progression to IBC (invasive)
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What characterises dysplasia?
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aypical proliferation of cells, characterized by nuclear enlargement and failure of maturation and differentiation, short of malignancy
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What is carcinoma in situ? carcinoma in situ breast cancer description, and what is the prognosis of this?
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full thickness dysplasia extending from the basement membrane to the surface of the epithelium.
ductal cells appear uniformly mitotic throughout, loss of cellular alignment or orientation, apparent decrease or absence of myoepithelial cells 10x risk for progression to IBC |
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Atypical hyperplasia is? and atypical hyperplasia in breast cancer is? and what is the prognosis of this?
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increased evidence for mitotic cells, cell growth is aligned along an axis
4x risk for progression to IBC |
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Describe invasive breast cancer:
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ductal cells are all invasive and show a ragged contour without an organized concentric wrap of extracellular matrix around them.
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What is desmoplasia?
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the change that occurs in the stroma as tumor invades, refers to the stroma composed of CT and blood vessels that surround the infiltrating tumor. The spindle shaped cells that make up the desmoplasia are not themselves neoplastic. Desmoplasia is a response to invasion of tissue by malignant tumor cells
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What does loss of structure mean?
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as tumors become lessa nd less differentiate, they resemble the tissue of origin less and less.
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What are some examples of new strucutes that some tumors have?
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cribriform: gland structures found in colon, endometrium cancers
papillary structures: also gland structures found in thyroid or bladder Herringbone arrangements found in saccomas |
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When does necrosis happen in malignancy?
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when the tumor out grows its blood supply
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What are the 3 main gross features of malignancy?
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-irregular borders
-necrosis -metastasis |
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What is a hallmark of transformation in cancer cells?
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disruption of actin filaments
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What is the pattern of cytology that happens in cancer?
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epithelial to mesenchymal transition
atypical hyperplasia --> cancer in situ --> invasive |
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What is a normal cell to cell communication?
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epithelial cells are attached to each other by adheren junctions, which contain E-cadherin, E-cadherens proteins traverse the cell membrane andinteract with each other like velcro
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What is seeding of the body caviditesa nd surfaces?
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when a malignant neoplasms penetrates into a natural "open field" such as peritoneal cavity, pleural space, pericardial cavity, ect. Most common examples: ovarian carcinoma, and mucin secreting ovarian and appendiceal carcinoma (pseudomyxoca peritonei)
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What is lymphatic spread?
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most common pathway for dissemination of carcinomas, (although sarcomas can also use this route), follows natrual drainage
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What is hematogenous spread?
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pathway is typical of sarcomas. Arteries are more difficult for tumor to penetrate than veins. With venous invasion, the blood-borne cells follow the venous flow draining the site of the tumor. Liver and lungs are frequently involved.
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What are the normal steps of progression for cancer?
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1. genetically altered cell (loosing cell cycle control)
2. hyperplasia 3. dysplasia 4. in situ cancer 5. invasive cancer 6. metastasis |
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Where does melanoma usually spread?
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to the lungs
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Where does prostate cancer usually spread?
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to the bone
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Where does colon cancer usually spread?
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liver and pancreas
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What usually is necessary for metastatic cell survival?
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there is some type of angiogenesis, in which the metastatic cells can feed themselves
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What are the three main underlying factors that cause breast cancer?
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-oncogenes in breast cancer
-changes in breast cancer cell membranes -inappropriate signals in breast cancer |
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How do we detect molecular changes associated with cancer progression?
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1. chromosomal analysis (FISH)
2. Laser captured microdissection (LCM) 3. DNA microarray 4. Proteomics |
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What is a cardinal example of a cancer that we use FISH techniques to diagnose?
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Chromosomal changes in Gastrointestinal Cancers
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How does Laser Captured Microdissection occur?
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LCM system is an inverted microscope fitted with a low-power near-infrared laser. Tissue sections are mounted on standard glass slides, and a transparent, 100-mm-thick, ethylene- vinyl acetate film is then placed over the dry sections.
The laser provides enough energy to transiently melt this thermoplastic film in a precise location, binding it to the targeted cells. The laser diameter can be adjusted from 7.5 to 30 micrometers so that the individual cells or cluster of cells can be selected. the cells are pulled from a tissue sample by directing the laser through the transfer film, as other cells are desired the gladd slide can be moved and the laser targeted to hit the new cells, the laser attaches the cells to the transfer filmd, and they are sipmly lifted from the main tissue for further analysis |
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What are the steps in DNA microarray?
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1. probe: cDNA/oligo with known identity
2. chip fabrication : putting probes on the chip 3. Target: fluorecently labeled sample 4. assay: hybridization, long, short, ligase, base addition, electric mS, electrophoresis, fluocytometry, PCR-direct, tagMan 5. Readout: fluorescence or probeless: conductance, MS electrophoresis, or electronics 6. Informatics: robotics control, image processing, DBMS, WWW bioinformatics, data mining and visualization |
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What are proteomics?
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indentification of proteins in a sample, uses mass spectrometry methods:
-idenfification achieved by "time of flight" -mixtures can be identified -purified proteins can be isolated and identified |
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What are the two types of mass spectrometers?
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MALDI and LC/MS-MS (ion trap)
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How does a second Dimension (SDS-Page) work?
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1. equilibrate strip in SDS and DTT
2. place strip at the top of the gel (cathode) 3. apply electric field (negatively charged proteins move towards anode) 4. proteins move depending on size (smallest move the fastest so they are at the bottom of the gel) |
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What does it mean if a protein is modified and appears twice on a gel?
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sign that the protein may be activated, excision and identification by mass spectrometry verify this
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How is a protein spot removed from a gel/
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using robotic arms: the protein eluted and identified by mass spectrometry (determine amino acid sequence), the predicted sequences are sent to bioinformatic databases for identification.
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What are some signals that promote breast cancer progression? found molecularly
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increase in allelic impairments (LOH):
-50% of hyperplasia's indicate some LOH ->90% of DCIS demonstrate LOH DNA microarray studies -indicate significant changes in mRNA profiles between normal and hyperplasia tissue, but changes are less prevalent when comparing hyperplasia with CIS or IBC -proteomic analyses are in agreement with DNA microarray studies -these studies support a hypothesis that predicts the clonal nature of breast cancer during progression -givent he known LOH changes that occur during progression, it is likely that microarray and proteomics are not yet sensitive enough to routinely identify changes that occur during progression |
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What are some signals that promote breast cancer progression when found cellularly?
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survival when invasive cells separate from the tumor mass
-increased resistance to apoptosis or anoikis increased motility -ability to form motility structures such as lamellipodia, filopodia, membrane ruffles -ability to relax the constraints of the actin-based cytoskeleton -ability to activate signals that regulate focal adhesion/contacts increased invasive potential -ability to form podosomes or invadopodia -upregulate activity of cell surface proteases |
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What signals promote progression to invasive breast cancer, enzymatically?
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activation of kinase signaling cascades
-receptors tyrosine kinases: ErbB2, EGFr, cMet, VEGFr family -nonreceptor kinases: Fak, Src, PKC -angiogenesis pathways: PI3K, --> Akt --> Hif1 --> VEGF Tumor microenvironment changes: -loss of cell-cell tumor suppressor signals -loss of TGFbeta from the stroma |
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genomic instability -
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acquisition of genetic changes over time
-the damage must be non-lethal and lead to transformation but not to cell death |
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Haploinsufficiency -
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one functional allele is not enough; two alleles required for normal function. One mutated allele will cause transformation
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what does generations of subclones lead to in malignant transformation?
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tumors that are mixed are more likely to survive selection pressure
therapy resistance |
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What does oncogene activation lead to?
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lack of requirement for growth signals, grow independently of soluble GFs or extracellular matrix,
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What usually causes an evasion of apoptosis?
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inactivation of the tumor suppressor p53
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What do proto-oncogenes do?
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unmutated oncogene, normal gene
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Oncoprotein -
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protein product of an oncogene, produced independently of external stimulation, similar to proto-oncoproteins, but may lack regulatory regions
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what are autocrine loops?
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many cancer cells are able to produce the growth factors to which they are responsive
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What is Flt3 associated with in cancer?
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this is a GF receptor found in myeloid leukemia as a prognosis factor
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What is EGF-receptor 1 associated with in cancers?
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colon, squamous cell carcinoma of lung, gliomas cancer of the head and neck, breast, or pancreas cancer, this is a prognostic marker and a target therapy
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What is EGF-receptor 2 associated with in cancer?
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breast cancer (targeted treatment - monoclonal antibodies), also found in adenocarcinomas in ovary, lung, stomach, and salivary glands
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What is KIT, PDGFR associated with in cancer?
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GIST targeted treatment (gastrointestinal stromal tumors)
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What is ABL's association with cancer?
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found in CML: chronic myeloid leukemia, and acute lymphoma leukemia
-works in signal transduction pathway |
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What is BRAF associated with in cancer?
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colon, melanomas (diagnostic), works in signal transduction pathway
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What is C-MYC associated with in cancer?
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burkitt lymphoma,
signal transduction pathway |
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What is N-MYC, L-MYC associated with in cancer?
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lung carcinoma (small cell), and neuroblastoma (N-MYC)
signal transduction pathway |
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What is cyclin D associated with in cancer?
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mantle cell lymphoma
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What is the most common known oncogene in human tumors?
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RAS family : KRAS, NRAS, and HRAS found in 20% of tumors
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What are the RAS modulating type cancers?
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adenocarcinomas and cholangiocarcinoma, colon cancer, endometrial, and thryroid cancers, adenocarcinomas and myeloid leukemias
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What is the mutation found in Neurofibromin 1?
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GAP: GTPase-activating protein: accelerates the conversion of GTP-bound, active RAS to the CGP-bound, inactive form,
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What are you at increased risk of getting if you have already been diagnoses with plexiform neurofibromas?
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increased risk of GIST and breast cancer
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What affect does KRAS have on cetuixmab?
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significantly decreases responses to cetuximad in advanced colon cancer, which cetuximad is a monoclonal antibody directed against EGFR
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How does BRAF related to cetuixmab?
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presence of BRAF mutation predicts no response to cetuximab, BRAF usually found in papillary thyroid carcinomas and melanomas
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What specific therapy is used to treat patients with BCR-ABL?
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Imatinib mesylate (gleevec) preotein tyrosine kinase inhibitor inhibits by binding to active site
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What causes Imatinib resistance?
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due to mutations in the fusion molecule
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What mutation is found in polycythemia vera, essential thrombocytosis, and myelofibrosis?
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highly associated with activating point mutation in the tyrosine kinase JAK2, making constitutivelyactive JAK2 kinase which activated STAT transcription factor, that promotes growth factor independent proliferation
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How does proto-oncogene MYC work?
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immediate early response gene, that undergoes a short burst of transcription of MYC when quiescent cells recieve a signal to divide, target genes include Cyclin D2
-leading to modulation of histone acetylation, reduced cell adhesion, increased cell motility, increased telomerase activity, increased protein synthesis, decreased proteinase activity |
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Where is N-MYC usually found?
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on chromosome 2p,
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What diagnostic feature is present in N-MYC neuroblastoma?
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gene becomes amplified and is seen either as extra chromosomal double minutes or as a chromosomally integrated, homogenous staining region (HSR) which can often involve other autosomes, such as 4, 9, or 13.
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Cyclin D is overexpressed in what cancer types?
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breast, esophagus, liver, and subset of lyphomas
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What is amplification of CDK4 gene found in?
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melanomas, sarcomas, and glioblastomas
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What are the 4 key regulators of the cell cycle that often undergo dysregulation and cause cancer?
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p16/INK4a, cyclin D, CDK4, RB (retinoblastoma protein)
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How is retinoblastoma inherited? and what type of cancer does it often cause?
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autosomal dominant trait --> increased risk for sarcomas
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What does RB protein do?
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cell cycle regulator:
-quiescent cells - active hypophosphorylated state --> RB protein complexing with E2F transcription factors, binds to DNA, recruits chromatin-remodeling factors (Histone deacetylases and histone methyltransferases, and inhibits transcription of genes whose products are required for the S phase of the cell cycle) -G1/S cell cycle transition - inactive hyperphosphorylated state (when RB is phosphorylated by the cyclin D-CDK4, and cyclin E -in G1, signals are integrated to determine whether the cell should enter the cell cycle, exit the cell cycle and differentiate, or die -RB is a key node in this decision process |
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How does HPV and other DNA viruses act?
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binding to RB prtoein and neutralizing it
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What is Knudson's "two-hit" hypothesis?
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pathogenesis of retinoblastoma, two mutations of the RB locus on chromosome 13q14 lead to neoplastic proliferation of the retinal cells.
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What is the difference between sporadic and familiar forms of retinolastoma?
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sporadic: both mutations at the RB locus are acquired by the retinal cells after birth
familial: one mutant RB gene from carrier and then the second mutation affects the RB locus in one of the retinal cells after birth (this is termed loss of hererozygosity - becoming homozygous at the RB locus) |
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Li-Fraumeni syndrome is?
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inherited mutation in p53 --> 25x greater chance of developing a malignant tumor by age 50 than general population
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How does p53 work normally?
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activation of p53 occurs by DNA-damaging agents or by hypoxia leading to cell cycle arrest in G1 and induction of DNA repair, by transciptional up-regulation of the cyclin-dependent kinase inhibitor CDKN1A and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence.
-p53 specifically mediates gene repression by activating transcription of mir34 family of miRNAs, this suppresses translation of both proliferative genes, such as cyclins, and anti-apoptotic genes, such as BCL2. |
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What are key initiators of the DNA-damage pathway?
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-ATM (ataxia-telangiectasia mutated)
-ATR (ataxia-telangiectasia and Rad3 related) |
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What role does p21 play in the cell cycle pathway?
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causes pausing of the cell cycle in late G1:
-inhibits cyclin-CDK complexes and phosphorylation of RB, thereby preventing cells from entering G1 phase -this is mainly by p53-dependent transcription of CDKN1A --> p21 |
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What specifically happens if the during the late G1 phase pause the repair is not successful?
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p53 upregulates MDM2, which will induce apoptosis or senescence
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What specifically does p53 do to induce apoptosis?
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pro-apoptotic genes including BAX and PUMA
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What specifically does HPV contain to cause cancer?
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E6 protein that will bind to and promote the degradation of p53
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What does sensitivity to irradiation and chemotherapy depend on?
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whether the tumor contains normal or mutated p53: these treatments mediate their effects by inducing DNA damage and subsequent apoptosis, tumors that retain normal p53 are more likely to repond
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What does APC (adenomatous polyposis coli) do?
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tumor suppressor, down regulates growth-promoting signals
-regulates the stability and function of Beta-catenin: resting cells Beta-catenin is complexed with APC which leads to degradation by ubiquitination -APC and Beta-catenin are components of the WNT signaling pathway following WNT stimulation the APC/beta-catenin complex is dissolved and Beta-catenin levels increase -beta-catenin translocated to the nucleus where it up-regulates proliferation by c-MYC, cyclin D1, ect -without APC cells proliferate as if they are under continuous WNT signaling |
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What is FAP?
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familial adenomatous polyposis -
-germline mutation at the APC (5q21) locus -all individuals born with one mutant allele develop thousands of adenomatous polyps in the colon during their teens or 20s -both copies of the APC gene must be lost for tumor formation -most sporadic colorectal carcinomas and adenomas also show homozygous loss of the APC gene |
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How does Beta catenin work? and what happens when it is lost?
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binds to the cytoplasmic tail of E-cadherin, a cell surface protein that maintains intercellular adhesiveness
-loss of cell-cell contact disrupts the interaction between E-cadherin and Beta-catenin, and allows beta-catenin to travel to the nucleus and stimulate proliferation |
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What does reduced cell surface expression of E-ccadherin do?
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will cause a loss of contact inhibition, and will allow Beta-catenin to travel to the nucleus and stimulate proliferation of the cell --> esophagus, colon, breast, ovary, and prostate cancer
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What does the INK4a/ARF gene code for?
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encodes two proteins:
-p16/INK4a -p14/ARF |
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What does the p16/INK4a protein do?
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maintains activity fo the RB checkpoint, blocks cyclin D/CDK2-mediated phosphorylation of RB
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What does p14/ARF protein do?
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-acivates the p53 pathway --> binds to and inhibits MDM2 which prevents its destruction of p53
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What does TGF-beta pathway do regarding cancer?
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dual function
inhibits proliferation in normal cells: -represses c-MYC -activates RB Promotes immune system suppression and angiogenesis so, net action, may be prevention or promotion of tumor growth depending on where the pathway is interrupted and the state of other genes in the cell |
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What is PTEN stand for and what does it do?
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phosphatase and tensin homologue:
-upregulates pro-growth PI3K/AKT signaling,both of which promote cell survival , a mutation here is common in cancer but not sufficient to induce tumor formation |
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What is Cowden Syndrome?
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autosomal dominant, germline mutation in PTEN
causes benign tumors: hamartomas - skin, mucosa, and internal organs malignant tumors: breast endometrium, thyoid macrocephaly mucocutaneous lesions, |
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What causes Tuberous Sclerosis? and what happens in this?
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mutations in TSC1 or TSC2
skin: hypomelanotic macules, facial angiofibromas, shagreen pathces, fibrous facial plaques, ungual fibromas brain: cortical tubers, subepependymal nodules, CNS tumors, seizures developmental delay kidney - cysts, angiomyolipomas heart - rhabdomyomas, arrhythmias |
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How do PI3K/AKT pathways play a role in Tuberous sclerosis?
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AKT inactivates the TSC1/TSC2 complex.
This unleashes the activity of mTOR (mammalian target of rapamycin) mTOR stimulates uptakes of nutrients needed for growth |
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What is the mutation for Neurofibromin 2? and what kind of gene is this?
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merlin 22q
-tumor suppressor gene |
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What is the pathology of neurofibrmatosis?
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meningiomas and ependymomas somatic mutations --> cells cannot establish stable cell-cell junctions and are insensitive to normal growth arrest signals generated by cell-cell contact
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Where is VHL found on the chromosome? and how does it normally work? and what happens if mutated?
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found on 3p
oxygenated tissues - HIF1alpha is hydroxylated and binds to the VHL protein, leading to ubiquitination/degradation, ischemic tissue - HIF1alpha is not hydroxylated, does not bind to VHL and VHL is not degraded, but activates gene involved in angiogenesis (VEGF, PFGF) -mutations in VHL prevent binding of HIF1alpha and has the same effect as ischemia (stimulation of angiogenesis) |
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Where is WT1 found and what is it's normal function?
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11p13
regulates kidney development, |
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What is Wilms tumor caused by and what is the pathology?
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germline/acquired mutation in WT1 causing pediatric kidney cancer
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How does a WT1 have oncogene effects in adults?
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will cause leukemias, breast, and these organs do not normally express WT1
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What What do PTCH1 and PTCH2 endoce? and what does this do? what happens if there is a mutation/loss here?
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cell membrane protein PATCHED
-the hedgehog/PATCHED pathway regulates TGF-beta, PDGFRA, PDGFRB pathways can cause basal cell carcinoma : Gorlin syndrome Gorlin syndrome: Jaw keratocysts, dysmorphic features and skeletal anomalies, children can develop medulloblastoma |
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What does overexpression of BCL2 cause?
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this is an example of overexpression of an apoptotic inhibitor leading to evasion of apoptosis
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What does reduced levels of component proteins CD95/Fas lead to?
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high levels of FLIP: binds death inducing signaling complex, preventing activation of caspase 8, so evasion of apoptosis
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What is responsible for limitless replicative potential?
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upregulation of telomerase
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What is the maximal size of a tumor without vascularization?
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1-2 mm in diameter
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How does p53 play a role in angiogenesis?
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can stimulate expression of anti-angiogenic molecules and repress expression of pro-angiogenic molecules such as VEGF
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What role does a mutation in RAS or MYC do regarding angiogenesis?
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up-regulates VEGF
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What happens that allows for invasion of cancer?
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Invasion:
-reduced adhesiveness of tumor cells leads to detachment -proteolytic gradation of basement membrane -binding to preoteolytically generated binding sites within the basement membrane is followed by tumor cell migration |
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What are some changes in cell=cell interaction that can lead to cancer?
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cell-cell interactions are mediated by cadherins: so downregulation of E-cadherin facilitates cell detachment,
Catenins are necessary for normal E-cadherin function, so any mutation here can lead to invasion normal integrin receptors bind laminin and collagen in BM and maintain normal cells in a resting, differentiated state, but with mutation cells can detach and evade apoptosis |
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What causes a local degradation of BM and what else does this lead to?
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tumor and stroma secrete proteolytic enzymes that break down the BM, this then can trigger angiogenic, and growth=promoting effects
MMP's cleave collagen (collagenase IV) and stimulates release of VEGF from ECM-sequestered pools |
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How does migration of tumor cells work?
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binding of tumor cells to novel sites created by cleavage stimulates migration
locomotion of tumor cells thorugh the degraded BM ameboid migration- tumor cells can actively squeeze through spaces in the matrix |
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What do tumor cells do to protect themselves in the vascular from all the sheer force?
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platelet-tumor aggregates in the circulation may enhance tumor cell survival and implantabliity
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WHere does most metastasis occur?
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in the first capillary bed available to the tumor
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What is organ tropism?
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preferential metastasis to specific tissuesm related to:
-specific adhesion molecules on tumors that match ligands on the endo cells of the target organ -tissue specific expression of chemokines that match receptors expressed by tumor cells -chemokine receptors expressed by tumor cells that bind to receptors in certain tissues |
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What molecular qualities do cancer's have that cause metastasis development? (3)
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greatly influenced by the tumor stroma: regulates angiogenesis, local invasiveness, and resistance to immune response
microRNA's may play a role in promotion/suppression of metastasis SNAIL and TWIST are candidate metastasis oncogenes which downregulate E-cadherin expression |
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What is the defect that causes Hereditary Nonpolyposis Colon Cancer syndrome?
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defects in mismatch repair genes: MLH1, MSH2, proofreaders of replicated DNA, prevent accumulation of errors/mutations
each individual inherits one defective and acquires the second hit "microsatellite instability" --> hallmark of this disease, variability in length of repeats regions in the genome caused by insufficient proofreading during replication |
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What is the defect in Xeroderma Pigmentosum? and what does this cause?
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repair by the nucleotide excision repair system is nor functional, increased risk for skin cancer, particularly follwoinge xposure to UV light, can't fix the cross-linking of pyrimidine residues,
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What 3 syndromes are caused by a defect in DNA repair by homologous recombinatioN?
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blood syndrome (hypersensitivity to ionizing radiation
ataxia telangiectasia: hypersensitivity to ionizing radiation fanconi anemia: hypersensitivity to DNA cross-linking agents |
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What is the Warburg Effect?
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cancer cells shift their glucose metabolism to aerobic glycolysis
this is how we use PET to visualize tumors, use labeled glucose |
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What 2 ways can translocation cause cancer?
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exposure of a proto-oncogene to a regulatory element of another gene, leading to overexpression of the proto-oncogene
formation of fusion genes composed of sequences from two different chromosomes, these might promote survival |
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What are chromosomal deletions most commonly found in? and what are they associated with?
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solid tumors, associated with the loss of particular tumor suppressor genes
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What three cancer's is gene amplification the cause of?
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N-MYC amplified in 30% of neuroblastomas
ERBB2 amplified in 2-% of breast cancers MYC amplification in small-cell cancer of the lung |
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What are the 4 epigenetic changes that can cause cancer?
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reversible, heritable changes in gene expression that occur without mutations/structural change of the basepairs in DNA
tumor suppressor genes may be silences by hypermethylation of promoter sequences loss of imprinting |
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What two roles do miRNA's play in cancer?
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miRNAs that inhibit translation of an oncogene gives rise to an excess of oncoproteins.
of overactivity of a miRNA that targets a tumor suppression gene reduces the production of the tumor suppressor protein. |
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What is the molecular model for the evolution of colorectal cancers through the adenoma=carcinoma sequence?
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APC mutation at 5q21 (germilne) --> methylation abnormalities inactivation of normal alleles (APC beta-caterin) --> proto-oncogene mutation: KRAS at 12p12 -->
wild type p53 --> oncogene-induced senescence and just polyp formation homozygous loss of additional cancer suppressor genes p53 or overexpression of COX-2 --> additional mutations gross chromosomal alteration |
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what was epithelioma of the scrotum attributed to?
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chimney sweepers from chronic exposure to soot
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What is the difference between direct initiation and indirect initiation of cancer?
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direct acting - do not require metabolic conversion to become carcinogenic
indirect acting - require metabolic conversion: benzopyrene in tobacco smoke, and polycyclic hydrocarbons in broiled and smoked meats and fish |
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What are the characteristics of promoters influence on cancer?
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changes do not affect DNA directly
changes are reversible capably of inducing tumors in initiated cells but not tumorigenic by themselves |
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How do carcinogens cause cancer, what is the sequence of events?
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carcinogen binds to DNA and adducts formation of DNA --> cell can die, repair, or have permanent DNA lesion which is called the initiated cell -->
cell proliferation: altered differentiation due to lesion, and promoter region influence --> preneoplastic clone: --> proliferation AND additional mutations --> malignant neoplasm |
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What makes CYP1A1 associated with significantly higher risk for lung cancer?
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highly inducible for of p-450
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What can Aflatoxin B1 cause? and how does it cause it ?
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-food contaminant
-associated with hepatocellular carcinoma -produces characteristic "signature" mutation in p53 |
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What are the elements of radiation carcionogenesis?
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UV rays --skin cancer
Ionizing electromagnetic (X-rays and gamma rays) Particulate (alpha particles, beta particles, protons, neutrons) -both electromagnetics and particulates have been shown to cause ALL, CML, thyroid, breast, lung, and salivary gland cancers |
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What are oncogenic DNA viruses?
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HPV
Epstein Barr virus Hepatits B virus Kaposi sarcoma herpesvirus Human T-cell Leukemia Virus Type 1 |
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What is Human T cell leukemia virus type 1?
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transmitted via sexual contact, blood products, or breastfeeding
virus has tropism for CD4 T cells, integrates into genome, tax protein activates transcription of host genes involved in proliferation, tax also interferes with DNA-repair functions increases genomic instability allows accumulation of mutations monoclonal neoplastic T cell population emerges |
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What two proteins are involved in the HPV cancer lineage?
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E6 blocks p53
and E7 blocks p21, p53, and RB-E2F, which are all apoptotic proteins, so downregulation of apoptotics will lead to evasion of apoptosis |
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What are the low risk HPV's?
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types 6 and 11 genital warts with low malignant potential, non integrated episomal form
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What are the High risk HPV's?
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type 16 and 18:
-squamous cell carcinoma of the cervix:oropharyngeal cancers -HPV genome integrated into host genome: integration leads to overexpression of oncoproteins E6 and E7 apolymorphism in p53 determines susceptibility to degradation by E6 and likelihood of developing cancer HPV infections itself is not suficient for carcinogenesis: environmental factors: cigarette smoking, coexicting mivrobial infections, dietary deficiencies, hormonal changes |
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What type of cancers does Epstein Barr Virus cause?
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B-cell lymphomas
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How does Epstein Barr Virus cause cancer?
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not directly oncogenic, facilitates acquisition of t(8;14), different mechanisms in different tumor types, attaches to Bcells trhough CD21 receptor
-viral LMP-1 and EBNA-2 act as oncogenes: expressed in some but not all EBV cancers -in normal individuals EBV infection leads to self-limited polyclonal B cell proliferation: infectious mononucleosis |
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How does Hepatitis B virus cause cancer?
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mechanism most likely related to chronic inflammation with loss of hepatocytes leading to regeneration and genomix damage:
-activated immune cells activate the NF-kappaB pathway in hepatocytes -block of apoptosis, allows the dividing hepatocytes to incur genotoxic stress and accumulate mutations -maladaptive immune response may promote tumor development |
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How does Helicobacter pylori cause cancer?
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H. pylori stimulates chronic inflammation and polyclonal B cell proliferation, some b cells acquire mutations that give a growth advatnage and form a monoclonal tumor,
dependent on Tcell stimulation causes lympohmas of mucoasa associated lymphoic tissue |
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How do you get rid of Helicobacter pylori induced cancer?
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eradication by antibiotics cures the lymphoma by removing antigenic stimulus for T cells:
-but if other mutations occurs in the meantime this might not stop the cancer, T cell stimulation of NF-kappaB no longer required --> -gastric adenocarcinomas |
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What mediates immune system suveillance/defense against tumors?
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CD9 T cells
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What make up tumor antigens that CD8 T cell will recognize?
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proteins derived from mutated genes are foreign to the body - may enter the class I MHC process, or may endter the class II following phagocytosis of the tumor cell
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What cancer is Tyrosinase expression indicative of?
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exclusively expressed in melanocytes and melanomas -- specifically the peptides derived from tyrosinase are rexognized as foreign by T cells from melanoma patients
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How do vaccines against HPV work?
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the proteins produced by oncogenic viruses are recognized by cytotoxic T cells,
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What are two oncofetal antigens? and what are oncofetal antigens?
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proteins epressed at high levels on cancer cellsa nd in fetal tissues, markers currently used in tumor diagnosis:
-CEA carcinoembryonic antigen -alpha-fetoprotein |
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How do glycolipids and glycoproteins play a role in cancer?
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overexpression and or abnormal variatns can be used as diagnostic markers, with potential targets for therapy
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What are the cells involved in the cell-mediated antitumor mechanism?
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-cytotoxic T lymphocytes
-Natural Killer cells -macrophages |
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What are the mechanisms by which tumor cells may escape ummunosurveillance?
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-selection of antigen-negative variants
-loss or reduced expression of MHC molecules -lack of expression of co-stimulatory molecules necessary for sensitization of T cells -immunosuppression -oncogenic tumor products: TGF-beta -antigen masking (overexpression of glycocalyx) -apoptosis of cytotoxic T cells (melanomas, hepatocellular carcinomas may induce apoptosis through FasL) |
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What are the mechanisms by which the immune system may promote tumor formation?
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growth factors produced by activated lymphocytes and macrophages
-suppression of host response to tumors by T cells -production of enzymes that stimulates tumor invasion (MMPs) |
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What are 7 critical features common to different cancers?
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-they stimulate their own growth
-they ignore growth-inhibiting signals -they avoid death by apoptosis -they develop a blood supply: angiogenesis -they leave their site of origin to invade other tissues: metastasis -they replicate continuously to expand their numbers -they evade or outrun the immune response |
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What are tumor rejection antigens?
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specific to individual tumors and prevent infectious transfer of tumors from one individual to another, could be used to treat cancer
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What are tumor specific antigens?
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can arise by expression of peptides from mutated cellular proteins, will be recognized as a foreign body
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What are tumor associated antigens?
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can arise by reactivation of embryonic genes, or by over expression of normal self proteins, will elicit an immune response
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What are some known tumor antigens recognized by CD8 CTLs?
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embryonic expression of: MAGE-1 and MAGE-3, normal testicular proteins found in melanoma, breast, and glioma
Abnormal MUC-1 underglycosylated mucin found in breast and pancreas cancer differentiation components Tyrosinase found in melanoma and surface immunoglobulin a specific immunoglobulin after gene rearrangements in B cell clone found in lymphoma mutated oncogenes: cyclin dependent kinase 4 - melanoma, beta-catenin-Melanoma, Caspase-8 - squamous cell carcinoma oncoviral protein: HPV type 16: E6 and E7 proteins: viral transofrming gene products, found in cervical carcionoma |
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What is the cutting and pasting affect of tumor antigens?
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some tumor antigens arise through the cutting and pasting of peptides from self proteins. Two noncontiguous peptides within the melanocyte glycoprotein gp100 are cut out and spliced together in the proteasome, the spliced glycoprotein is presented by HLA-A32 and recognized as foreign by the patient's CD8 T cell
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What are mechanisms by which tumors escape immune recognition?
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low immunogenicity: no peptides, no adhesion molecules, no co-stimulatory molecules
antigenic modulation: antibody against tumor cell-surface antigens can induce endocytosis and degradation of the antigen. Immune selection of antigen loss variants tumor-induced immune suppression: factors (TGF-Beta) secreted by tumor cells inhibit T cells directly Loss of HLA expression (prostate gland cancer) altering MIC expression: secretion of immunomodulatory cytokines |
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How does altering MIX expression lead to tumor cells evading surveillance by immune system?
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tumor cells have increased MIX expression -->
NKG2D on NK cells and gamma:sigma T cells bind MIX: the tumor cells are killed --> a variant tumor cell cleaves MIX from its cell surface, soluble MIX then binds NKG2D on lymphocytes --> variant tumor cell is not killed and survives to proliferate and cause cancer |
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How does loss of HLA class I expression on tumor cells lead to evasion of immune system?
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decreased susceptibility to cytotoxic T lymphocytes but increased susceptibility to natural killer cells, but overtime tumor will still be able to grow even though they are more susceptible to NK cells
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How can secretion of immunomodulatory cytokines lead to evasion of the immune system for cancer?
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cells can release TGF-beta which will then suppress the immune response and lead to a decrease susceptibility
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How does the Melanoma peptide vaccine work?
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MAGE1/MAGE3 peptides induces anti-melanoma CD8 CTLs and regression of melanoma tumor,
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How do tumor antigens get presented to T cells?
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tumor antigens are carried by heat-shock proteins from a dying tumor cell and can be taken up by dendritic cells and presented to CD4 T cells, and cross-presented to CD8 T cells
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What are some humanized monoclonal antibodies used to treat cancer?
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rituximad - B cell signaling receptor: non-hodgkin's lymphoma
Trastuzumab - GF receptor: breast cancer Alemtuzumab - differentiation antigen: chronic lymphocytic leukemia cetruximab - EGFR - colorectal cancer Bevacizumab - VEGF: colorectal cancer and non-small cell lung cancer |
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How can conjugated monoclonal antibodies work? and specifically describe using gemtuzumab and ozogamicin
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can target toxins to the tumor cell surface:
Anti-CD33 (gemtuzumab) conjugated to toxin (ozogamicin) --> antibody-toxin conjugates bind to CD33 on the acute myeloid leukemia cell and are internalized. The toxin is cleaved from the anitbody, activated, and passes to the nucleus --> toxin induces double-strand breaks in nuclear DNA --> acute myeloid leukemia cell dies by apoptosis |
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How does Rituximab work?
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conjugated monoclonal antibodies can target radioactive isotopes to the tumor-cell surface
Anti-CD20 conjugated to radionuclide --> radioactive antibody binds to the malignant B cells and irradiates them --> radiation damages the cell's DNA and kills them |
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What are 3 examples of conjugated monoclonal antibodies used in the treatment of cancer?
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gemtuzumab: CD33 --> acute myelogenous leukemia
Ibritumomab: CD20 --> non-hodgkin's lymphoma Tositumomab CD20 --> non-hodgkin's lymphoma |
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What can trasnfrection of tumor cells lead to and what two things are used to trasnfect?
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transfection of tumors with the gene for B7 or GM-CSF can enhance tumor immunogenicity:
B7 --> tumor cells expressing B7 can axtivate TRA-specific CD8 T cells to express tumor rejection antigen (TRA) --> activated CD8 CTL eliminating the tumor GM-CSF --> GM-CSF recruits dendritic cells, which can present tumor antigens to T cells --> activating CD8 CTL |
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choristoma -
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an ectopic rest of normal tissue
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Hamartoma -
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a mass of disorganized but mature specialized cells indigenous to a particular site
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Benign neoplasms -
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cohesive, expansile masses
remain localized to their site of origin well-differentiated slow growth |
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Malignant neoplasms -
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invade adjacent structures and spread to distant sites
may be poorly differentiated or undifferentiated may grow rapidly "cancer" |
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Desmoplasia -
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the formation of an abundant collagenous stroma in response to tumor growth and invasion
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Differentiation of neoplastic cell -
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the extent to which neoplastic cells resemble comparable normal cells
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Anaplasia -
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lack of differentiation
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pleomorphism -
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variation in cell size and shape
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Abnormal nuclear morphology -
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hyperchromasia, increased nucleus/cytoplasm ratio, large nucleoli
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Tumor giant cells -
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contains a single large polyploid nucleus or multiple nuclei
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Carcinoma in-situ -
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full-thickness dysplasia, nearly going to invade and become malignant
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Direct seeding -
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penetration of tumor into a natural open space (peritoneal, pleural, or pericardial cavities or subarachnoid or joint spaces)
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lymphatic spread -
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epithelial malignancies
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Hematogenous spread -
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mesenchymal malignancies (sarcomas mostly, but some carcinomas: veins are more frequently invaded because of their thin walls, lung, liver, brain and bone are the most common places of spreading)
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Benign epithelial neoplasm - adenomas:
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-papillary adenoma = papilloma
-cystic adenoma =cystadenoma |
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Malignant epithelial neoplasm - carcinoma:
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-adenocarcinoma
-squamous cell carcinoma |
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Mesenchymal neoplasms:
benign - end in - malignant - end-in - |
benign: -OMA :fibroma, leiomyoma, osteroma, chondroma, lipoma
Malignant - SARCOMA (fibrosarcoma, leiomyosarcoma, osterosarcoma, chondrosarcoma, liposarcoma) |
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What is a neoplasma in the placenta -
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hydatidiform mole/choriocarcinoma
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Wilm's tumor
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kidney cancer that occurs in children
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Ewing sarcoma -
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rare round cell cancer, in which the cancer if found in the bone or soft tissue
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Diagnosis cancer: Grade -
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expression of the level of differentiation of a malignant neoplasm, and the number of mitosis in the tumor, grades I - IV, and often correlate with the aggressiveness of the neoplasm (the higher the grade, the less differentiated)
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Diagnosis cancer: Stage -
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extent of spread of cancer within the patient
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What does a grade 1 and 2 mean in the gleason grading system?
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resemble normal prostate, with really little improvement on prognosis than a grade 3. grades are composed by mass, grade 2 they are more lossely aggregated, and some glands invade the surround muscle stroma
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What does a gleason grade 3 indicate?
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normal "gland unit" like that of a normal prostate, every cell is part of a circular row which forms the lining of a central space, invasion of glands is very prominent and is the main defining feature, cells are dark and more variable shapes,
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What does a gleason grade 4 mean?
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worsened prognosis by a considerable degree, first appearance of loss of the normal gland unit, inability to form individual separate glands form one another,
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What does a gleason grade 5 indicate?
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predicts another significant step towards poor prognosis, There is no evidence of any attempt to form gland units, sea of black nuclei with no pattern, fairly uniform in the undifferentiation
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How do we do staging of the cancer?
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based on the size of the primary lesion, its extent of spread to regional lymph nodes, and the presences or absence of blood-borne metastases
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What is the TNM system used for and how does it work (what is the total grading scale)?
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staging method:
T-primary tumor size and extent of invasion N-regional lymph node involvement M-metastases Tis: in situ, non-invasive T1: small, minimally invasive T2: larger, more invasive T3: larger and/or invasive beyond margins of primary organ site T4: very large and/or very invasive, spread to adjacent organs N0- no lymph node involvement N1: regional lymph node involvement N2: extensive regional lympoh node involvement N3: more distant lymph node involvement MO: no distant metastases M1: distant metastases present |
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What are the 4 ways in which to do a histologic diagnosis of cancer?
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excision: evaluation of margins
Biopsy autopsy frozen sections: immediate diagnosis but induces artifacts |
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What are the ways in which to do a cytologic diagnosis of cancer?
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fine-needle aspiration - used most commonly for readily palpable lesions (thyroid, lymph nodes)
cytologic smears: -pap smear -urine; pleural, abdominal, and joint fluids; CSF smears |
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what can Immunohistochemistry be used for?
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categorization of undifferentiated malignant neoplasms
categorization of leukemias and lymphomas determintation of site of origin of metastatic tumors detection of molecules that have prognostic or therapeutic significance |
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What is most useful in determining cell of origin in undifferentiated tumors?
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antibodies to intermediate filaments and other molecules
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What antibody is used to classify carcinomas - epithelial origin?
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cytokeratin
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What antibody is useful to classify sarcomas?
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vimentin
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What antibody is used to classify lymphomas?
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leukocyte common antigen CD45
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What antibody is used to classify melanomas?
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S-100 protein/HMB-45/Mart-1
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What antibody is used to classify gliomas?
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glial fibrillary acidic protein
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What antibody is used to classify neuroendocrine tumors?
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chromogranin/synaptophysin
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What is the marker of determination of site or origin of metastatic tumors from prostate?
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PSA
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What is the marker of site of origin of metastatic tumors from lung and thyroid?
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thryoid transcription factor 1
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What site or origin markers of metastatic tumors are used for various epithelial neoplasms?
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cytokeratin subsets
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How can hormone receptors help with prognostic/therapeutic effects?
|
if hormone receptors are postitive in tumors they have a better prognosis, determines susceptibility to antiestrogen therapy in breast cancer,
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What is an example of protein products present in breast cancer that reflects prognosis?
|
overexpression of c-erb-B2 protein --> poor prognosis in breast cancer
onverall protein products of oncogenes are reflective of prognosis, |
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What can molecular diagnostics tell you about B and T cell benign vs malignant proliferation?
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benign -- polyclonal
malignant -- monoclonal this is found in B and T cell gene rearrangements |
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What are the two results using mocleular diagnosis that support malignant neoplasms?
|
- monoclonal proliferations (malignant) vs polyclonal proliferation (benign)
detection of translocations that activate oncogenes - hematopoietic neoplasms, sarcomas, childhood neoplasms |
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What is FISH analysis primarily used for?
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most extensively in the diagnosis of lymphoid neoplasms because such tumors are associated with clonal rearrangements of T-cell and B-cell antigen receptor genes
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What is oncogene detection used for and what are some examples?
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prognosis of malignant neoplasms - amplification of N-MYC --> poor prognosis in neuroblastoma
-loss of chromosomes 1p and 19q --> good response to chemotherapy in oligodendroglioma detection of minimal residual disease diagnosis of hereditary predisposition to cancer - germ line mutations in tumor suppressor genes (BRCA1, BRCA2, RET), this is done by detection of fusion gene product |
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What are some examples of serum tumor markers?
|
Carcinoembryonic antigen (CEA) - various carcinomas and benign disorders
alpha-fetoprotein - hepatocellular carcinoma, germ cell tumors prostate-specific antigen human chorionic gonadotropin - trophoblastic and germ cell tumors CA125 - ovarian tumors CA19-9 - pancreatic and colonic cancers |
