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Devendra Block 2 Flashcards

1
Q

Major Treatments (directed @ clinical phenotype)

A
  • Supportive: Decrease symptoms
  • Product def : Give product exogenously
  • Substrate def : Give substrate exogenously
  • Gene Therapy: Still too primitive to be viable
  • Treat clinical phenotype - Limit UV exposure in albinism, Pharm intervention (beta blockers - marfan syndrome), surgical procedure (cong. heart malformations)
  • Metab interventions - Avoidance (certain triggers of symptoms), G6PD def antimalarial drugs
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74
Q

Treatment of genetic diseases (Single gene disorder)

A
  • Medelian disorders
  • Replace the defective protein, improve the function, minimize the consequence of the def.
  • Treatment is Deficient
  1. Unknown causing genes = Pathogenesis not understood (50% of genetic diseases UNKNOWN mutant locus)
  2. Pre-diagnostic fetal damage = Some mutations affect early development, leads to irreversible changes b4 diagnosis
  3. Severe Phenotypes LESS likely to respond to interventions = lead to absence of protein–>Severe phenotype
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75
Q

Treatment of single gene disorder (diet restriction)

A
  • MOST effective, require lifelong compliance
  • Phenylketouria - phenylalanine intake restrictions
  • Classical galactosemia - Lactose restriction
  • Maple urine disease - Branched chain AA
  • Familial hypercholesolemia - cholesterol intake
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76
Q

Treatment of single gene disorder (Product replacement)

A
  • Replace metabolite NOT made endogenously
  • Ex. Von Geirke’s disease: continuous nocturnal feeding w/glucose, Hereditary oroticaciduria: treat w/uridine-decrease orotate production
  • Diversion: enhanced use of alt pathway reduce conc of harmful metabolite=excretion pathways
  • Ex. Urea cycle disorders-Sodium benzoate + phenyl acetate=conj glycine & glutamate
  • Inhibition: alt pathway overflows produces toxic lvls of metabolite=inhibition of prior step in pathway
  • Ex. Allopurinol: treat GOUT inhibiting xanthine oxidase
  • Depletion: remove harmful compound build up
  • Ex. Hemochromatosis=blood letting to remove excess Fe+3
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77
Q

Mol Treatment of disease (level of protein)

A
  • Enhancement of mutant protein w/small mol therapy
  • Useful if phenotype is due to:
  • Defective synthesis of coenzyme from vitamin precursors
  • Decreased affinity of apo-enzyme for cofactor
  • Destabilization of protein partially overcome increased cofactor conc
  • Ex. Homocystinuria = Def of cystathionine beta synthase - treat w/B6
  • Small mol increase activity of misfolded mutant polypeptide - normally degraded
  • Small mol allow skipping over mutant stop codons-allow translation past stop codon=full protein made
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78
Q

Protein augmentation

A
  • Replacement of extracell protein
  • Ex. Hemophilia - treat w/factor 7 replacement
  • Extracell augmentation of intracell enzyme
  • Ex. Adenosine deaminase Def-PEG_ADA
  • Targeted aug of intracell enzyme
  • Ex. Gaucher’s disease remove term sugar of glucocebroside
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79
Q

Modulation of gene expression

A
  • Increase gene expression from the wild type/mutant locus
  • Ex. Hereditary angioedema: mutation in gene for C1 esterase inhibitor) Danazol = increase in C1 esterase inhib synthesis from normal & mutant loci
  • Increase gene expression from UNaffected locus
  • Ex. Beta thalassemia=Decitabine=hypomethylation of gamma globin genes-MORE gamma Hb synthesis
  • Reduce Expression of dom mutant gene product
  • VIA RNA interference (RNA1) binds to target RNA & degrades it
  • Ex. Huntington’s-remove toxic gene product
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80
Q

Mod of somatic genome by transplantation

A
  • Gene transfer therapy leads to mod of somatic genome
  • Introduce wild type copies of gene pt w/mutations in that gene
  • Ex. Familial hypercholesterolemia-Treat w/liver transplant
  • Cell replacement-compensate for organ demaged by disease
  • Ex. Alpha 1 antitryp def = treat w/liver call replacement
  • Hemapoietic stem cell transplantation-Non storage disease=cancer management, immunodef, thalassemais & LSD = gaucher, krabbe, Hurler
  • Source for stem cell placental cord blood
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81
Q

Gene Therapy

A
  • Goals= correct loss of fnx mutation & replace OR inactivate dom mutant allele
  • Target cell = Stem cell (progenitor cell) w/replication potential & long 1/2 life
  • Direct delivery = IN vivo (gene + into tissue or ECF)
  • Cell based delivery = EX vivo (gene + to cell culture & reintroduced into pt)
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82
Q

Gene Therapy (DNA transfer)

A
  • Viral vectors:
  1. Retrovirus = Only dividing cells
  2. Adenoviruses = Strong immune/inflammatory response initiated
  3. Adeno-Assoc virus=accomodate small inserts ONLY
  • NON viral vectors:
  1. Naked DNA
  2. DNA packaged
  3. Protein DNA conj
  4. Artificial chromosomes
  • Risks = Adverse rxn, Onocogene activation or tumor supressor inactivation
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83
Q

Developmental Genetics & Birth Defects (Malformations)

A
  • Intrinsic abnormalities 1+ genetic programs operating in development
  • 50% due to complex inheritance (multifactoral)
  • Specific mutations causing Specific phenotype
  • Ex. Greigcephalopolysyndactyly = Loss of function in GL13 gene
  • GL13 = mols that cause development of distal end of upper limb into a hand of 5 fingers
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84
Q

Developmental Genetics & Birth Defects (deformations)

A
  • Extrinsic factors impinging on fetal development
  • Alterations shape/position of normal tissue (REVERSIBLE)
  • Ex. Arthrogryposes-multiple joint contractures & deformation of developing skull constrait of fetus due to twin/triplet preg OR prolonged amniotic fluid leakage
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85
Q

Developmental Genetics & Birth Defects (disruptions)

A
  • Destruction of previously formed fetal tissue (IRREVERSIBLE)
  • Ex. Amnion disruption=partial amputation of fetal limb associated w/strands of amniotic tissue
  • Presence of partial & irregular amps w/constriction rings
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86
Q

Developmental Genetics & Birth Defects (syndrome)

A
  • Related to pleiotrophy=Single underlying causative agent results in abnormalities 1+ organ systems
  • Ex. branchioto renal dysplasia-Loss of function protein phosphatase ear/kidney development
  • Ex. Rubenstein Taybi-Broad thumb-hallux syndrome-Loss of function transcriptional co-activator CREB-BP-Cell growth & division
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87
Q

Developmental Genetics & Birth Defects (Sequence)

A
  • Series of events due to causative agent or 1 primary effect leading to several
  • Robin sequence-U-shaped cleft palate, micrognathia (Small jaw) due diff primary abnormalities
  • Primary = Stickler (collagen formation), Neurogenic hypotonia (Flaccid bladder), oligohydraminos (Def. of amniotic fluid)
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88
Q

Mutagens VS Teratogens

A
  • Mutagens damage creating heritable condition
  • Teratogens act directly of developing embryo
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89
Q

Teratogens (malformations)

A
  • Fetal retinoid syndome=anti-acne meds (isotretinoin), microcephaly, cleft palate, mental retardation
  • Thalidomide syndrome=Seal limbs
  • Fetal alcohol=small eye openings. smooth philtrum (indention in upper lip), thin upperlip
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90
Q

Development of embyro

A
  1. Proliferate
  2. differentiate
  3. migrate
  4. Undergo apoptosis
  • embryogenesis: Inner cell mass sep. into Epiblast (makes embryo) & Hypoblast (amniotic membrane)
  • Gasturlation: Cell rearrange to 3 layers
  1. Ectoderm (CNS, PNS, Skin)
  2. Mesoderm (Kidneys, heart, vasaculature, bones, Muscles)
  3. Endoderm (Central visceral core, Airways, GUT)
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91
Q

Regulative & Mosaic

A
  • Reg development: Early, removal or ablation part of embryo compensated by remaining similar cells (monozygomatic)
  • Mosaic development: Late, loss of portion of embryo, leads to failure of development specific structures=specific fate (Conjoined twins)
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92
Q

Axis Specification

A
  • Cranial-caudal (ant to post) axis=Early, determined by entry of sperm fertilizing egg
  • Dorsal-ventral axis=proteins & signaling pathways (Sonic hedgehog genes) set up axis
  • Left-Right Axis=Proper heart/visceral development-requires normal ZIC3 gene activity (Situsinversus = defect in ZIC3)
  • Basal apical axis=Cellular lvl function of renal tubules & neurons
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93
Q

Pattern formation

A
  • After Axis formation
  • REQUIRES HOX genes
  • Hox Genes=Transcription factors w/conserved DNA binding domains (in cluster) expressed in fetal development
  • HOX A,B,C,D
  1. Early development=Ant/post axis HOXA & HOXB
  2. Later in development=regional ID & developing limb HOXA &HOXD
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94
Q

Mech. of development (gene reg/transcription factors)

A
  • Proteins bind to enhancer/promoter regions of DNA=diff combos of TF expressed @ diff places & times DIRECT spatiotemporal reg of development
  • Functions = Stabalize/block RNA polymerase, Histone acetylase (HAT) activity, Histone deacetylase (HDAC) activity
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95
Q

Mech. of development (Structure)

A
  • Structure:
  1. DNA binding domain=specific nucleotide sequences on DNA (helix turn helix, leucine zipper, zinc fingers, helix loop helix)
  2. Activation domain=bind to other transcription factors, HAT & HDAC activity, Stabilize RNA poly
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96
Q

Mech. of development (Types)

A
  • Basal transcription factors=bind to promoter regions (TATA & CAAT)
  • Ex. TF 2 D& A
  • Activators=Bind to enhancer regions & increase transcription 1000 X
  • Ex. Steroids & Vit A
  • Co-repressors=Bind to repressor region & inhibit transcription
  • Co-activators=Bind to activators & co repressors
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97
Q

Transcription Factor (Steroid)

A
  • DNA binding domain=Zinc finger
  • Response element=HRE
  • Fnx=Steroid response
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98
Q

Transcription factor (CREB protein)

A
  • DNA binding domain: Leucine zipper
  • Response element: CRE
  • Fnx: Response to cAMP
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99
Q

Transcription Factor (HOX & MyoD)

A

Hox:

  • DNA binding domain: Helix turn Helix
  • FNX: Development of tissue/limbs

MyoD:

  • DNA binding domain: Helix turn helix
  • FNX: myogenic reg-morphogenesis
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100
Q

Mutation of HOXD13 gene

A
  • Synpolydactyly
  • Heterozygotes=Interphalangeal webbing & extra digits hands/feet
  • Homozygotes=Similar symptoms & bone abnormalities in hands, wrists, feet, ankles
  • Expansion of polyalanine tract in amino terminal domain
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101
Q

Morphogens & cell to cell signaling

A
  • Cells comm w/each other develop proper spatial arrangements of tissues (receptor-ligand interactions=paracrine)
  • _Fibroblast growth factors receptor abnormalitie_s=Achondroplasia & cranisynostosis (JAK-STAT =GF help in diff)
  • Bone growth factors, DISORDERS-mutations of FGFR3 genes
  • Sonic hedge hog loss=holoprosencphaly (dorsal/ventral diff)
  • Notochord-induces/organizes diff types of cell & tissues in developing brain/SC
  • Limb bud zone, polarizing activity generate asymmetrical pattern of digits
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102
Q

Holoproencphaly

A
  • Failure of midface & forebrain to develop, cleft lip/palate, hypertelorism (wide spaced eyes)
  • _Variable expressivity=_based on amount of SHH protein
  • SHH receptor defect=Gorlin syndrome
  • cysts of jaw, basal cell carcinoma
  • Mutation=PATCHED gene
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103
Q

WnT Genes

A
  • Involved in specifications of dorsal/ventral axis & formation of brain, muscle, gonads, kidneys
  • Homozygotes for mutation=absence of 4 limbs
  • Abnormal signaling=Tumor formation
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104
Q

Cell shape & organization

A
  • Organized in particular positiions w/particular polarities
  • Kidney epithelial cells (polysistin 1 & 2)
  • Need apical & basal sides
  • Polycysitc kidney disease=Loss of fnx of polysistin 1/2
  • Failure to sense fluid flow=cells continue to proliferate=CYSTS
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105
Q

Cell Migration

A
  • Cells assist in moving particular areas to carry out fnxs
  • Lissencephaly (Miller-Dieker)=Deletion of L1S1 gene=”smooth brain”
  • Waardenburg syndrome=Defect in migration of neural crest cells (melanocytes), SEE (sensory hearing loss, 2 diff colored iris, hair hypopigmentation forelock) Dystopia canthorum (eyes-nose WIDE)
  • Hirschsprung disease=Cells from neural crest Doesn’t form Auerbach’s plexus, CHRONIC constipation in newborns
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106
Q

Apoptosis

A
  • Cell Death required to remodel or form appropriate tissues
  • Normal positioning of aortic & pulmonary vessels
  • Separation of indivdual digits
  • Perforation of anal membrane
  • Comm between uterus & vagina
  • Eliminate lymphocyte lineages that react to self (Defect=auto immune)
  • Thymus breakdown lymphocytes
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107
Q

Prenatal Diagnosis (Goals)

A
  1. Provide informed choice
  2. Termination of pregs
  3. Allow option for appropriate manage for birth of child w/genetic disorder
  • Psycholigical prep
  • Pregs/delivery management
  • Post natal care
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108
Q

Indications for prenatal testing (Invasive)

A
  • Advanced maternal age (35+)
  • Previous child w/aneuploidy
  • Structure abnormalality in 1 of the parents (Roberstonian Translocation)
  • Family history of genetic disorders
  • Family history of X-linked disorders
  • Abnormal maternal serum screening
  • Risk of neural tube defects
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109
Q

Invasive Prenatal Testing

A
  • Chronic Villus Sampling: (ADVANTAGE diagnosis 1st trimester)
  • Biopsy of chorionic tissues from chorionic frondosum (placenta)
  • 10-12 weeks
  • Fetal trophoblastic cells=direct karotyping
  • RISK=1-2% inducing abortion
  • Amniocentesis:
  • Aspiration of amniotic fluid under ultrasound guidance
  • 15-16 weeks
  • Use of alpha-fetoprotein to screen for neural tube defects
  • RISK=inducing miscarriage, leakage of fluid, infection
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110
Q

Invasive prenatal testing

A
  • Cordocentesis:
  • used for blood disorders (anemia) & detection of Rh isoimmunization
  • ALSO detect infections=Toxoplasmosis & rubella(virus measles)
  • If blood order detected can use blood transfusions to fetus & medication directly to fetus
  • **HIGHEST risk for spontaneous abortion **
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111
Q

Noninvasive Testing

A
  • Maternal serum Alpha-fetoprotein:
  • Detect neural tube defects & aneuplodies
  • Values HIGHER than normal=possible defect @ 16 weeks
  • Used to prevent neural tube defects w/folic acid through pregs
  • Produced in fetal yolk sac & fetal liver-enters maternal blood VIA placenta
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112
Q

Alpha-fetoprotein

A
  • Elevated in:
  • Multiple pregs
  • fetal death
  • abdominal wall defects
  • neural tube defects
  • renal anomalies
  • GI tract anomalies
  • Decreased in:
  • ANEUPLODIES
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113
Q

Screening for aneuplodies

A
  • _1st trimester: _
  • Pregs associated plasma protein A (PAPP-A)
  • Human chorionic gonadtophin (Beta-HCG)
  • 2nd trimester:
  • MSAFP, beta-HCG, unconj estriol = TRIPLE SCREENING
  • Triple screening + inhibin A = quadruple screening = BEST
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114
Q

Serum Markers for aneuploidies

A
  • Trisomy 21:
  • INCREASED=nuchal transluceny (back of neck of fetus), free-beta HCG, inhibin A
  • DECREASED=PAPP-A, uncon E3, AFP
  • Trisomy 18:(Edward)
  • INCREASED=nuchal transluceny
  • DECREASED=PAPP-A, free beta hCG, uncon E3, AFP
  • Trisomy 13:(Patau)
  • INCREASED=nuchal transluceny
  • DECREASED=PAPP-A, Free beta hCG, Uncon E3, AFP
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115
Q

Serum markers Defined

A
  • Unconj Esteriol (Uncon E3):
  • Synth in fetal liver
  • Decreased in=Trisomy 18,21, Triploidy, Fetal demise, Cong adrenal hypoplasia
  • Human chorionic gonadotropin:
  • Secreted by corpus luteum (maintains pregs)
  • Elevated LVLs=Hydotiform moles & down syndrome
  • Decreased LVLs=Trisomy 13,18
  • Inhibin A:
  • Secreted by granulosa & sertoli cells (fetoplacental unit) = INHIBITS FSH & menstrual cycle
  • Increased LVLS=down syndrome & ovarian cancer
116
Q

Ultrasonography

A
  • Confirm pregs
  • Determine fetal age
  • ID multiple pregs
  • Fetal Assessment & determination of morpholocial anomalies
  • MID-trimester=determine detal sex & screen for X-linked recessive cond.
  • 2 types:
  1. Transabdominal =simple
  2. Transvaginal=More sensitive & specific (early predictor)
117
Q

Isolation of fetal cells (mosacism)

A
  • Source from maternal circulation
  • Problems: Mosacism (presence of 2 or more cell lines)
  • True mosacism=detected in multiple tissue samples and or cultures
  • Pseudomosaicism=single unusual cell line detected, involving several colonies of cells in SINGLE primary culture, OR contamination from maternal cells
  • Confined placental mosaicism=trisomy rescue, uniparentaldisomy
118
Q

Cell Cycle Definitions

A
  • Labile cells=Continually cycling (epithelial & stem cells)
  • Stable cells=exit G1 to G0 metab active BUT NOT proliferating (skin fibroblasts, hepatocyctes) RE-enter G1 if stimulated
  • Permanent cells=non dividing cells (neurons, cardiamyocytes, beta cells of pancreas)
119
Q

Defects in Cell cycle (Cancer)

A
  • _Regulation: _
  • Cell cycle response to extracell growth factors & intracellular (cell size) signals
  • NO growth factor=enter G0
120
Q

Defects in Cell Cycle (Reg. pnts)

A
  1. GI restriction point = deactivate of nutrients & signals (Cyclin D, CDK 6&4)
    * Cyclin D (CD K 6,4)=phospho of Rb gene
  2. G1/S check point=Check for DNA damage (Cyclin E, CDK-2)
    * Prevented by retinoblastoma protein
  3. S check point=Check for DNA damage & replication defects (cyclin A, CDK-2)
  4. G2/M check point=prevent mitosis until replication completed (CyclinB, CDK-1)
  5. Spindle assembly check points=make sure chromosomes are aligned properly
121
Q

Associated Proteins (cell reg)

A
  • Cyclin dependent Kinases (CDK)-Protein kinases play prom. role in cell cycle progeression reg. (phosphor active sites)
  • Activation=phosphor of threonine-160-attachment of cyclins
  • Inhibition=phosphor of threonine-14 & tyrosine 15, CKI’s (CDK inhibitors)
  • Stimulation=Activates RAS, RAF, ERK, MEK pathways->stims cyclin D1 synthesis
  • D1=Complexes w/CDK 4&6 to phosphor Rb protein
122
Q

Proteins of cell reg

A
  1. CKI’s-P21, P27, P57=block cell cycle by binding to cyclin E, A, B, CDK2 & 1 complexes
  2. INK4-P16, P15, P14 (REG 1st step): Inhibit Rb gene phosphorylation by binding to CDK4, 6 & cyclin D
  3. ARF-Increases P53 by inhibiting MDM-2
  • Cyclins=Reg subunits req for catalytic activity of CDKs
  • GF=Control progression through G1 restriction pnt
123
Q

High LVL regulators (oncogenes)

A
  • Oncogenes: Drive cell proliferation=Mutations LEAD to increased cell prolif - Gain of function
  • Related GF=Ras, Raf, Cyclins, Ret, Myc
124
Q

High LVL regulators (Tumor supressor gene)

A
  • Act as BREAKs in cell cycle
  • Loss of Fnx leads to INCREASED cell prolif
  • Related to=Rb protein, P53, ATM
125
Q

Regulation of Rb proteins

A
  • Normal: Dephosphor, binds to E2F (transcription factor) & keeps inactive
  • Phosphorylation by CDK6,4 & cyclin D=release E2F->Activation of target genes & INCREASE in cyclin E synthesis
  • CDK/Cyclin E complex=Allow G1 to S transition->Activate MCM helicase=replication inititation & entry into S phase
126
Q

Regulation of ATM & ATR

A
  • ATM: Reg the G2-Mphase->ID double stranded DNA breaks->Activates ATM to phosphorylate check point kinases
  • MUTATION in ATM=ataxia telangeictasia (++ of broken strands)
127
Q

Regulation BY P53

A
  • Commonly involved in Cancers
  • Causes cell arrest & apoptosis
  • Stims apoptosis=BAX gene
  • Regulates BY MDM-2 (feedback)
  • Ubiquitin protein ligase(MDM2)=low conc of P53
  • DNA damage=INK4/ARF (INK inhibit Rb phosopho binding & ARF inhibits MDM-2) activated=>phophorylates MDM=INCREASED P53=INCREASED CIP/KIP->INHIBITs G1/S transition
  • Main control pnt for G1/S phase
128
Q

Cell Cycle Phases

A
  1. G0=Post miotic, senescent stage, permanent for fully differentiated cells
    * Interphase (prep stage)
  2. G1=1st growth stage
  • End of previous mitosis to begin DNA synthesis
  • Increased biosynthetic activity in cells=Synthesize enzymes for S phase
  • Duration 10-12hrs
129
Q

Cell Cycle Phases

A
  1. S=Synthetic phase
  • DNA synthesis-_Double DNA content (replication)_
  • LOW protein synthesis (histones)
  • 6-8 hours
  1. G2=2nd growth factor
  • Microtubule formation
  • 2-4hours
  1. M phase=mitosis
130
Q

Why does Apoptosis Happen?

A
  • Needed in proper development - ex. separation of fingers & toes, sloughing off of uterus, perforation of orifices (anus)
  • Irreversible adjustments to body
131
Q

Apoptosis Signals for Intiation

A
  1. Withdrawal of + signs (GF & interleukin 2-control WBCs)
  2. Receives - signals = trigger apoptosis binding to death receptors
  • Increased LVLs of oxidants
  • DNA damage
  • Death activators=
  • TNF-alpha (tumor necrosis factor alpha)
  • TNF-beta (Lymphotoxin)
  • FasL (fas ligand)
132
Q

Morphology of Apoptosis

A
  1. Pyknosis (irreversable cond of chromatin)
  2. Karryorhexis (Nuclear fragmentation)
  3. Karyolysis (Complete dissolution of chormatin)
  • Blebbing:
  1. Allows formation of controlled apoptotic bodies
  2. recognized & phagocytosed
  3. Trigger cytochrome C moving it out of mitochondria = START of apoptosis
133
Q

Steps in Apoptosis

A
  1. signal intiation: FAS ligand, hormone withdrawl, P53 gene, cell injury, cytotoxic T cell
  2. Control & integration of process: Via BCL-2 family (reg. death by apoptosis or continue cell life)-BCL2: inhibit & BAX promotes
  3. Execusion: Via capsases
  4. Phagocytosis
134
Q

Apoptosis Pathways (intrinsic)

A
  • Intrinsic: involves MITOCHONDRIA comp-cytochrome C is released-Activates Caspases (executioner proteins)

Pathway=

  1. DNA damage = P53 activation
  2. Mitochondrial cytochrome C release
  3. I_nitator capase 9_
  4. Effector capase 3= APOPTOSIS
135
Q

Apoptosis Pathways (extrinsic)

A
  • Extrinsic: Ligands bind to death receptors (independent of BCL family)
  • _Pathway: _
  1. Death ligand bind to death receptor
  2. Activate Capase 8
  3. Effector capase 3
  4. Apoptosis
136
Q

Capases Steps

A
  • Proteases, cysteine, residues in active site, cleave after aspartate residues in substrate proteins
  • Key target proteins: DNAase, Nuclear lamins, Cytoskeletal proteins
  • Made as inactive precursors->require activation by proteolytic cleavage
  • ACTIVATED by binding to APaf-1 & cytochrome C = apoptosome
  • Apoptosome-cleaves & activated effector capases (3/7) = CELL DEATH (instrinsic pathway)
137
Q

Classification of Caspases

A
  • Initiator caspases: 6, 8, 9, 12
  • Effector caspases: 2, 3, 7
138
Q

Regulation of apoptosis (BCL-2)

A
  • BCL-2 Family - Catalytic :
  • Form oligomers on mitochondrial outer membrane->act as pores->release cytochrome C = ACTIVE CASPASES
  • BCL-2/BCL-x: favor cell survival (antipoptic)
  • Bax/Bak: favor cell apoptosis (multi domain)
  • BH3: PROapoptotic->form pores (1 domain)
139
Q

Regulation of apoptosis

A
  • IAP = Inhibit Caspases
  • Activation of apoptosis=
  • DNA damage
  • ATM senses damage
  • Activates CHK1/2
  • Phosphorylates P53 (cytosol)
  • Intiates transcription of PUMA & Noxa
  • Trigger release of proapoptotic factors
140
Q

Cell Survival

A
  • PIP-3 (auto-phosophorylates) activates mTOR
  • mTOR activates AKt
  • AKt phosphorylates BAD
  • Cell survival
  • AKt phosphorylates FOXO->sequesters Bam=Cell survival
  • AKt phophorylates MDM2=inactive
141
Q

Phagocytosis

A
  • Phosphatidyl serine marker (normally inside)
  • Exposed to outside of apoptotic bodies
  • Bodies recognized by macrophages
142
Q

Cancer genetics Somatic/Germline

A
  • Somatic=sporadic mutations
  • Germline=familial transmission of cancer
143
Q

Oncogenes

A
  • Mutant forms of proto-oncogenes
  • Affect proteins in signaling pathways
  • Abnormal stimulation of cell division & proliferation (gain of fnx mutation)
144
Q

Growth Factors, Transcription fac, inhibition of Apoptosis & Oncogenes

A
  • SIS activation=glioma (tumor started from glial cells)-GF
  • Myc activation=Burkitt lymphoma-_Transcription Factor_
  • Bcl2 activation=Chronic lymphocytic leukemia-_Inhibit apoptosis_
145
Q

Receptors/Transduction Pathway & oncogenes

A
  • Tyrosine Kinase receptor (Ret gene)=multiple endocrine adenomatosis 2
  • Cytoplasmic tryosine kinase (Abl gene)=Chronic myelogenous leukemia
  • G protein signaling (K-Ras2)=pancreatic cancer
  • Phosotidylinostiol 3 kinase(PTEN gene)=Breast cancer, glioma
146
Q

Oncogenes & Hereditary Syndrome

A
  • Pnt mutation activation=MEN-2
  • Multiple endocrine adenomatosis
  • **Type 2a: **Sipple syndrome=medullary thyroid cancer & pheochromocytoma
  • Type 2b: 2a & neuromas & marfanoid habitus (tumor in NS & marfran like symptoms)
  • Cause=Pnt mutation in RET proto-oncogene
  • Gain of fnx mutation
  • Normally encodes tyrosine kinase receptors = activation of receptor w/o GF
  • Auto-phosphorylates=PROLONGED activity
147
Q

Oncogenes & Hereditary Syndrome

A
  • Hirschprung disease: Loss of fnx in RET-proto oncogene
  • Hereditary papillary renal carcinoma (multiple kidney tumors)
148
Q

Chromosomal translocation activation

A
  • Chronic myelogenous leukemia:
  • Increased & unregulated growth of predom. myeloid cells in BONE marrow
  • Proliferation of mature granulocyctes (neutrophils, eosinophils, basophils)
  • Hepatosplenomegaly DUE to ++ of myeloid cells in blood
  • Caused by Philadelphia chromosome (translocation of 9q & 22q)
  • UNregulated tyrosine kinase activity
149
Q

Chromosomal translocation activation

A
  • Burkitt Lymphoma:
  • B-cell tumor on Jaw (Epstein barr virus implicated-Herpes)
  • Starry sky appearance of cells (Lipids)
  • Translocation of 8 & 14
  • Increased transcription of MYc = HIGHER cell growth
150
Q

Chromosomal translocation activation

A
  • Follicular B-cell lymphoma:
  • Translocation of 14 & 18
  • BCL-2 goes from 18 to promoter region of IgH on 14
  • Overexpression of BCL-2 = antiapoptotic effect on lymphocytes
  • MASSIVE expansion of B-cells (NO apoptosis)
151
Q

Tumor Supressor Genes (RB1)

A
  • Loss of function=Cancer
  • RB1=cell cycle reg
  • Controls G1-S checkpnt by binding to E2F=Hyperphospho ALLOWS transition to S phase
  • Loss of Rb eliminates G1 checkpnt
152
Q

RB1 & disease

A
  • Familial Retinoblastoma:
  • Malignant tumor of retina
  • Inherited as AD w/ incomplete penetrance (second hit)
  • 400 x greater risk after radiation exposure
  • Sporadic Retinoblastoma:
  • Small cell lung carcinoma, breast cancer
  • Majority are sporadic
153
Q

TP53 (cell cycle regulation)

A
  • Loss of P53=decreased production of Cip/Kip mols - avoidance of apoptosis
  • Familial Li Fraumeni syndrome(majority)
  • Diff types of cancers in diff members of family early in life
  • Bone, soft tissue, breast cancer, brain, leukemia
  • Due to Loss of fnx TP53 gene
  • Sporadic Li Fraumani syndrome
  • Lung cancer, breast cancer, etc..
154
Q

TP53 & DCC receptors

A
  • Decreases cell survival in the absence of survival signs
  • Associtated w/Sporadic colorectal cancer
155
Q

TP53 & VHL

A
  • part of cytoplasmic destruction complex
  • Inhibits induction of Blood vessel growth w/ O2 present
  • Familial Von-Hippel Lindau syndrome:
  • benign cyst-like tumors
  • Sporadic clear cell renal carcinoma:
156
Q

Tumor supressor genes & Caretaker TSGs

A
  • responsible for detecting & repairing mutations, maintaining genomic integrity
  • Loss of Fnx=mutations ++=INDIRECTLY leads to cancer
  • Neurofibromatosis: Mutation in TSG of neurofibromin 1 (chr 17)
  • Schannomas, cafe-au-lait spots, neurofibromas, freckles & lisch nodules
  • NF1 normally acts w/RAS to regulate proliferation (inactivate RAS)
157
Q

Caretaker genes (BRCA1 & 2)

A
  • Chromosome repair in response to double strand breaks
  • Familial breast cancer & ovarian cancer:
  • Dom mendelian inheritance
  • BRCA 1= 50% AD (chromsome 17)
  • Increased risk of ovary cancers, prostate, colon
  • BRCA2=33% AD (chromsome 13)
  • Increased risk of MALE breast cancer, ovarian, melanomas, pancreatic tumors
  • Sporadic Breast & ovarian
158
Q

Caretaker genes (MLH1 & 2)

A
  • Repair nucleotide mismatches between strands of DNA
  • Familial hereditary nonpolyposis colon cancer
  • Mutations in microsat repeat regions
  • Onset early adulthood
  • Males=90% chance of 2nd hit
  • Females=70% chance of 2nd hit (also ovarian cancer)
  • Sporadic colorectal cancer
  • Many associated genes
  • AD
159
Q

Caretaker genes & chromosome instability

A
  • All autosomal recessive
  • Ataxia Telangiectasia:
  • Double strand breaks
  • LOF mutation @ ATM gene on chr 11
  • Presentation early in life=cerebellar ataxia, ocular apraxia, telangiectasia(spider veins @ mucous membranes), immunodef. & lymphoid cancers
160
Q

Caretaker genes & chromosome instability

A
  • Fanconi Symdrome:
  • Double strand breaks=NO activation of DNA repair mech
  • Skeletal malformations, uninary tract, GI, heart, & CNS malformations (triad)
  • Bone marrow failure (low prod of RBCs)
161
Q

Caretaker genes & chromosome instability

A
  • Bloom syndrome:
  • Double strand breaks=NO fnx of REcQ (unwinds DNA)
  • Ineffective DNA repair
  • Short stature, long face, micrognathia (small jaw), butterfly rash (sunexposed area), hypogonadism (azospermia)
162
Q

Caretaker genes & chromosome instability

A
  • Xerodermapigmentosa:
  • Nuceotide excision repair defect
  • ++ of pyrimidine dimers DUE to defective exinuclease
  • Extreme UV light sensivity, Excessive freckling, multiple skin cancers, corneal ulcerations
163
Q

Gene alterations

A
  • Gene amplifications
  • promoter mutations
  • point mutations
  • MiRNAs (microRNAs)=RNA mediated inhibition of gene expression by inducing degradation of target mRNAs OR blocking translation
  • Oncomirs=OVER or under expressed miRNAs - 10% of ALL cancers
  • Chromosome translocations
    • or - function mutations
164
Q

Telomerase

A
  • Reverse Transcriptase=Normally maintains ends of DNA
  • Presistant in Stem cells & rapidly multi cells = Upregulated by oncogenes
  • Mutation initiated=++ of additional genetic damage through mutation in caretaker genes (cancer stem cells)
165
Q

2 Hit Hypothesis

A
  • Dominant
  • Sporadic=mutation in 1 copy=deletion in other copy= Tumor PROgression
  • Familial=Inherit germline mutation=deletion in other copy=Tumor PROgression
  • 2nd hit always due to mutation
  • Epigenetic role=Methylation of functional gene=causes transcriptional inactivation
166
Q

DNA double strand breaks

A
  • Activated by ATM after ID damage
  • NHEJ pathway=requires Ku protein & DNA dependent protein kinase
  • HR pathway=Requires RAD 51,52 & BRCA-1
  • Occurs late S & G2 phase
167
Q

DNA double strand breaks

A
  • APC tumor supressor gene mutation=Familial colon cancers
  • _Loss of APC=_Beta catenin dephosphor acts as transcription factor
  • Adenomatous polyposis coli:
  • AD=Loss of heterozygosity
  • Numerous adenomatous polyps by 10
  • Gardner syndrome:
  • AD, LOH=Familial colon
  • See polyps, osteomas of jaw & desmoid tumors
168
Q

Pharmokinetics & Cytochrome P450

A
  • Rate @ which body absorbs, transports, metabolizes/excretes drugs or metabolites
  • Hydrophobic to hydrophilic
  • Mitochondrial = conversion of chelosterol to steroids, bile acid synthesis, hydroxylation of Vit D
  • Microsomal = detox of drugs, carcinogens, petroleum products, pesticides, etc…
169
Q

Microsomal Pharmokinetics

A
  • Exclusively in Liver
  • Phase 1 metab:
  • Hydrophoic to hydrophilic
  • enzymes are monooxygenase group
  • Heme containing
  • Use of NADPH as electron donor
170
Q

Variation in Cytochrome P450

A
  • Wild type: Normal fnx
  • Reduced: low activity due to missense mutation
  • Absent: no activity due to frameshift, splicing mutations
  • Increased: elevated activity due to copy # polymorphisms-_ Have to provide higher amounts of drugs to a given blood conc_ (faster metab of drugs)
171
Q

Drugs activated by cytochrome P450

A
  • Codine coverted into morphine
  • Ultrafast metab = risk overdose due to standard higher dose
  • Poor metab = No benefit
172
Q

Phase 2 Metab Conjugation (Glucuronidation)

A
  • With polymorphism = toxicity to camptothecin (topoisomerase inhibitor in chemo)
  • Type 1 topoisomerase: inhibited by topotecan & irinotecan
  • Type 2 topoisomerase: inhibited by etoposide, teneposide
  • Gyrase (relieves strain while DNA is being unwound): inhibited by quinolone antibiotics (bacterial) - Cipro
173
Q

Phase 2 Metab Conjugation (Actylation)

A
  • NAT 2 gene shows polymorphic variation
  • INH=Treatment for tuberculosis
  • SLOW acetylators = peripheral neuropathy
  • FAST acetylators = more drug to maintain response
174
Q

Phase 2 Metab Conjugation (Methylation)

A
  • common affect of anti-cancer drugs (leukemia)
  • Increase effectiveness or render toxic (dose dependent) - hair loss, bone marrow
  • Common polymorphisms in mehtyltransferases
175
Q

Cholinesterase polymorphism

A
  • Diff rates of metab of cholinergic drugs
  • related to methylation
  • Ex: Succinyl choline used for skeletal paralysis
  • BCHE=lower activity-stronger effect of drug-prolonged paralysis
176
Q

G6PD def.

A
  • X linked
  • common in malaria endemic areas
  • Require NADPH to maintain glutathione in reduced states
  • Stress to system w/oxidative drugs
  • Ex. Primaquine (antimalaria) & sulfonamides (antibacterial)
177
Q

Malignant Hyperthermia

A
  • AD
  • Adverse rxn to halothene (anesthetic) or succinyl choline (relaxes muscle)
  • Life threatening fever, muscle contractions, & hyper catabolism
  • DUE to: increased intracell Ca+2
  • Defective ryanodine receptors (ca+2 induced ca+2 induced) or dihydropyridine Ca+2 channels
  • Treatment=Dentrolene Sodium
178
Q

Warfarin Therapy

A
  • Inhibits Vit K epoxide reductase complex
  • Treatment of thrombolic phenomenon=Blocks clotting factors 2, 7, 9, 10
  • 2 haplotypes:
  • AA = least dosage
  • BB = most dosage
  • Detox via CYP2C9 (phase 1 cytochrome p450 system)

Genetics Block 2 (2 decks)

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