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92 Cards in this Set
- Front
- Back
- 3rd side (hint)
Are most cancers somatic or germ line?
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Somatic
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What is an example of an inherited cancer?
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xeroderma pigmentosa
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Objectives:
1. list 5 steps of oncogenesis 2. explain multi-hit model of cancer 3. list 6 types of genes that contribute to carcinogenesis 4. distinguish between oncogenes and tumor suppressors and list examples presented for each 5. explain the 2 hit model for retinoblastoma 6. descrive the 2 carcinogenic tranlocations that are explained 7. Describe the 2 types of carcinogenic gene amplification 8. define chromosome instability syndromes |
here we go
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What are the stages of the oncogenic transformation?
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1. cancer is a progressive thing
2. uncontrolled cell cycle progression****EXAM (bell ding shit) 3. Growth factor insensitivity - independence from induction and resistance to inhibition 4. Immortalization - unlimited replication and division**** by pass signals, p53 and telomers associated 5. Evasion of Apoptosis - programed cell death 6. Escape from immunity - immune system can detect 7. Angiogenesis - 2nd half of cancer - interact with environment and change cells - such as increase blood vessels 6. |
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Multiple Hit Model of Carcinogenesis
***EXAM (Bell ding) |
Multiple genes must be mutated!***
one mutation is not enough to the cell need to bypass several problems |
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there are multiple checkpoints in the cell cycle:
what are the 2 most important checkpoints you need to know and will be responsible for on EXAM ***EXAM |
p53
Rb |
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cell cycle regulation is important and has many factors to control what 2 things?
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Cell replication
or Apoptosis |
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What are the 2 MAJOR cancer genes?
***EXAM (bell ding) |
Oncogene
& Tumor Suppressor |
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What are oncogenes?
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PROMOTES THE CELL CYCLE
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What is a Tumor Suppressor gene?
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INHIBITS THE CELL CYCLE
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Would an oncogene be a gain or loss of function mutation?
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gain of function
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Would a tumor suppressor gene be gain or loss of mutation?
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loss of funciton
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Are oncogenes dominant or recessive?
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dominant
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Are tumor suppressor genes dominant or recessive?
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recessive
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What gene is involved with immortalization?
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Telomerase
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What is the function of telomerase?
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Limited cell life
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What is a mutation of telomerase?
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gain of function
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What is the inheritance pattern of telomerase?
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somatic
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For Cancer gene "DNA repair"
What is the: Wild type function? Mutation type? Inheritance pattern? |
Wild type function?
corrects mutations Mutation type? loss of function Inheritance pattern? recessive |
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For the Apoptotic Genes
What is the: Wild type function? Mutation type? Inheritance pattern? |
Wild type function?
Programmed cell death Mutation type? both gain and loss of function Inheritance pattern? both dominant and recessive |
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For the gene: Cadherins
What is the: Wild type function? Mutation type? Inheritance pattern? |
Wild type function?
Cell adhesion Mutation type? loss of function Inheritance pattern? somatic |
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You need to know oncogenes and tumor suppressor genes
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.....so review it ok
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What is a viral oncogene?
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an oncogene carried by a virus
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What is Proto-oncogene?
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an oncogene before its mutated
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What is a cellular oncogene?
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an oncogene carried on a cellular chromosome
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Oncogenes not on exam
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just know them
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What is an example of a oncogene?
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Ras signaling pathway
not on exam |
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What do most or all cancers have mutations in what 2 tumor suppressor genes?
***EXAM |
Retinoblastoma (Rb)
p53 |
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What does retinoblastoma gene control?
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controls G1 to S transition
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What does p53 tumor suppressor gene control?
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Blocks G1 to S
Blocks G2 to M Induces Apoptosis in response to DNA damage Induces Apoptosis in repsonse to certain oncogenes |
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Incase the picture does not show how does Rb control G1 to S transition
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increase in cycline -->
cyclines phosphoylate Rb --> hyperphos of Rb causes a conformation chnage of Rb --> Rb then activates E2F --> E2F activated transcription factors to control cell cycle progression E2F also has positive feedback and activated itself and cyclins to to promote G1 to S transition |
Thus if you have a mutation in Rb
E2F is always on which increases G1 to S cell cycle progression |
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How does p53 work?
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p53 is always being expressed
labile protein - expressed and then degraded if cell thinks it is damage there are things that will stabilze the p53 p53 is a transcription factor |
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What does p53 transcribe?
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p21
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What does p21 do?
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inhibits G1 and G2 cyclins
prevents G1 to S and G2 to M |
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p53 also causes apoptosis
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know these
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Is the 2 hit model the same as multiple hit model?
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NOPE
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If on exam for a child you see a tumor
developing on the retina for a child what is this? |
Retinoblastoma
See white on eye exam |
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What # hit model is retinoblastoma?
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2 hit model
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What are the 2 forms of retinoblastoma?
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inherited
sporadic |
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What is the difference between inherited and sporadic retinoblastoma forms
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inherited:
bilateral multifocal early age of onset autosomal dominant reduced penetrance |
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Sporadic is......
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Aymmetric
isolated tumor later in life NO inheritance pattern |
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Explain the 2 hit model of retinoblastoma
****EXAM |
BOTH Rb alleles MUST BE mutated
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Why is familial Rb more likely to get cancer?
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bc every retinoblast begins with a mutated Rb allele
every mutation of the other allele results in a tumor |
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How do cells become metastatic?
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Detachment
basement membrane invasion migration deposition angiogenesis tumor growth |
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What is E-cadherin?
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common in cancer genes
involved in metastasis detachement mediates intercellular signaling as well as adhesion |
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What factors are released by the metastatic tumor cell that allow it to deposit at a new location
said imp on audio |
Metastatic cells often alter the local environment at their target site by secreting:
growth factors, proteases and extracellular matrix proteins |
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Where does CML
chronic Myelogenous Leukemia translocation occur? |
T(9;22)
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What is the CML chromosome called?
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Philadelphia chromosome
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what happens in CML?
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Produces a fusion protein between the:
abl oncogene and the Breakpoint Cluster Region (BCR) gene overactivates "abl" and causes leukemia know this |
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What happens in Burkitt's Lymphoma?
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Translocation link!
T(8;14) Translocation links immunoglobulin enhancer on chromosome 14 with c-myc oncogene on 8 |
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Where is Burkitt's lymphoma expressed?
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in WBCs
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What happens to the regulation of c-myc with Burkitt's lymphoma?
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Up regulation of c-myc
chromosome 14 Ig Enhancer switches with chromosome 8 myc |
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What is Neuroblastoma an example of?
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Gene amplification
double minutes leads to overexpression forms these circular thing |
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What is Homogeneous Staining Regions? (HSR)
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regions of the DNA that have been over duplicated and now if cancer gene is duplicated more likely to cause cancer
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What are chromosome instability syndromes a result of?
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cannot repair DNA enzymes
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What disease results from defective:
UV specific endonucleases & Thymine Dimmer Repair enzymes |
Xeroderma Pigmentosa
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What is an example of stem cell therapy?
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Bone Marrow
Umbilical Cord Peripheral Blood |
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What are 3 main challenges we face for stem cell therapy?
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1. seed threshold
2. cell culture expansion 3. controlling differentiation |
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What is seed threshold?
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Stem cell transplantations fail if the quality isn't high enough
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What is cell culture expansion?
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The quantity of stem cells can be increased by propagating them invivo
However.... many cells will differentiate as they grow so you may start with a pure population of stem cells and end up with a small fraction remain in culture |
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What is controlling differentiation?
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Growth factors can potentially be used to control differentiation
prevent premature differentiation and induce differentiation into a desired cell type |
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What are 3 more challenges of stem cell Rx?
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4. Immunogenic Rejection***
5. Autologous 6. Allogenic |
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Why is immunogenic rejection a problem?
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The treatment will fail if the pts immune system
rejects the transformed cells |
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what is autologous?
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Autologous cells were originally extracted from the pt
ex: umbilical cord minimize the risk of immunorejection |
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What is allogenic?
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if health cells from the pt are no available
they must be taken from SOMEONE ELSE these are called allogenic cells are subject to immunorejection must find a histocompatabile donor |
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What are 2 more challenges of stem cell Rx?
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7. Development of 2nd cancer
8. Infection |
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How can you develop 2nd cancer?
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stem cells proliferate rapidly
there is risk of cancer if they divide out of control |
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How can you get infection?
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contaminated stem cells
can produce life threatening infections |
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What are Adult Stem Cells?
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Stem cells from Non-hematopotetic tissues
1. Mesenchymal cells: infiltrate most tissues and are a source of adult stem cells 2. Undifferentiated although these will differentiate into specific cells types they are more differentiated than embryonic cells so their potential is more restrictive |
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How do you get Embryonic Stem cells?
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Isolated from inner cell mass of the
MORULA stage of embryo Cells are then purified by centrifugation and propagated on collagen |
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What is the advantage of embryonic stem cells?
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Pluripotent!
Can develop into any type of tissue Much more powerful but ethical issues |
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What is gene therapy?
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introduce genes into a pt for Rx uses
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What are 2 strategies under investigation for gene therapy?
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1. Somatic Transformation
2. Germ Line Transformation |
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What are somatic transformations?
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deliver a wild type gene to somatic cells of an adult or child
w/out eliminating the mutant allele |
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Important for exam about somatic transformations
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all Rx trials investigate somatic transformation
germ line transformation is powerful but not efficient or predictable enough for humans |
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What is Germ Line Transformation?
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replace a mutant gene with a wild type allele in the germ line
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What is in vivo gene Rx?
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transformation of cells within the body
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What is Ex vivo Rx?
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Transformation of extracted cells which are then re implicated back into the body
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In vivo strategies deliver genes directly
ex vivo combine stem cell and gene Rx |
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Compare Direct and Indirect Gene Therapies
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Direct - are used for specific mutations
such as Cystic Fibrosis and Duchennes Indirect - Used to target cancers |
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What are 2 examples of direct gene therapies?
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Gene reconstitution: add wild type
gene to cells with mutant genes RNAi: Inhibits expression of a spefiic gene |
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What are 3 examples of Indirect gene therapies?
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Immune Response: antigenic genes - tranformed cells cleared
Suicide Genes: Gene expression kills transformed cells Tumor Suppressor Genes: genes that inhibit tumorgenesis, ex p53 |
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What is the main therapy problem for gene therapy?
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transformation stability
transient due to degradation of DNA vector as an antiviral mechanism the nucleus automatically degrades DNA that is free of a chromosome therefore extrachromosomal transformations are transient Chromosomal integration - stable and passed to daughter cells |
A transformation is stabilized if the vector is inserted into a chromosome
the cell will propagate the inserts with the chromosome |
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How is Immunogenicity a problem with gene Rx?
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Transformed cells cleared, often increases with repeated treatments
This results in transient transformations similar to extrachromosomal vectors exceots that the pt becomes non-responsive to further treatments |
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What are multifactorial traits?
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numerous genes contribute to a multifactorial trait.
Its not practical to transform a pt with a wild type allele for each. It may be possible to cure a pt by transforming him or her with a few critical genes |
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What is transgene size?
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vectors can accept limited insert sizes
this becomes a issue with very large genes |
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What is a major complication of gene therapy?
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immunologic reactions
allergic reactions |
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What is a bad consequence of horizontal transformation?
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prevent transformation from spreading to uninteded cells
consequences unpredictable e.g. somatic to germ line cells |
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Insertional mutagenesis
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When a gene inserts into a chromosome
it can disrupt expression of adjacent genes occured with XSCID trial |
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What does most gene therapy target?
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Mosts gene therapy targets cancer
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What are viral vectors?
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Viral vectors advantage make them useful for gene therapy
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naturally infect host cells - viruses carry therapeutic gene
cell type specificity - target specific type of tissue Genetic Engineering |
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What are retroviral vectors?
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RNA viruses - the greatest successes have used retroviral vectors!
chromosomal integration require dividing cells small transgene capacity |
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SCIDS trial - has been cured in several clinical trials
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Severe combined immunodeficiency
must live in a sterile environment bubble boy x-linked |
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