BIOE 301Amniocentesis ExamplePossible Test ResultsDependence on PrevalenceIs it Hard to Screen for Rare Disease?Slide 6Cancer OverviewCauses of Mortality, 1996Importance of Cancer ScreeningCell transformation: precancer to cancerSlide 11Process of Cancer DevelopmentChange in the US Death Rates* by Cause, 1950 & 2001Molecular basis of cancerSlide 15Slide 16Slide 17Slide 18Slide 19Genetic CodeSlide 21Slide 22Bioengineering and CancerCase StudiesBioengineering and Cervical CancerStatistics on cervical cancerGlobal Burden of Cervical CancerRisk factorsHuman papilloma virus (HPV)HPV and cervical cancerSlide 31PathophysiologyHPV vaccineHow Do We Detect Early Cervical Cancer?Pap SmearColposcopy and BiopsyColposcopy and TreatmentDetection and TreatmentScreening Guidelines, ACSSlide 40Slide 42HPV DNA TestSlide 44Liquid Based Pap SmearAutomated Pap Smear ScreeningOptical technologiesCostsNext TimeBIOE 301Lecture ThirteenDavid J. [email protected] Hours: Mon 1-4 PMAmniocentesis ExampleAmniocentesis:Procedure to detect abnormal fetal chromosomes Efficacy:1,000 40-year-old women given the test28 children born with chromosomal abnormalities32 amniocentesis test were positive, and of those 25 were truly positiveCalculate:Se, Sp, PPV, NPVPossible Test ResultsTest PositiveTest NegativeDisease Present25 3 # with Disease = 28Disease Absent7 965 #without Disease = 972# Test Pos = 32# Test Neg = 968Total Tested = 1,000Se = 25/28 = 89% Sp =965/972 = 99.3%PPV = 25/32 = 78% NPV =965/968 = 99.7%Dependence on Prevalence Prevalence – is a disease common or rare?p = (# with disease)/total #p = (TP+FN)/(TP+FP+TN+FN)Does our test accuracy depend on p?Se/Sp do not depend on prevalencePPV/NPV are highly dependent on prevalenceIs it Hard to Screen for Rare Disease?Amniocentesis:Usually offered to women > 35 yrs Efficacy:1,000 20-year-old women given the testPrevalence of chromosomal abnormalities is expected to be 2.8/1000Calculate:Se, Sp, PPV, NPVPossible Test ResultsTest PositiveTest NegativeDisease Present2.5 .3 # with Disease = 2.8Disease Absent6.98 990.2 #without Disease = 997.2# Test Pos = 9.48# Test Neg = 990.5Total Tested = 1,000Se = 2.5/2.8 = 89.3% Sp 990.2/997.2= 99.3%PPV = 2.5/9.48 = 26.3% NPV =990.2/990.5 = 99.97%Cancer OverviewMalignant tumor“The Crab”Causes of Mortality, 1996Importance of Cancer ScreeningCell transformation: precancer to cancerCancer cells to metastatic tumorsProcess of Cancer DevelopmentChange in the US Death Rates* by Cause, 1950 & 2001* Age-adjusted to 2000 US standard population.Sources: 1950 Mortality Data - CDC/NCHS, NVSS, Mortality Revised.2001 Mortality Data–NVSR-Death Final Data 2001–Volume 52, No. 3. http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdfHeartDiseasesCerebrovascularDiseasesPneumonia/InfluenzaCancer19502001Rate Per 100,000Molecular basis of cancerCell physiologyFrancis Crick, Nobel Prize in Medicine 1962“ The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred back from protein to either protein or nucleic acid.” Central dogma of molecular biologyDNA RNA ProteinDNA and RNAProteinCentral dogma of molecular biologyDNAPROTEINAA1AA2AA3AA4AA5AA6AA7RNAGenetic Code2nd baseU C A G1stbaseUUUU(Phe/F)PhenylalanineUUC(Phe/F)PhenylalanineUUA(Leu/L)LeucineUUG(Leu/L)LeucineUCU(Ser/S)SerineUCC(Ser/S)SerineUCA(Ser/S)SerineUCG(Ser/S)SerineUAU(Tyr/Y)TyrosineUAC(Tyr/Y)TyrosineUAAOchre(Stop)UAGAmber(Stop)UGU(Cys/C)CysteineUGC(Cys/C)CysteineUGAOpal(Stop)UGG(Trp/W)TryptophanCCUU(Leu/L)LeucineCUC(Leu/L)LeucineCUA(Leu/L)LeucineCUG(Leu/L)LeucineCCU(Pro/P)ProlineCCC(Pro/P)ProlineCCA(Pro/P)ProlineCCG(Pro/P)ProlineCAU(His/H)HistidineCAC(His/H)HistidineCAA(Gln/Q)GlutamineCAG(Gln/Q)GlutamineCGU(Arg/R)ArginineCGC(Arg/R)ArginineCGA(Arg/R)ArginineCGG(Arg/R)ArginineAAUU(Ile/I)IsoleucineAUC(Ile/I)IsoleucineAUA(Ile/I)IsoleucineAUG(Met/M)Methionine,Start[1]ACU(Thr/T)ThreonineACC(Thr/T)ThreonineACA(Thr/T)ThreonineACG(Thr/T)ThreonineAAU(Asn/N)AsparagineAAC(Asn/N)AsparagineAAA(Lys/K)LysineAAG(Lys/K)LysineAGU(Ser/S)SerineAGC(Ser/S)SerineAGA(Arg/R)ArginineAGG(Arg/R)ArginineGGUU(Val/V)ValineGUC(Val/V)ValineGUA(Val/V)ValineGUG(Val/V)ValineGCU(Ala/A)AlanineGCC(Ala/A)AlanineGCA(Ala/A)AlanineGCG(Ala/A)AlanineGAU(Asp/D)AsparticacidGAC(Asp/D)AsparticacidGAA(Glu/E)GlutamicacidGAG(Glu/E)GlutamicacidGGU(Gly/G)GlycineGGC(Gly/G)GlycineGGA(Gly/G)GlycineGGG(Gly/G)GlycineMolecular basis of cancerMutation• Good or bad• Single or multiple• Duration• CausesDNARNAProteinAlterations in cell physiology: (1) Develop self-sufficiency in growth signals (2) Become insensitive to signals of growth inhabitation, (3) Evade programmed cell death, (4) Develop limitless replicative potential(5) Sustain angiogenesis(6) Acquire the ability to invade tissue and metastasize.Central dogma of molecular biologyMultiple causesMultiple sitesMultiple treatmentMultiple challengesMolecular basis of cancerMUTATIONRisk factorsDetectionTreatmentChallengesNew technologiesBioengineering and CancerCANCERCase StudiesCervical CancerProstate CancerOvarian and Lung CancerAmerican Cancer Society (cancer.org)National Cancer Institute (cancer.gov)Dr. KoopBioengineering and Cervical CancerStatistics on cervical cancerUS data (2007)Incidence: 11,150Mortality: 3,670World data (2004)Incidence: 510,000 (80% developing world)Mortality288,000 deaths per year worldwideGlobal Burden of Cervical CancerHighest incidence in:Central and South America, Southern Afica, AsiaRisk factorsHPV infectionHPV infection is the central causative factor in squamous cell carcinoma of the cervix Sexual behaviors Sex at an early ageMultiple sexual partnersCigarette smokingHuman papilloma virus (HPV)Most common STD>70 subtypesAsymptomatic infections in 5-40% of women of reproductive ageHPV infections are transientHPV and cervical cancerWhat Initiates Transformation?PathophysiologyHPV vaccineVirus-like particles (VLP) made from the L1 protein of HPV 16approved for use in girls and women aged 9 to 26 years in the USnot effective to women already exposed to HPVEffective on 4 HPV
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