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359 Cards in this Set
- Front
- Back
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What must CDKs be bound to to have activity?
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a cyclin
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What is a cyclin?
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a regulatory subunit that controls the activity of cyclin dependent kinases throughout the cell cycle
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True or false: A cyclin bound to CDK is always active.
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false, the complexes are subject to regulation that can turn off the kinase activity of the CDK
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Which cyclin/CDK complex is associated with the early G1 phase?
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Cyclin D/CDK 4 or 6
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Which cyclin/CDK complex is associated with the late G1 phase?
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Cyclin E/CDK 2
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Which cyclin/CDK complex is associated with the M phase?
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Cyclin B/CDC2 (CDK 1)
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What confers substrate specificity to the CDK? (determines which proteins the CDK can phosphorylate)
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cyclin
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When are cyclin dependent kinases present?
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ALL cell cycle phases
ie. their presence is not cyclic like that of cyclins |
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When are cyclins present during the cell cycle?
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they are synthesized when needed and degraded when they are not (before the next cell cycle phase)
-each cyclin is specific to a specific stage in the cell cycle and that is the only time it will by synthesized |
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What is a cell cycle checkpoint?
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all normal proliferating cells go through these, they are scheduled cell cycle checkpoints in which further progression through the cell cycle is halted until specific conditions are met
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What is the restriction point and in what phase of the cell cycle is it found in?
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in G1, it is also called environmental checkpoint, it blocks entry of the cell into the cell cycle by default, cells can begin cycling through G1 once the appropriate EXTRACELLULAR growth stimulatory signals are received
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What are the 2 "DNA-integrity checkpoints"?
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the G2-M checkpoint
the M phase checkpoint (also called spindle assembly checkpoint) |
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Which cyclin/CDK complex plays an important role in both of the DNA integrity checkpoints?
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cyclin B/cdc2
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What is a mitogen?
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an extracellular ligand that initiates a signaling response which ultimately results in cell division
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Describe the signaling pathway initiated by mitogens.
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mitogens bind to receptors on cell surface-->activates a phosphorylation cascade starting with Ras-->activates the MAP kinase cascade-->increases the synthesis and activity of the transcription factor MYC-->increases expression of cyclin D = cyclin D/CDK4/6 complex is the first active cyclin/CDK complex of the cell cycle
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Which cell cycle checkpoint is dependent on mitogen-initiated signaling for cell cycle progression?
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G1
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Without a mitogen, what happens to the cell cycle?
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cyclin D levels remain too low to stimulate CDK4/6 activity and the cell enters the quiescent state G0
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Which cells cannot reenter the cell cycle once they enter the G0 state?
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nerve cells and skeletal mm. cells
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What is the only cyclin whose synthesis is dependent upon external signals (mitogens)?
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cyclin D
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Which cyclin/CDK complexes are needed for a cell to pass through the restriction point?
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cyclin D/CDK4/6 (first) and then cyclin E/CDK2 (second)
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Describe the phosphorylation of Rb as it relates to a cell passing the restriction point.
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growth factor signaling causes increases synthesis of cyclin D which complexes with CDK 4 or 6-->the active D/4 or D/6 complexes phosphorylate only a few serine and threonine residues on the Rb protein (=hypophosphorylation)-->E/CDK2 then phos. Rb at many more serine or threonine residues (=hyperphosphorylation)-->this causes Rb to undgergo a conformational change and let go of E2F (transcription factor)-->can then bind to promoter sequences (if not bound already) and activate transcription of S-phase genes
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What genes does E2F increase the expression of?
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S-phase genes required for DNA replication including DNA polymerases, PCNA, nucleotide biosynthetic enzymes (like thymidine kinase and ribonucleotide reductase)
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Which cyclin complex regulated the the progression from G2->M->G1?
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cyclin B/Cdc2 (also called CDK1)
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What is maturation promoting factor (MPF)?
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it's another name for cyclin B/cdc2 complex AS A UNIT
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What is the purpose of the G2-M checkpoint?
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to make sure that all of the DNA has been replicated correctly, it regulates progression out of G2 and into M phase
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What actually pushes the cell OUT of G2 and into M phase?
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the activation of MPF which happens when the cell sends a "ready" signal after it detects a normal state in the DNA
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In which cell cycle phase is cyclin B produced?
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G2 (one phase before it is needed)
it immediately binds to existing cdc2 molecules in the cell to form MPF but these complexes are not yet active |
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What happens to cdc2 during the G2 phase?
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it is phosphorylated on 3 amino acids
-2 inactivating phosphates -1 activating phosphate =still inactive b/c the 2 inactivating phosphates "win out" |
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What is cdc25?
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it is a phosphatase activated when the cell generates its "ready" signal after DNA synthesis is complete
-after activated, it pulls off the inactivating phosphate residues from cdc2 which activates MPF to its full activity |
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What does the M-phase or spindle assembly checkpoint look for?
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it checks to make sure that all duplicated chromosomes are properly aligned on the spindle
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What is passage through the spindle assembly checkpoint dependent upon?
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inactivation of MPF
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What does APC (anaphase promoting complex) do?
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it is activated when all chromosomes are aligned at the spindle and an all clear signal is given
-APC is a ubiquitin ligase that targets cohesins and cyclin B for degradation by the proteasome |
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What is the purpose of degrading cohesins by APC?
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it allows the sister chromatids to separate, initiating anaphase
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What is the purpose of APC degrading cyclin B?
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to decrease cdc2 activity
-decreased activity of cdc2 is necessary to ensure the dephosphorylated state of certain cdc2 substrates (will be needed for concluding events of mitosis) |
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What are cohesin proteins?
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they hold together sister chromatids prior to anaphase
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What is separase?
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acts on cohesins to degrade them and allow sister chromatids to separate at anaphase
-separase usually kept in an inactive form by binding to inhibitory subunit securin |
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How does APC activate cleavage of cohesins?
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APC, once active, ubiquitinates securin leading to its proteolysis and freeing the enzyme separase = now active, activated separase then degrades cohesin and siste chromatids separate
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What does the presence of APC do to cyclin B?
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it ubiquitinates cyclin B and it is degraded by proteasomes, this inactivates cdc2 and it is then dephosphorylated (which doesn't matter b/c it's already inactive) phosphatases can then act unopposed and dephos. cdc2 substrates which is critical for completion of mitosis
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What is one example of why cdc2 substrates must be dephosphorylated for mitosis to complete?
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reassembly of nuclear envelope requires the dephos. form of laminin, a protein that was phos. at the beginning of M phase due to increased cyclin B/cdc2 activity
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What are CDKI's?
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cyclin dependent kinase inhibitors-they can halt the cell cycle at any phase if DNA damage is detected
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What are the 2 groups of CDKI's and what does each do?
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INK4-includes the protein p16 and this group only inhibits CDK4 and CDK6
WAF1/CIP1-includes p21 and they inhibit all cyclin/CDKs except for CDK4/6 |
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When is p21 induced?
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during times of DNA damage
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When is p16 induced?
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during times of environmental stress
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What are driver mutations in a cell?
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mutations that occur and are able to confer a growth or survival advantage
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What are passenger mutations in a cell?
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mutations that are biologically inert do not contribute to the aggressiveness or development of a tumor
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What are the 2 major classes of genes affected by driver mutations?
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tumor suppressor genes
proto-oncogenes |
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What are tumor suppressor genes?
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they code for proteins that protect the integrity of the genome
-they can slow or halt the cell cycle, repair damaged DNA, or induce a death response |
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What is an inactivated tumor suppressor?
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the mutated version of a tumor suppressor
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What are proto-oncogenes?
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they code for non-mutated proteins that stimulate normal cell proliferation or promote cell survival
-growth associated proto-oncogenes usually indirectly stimulate the activity of CDK4/6 to put a cell past restriction point |
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What is an oncogene?
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a mutated version of a proto-oncogene
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What is a neoplasm?
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a tumor resulting from abnormal growth
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What 2 conditions are necessary for formation of a neoplasm?
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mutations in at least one proto-oncogene AND one tumor suppressor
=abnormal cell growth |
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What must a cell do to preserve the integrity of its DNA once damage has occurred?
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1. slow or halt the cell cycle to provide adequate time for DNA repair
2. repair damaged DNA in a manner that preserves sequence integrity |
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What are gatekeeper genes?
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tumor suppressor proteins that interrupt growth associated signaling pthways. or induce the death of irrevocably damaged cells (many act to inhibit the cell cycle)
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What are caretaker genes?
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tumor suppressor proteins that protect the integrity of the genome, many DNA repair proteins for example
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Describe the following for the Rb gene:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
Gatekeeper gene
restriction point control retinoblastoma dominant |
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Describe the following for the p53 gene:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
gatekeeper gene
DNA damage/apoptosis Li-Fraumeni dominant |
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Describe the following for the APC gene:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
gatekeeper gene
prevents B-catenin growth signaling familial adenomatous polyposis (FAP) dominant |
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Describe the following for the NF1 gene:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
Gatekeeper gene
inhibits RAS signaling NF1 dominant |
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Describe the following for the ATM gene:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
caretaker gene
DNA damage sensor Ataxia telangectasia recessive |
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Describe the following for the BRCA1 and BRCA2 genes:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
caretaker genes
DNA break repair familial breast cancer dominant |
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Describe the following for the MSH2, MLH1 genes:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
caretaker genes
DNA mismatch repair (newly synthesized DNA) hereditary nonpolyposis colon cancer dominant |
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Describe the following for the XP genes:
Type of gene Pathway affected Familial cancer syndrome inheritance pattern |
caretaker genes
pyrimidine dimer repair xeroderma pigmentosa recessive |
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How are the majority of tumor suppressors inactivated?
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loss of function
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What is "loss of heterozygosity"?
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the loss of the last remaining normal copy of a tumor suppressor as the cell becomes homozygous for the mutated gene
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What 2 detrimental effects does mutated Rb have on the cell?
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1)E2F is unrestrained, allowing mutated cells to proliferate in the absence of a growth signal
2)cell cycle inhibitors that would normally act through Rb to restrain cell cycling cannot halt the cell cycle if the DNA sustains damage (=no time provided for repair) |
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What normally prevents the hyperphosphorylation of Rb?
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p21 and p16
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What are the 2 forms of retinoblastoma?
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1)familial -occurs in family cluster (usually bilateral)
2)sporadic-occurs in children with no family hx of the disease (affected children usually only develop a tumor in one eye) |
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What is Knudsen's two hit hypothesis?
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basically states that the mutation of 2 copies of Rb is required to give rise to a retinoblastoma
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What is mitotic recombination and what sort of implications does it have for the cell?
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some actively dividing cells can undergo mitotic recombination similar to that found in meiosis in the germ cells, this is typically what happens in retinoblastoma to produce the second mutation needed to manifest the disease
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In healthy cells, what happens to p53?
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non-phosphorylated p53 is targeted for ubiquitination and degraded by ubiquitin ligase MDM2= p53 levels normally kept low in a normal healthy cell
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What is the function of ATM (ataxia telangiectasia mutated)?
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it is a protein kinase (also a tumor suppressor) that becomes activated when double--stranded breaks are detected in the DNA, it phos. p53 causing it to dissociate from MDM2, this stabilizes p53 against degradation and p53 can then bind to DNA to function as a transcription factor
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What does mutation of the ATM protein kinase do to the cell?
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it compromises the cell's ability to detect and repair double strand breaks=people with this disorder have an increases risk of developing cancers
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Once bound to DNA, what does p53 stimulate transcription of specifically?
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p21 which can arrest the cell cycle to allow adequate time for DNA repair
-can also induce transcription of Bax (pro-apoptotic protein) if cell is not repairable |
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What are "death substrates"?
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cytoskeletal proteins that are acted on by enzymes called executioner caspases during apoptosis
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What are executioner caspases?
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they are enzymes that carry out the proteolysis of cytoskeletal proteins during apoptosis
-in non-apoptotic cells, they are present as zymogens |
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How are caspases activated?
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they are sequentially activated (one activated zymogen cleaves another) to ultimately activate the entire caspase family
-first caspase activated is caspase 9 which forms an apoptosome that can proteolytically activate other caspases |
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Describe the process of apoptosis starting with events in the mitochondria.
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it is initiated when membranes of the mito. become depolarized and cytochrome C is released from the mito. into cytoplasm-->cyt. C assembles with the protein Apaf-1 and caspase 9 to form a proteolytically active apoptosome-->this cleaves several downstream caspases that degrade the cytoskeleton of the cell
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What can stimulate the transcription of Apaf-1?
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p53
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What is Bcl-2?
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an oncogene that inhibits the release of cytochrome C from the mito. which prevents caspase activation and apoptosis=associated with cancer
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What type of mutations are present in most tumor suppressor mutated genes?
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frameshift or nonsense=protein never made
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What type of mutations are the majority of p53 mutations?
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missense=full length p53 is made but some functions are intact and some aren't
-most are gain of function mutations |
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Describe the structure of p53.
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it consists of four identical subunit proteins that bind to each other to form a tetramer
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Which portion of the p53 gene is most commonly mutated?
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the DNA binding domain
-this can act in a dominant fashion to interfere with the function of normal subunits b/c they can't bind DNA if the mutated subunit can't |
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What is Li-Fraumeni syndrome?
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it is a hereditary defect in the p53 gene, individuals have a 90% chance of developing cancer, it is rare
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What does the Human Papilloma Virus do to interfere with normal DNA damage control mechanisms?
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the virus encodes 2 proteins:
E6-->leads to destruction of p53 and prevents it from halting the cell cycle or inducing apoptosis E7-->binds to Rb, liberating E2F which then stimulates transcription of S-phase genes |
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What is Gardasil?
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the vaccine for HPV, it is made up of the coat proteins of the 2 HPV strains that cause 70% of cervical cancers and 90% of genial warts
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What causes Familial Adenomatous Polyposis?
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a heritable mutation in the APC (adenomatous polyposis coli) gene
-individuals inherit one defective copy of APC and then lose the other copy in some cells of the colon or rectum which predisposes these tissues to tumor formation, entire colon MUST be removed |
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What is B-catenin?
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it is a component of adherens junctions in epithelial cells as well as a transcription factor that can stimulate gene expression
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In normal cells, what prevents B-catenin from constantly stimulating cell growth?
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a complex containing APC (adenomatous polyposis coli) that stimulates the degradation of free B-catenin
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What is the function of WNT?
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it is a signaling molecule (mitogen) that when bound to its receptor triggers a signaling cascade that inhibits the action of APC (adenomatous polyposis coli) and protects B-catenin from degradation (B-catenin can then enter the nucleus and promotes transcription of growth associated genes along with TCF)
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What is happening with B-catenin in APC mutated cells?
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B-catenin is always active and in the nucleus stimulating proliferation even when a growth signal is not present,
APC complex is not present to degrade B-catenin as would happen in normal cells |
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What is the normal function of WNT in colon stromal cells?
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normally the stromal cells secrete Wnt that binds to its receptor on colonic stem cells in the base of the crypt, as cells migrate upwards within the crypt they get farther away from the source of the Wnt ligand causes cells at the top of the crypt to stop dividing and continue differentiating until they are sloughed off
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What it the normal function of the neurofibromin protein in cells?
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it is a GAP (GTPase activating protein) and facilitates the deactivation of Ras by stimulating the RAS GTPase activity (makes it give up a phosphate)
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What happens without adequate levels of neurofibromin protein?
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Ras remains in an active state for a longer period of time and is able to stimulate cell division
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What is the function of BRCA1 and BRCA2?
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they are DNA proteins that participate in homologous recombination (highest quality method of repair for DS DNA breaks)
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What does mutation of BRCA1 and BRCA2 cause in the cell?
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does NOT drive cell proliferation by itself, the mutation decreases the likelihood of efficient double stranded DNA break repair and leads to increased mutations of other genes
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Who is at increases risk for developing breast and ovarian cancers?
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individuals with a heritable, HARMFUL mutation in BRCA1 or BRCA2
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What is hereditary non-polyposis colon cancer? (HNPCC)
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also called Lynch syndrome, it is a familial cancer syndrome that represents 2-3% of all colon cancer cases, autosomal dom., caused by mutations in multiple genes involved in strand-directed mismatch repair including Msh2 (60% of cases) and Mlh1
-b/c DNA repair is compromised progression from an adenoma to a carcinoma takes place in only 2-3 years vs. 8-10 years in non HNPCC pts. |
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What causes Xeroderma pigmentosum?
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autosomal recessive caused by defects in the nucleotide excision repair pathway, pyrimidine dimers formed upon sunlight exposure are not repaired properly so these pts. are extremely intolerant to sunlight, at increased risk for developing skin cancer and cancer of tip of the tongue
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What type of mutation leads to the formation of an oncogene?
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gain of function, functions as a dominant mutation in the cell b/c one altered copy can exert its effect even when one normal copy of the gene is present
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Describe the RAS oncogene.
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happens in roughly 1/3 of human tumors, Ras becomes mutated (pt. mutation) such that it cannot hydrolyze GTP to turn off its signal response=growth signal sent into cell without the presence of mitogens,
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Describe the MYC oncogene.
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it is normally a TF that stim. expression of 15% of known genes, the MYC oncogene is NOT mutated in human tumors, it behaves as an oncogene when an abnormally large amount of the protein is synthesized in the cell
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What are the 2 types of genetic alterations that can lead to increased MYC synthesis?
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1)chromosomal rearrangement such that transcription of a normal MYC gene falls under control of a very active gene promoter (# of MYC mRNA transcripts is increased)
2)the MYC gene can become amplified such that one or more chromosomes contains multiple copies of the normal MYC gene (MYC mRNA transcripts are elevated due to increased copies of the MYC gene in the cell) |
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What causes Burkitt's lymphoma? What is it?
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a childhood cancer of the lymphocytes associated with infection by the Epstein-Barr virus or HIV, infection by these viruses is believe to trigger a chromosomal translocation btwn. portions of ch. 8 and 14 in lymphocyte cells-->a Normal copy of the MYC gene is positioned near a very active immunoglobulin promoter that directs high levels of expression the MYC gene=cell growth stim. by increasing transcription of growth-associated genes
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What is the Philadelphia chromosome?
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an abnormal version of ch. 22 that is found in 95% of all cases of CML (chronic myelogenous leukemia), created by the reciprocal exchange of portions of ch. 9 and 22, the break points lie within the coding sequences of the proteins abl and bcr, the translocation results in the creation of a fusion gene called BCR-ABL=oncogene
-bcr-abl gene possesses constitutively active tyrosine kinase acitivity (normal version of abl is dependent on growth signaling for tyrosine kinase activity)=cell proliferation |
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What is clonal expansion?
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the process of a single cell giving rise to a subpopulation of genetically identical cells
-many cancers thought to arise in this way |
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What are the 3 phases of tumor development?
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1)initiation
2)promotion 3)progression |
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What is the initiation phase of tumor development?
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a cell undergoes a mutation that has the potential to give the cell a growth advantage
-but with fully active cell cycle checkpoint mechanisms the growth of the cell is still restrained |
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What is the promotion phase of tumor development?
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initiated cells are exposed to agents which cause these cells (but not normal cells) to proliferate
-tumor promoters temporarily turn off cell cycle checkpoints to allow the initiating mutation to inappropriately drive cell division -tumor promoters DO NOT cause abnormal cell growth in normal cells, only mutated cells |
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What is the progression phase of tumor development?
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the cell begins to progress from a benign to a malignant tumor, the cell undergoes mutations in cell cycle checkpoint genes (such as p53) which compromise DNA repair and allow the cell to proliferate in the absence of a tumor promoter
-both an oncogene and an inactivated tumor suppressor must be present for tumor progression |
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What happens to tumors when they reach a point in their size where the inner cells become oxygen and nutrient starved?
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they can secrete a variety of growth factors such as VEGF to stimulate proliferation of endothelial cells and promote blood vessel development around the tumor
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In what 3 ways does angiogenesis support tumor development?
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1)provides oxygen to tumor cells
2)provides nutrients to tumor cells 3)facilitates access to the circ. system for metastasis |
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What defines a tumor as being malignant?
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if it has broken thorugh the basal lamina and invaded underlying tissue it is considered to be malignant
-also implies metastatic potential |
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How do malignant cells break through the basal lamina ?
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they secrete a family of proteases called "matrix metalloproteinases" (MMPs) that enable the cell to digest the basal lamina components and clear a path to the nearest blood vessel, cell then enters the lymph or blood where it can travel to other part of the body
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Where do most cancers of the GI tract metastasize to?
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usually in the liver...the capillary beds there
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On average, how much iron is in storage in the body?
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25% (mostly stored in resident macrophages)
-75% is in use in different proteins |
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How much iron, on average, is contained in the adult that weighs about 70kg?
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4g
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How much iron is in Hgb in our RBCs?
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2.5g
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Rank the four forms of iron in terms of increasing bioavailability.
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Elemental iron(Fe0)<Ferric Iron (3+)<Ferrous iron (2+) <<Heme
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Where is heme iron mainly found?
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in meat
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What would cause the bioavailability of ferric iron to be greatly decreased?
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individuals with achlorhydria (decreased HCl levels from gastric juice) b/c ferric iron is solubilized by the acidic pH in the stomach
-antacids also diminish the iron availability |
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Meal composition affects the iron bioavailability of all forms of iron. T or F
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False, it doesn't affect the bioavailability of heme iron b/c the porphyrin ring shields iron from dietary enhancers/inhibitors
-ONLY AFFECTS NON-HEME IRON |
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Name some enhancers of iron absorption.
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-Reducing molecules (ex. Vitamin C, sorbitol, fructose), vit. C reduces Ferric iron to ferrous iron and also can form complexes with ferrous iron which increase the bioavailability,
-Amino acids (fish and meat) -Acidic foods which increase gastric acid production |
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Name some inhibitors of iron absorption.
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-Phytates-(esp. high in cereal grains)form insoluble chelates with divalent cations (Fe2+, Ca2+, etc) thus decreasing mineral absorption
-Polyphenols-also form insoluble chelates with various divalent cations (ex. tannic acid in coffee and tea) -Phosphates and phosphoproteins-forms insoluble chelates with ferrous and ferric iron (egg yolk) -Oxalate-chelate non heme iron (ex. spinach) -Calcium or zinc |
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Are vegetarians at increased risk for becoming iron deficient?
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not necessarily b/c they eat more of the enhancer Vitamin C
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What does iron "uptake" mean?
What does "absorption" mean? |
uptake=iron from circulation moving into cells in body tissues
absorption=dietary iron moving through enterocytes into circulation |
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Where are heme iron and non-heme iron absorbed? (location)
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at the enterocytes of the duodenum and upper jejunum
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Describe how heme iron is absorbed.
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on the apical side of enterocytes, heme iron is taken up intact and then degraded by heme oxygenase (HO1) releasing iron in the enterocyte
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Describe how non-heme iron is absorbed.
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it is absorbed on the apical side of the enterocyte via DMT1, a specific carrier for non-heme iron
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What happens to cytosolic iron once it has been absorbed into the enterocyte?
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both heme and non-heme iron enter the same pool and is bound by mobilferrin-like transport proteins and then iron can be used for the formation of new iron-containing protein cofactors (heme groups, etc), iron can be stored in ferritin, excess iron stays in the enterocyte so excess iron is lost in the stool as cells are sloughed off
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What is mobilferrin?
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transports Fe through the enterocyte
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Where does export of iron from the enterocyte occur?
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on the basolateral surface via iron exporter ferroportin (FPN)
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Where is ferroportin found?
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only found in duodenal enterocytes, macrophages, hepatocytes and trophoblasts of the placenta
-AKA iron can only be mobilized from these cells once taken up |
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Why is unbound iron toxic?
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unbound iron (ferrous form) non-enzymatically catalyzes the formation of the highly destructive hydroxyl radical (OH*) = FENTON RXN
-these radicals can damage many cellular components |
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What is the fenton reaction?
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H2O2 + Fe 2+ -->Fe3+ + OH- + OH* (BAD!)
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What is transferrin?
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it is an Fe transport protein, it functions like mobilferrin but is located outside of the cells, it binds ferric iron with high affinity
its functions include: -solubilizes iron -attenuates iron reactivity -delivers iron to sites of use and storage |
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How many atoms of Fe3+ can transferrin bind?
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2
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What is apotransferrin?
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transferrin that is not bound to iron
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What is transferrin that is bound to one atom of iron called?
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monoferric transferrin
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What is transferrin that is bound to 2 iron atoms called?
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diferric transferrin
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What form is iron in outside of cells?
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always ferric iron (3+)
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How is iron taken up into growing cells?
|
all growing cells REQUIRE iron but iron cannot cross the lipid bilayer directly so all growing cells have transferrin receptors which bind and mediate the uptake of the iron-transferrin complex
-endocytosis of iron-transferrin complex and transferrin receptor results in the formation of an endosome which contains a proton pump (the iron-transferrin complex releases its iron as the endosome acidifies) -apotransferrina nd TfR are returned to the extracellular fluid and plasma membrane respectively=RECYCLING, THEY ARE TREE HUGGERS! :) |
|
|
What is ferritin?
|
an intracellular protein used to store iron, found in all cells but esp. prominent in macrophages of the liver, spleen, and bone marrow
|
|
|
Describe the entering and storage of iron in ferritin.
|
Fe2+ enters ferritin through pores where it is oxidized to Fe3+ and stored as iron microcrystals (this iron cannot catalyze the fenton rxn)
|
|
|
What is used to assess the quantity of intracellular ferritin?
|
serum ferritin levels b/c even though it is an intracellular protein, some of it is lysed and released through normal cell lysis and turnover
-also the best test to assess body iron stores |
|
|
What is Hemosiderin?
|
another form of ferritin that has been partially degraded in lysosomes, it stores iron that is insoluble and contains 30% more stored iron than ferritin (in humans, it is found in conditions of iron overload)
|
|
|
What is hepcidin?
|
it is a peptide produced by the liver hepatocytes that plays a major role in controlling iron egress from cells, it the the "iron hormone" that controls iron absorption and mobilization
|
|
|
How does hepcidin work?
|
it is secreted into the plasma and functions by binding ferroportin which induces the internalization by endocytosis and the degradation of ferroportin (therefore it prevents the release of iron from the cells containing ferroportin)
|
|
|
What happens when hepcidin levels are low?
|
the rate of ferroportin degradation are decreased and the absorption of dietary iron is increased, iron release from macrophages and hepatocytes is also increased
|
|
|
What happens when hepcidin levels are high?
|
the rate of ferroportin degradation is increased and absorption of dietary iron is decreased, iron stores are increased b/c iron release from macrophages and hepatocytes is decreased
|
|
|
What are some positive regulators of hepcidin?
|
these scenarios induce hepcidin production
-increased iron stores and plasma iron levels -infection and inflammation |
|
|
What are some negative regulators of hepcidin?
|
decreased iron stores and plasma iron levels
-hypoxia -increased erythroid demand (very important implications in cases of anemia) |
|
|
What is lactoferrin?
|
a natural defense iron-binding protein that is similar in structure to transferrin, it is made by neutrophils during inflammation and infection
|
|
|
Where is lactoferrin bound iron stored?
|
in macrophages which contributes to hypoferremia seen during infection/inflammation, this limits bacterial growth and hydroxyl radical formation (the concentration of H2O2 increases during infection which would increase the likelihood of the Fenton rxn if excess iron wasn't being taken out of circulation)
|
|
|
What do infection and inflammation signal macrophages to do?
|
it stimulates macrophages to release IL1-stimulates neutrophils to produce lactoferrin which binds iron and transports it to macrophages for storage, also increases the rate of RBC phagocytosis (can slow down erythropoiesis)
IL6-stimulates the liver to release hepcidin which lowers ferroportin levels in macrophages and limits the amount of iron available to bone marrow for RBC production |
|
|
What is anemia of chronic disease?
|
hypoferremia caused by chronic infection or inflammation that results in anemia
-anemia due to chronic high hepcidin levels=inadequate iron being delivered to the bone marrow |
|
|
How is excess iron eliminated from the body?
|
there is no way other than blood loss
or a VERY SMALL amount from cells sloughing off and defecation |
|
|
How much iron does 1 mL of blood contain?
|
0.5 mg
|
|
|
What is the most common cause of iron deficiency in the US?
|
acute or chronic blood loss
|
|
|
What are the 4 criteria defined under the term DRI?
|
Estimated average requirement, recommended dietary allowance, adequate intake, upper limit
|
|
|
What is the EAR (estimated average requirement)?
|
the quantity of nutrient required to meet the needs of half the population, in other words, the intake at which the risk of inadequacy is fifty percent
|
|
|
What is the RDA (recommended dietary allowance)?
|
the intake at which the risk of inadequacy is 2-3%, based on the EAR plus 2 standard deviations (will meet the need of about 98% of the pop.)
|
|
|
What is the upper limit?
|
at an intake above the UI, risk of adverse effects increases
|
|
|
What is adequate intake?
|
does not bear a predicable rlthshp. with EAR or RDA, it is based on an estimate of nutrient intake of healthy people
|
|
|
What do DRIs vary with? (what factors)
|
age, gender, weight, energy consumption and protein intake, pregnancy and lactation
|
|
|
DRIs give recommendations for what type of nutrient?
|
micronutrients
|
|
|
WHat are the 4 macronutrients?
|
fat, carbs, protein, fiber
|
|
|
What is the EER? (estimated energy requirement)?
|
the average caloric intake needed to maintain energy balance in 50% of the adult population
|
|
|
What is energy balance?
|
the difference btwn. energy intake and energy expenditure
energy intake-energy expenditure +=weight gain -=weight loss |
|
|
What are the 3 components of energy expenditure?
|
RMR, TEF, physical activity
|
|
|
How many calories come from each of the macronutrients?
|
fat=9 kcal/g
protein=4 carbs=4 alcohol=7 |
|
|
How is metabolic rate usually measured?
|
using indirect calorimetry which uses a face mask to quantitate CO2 expired and O2 consumed (this is proportional to the calories burned to do metabolic work within the body)
|
|
|
What is RMR?
|
resting metabolic rate is equivalent to the number of calories used in a fasting individual at rest (makes up the largest portion of our daily energy expenditure)
-it is proportional to LBM therefore women have lower RMR than men b/c they have more body fat |
|
|
What effect does starvation have on the RMR?
|
it decreases it
|
|
|
What is the MET?
|
physical activity is reported as this, it is the ratio of the metabolic rate of the active individual to the metabolic rate of the fasting individual at rest
ex:someone exercising at METs is exercising at an intensity that is 4 times RMR |
|
|
How do you calculate energy spent during activity using MET?
|
MET value of activity X body weight (kg) X duration (hrs)
|
|
|
What is NEAT?
|
one of the components of physical activity, any other physical movement that is not bodily exertion for the sake of developing or maintaining physical fitness such as walking, driving, reading, etc...
|
|
|
What is TEF (thermic effect of food)?
|
the rise in the metabolic rate induced by eating
-it is the difference btwn. the postprandial metabolic rate and the RMR -protein rqrs. the most amount of energy to digest |
|
|
How are daily caloric needs estimated?
|
RMR + physical activity + TEF
|
|
|
How is the RMR calculated?
|
Men: body wt (KG) X 1 Kcal/kg/hr X 24 hrs
Women: body wt X 0.9 kcal/kg/hr X 24 hrs |
|
|
How are caloric needs for physical activity calculated?
|
by using an activity level chart which shows the percent of the RMR that the activity costs a person
|
|
|
How is TEF calculated?
|
it is 10% of the calories needed for RMR + physical activity
TEF=(RMR+physical activity)0.10 |
|
|
What are the dietary and lifestyle recommendation of the USDA and DHHS?
|
maintain a healthy weight (within 5-10 lbs at age 20)
-be physically active everyday (30=reduce chronic disease, 60=prevent weight gain, 90=sustain weight loss) -lots of fiber, fruits, low SF, low sodium, alcohol in moderation, etc.. |
|
|
What is the purpose of the nutritional assessment?
|
to make a diagnosis of obesity or malnutrition
to determine when to screen for disease to establish the adequacy of a diet to start developing a nutritional care plan |
|
|
What are the ABCDs of nutritional assessment?
|
anthropomorphic measurements such as ht. and wt.
-Biochemical parameters (lab tests for prealbumin, iron, B12) -Clnical evaluation Dietary history |
|
|
What is the single most significant measure of nutritional status?
|
body weight, that is why serial weight measurement are done and are compared to one's "usual" weight
|
|
|
WHat are the 4 macronutrients?
|
fat, carbs, protein, fiber
|
|
|
What is the EER? (estimated energy requirement)?
|
the average caloric intake needed to maintain energy balance in 50% of the adult population
|
|
|
What is energy balance?
|
the difference btwn. energy intake and energy expenditure
energy intake-energy expenditure +=weight gain -=weight loss |
|
|
What are the 3 components of energy expenditure?
|
RMR, TEF, physical activity
|
|
|
How many calories come from each of the macronutrients?
|
fat=9 kcal/g
protein=4 carbs=4 alcohol=7 |
|
|
How is metabolic rate usually measured?
|
using indirect calorimetry which uses a face mask to quantitate CO2 expired and O2 consumed (this is proportional to the calories burned to do metabolic work within the body)
|
|
|
What is RMR?
|
resting metabolic rate is equivalent to the number of calories used in a fasting individual at rest (makes up the largest portion of our daily energy expenditure)
-it is proportional to LBM therefore women have lower RMR than men b/c they have more body fat |
|
|
What effect does starvation have on the RMR?
|
it decreases it
|
|
|
What is the MET?
|
physical activity is reported as this, it is the ratio of the metabolic rate of the active individual to the metabolic rate of the fasting individual at rest
ex:someone exercising at METs is exercising at an intensity that is 4 times RMR |
|
|
How do you calculate energy spent during activity using MET?
|
MET value of activity X body weight (kg) X duration (hrs)
|
|
|
What is NEAT?
|
one of the components of physical activity, any other physical movement that is not bodily exertion for the sake of developing or maintaining physical fitness such as walking, driving, reading, etc...
|
|
|
What is TEF (thermic effect of food)?
|
the rise in the metabolic rate induced by eating
-it is the difference btwn. the postprandial metabolic rate and the RMR -protein rqrs. the most amount of energy to digest |
|
|
How are daily caloric needs estimated?
|
RMR + physical activity + TEF
|
|
|
How is the RMR calculated?
|
Men: body wt (KG) X 1 Kcal/kg/hr X 24 hrs
Women: body wt X 0.9 kcal/kg/hr X 24 hrs |
|
|
How are caloric needs for physical activity calculated?
|
by using an activity level chart which shows the percent of the RMR that the activity costs a person
|
|
|
How is TEF calculated?
|
it is 10% of the calories needed for RMR + physical activity
TEF=(RMR+physical activity)0.10 |
|
|
What are the dietary and lifestyle recommendation of the USDA and DHHS?
|
maintain a healthy weight (within 5-10 lbs at age 20)
-be physically active everyday (30=reduce chronic disease, 60=prevent weight gain, 90=sustain weight loss) -lots of fiber, fruits, low SF, low sodium, alcohol in moderation, etc.. |
|
|
What is the purpose of the nutritional assessment?
|
to make a diagnosis of obesity or malnutrition
to determine when to screen for disease to establish the adequacy of a diet to start developing a nutritional care plan |
|
|
What are the ABCDs of nutritional assessment?
|
anthropomorphic measurements such as ht. and wt.
-Biochemical parameters (lab tests for prealbumin, iron, B12) -Clnical evaluation Dietary history |
|
|
What is the single most significant measure of nutritional status?
|
body weight, that is why serial weight measurement are done and are compared to one's "usual" weight
|
|
|
Which vitamins are stored in large quantities?
|
B12 and Vitamin A (body stores could last for years)
|
|
|
What are some sources of vitamin depletion?
|
dietary-malnutrition, life style choices, food faddism
malabsorption-alcoholism, GI diseases, GI surgeries, lack of bile salt excretion to fat soluble vitamins increased demand-pregnancy and lactation, alcoholism, stress increased loss-excretion, hemodialysis which removes water soluble vits. |
|
|
Which vitamins will have adverse effects if taken in high doses?
|
ADEK, C, niacin, folate, B6
|
|
|
Causes for Thiamine deficiency.
|
prego and bfing, chronic illness, eating anti-thiamine factors such as certain plant products (coffee, tea, betel nuts contain thiamine antagonists), consumption of raw fish (thiaminases)
alcoholics and then the other obvious reasons for vit. defic. |
|
|
Sx of Thiamine deficiency.
|
neural and cardiac tissues primarily affected from decreased ATP production
|
|
|
What is beriberi?
|
caused by thiamine deficiency, it is a peripheral neuropathy (dry) in which there is weakness, burning feet syndrome, abnormal sensations in arms and legs, mm. pain, seizures,
-in wet beriberi cv sx appear with tachycardia, heart enlargement and edemas and CHF |
|
|
What is cerebral beriberi? (central neuropathy)
|
occurs mostly in alcoholics
-wernicke's encephalopathy-triad of nystagmus, confusion, gait and stance problems (ataxia) -Korsakoff's psychosis-memory disorder, amnesia =WKS |
|
|
Drug interaction for Thiamine deficiency.
|
5-fluorouracil b/c it prevents conversion of thiamine to TPP (this drug is an irreversible inhibitor of thymidylate synthase)
|
|
|
Drug interactions for B6?
|
L-dopa
Isoniazid |
|
|
Symptoms of overdose for B6.
|
>1000mg/day
causes painful neurological sx called sensory neuropathy |
|
|
Sx of B3 deficiency (niacin).
|
Pellagra=rough skin is the late stage name
The 4 D's: dermatitis, dementia, death, diarrhea |
|
|
Currently in the US, in what population is Pellagra most often observed?
|
alcoholics
also seen in those with Hartnup disease (b/c cannot transport Tryptophan) |
|
|
Drug interactions for Niacin (B3) deficiency?
|
5-fluorouracil b/c inhibits the conversion of tryptophan to nicotinic acid
-long term admin. usually causes sx like Pellagra |
|
|
What are the sx of B12 deficiency?
|
neurological dysfunction, megaloblastic, macrocytic anemia, RBC production of insufficient and ineffective
|
|
|
What population is at increased risk of B12 deficiency?
|
vegans and vegetarians
|
|
|
What are the sx of folate deficiency?
|
macrocytic, megaloblastic anemia, Neural tube defects in developing fetuses,
|
|
|
What population is at increased risk for folate deficiency?
|
alcoholics, pregnant women b/c of growth of the fetus putting increased demand on amount of folate needed
|
|
|
Drug interactions for folate?
|
methotrexate-inhibits dihydrofolate reductase and casues a functional folate deficiency
|
|
|
Drug interactions for B12?
|
excess folic acid b/c it masks B12 deficiency which can lead to irreversible neural defects
|
|
|
Active forms of Vitamin A.
|
retinol, retinal, retinoic acid
|
|
|
Functions of Vitamin A.
|
Retinal=vision, reproduction
Retinoic acid-controls gene expression of genes involved in regulation of cell growth, differentiation, and morphogenesis (inhibits keratin synthesis) |
|
|
Main source of Vitamin A.
|
provitamin A found in colored leafy green veggies
|
|
|
Who is at risk for becoming Vit. A deficient?
|
rare in the US, common in developing countries, alcoholism, Crohn's disease, any disease with fat malabsorption
|
|
|
Sx. of Vitamin A deficiency.
|
night blindness, hyperkeratosis of the skin due to decreased inihibition of keratin formation), severe deficiency leads to xeropthalmia
|
|
|
Toxicity of Vitamin A.
|
isotretinoin, an oral drug against severe acne is teratogenic so pregnancy must be excluded in treatment
-excessive intake of Vit A saturates the stores in the liver which can lead to hypervitaminosis A=dry skin, liver abnormalities, and CNS disorders |
|
|
Vitamin K function.
|
cofactor for carboxylation of glutamate residues to form carboxyglutamate on clotting factors for fibrin formation and hemostasis
-functions in clotting in other words |
|
|
Who is at risk of a vit K deficiency?
|
it is rare, newborns are at risk b/c intestines are sterile, vit K cannot easily cross the placenta and breast milk and formula are low in vit K
|
|
|
Sx of vit K deficiency?
|
increased bleeding tendency
|
|
|
Toxicity of Vit, K?
|
prolonged admin could lead to destruction of membranes of RBC's and lead to hemolytic anemia and jaundice
|
|
|
How are ROS species formed?
|
oxidative metabolism, rxn with metal ions, rxn with drugs, rxn with environmental toxins
|
|
|
Under normal conditions, when would ROS be useful?
|
serve as gene expression factors, local hormones (NO for vasodilation)
|
|
|
What are sources for ROS?
|
1)mitochondrial sources (90%)- ETC, coenzyme Q major culprit b/c it transfers e- from complex 1 and 2 to complex 3, accidental reduction of oxygen produces a superoxide radical
2)extramitochondrial |
|
|
Describe the extramitochondrial sources for ROS production.
|
1)formation by heme-bound iron-heme bound ferrous iron can react with oxygen to ferric iron producing superoxide radicals (formation of methemoglobin and cytochrome p450 enzymes)
2)formation of H2O2 and hydroxyl radical-superoxide radicals can react with any reducing agent to produce H2O2 which then reacts with free ferrous iron to produce hydroxyl radicals 3)radical formation by radiation-generates hydroxyl radicals from H2O |
|
|
How do ROS contribute to immune defense?
|
activated phagocytic cells generate radicals to kill endocytosed bacteria, NADPH oxidase catalyzes the formation of superoxide radicals in a respiratory burst
-in neutrophils, myeloperoxidase catalyzes formation of hypochlorous acid (powerful antibac. agent) |
|
|
What is chronic granulomatous disease?
|
a deficiency of NADPH oxidase in which patients suffer severe, persistent bacterial infections
|
|
|
What is lipid peroxidation?
|
a specific type of oxidative damage to membranes by a hydroxyl radical, the ROS attach polyunsaturated FAs, a hydroxyl radical removes a hydrogen atom from a C atom forming a radical, this radical then reacts with O2 forming peroxide radical, a chain rxn starts when the peroxide radicals react with other FAs and causes conversion of many hundred FA side chains into lipid peroxides altering the arrangement of amphipathic phospholipids=accumulation of altered lipids causes leaks in membranes=CELL DEATH!
|
|
|
Name the antioxidant enzymes.
|
superoxide dismutase, catalase, glutathione peroxidase
|
|
|
What are the endogenous antioxidants?
|
uric acid, glutathione
|
|
|
What are the exogenous antioxidants?
|
essential from the diet
carotenoids (provitamin A) Vit. E Vit. C phytochemicals (flavonoids, tannins, lignans) |
|
|
What does superoxide dismutase do?
|
accelerates the conversion of superoxide radicals to H2O2
|
|
|
What is amyotropic lateral sclerosis associated with?
|
-10% are correlated with a loss of function mutation in the SOD gene (superoxide dismutase)
-lack of SOD also associated with Parkinsons |
|
|
What do catalase and glutathione peroxidase do?
|
enzymes that detoxify H2O2
catalase-commonly in peroxisomes (contains heme) glutathione peroxidase-more abundant than catalase -needs selenium as cofactor -uses glutathione as substrate |
|
|
What is the cofactor for glutathione peroxidase?
|
selenium
|
|
|
Describe glutathione.
|
it is a tripeptide with a SH group, when oxidized it forms a disulfide with itself or with sulfhydryl groups in proteins, synthesis needs ATP and AAs, synthesis can be stimulated by kale, leek, strawberries, turmeric, garlic
|
|
|
Active forms of Vitamin C.
|
ascorbate and dehydro-ascorbic acid
|
|
|
Function of vitamin C.
|
reducing agent, water soluble radical scavenger, recycles vitamin E, cofactor for iron/copper containing compounds, synthesis of carnitine, norepi, and bile acid, enhances absorption of dietary iron
|
|
|
Deficiency of vitamin C causes what?
|
long term depletion leads to scurvy, gum bleeding, loose teeth, corkscrew hairs,
|
|
|
Causes of vit. C deficiency.
|
about 3 months w/o fresh fruit or veggies, alcoholism, smoking increases demand
|
|
|
Toxicity of Vitamin C?
|
not likely b/c blood vit. C levels are regulated by transporter activity for intestinal absorption and renal reabsorption, but high doses on a daily basis can lead to diarrhea and kidney stones
|
|
|
Active form of Vit. E?
|
alpha tocopherol
|
|
|
Function of Vitamin E?
|
antioxidants, combines with free radicals to form quinone intermediates (fairly stable which terminates the radical chain rxn.), can be regenerated to alpha tocopherol using L-ascorbate or other reducing agents or degraded to inactive products and excreted
|
|
|
Is vitamin E stored?
|
no, excess vit. E is degraded in the liver
|
|
|
Deficiency of Vitamin E.
|
extremely rare, almost entirely restriced to premature infants with defective lipid absorption or transport
sx include:retinopathy and peripheral neuropathy |
|
|
Toxicity of Vitamin E.
|
least toxic of fat soluble but can interact with vitamin K and inhibit platelet activity=increased risk of bleeding
|
|
|
Sx of selenium overdose.
|
called selenosis, nair and hair brittleness, garlic odor, abnormalities of nervous system
|
|
|
Vitamin A is a powerful antioxidant. T or F?
|
false, in lab carotenoids do but not sure if they have same function in body
|
|
|
What is an incomplete carcinogen?
|
a carcinogen that only acts as an initiator or promoter
|
|
|
What is a complete carcinogen?
|
an agent that can act as an initiator and tumor promoter in the same tissue (such as tobacco)
|
|
|
What are the 2 classes of carcinogens?
|
initiating agents
tumor promoters |
|
|
What is the Ames test?
|
developed to rapidly assess the mutagenic ability of suspected carcinogens, it uses bacteria whose genome has been previously modified to introduce either a frameshift or pt. mutation in a gene necessary for the synthesis of an AA (usually histidine), exposure to a mutagen neutralizes the mutation so function of gene is restored
-can also be used to detect the carcinogenicity of "precarcinogens" -does not show effects of tumor promoters |
|
|
How does the Ames test detect the carcinogenicity or precarcinogens?
|
incubates the suspected carcinogen with or without liver homogenate (rich in p450 enzymes) prior to plating
|
|
|
Normal BMI range.
|
18.5-24.9
|
|
|
Overweight BMI.
|
25-29.9
|
|
|
Obese BMI.
|
>30
|
|
|
What is the definition of obesity based on?
|
the relationship between BMI and premature death
|
|
|
What is hypertrophy?
Hyperplasia? |
hypertrophy=adipocytes increase in size
hyperplasia=increase in the number of adipocytes -in obesity there is both |
|
|
What molecule is required for fat cell development?
|
the Transcription factor PPAR, it is regulated by FFAs and their metabolites, activation of PPAR promotes both hypertrophy and hyperplasia
|
|
|
What are the 5 categories of genes involved in obesity?
|
hyperphagic (appetite regulation)
sedentary (NEAT) mitochondrial efficiency low lipid oxidation hyperplastic |
|
|
How many americans are obese?
|
>30%
|
|
|
Describe the set point defense that happens when people try to lose weight.
|
there appears to be a genetically determined "set point" for weight, wt. loss triggers positive energy balance
1)increase in energy intake (strong hyperphagia response) 2)decrease in energy expenditure (decreased RMR) -wt loss plus decrease in caloric intake triggers a 15% decrease in RMR (true for obese or non-obese and this decrease will be maintained for years) -decreased RMR minimizes any further wt. loss (lowering RMR during a famine increases survival=evolutionary advantage) -decrease in T3 (thyroid hormone) levels contributes to decreased RMR |
|
|
How does T3 contribute to regulating RMR?
|
it regulates the level of Na/K ATPase and lipid oxidation (Na/K ATPase accounts for 20% of RMR)
|
|
|
How does wt. gain trigger set point defense?
|
it triggers a negative energy balance
1)activation of satiety center (initially) 2)increase in energy expenditure (increase in RMR and NEAT) -not everyone returns to set point after over eating episodes (=obesity) -control mechanism is slightly biased in favor of preserving fat=survival value -energy balance rqrd to maintain wt. is controlled within 10 to 20 Kcal/day (that's one potato chip) so the control mechanism is very important |
|
|
Is NEAT genetic or a choice?
|
they think it's genetic b/c when they did studies of ppl with a low and high BMI, those with a higher BMI were seated longer than leaner participants even when they lost weight and vice versa
|
|
|
What do POMC neurons do?
|
they are a pop. of neurons in the hypothalamus that produce alpha-MSH that inhibits appetite and increases Energy expenditure
|
|
|
What do Neuropeptide Y and AgRP do?
|
they stimulate appetite and decrease energy expenditure in the hypothalamus, cause infertility
|
|
|
What does Leptin do to appetite?
|
it suppresses it
|
|
|
What does Ghrelin do to appetite?
|
it stimulates it
|
|
|
What does Leptin do to NPY?
|
it inhibits its release b/c it suppresses appetite
|
|
|
What is the receptor for alpha MSH called?
|
MC4R
|
|
|
What does AgRP do to alpha MSH?
|
it inhibits the release of MSH and blocks the MC4R receptor
|
|
|
What effect does fasting have to increase appetite?
|
it stimulates the release of Ghrelin from the stomach which increases appetite by increasing NPY,
|
|
|
How do meals make us feel full?
|
1)GLP-1-release triggered by glucose and fat in meal, decreases appetite by increasing alpha-MSH
2)CCK-release triggered by AA and lipids in meal, decreases appetite in satiety center 3)vagus nerve monitor distension of stomach and intestine |
|
|
What does PYY do?
|
it inhibits appetite by inhibiting the release of neuropeptide Y
|
|
|
What is leptin?
|
it is a peptide hormone produced in adipose tissue and levels are proportional to fat stores, it regulates long term energy balance
-high leptin levels inhibit appetite and energy expenditure by inhibiting synthesis and release of NPY, stimulates synthesis and release of alpha-MSH |
|
|
Why doesn't Leptin cause weight loss in obese individuals?
|
b/c they develop a resistance to leptin, so even though their leptin levels are high due to more fat stores, they are resistant to its normal effects
|
|
|
How does low leptin and insulin stimulate appetite?
|
by decreasing alpha-MSH synthesis and increasing NPY and AgRP,
-leptin is better at preventing wt. loss than preventing wt. gain |
|
|
What is the correlation between sleep deprivation and leptin?
|
sleep deprivation is correlated with a decrease in leptin and an increase in ghrelin
|
|
|
What happens to appetite when there is a lack of insulin as in Type I DM?
|
appetite is increased because there is increased NPY/AgRP,
-leads to polyphagia (3 P's of diabetes) |
|
|
How does obesity lead to insulin resistance?
|
there is an increase in inflammation, the number of macrophages in the adipose tissue increases and they release proinflammatory cytokines which trigger IR
|
|
|
How much weight would someone have to lose to see health benefits?
|
7-10%
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What are the criteria for evaluating weight loss diets?
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is the diet sustainable for a lifetime
does the diet conform to the dietary guidelines for americans and mypyramid.gov is an exercise program part of the diet plan |
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FOr a given meal, what is appetite based on?
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the volume (or weight) of the food, not Kcal
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Normal BP.
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<120/<80
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Prehypertension.
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120-139/80-89
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Hypertension.
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>140/>90
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What contributes to the age related rise in BP?
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mostly lifestyle factors, in non-industrialized societies who consume a low sodium diet, the age related rise in BP is not seen
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What is the relationship between obesity and HTN?
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direct linear relationship
-20-30% of all HTN is due to obesity |
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How does obesity lead to HTN?
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increased peripheral resistance, increase Na intake, overeating causes thyroid hormone which increases Beta adrenergic receptors and leads to vasoconstriction, insulin resistance and central obesity, decrease NO formation,
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How does Na increase blood pressure?
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salt intake increases water intake and retention, the increase in plasma volume increases CO and arterial pressure,
-30-50% of ppl with HTN are NaCl sensitive |
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In which populations is the effect of NaCl on BP more pronounced? (who would likely benefit from a decrease of salt in their diet?)
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older patients
aftrican americans obese pts diabetic pts hypertensive pts individuals with a family hx of HTN (even if the individual is normotensive) |
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What is the prinicipal cause of HTN in the US?
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excess salt
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What is the UL for sodium?
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2400 mg, or 6 gm NaCl/day <25 years of age
-1300 mg Na or 3.25 g NaCl/day >25 years old |
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Which type of sodium causes an expansion of plasma volume and a rise in BP?
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only NaCl
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How does potassium affect BP?
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inverse relationship, a low potassium diet is associated with an increase in BP
-low K diet causes Na retention -K is most effective in salt-sensitive individuals -K increases Na excretion by kidney |
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How do fish oil supplements affect BP?
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fish oils lower BP, studies showed no effect in normotensive ppl and dose-response in hypertensive individuals
-Omega-3 FAs are used to synthesize prostaglandins which help regulate vascular resistance and renal blood flow |
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What is the relationship between BP and Ca?
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the relationship is controversial, meta analysis found an inverse relationship between the two, low Ca diet may amplify effect of a high salt diet on BP
-diets with less than 600 mg/d of Ca most clearly associated with HTN -higher Ca intakes in ppl with adequate Ca may have no BP lowering effect tho |
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Relationship between fiber and HTN?
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fiber lowers BP in hypertensive adults, fiber may prevent Na absorption on the intestine or decrease insulin resistance
- |
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What does the DASH diet decrease risk of?
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hypertension, CHD, stroke, osteoporosis, cancer, and improves insulin sensitivity
-reductions in BP occurred within 2 wks of adopting the diet |
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What is the DASH diet?
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low cholesterol, low SF, decreases LDL, and lowers BP, eat the most servings of whole grains (7-8 day), then next is veggies and fruits (4-5 day), low fat dairy products, meat, fish , poultry, and nuts, seeds and dry beans, 27% of calories from fat (not a low fat diet)
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What are the 5 strategies to lower BP or prevent it from rising as one ages?
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lose excess weight
DASH diet exercise daily limit salt limit alcohol |
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Where is Calcium absorbed in the body?
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primarily in the intestine
-90% in sm. intestine -mostly ileum-paracellular jejunum-paracellular duodenum-transcellular -10% in colon-paracellular |
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What inhibits Ca absorption?
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many of the same things that inhibit absorption of iron
Phytates polyphenols oxalate |
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What physiological factors would increase the efficiency of Ca absorption?
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low Ca diets, and growth, pregnancy and lactation
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Describe paracellular absorption of Ca.
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between cells, through tight junctions, not dependent on Vitamin D, diffusion based, nosaturable and unregulated,
-proportional to dietary Ca levels and time required for chyme passage, -Ca intake needs to be adequate or high to use this pthway |
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How should Ca supplements be taken to optimize absorption?
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3 doses of <500 mg and taken with meals to maximize the paracellular pthway
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Describe paracellular absorption of Ca in the colon.
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fermentation of prebiotics favor Ca absorption in the colon
-prebiotics are primarily nondigestible oligosaccharides (soluble fiber) that stimulate growth of intestinal bacteria which lowers the colonic pH -low pH increases the solubility of Ca and bioavailability via paracellular route |
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How does low pH in the colon increase the bioavailability of Ca?
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lower pH minimizes the quantity of deprotonated phosphate available to form insoluble calcium phosphate
(in cells and fluids, the body keeps phosphate and Ca separate for this reason) |
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When does transcellular absorption of Ca play a significant role in the body?
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when dietary Ca is low
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Active form of Vitamin D?
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calcitriol (1,25(OH)2D3)
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Describe transcellular absorption of Ca in duodenum.
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active transport dependent upon vitamin D, it is saturable and expression regulated only by active vitamin D
-calcitriol binds vitamin D receptor (transcription factor) which bind to nuclear DNA and control synthesis of apical membrane Ca channels, calbindin, Ca ATPase, and Na/Ca exchanger |
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Describe the mechanism of transcellular transport of Ca in duodenum.
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1)Ca enters apically through epithelial Ca channels TRPV5 (kidney) and TRPV6 (intestine)
-this transport is high to low concentration 2)cytosolic diffusion bound to calbindins -they bind to Ca at cell surface and prevent its use in signaling and ppt with phosphate 3)extrusion across the basolateral membranes by the Ca/ATPase (PMCA1b) and NA/Ca exchanger (active/secondary active transport) |
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Food sources of Vitamin D.
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fortified milk, cereals, fatty fish
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How is vitamin D made?
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in the skin from 7-dehydrocholesterol in a nonenzymatic rxn catalyzed by UV light which makes cholecalciferol
-then must be hydroxylated to active form -calcidiol in liver by at least 2 25-hydroxylase enzymes and calcitriol in kidney via 25(OH)D3-1alpha-hydroxylase in mito. |
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What does decreasing plasma Ca do to PTH secretion?
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it stimulates the release of PTH (as does vitamin D deficiency)
-PTH then activates renal 25-(OH)D3-alpha hydroxylase which catalyzes formation of 1,25(OH)2D3 -PTH and 1,25(OH)2D3 act together to enhance renal reabsorption (mainly in PCT) of Ca and mobilize Ca stores from bone |
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What does 1,25(OH)2D3 do to intestinal absorption of dietary Ca?
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it increases it, rationale for co-supplementation of vit. D and Ca
-sufficient vitamin D suppresses PTH secretion |
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What effect does dietary NaCl have on urinary Ca losses?
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it increases urinary Ca losses (calciuria, only seen when using NaCl, not just Na+)
Na and Ca compete for the same reabsorption mechanism |
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When does calciuria due to Na+ become a problem?
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when Ca homeostasis is compromised
-absorptive compensation will occur normally (PTH, vitamin D) but middle aged women may have a problem with this -loss of estrogen will compromise absorptive compensation -increasing PTH and decreasing Ca will further compromise bone |
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What counteracts the effect of NaCl on urinary Ca?
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potassium citrate,
-K and bicarb anion from citrate act in distal renal tubule to facilitate reabsorption of Ca outcompeted by Na in proximal tubule -fruits and veggies are a good source of this and appear to protect bone health |
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What effect does increased (overcorrected) plasma Ca have on the thyroid gland?
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stimulates the thyroid to release calcitonin which blocks bone Ca mobilization and regulates Vit. D for noncalcemic needs
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How is a diagnosis of osteoporosis made?
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body Ca stores are assessed using Bone mineral density in the spine, hip and wrist using DXA (or other methods)
-normal BMD is defined as no lower than 1 SD below mean BMD of young healthy adults -osteopenia=BMD between 1 and 2.5 SD below mean (-1 to -2.5) -osteoporosis-T score <-2.5 |
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What is the Z-score?
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# of SD from mean of age and gender matched population (pt. compared to peers)
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What's a normal T score?
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-1 or above
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What is the incidence of osteoporosis?
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38% of postmenopausal women exhibit osteopenia
-20% of white women post menopausal exhibit osteoporosis -15% mexican american 8% AA |
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What height change is a warning sign of osteoporosis?
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a decrease of >1.5 inches from premenopausal height
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What are the risk factors for osteoporosis?
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1)aging-estrogen deficiency related bone loss in women, age related in both sexes
sarcopenia-decrease in mm strength with age increases risk of fracture 2)low peak BMD at age 30 -peak BMD attained by age 30 and is most important determinant of life-long skeletal health (genetics and environment) 3)menopause-15% loss of bone over 5 years |
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What is senescence related bone loss?
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starts btwn 35 and 45 Y.O.
-Ca absorption decreases with age -vitamin D synthesis decreases with age -skeletal reserves are used, decreasing BMD, aggravated by decreased exercise with age -vitamin D and Ca supplements help |
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When does peak Bone mineral density occur in women? men?
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99% at 26 years old
about 1.5 years later in men |
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How does estrogen work to slow bone loss?
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-inhibits osteoclasts
-transcriptional activation of Ca import machinery in enterocyte -triggers buildup of Ca reserves in bone from which Ca can be released during pregnancy and lactation |
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How can osteoporosis be prevented?
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-acheive genetically determined peak BMD
-increase wt. bearing exercise -increase Ca intake throughout life -increase vit. D intake or get plenty of sunshine -diet rich in fruits and veggies -avoid smoking, use alcohol in moderation |
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How are carcinogenicity studies in animals performed?
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by exposing different groups of animals to increasing dosages of carcinogen and examining effects on tumor development
-if cancer rates increase as the dose increases it provides strong evidence that the chemical casues cancer in animals |
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What type of carcinogens generally exhibit a linear correlation between carcinogen dose and tumor development?
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initiating agents (greater concentrations of mutagen increase the changes of DNA mutations)
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What are the pitfalls in animal dose-response studies?
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to speed things along and minimize animals use, researchers use much higher dosages of chemicals to induce tumor formation, they can then mathematically extrapolate data for lower dosages if response is linear
-many carcinogens are associated with a threshold model below which the changes of tumor formation are minimal and this linear extrapolation is highly inaccurate -this can overestimate risk of cancer |
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What is the Delaney Amendment?
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has been used to prohibit the use of certain pestcides, coloring agents, and food additives if found to cause cancer in man or experimental animals, but the exact conditions under which agents were shown to cause cancer was not specified
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What are the 5 types of bias in epidemiological studies?
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1)selection bias-volunteer participants may skew to one type of group or possess certain lifestyle characteristics that contribute to the outcome being tested
2)experimenter bias-when scientists are influenced by additional factors that influence their objective evaluation of the data 3)detection bias-detection of cancer incidence of one population may be skewed by a completely unrelated factor 4)publication bias- 5)confounding factors-related to factor being investigated but independently affect risk, often complicate results of studies |
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What is meta-analysis?
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statistical means of examining the results of several independently conducted prior studies to derive general conclusions
-frequently used in cancer studies |
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In the American Institute for Cancer Research meta-analysis, what was shown to increase the risk of cancer?
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1)red meat and processed meat (bacon, lunchmeats,etc)
2)salted food 3)alcohol 4)obesity |
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Why are certain cooked meats associated with carcinogens?
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b/c cooking mm. meats at high temps. causes AA to react with creatine forming carcinogenic heterocyclic amines
-these form DNA adducts and chromosomal breaks introducing mutations into cells of digestive system -they enter the body as precarcinogens and are metabolized by the P450 system into carcinogens |
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What are Polycyclic aromatic hydrocarbons?
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can be formed when fat from meat drops onto a hot fire during the grilling process
-PAHs are carried in the smoke and coat the surface of the food -they are bulky and can form either stable or depurinating DNA adducts introducing mutations=initiators |
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Describe carcinogenic effect of processed meats with sodium nitrite.
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nitrite is the conjugate base of nitrous acid which oxidatively deaminates primary aromatic amines resulting in base mispairing and eventual mutation of newly made DNA
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Describe the carcinogenic effects of salt.
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increased risk of stomach cancer, a high salt intake damages the stomach lining causing cell proliferation
=tumor promoter |
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Describe the carcinogenic effect of alcohol.
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in the mouth, oral bacterial metabolize salivary alcohol to acetaldehyde which can act as an initiating agent facilitating DNA mutation by:
-directly causing pt. muts. -directly causing DNA adducts -bind to and inactivate DNA repair proteins |
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Why does physical activity decrease the risk of cancer?
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active ppl have lower levels of circulating hormones associated with body fat which would otherwise contribute to colon and breast cancer progression,
-when ppl of same wt. are compared, those who are physically active still have lower cancer rates than their inactive counterparts -BOTTOM LINE: WE DON'T REALLY KNOW Y THIS DECREASES CANCER RISK |
