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241 Cards in this Set
- Front
- Back
Genetic damage:
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Can lead to Increased transcription, on all the time,
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Chromosomal genetic defects
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Entire chromosomal deletions/additions, translocations
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Or, can have addition/deletion of an entire chromosome.
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Translocation
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Error in meiosis/crossover - can disrupt the middle of a gene or the transcription sequence can be lost - applying to a dfferent gent
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Mutations
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Nucleotide Insertion/ deletion, point mutation
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Cell division leads to more copies of gene
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Gene amplification - ultra metabolizers, extra p450 patients hard to dose
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Detection methods of genetic defects
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How they work, when to use - different resolutions - cytogenetics, FISH, molecular
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Look at bands
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"That's chromosme 1 but this tail came from 13"
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How to compare karyotype
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Scissors and a glue stick (now still same only digital.)
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Molecular detection (genetic)
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Highest resolution - single mutations, small insertions, deletions
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PCR:
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Method of amplifying nucleic acid with enzymes and temperature cycling to make more copies. Is higest resolution for finding a sequence. In molecular genetic detection
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Sequencing
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Cheaper and easier than it used to be
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Extra copy of chromosome 21
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downs
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Monosomies
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do not survive
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Cystic fibrosis
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Recessive disease - need a defect in both alleles. Defect in chloride channel leading to abnormal secretions - lung pancreas, male sterility
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CF
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Some private OB practices will screen for common mutations. PCR screens for most common
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57 isoforms?
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Given same dose of coumadin, one may bleed.
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P450 Matabolism differences; major bleeding events
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Molecular pathology
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Application of the techniques of molecular biology to the study for disease
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Pathology
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Study of disease
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Pharmacogenomic pathology
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Molecular, stil trying to study disease
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Human disease determination?
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Genetic, environment, both (most common) - obesity, cancer, diabetes
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3 Categories of genetic disorder
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Single gene defect (simplistic, but not common), ploydenic/multifactorial (obesity, cancer, diabetes), chromosomal
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Chromosomal/cytogenetic
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Chromosomal disorders
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Germ line or somatic (mosaic, death or cell, neoplasia - but not passed on)
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Germ line
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Sperm has extra chromosome 21
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Somatic embryonic
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Mosaic, happens to only some cells
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An individual's genetic defects can be
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Inherited or acquired
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Ways to inherit
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Autosomal … (4 types)
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Acquired genetic alterations
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Not from parents, not passed on
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A gene is turned on how?
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Transcription factor binding to upstream regulatory sequences
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What do you get when a gene is transcribe?
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mRNA with poly-A tail (normal!)
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Absent gene product, abnormalgene prodcut, gener regulation disorder (on/off all the time)
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Upstream regulatory sequences
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Every gene
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Culture of cells to gest genetic
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Cytogenetics, e.x Downs syndrome on child or fetus (amniocentesis)
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Cytogenetic technique
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Obtain cells, Culture, synch division, stop division in metaphase when tightly coil -(condensed), squash, stain, pair bands and look for differences from normal (alters from predictable banding)
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When stopping cell division for cytogenesis, what do you do?
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Stop in metaphase, using colchicine
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Gene alteration leading to absence of product
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Ex: stop codon
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Genetic damage:
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Can lead to altered product
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Heritable disease
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Got it from parents - might be able to treat/correct - pku
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Genetic counseling
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Diagnosis esp important to conduct prenatal counseling
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Cystic fibrosis
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Common chromosomal abnormalities
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Downs trisomy 21
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Downs
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Related to maternal age, most common chromosomal disorder, facial:epicanthic folds - flat profile, retardation, increased Alzheimers and leukemia risk, cardiac other congenital
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Tumors
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Malignant transformation of a single somatic cell - dividing incorrectly and daughter cells have same change
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Molecular diagnostic to cancer
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Classify, diagnose, by PCR see if still there or coming back
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Infectious disease genetics
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Now we're testing for something that's not us.
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Conserved sequence testing
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Testing?
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Bacterial meningitis - give antibiotics before you know - still find nucleic acid if org is dead
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New medicine
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Required genetic testing - severe rxn, metabolism dosing, adverse reactions
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Matabolism of anticancer agents
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Tight therapeutic window, polymorphism
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Applications for molecular testing of infectious disease
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Melting curve at which a dsDNA strand comes aparth is very specific to its sequence - related to G-C content
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More use of genetics before therapy - pharmacogenomics - testing before prescribing
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On translocation, may have disruption in the middle of a gene, turns on the wrong gene
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SNPs and pharmacogenomics
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Summary
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Vysis sells screening kits for FISH of Downs, sex
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What genetic damages cause disease?
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The Plasias
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Hyper - lots (Ex: lactation); Meta - change (GERD esophagus change to underlying type, Dysplasia is disordered growth; Anaplasia;Neoplasia
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Hyperplasia
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Breast Many more cells per ductile structure
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Pre-neoplasia = dysplasia
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Disordered growth; Pre-malignant epithelial changes in the cell
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Dog his dysplasia
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Not pre-neoplastic, disordered___
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Malignant breast tissue picture - Can be well differentiated or poorly differentiated.
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How closely does it look like the cells around it - the more deranged it gets..
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Benign tumor margins
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Well circumscribed, encapsulated
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Malignant tumor margins
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Invasive fingers, poorly circumscribed
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Tumor absolutes:
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benign tumors do not metastasize and do not invade.
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Malignancies spread
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Vascular, lymphatic, ex: normal colon cell won't travel, usually it has gotten pretty bad before cells have these skills
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Identifying traveled malignancy
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Tough, just have to match in loocks or do molecular testing
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Will a cell matastasize
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No molecular or visual way to tell whether cell will metastasize.
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Which cells likely to metastasize
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Larger, more anaplastic ones have most potential, but not predictable.
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Metastasis
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One little cell traveled and started to grow.
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Degree of differentiation
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These features aren't absolute, but still useful.
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Benign/malignant cytological characteristics
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Benign/malignant cytological characteristics - Nuclei
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Regular/irreg shape & size
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Benign/malignant cytological characteristics - Cytoplasm development
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Well developed/variable
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Nucleoli
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Distribution of chromatie
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Monster cells
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The right slide doesn't look like anything normal, divide but don't separate
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Seminoma
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Testicular cell carcinoma
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Hepatoma
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Now hepatocellular carcinoma
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Lymphomas
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Solid tumors that are neoplastic collections of hematopoeitic cells
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Leukemias
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When neloplastic hematopoeitic cells circulate
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Neoplasia
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"new growth" abnormal, exceeds normal tissue growth, uncoordinated, persists despite regulation
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Oncology
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Oncos = tumor
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Cancer
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Malignant tumor - extend into other tissue - like claws
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Tumor
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"swelling" usually neoplastic
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Metaplasia
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Barrett's esophagus, lung
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Neoplasia
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Autonomous excessive growth not coordinated with the tissues around it = Pictures of breast (benign & malignant)
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Degree of differentiation
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Benign tend to be welldifferentiated, resembling the tissue of origin.
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Benign/malignant cell growth cycle
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Malignant grow faster, vary within self
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Leiomyoma
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Benign uterine tumor, tissue look like smooth muscle still
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Benign naming
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-oma
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Malignant naming
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Add tp cell of origin (carcinoma - epithelial)/ (sarcoma - mesenchymal)
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Sarcoma
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Malignant neoplasm derive from mesenchmal tissue (muscle, bone, nerve)
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Carcinoma
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Malignant neoplasm of epithelial origin (adenocarcinoma)
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Lymphoma
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Malignant neoplasm of hematopoietic cell ofigin (eg b cells)
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Nomenclature
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Adipose
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cartilage
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Smooth muschle
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Striated muscle
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gland
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Adenoma/adenocarcinoma
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squamous
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papilloma
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Menchymal origin
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Epithelial origin
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Papilloma/squamous cell carcinoma
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Why name tumors?
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Id, treat, prognosis
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Staging vs. grading
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Stagin more predictive
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TNM
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T:size; N:regional lymph node involvement; M=distant metastases
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Prostate staging
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t/1-4/a-c, n0-n3; m0-1
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Other than prostate
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Some grading not very specific - well/mod/poorly differentiated
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Local features of neoplasia
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Destruct vital structure; obstruction; ulceration; necrosis and bleeding
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Loss of integrity
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Bone fracture
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GI tract tumor
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Grows and obstructs
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Systemic features of neoplasia
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Anorexia (cachexia), weigh loss fever, anemia decreased resistance to infection
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Paraneoplastic syndromes
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Symptoms that are explained by products of the tumor (eg creating hormones, cushing's syndrom due to cortisol when made by lung - nt usually made by lung)
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Neoplasia/cancer
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Not a single disease - highly variable
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Neoplasias manifest
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Variably, may present with different symptoms
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Immune status of host, histologic grade, location, sensitivity of tumor cells to therapy
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Anaplasia - the worst differentiation a cell can have. Seen in tumors, May have to stain for protein markers to see where it came from. Not identifiable as to where it cam from
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Anaplasia is not in "the sequence"
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Barrett's esophagus pictures - metaplasia led to dysplasia and to adenocarcinoma. Different arrangement of cells.
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Benign and malignant included in "neoplasia" - and all are autonomous (ignore growth factors); excessive, disorganized
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Benign v. Malignant: growth, metastases, capsule, nnecrosis, hemorrhage, differentiation, nuclei, mitoses
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Breast cancer progression pictures. Not all of these progress. For instance, breast hyperplasia can come & Go.
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Characteristics of Malignancy
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Invasion metastasis
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Benign tumors still expand /invade into other tissues - usually means benign ones are encapuslates and have well defined margins
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Differences in size and shape of cell. Neuceloli are off to the side, some extremely large "monster" cells.
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Impingment - Benign, but still fatal. Can't put that much pressure on brain
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Melanoma has just kept name but is highly malignant
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Metaplasia is not pre-neoplastic, but could lead there. Dysplasia is pre-neoplastic process
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Necrosis due to too fast growth where they outgrow their blood supply.
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PICS Thinks salivary gland tumor / oncocytic tumor in the kidney benign look benign
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Plasias all reversible except neoplasia
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Pleo-many morph-shapes
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Prostate diagram showing various differentiation
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The deeper a tumor spreads into tissue layers, the more likely it has access to vascular components to spread. (worse prognosis) T goes up.
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Genetic hypothesis of neoplasia
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Multiple damage (mutations, lead to cell death or disruption in regulation
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Neoplasms are accumulations of genetic events
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Alter cell regulation
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Ase we age, the is more chance for the spontaneous damage
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More replication,
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Not just any genetic damage
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- cell cycle abnormalities in one of the (many) regulatory factors (remember excessive uncontrolled autonomous growth?)
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Steps in cell proliferation:These are all different places where something can go wrong.
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Growth factor binds to receptor; receptor temp activated; signalling activiated, binds to DNA to turn on growth factors SEE LIST
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The kind of genes that can be damaged and lead to neoplasia.
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Proto-oncogenes;
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GGW: Protooncogene
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EX: maybe normal for fetal development but shut off - mutation turns it back on
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GGW: Recessive oncogenes
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Inhibitory factors ("the brakes") when go out lose control
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GGW: Genes that regulate programmed cell death
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Apoptosis - things live when they should not
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GGW: repair
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Damage to DNA repair genes
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Over 90% of tumors have telomerase wrong
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this as one of the things wrong - it's able to turon on telomerase.
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Sustained antiogenesis
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Tumors have to feed themselves or they can't grow. You don't have normal arteriole or venous capillary bedys. Realy important for tumor growth
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Cell migration
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Ability to metstasize requires collagenase, etc to get out and let go of neighbors
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Molecular basis of neoplasia
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Explains tumor cell behavior, influenc of geography, culture, environment, age, heredity
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Why cells become neoplastic?
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Genetic damage, maybe hereditary, lead to instability, lead to further instability
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Cell division/DNA replication
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Highly regulated, stops when proliferation no longer needed (liver regeneration, heal skin/ colon disease can cause sloughing and regenerates perfectly)
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Differentiation
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Specialized function is normal, when see changes in differentiation indiactes
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Cell cycle
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A simplistic circle not real - in reality is a complex and redundant system that regulates - it takes multiple changes to accumulate and lead to neoplasm
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Carcinogenesis
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Multi-step process, different for everyone even if have the same organ
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Single mutation
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Cannot fully transform a cell to neoplasm , most cancers involve several oncogenes and loss of 2 or more suppressor genes
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Gene expression
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Look for a pattern of changes to asses prognosis - what patterns are associated with different behavior in patients? Moving toward real patient care.
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protein profiles
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What is being produced by genes that indicates pattern of neoplastic behavior
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Dysregulation categories - growth
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Growth factors changes binding kinetics; GF receptor (common); transduction proteins, nuclear regulatory proteins, cell-cycle regulator
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Inhibitory dyregulation categories
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Insensitive to growth-inhibitory signals (nuclear reg proteins, transcrip factors, other); evasion of apoptosis
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BCL2/p53
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Balance between living/apoptosis; if BCL2 is overexpressed the too many cells escape apoptosis; if p53 is damaged not enough apoptosis occurs
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DNA repair defect
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If inherited - genomic instability syndromes; NER repair of UV induced cross linking - without it suscept to skin cancer
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An example of a common sequence in breast cancer, not always the same
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Progress toward dysplasia, multi-steps to neoplasia
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Pancreatic cancer sequence
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Telomere shortening, K-RAS, p16, p53 - one example of path to invasive carcinoma
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Colon cancer sample pat
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Normal, inherited predisposition, many other change, then p53, then telomeras, many genes.
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P53
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Proapoptotic but also other regulation in cell cycle
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Tumor suppression gene
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Usually recessive, so when one allele fails can develop cancer
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Generalized diagram with timeline of cancers
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Skin cancer might have change at age 15; bladder cancer 20 years;
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Think of odds of cancer
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Damage, slips through repair, happens to be one of the genes impt to regulation, AND need to have multiple of these damaging events
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Ulcerative colitis
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Flat areas of dysplasia lead to cancer, sometimes have colon removed
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These genes aren't normally turned on - shut down after angiogenesis. These types of alteratations are harder to cure.
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Growth factor binds to receptor; receptor temp activated; signalling activiated, binds to DNA to turn on growth factors SEE LIST
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this as one of the things wrong - it's able to turon on telomerase.
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Molecular basis of neoplasia - unifying concept
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Tumor cell behavior; influend of G C E A H
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Genetic hypothesis of neoplasia
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GROUP of disorders to REGULATORY geneswhich alter normal replication. Incl: chromosomal brakage, translocation, point mutation
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Sonpaneous, environmen, familial
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Incidence
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New cases in a specific period, &population
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Prevalence
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All cases
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Bad stuff in environment
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Sunlight, inhaled carcinogens, hot dogs, etc
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Radiation
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UV exposure every day: melanoma (aggressive); squamous cell carcinoma, basa call carcinoma
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X-ray exposure
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Chernoble, factory: leukemia, thyroid, breast, colonic
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Chemicals/toxins
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Cigaretts-squamous cell carcinoma of lung plus other areas where some goes
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Asbestos
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mesothelioma
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Aflatoxin
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Hepatocellular
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Know that radiaition
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Causes cancer
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Alcohol
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Hepatocellular carcinoma
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Virus leads to cancer
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Integration of viral DNA can cause genetic damage - separate from regulatory sequence
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Chronic injury/repair
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Esp viral hepatitis C causes injured cells that need to be replicated/repaired - increase chance of an error
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HPV
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Infects skin/mucosal; low risk subtype leads to warts, high risk leads to sq cell carcinoma
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Hepatitis B
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Acute/chronic liver infection predisposes to hepatocellular carcinoma
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EBV
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Infects B cells, gives you mono, once you have it is for life, in some cells it can transform to lymphoma
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Different areas of the world have different incidence of cancer
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Cultural practice - smoked foods, etc Stomach cancer high in asia, low in US; lung cancer high in US
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Stomach cancer
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Associated with smoked fish
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Breast/prostate cancer
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Overfed populations
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Lung
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Who's smoking
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Age:
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Dna damage/repair ongoing, older people have more opportunity for damage, 55-75 is most deaths
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Familial predisposition
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Remember it's accumulation of damage - this is one strike against you. Colon cancer for same reason, but get at 25 instead of 55
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Retinoblastoma
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Inherited damaged RB gene, in eye of infants
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Familial adenomatous polyposis of colon
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See polyps at young age in colonoscopy - end up with prophylactic colectomy by age 30(?) 100% of these patients have cancer by age 30.
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BRCA1; BRCA2
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Prophylactic mastectomy debate
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Understanding molecular basis of cancer
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Helps diagnose, pick better chemotherapy; better take steps to prevent; screen better
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Molecular techniques for dx
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Classify, evaluate residual, monitor relapse, ident appropriate therapy
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A particular molecular change
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Might indicate one is going to do worse
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Carcinogenesis
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Result from single cell transformation, passed along
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Cell cycle
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Where to look for the change
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CML
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Has one characteristic change (has others thought) that defines it - Philadelphia chromosome - tyrosine kinase "on" all the time.
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Phildelphia chromosome
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In CML, Translocation detectable by cytogenetics, FISH, molecular methods
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FISH
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Shows CML where ABL and BCR are separated in one cell and together in another
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Can specialize chemotherapy to be more specific
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Gleevec
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Tyrosine-kinase inhibitor for CML, also inhibits GIST - drug blocks TK that is on all the time
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Herceptin
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Ab blocks HER2-neu a growth factor receptor. Human Epidermal growth factor Receptor 2 HER2 - more receptors on cell surface
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HER2
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20-25% of breast cancer patients assoc with decreased survival, give Herceptin to make monoclonal Ab block the receptor
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HER2 testing
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Immunohistochemistry / FISH
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Prevention
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Earlier screenings, sunscrean for xeroder…., prophylactic colon removal (extreme)
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Prevention avoidance
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Radiation therapy, sun clothing
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Physical carcinogen protection
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Clothing sunscreen, radiation safety
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Lifestyle
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Smoking
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Occupational health
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Viral prevention
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Safe sex, HPV vaccine, HPB vaccine and avoid exposure; HTLV-1 screen blood supply
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Cancer screening
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Identify premalignant lesions and/or early malignant lesions before they get big and behave badly
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Pap smear
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Screen for cervical carcinoma - cancer arises at transitionfrom inner/outer part of cervix; remove cels with brush; visually inspect for changes
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Normal cervical cell picture
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Cervical cancer pictures
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Colon cancer screening
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If see lesion, take it out; stalk occurs due to the way colon moves. No problem.
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Incidence rates exclude skin; shows some more deadly - #s don't match
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Safeguards against cancers
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Molecular basis of neoplasia - unifying concept
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