BIOE 301Lecture ThirteenDavid J. [email protected] Hours: Mon 1-4 PMAmniocentesis Example Amniocentesis: Procedure to detect abnormal fetal chromosomes Efficacy: 1,000 40-year-old women given the test 28 children born with chromosomal abnormalities 32 amniocentesis test were positive, and of those 25 were truly positive Calculate: Se, Sp, PPV, NPVPossible Test Results# Test Neg= 9689653Test Negative#without Disease = 9727Disease AbsentTotal Tested = 1,000# Test Pos = 32# with Disease = 2825Disease PresentTest PositiveSe = 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 prevalence PPV/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 test Prevalence of chromosomal abnormalities is expected to be 2.8/1000 Calculate: Se, Sp, PPV, NPVPossible Test Results# Test Neg= 990.5990.2.3Test Negative#without Disease = 997.26.98Disease AbsentTotal Tested = 1,000# Test Pos = 9.48# with Disease = 2.82.5Disease PresentTest PositiveSe = 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, 199605101520253035404550Percentage of DeathsCancer Circ Sys Infectious Other Resp Peri/NeoDevelopedWorldDevelopingWorldImportance of Cancer Screening Five-Year Relative Survival Rates by Stage at Diagnosis0102030405060708090100Colon &RectumMelanoma Oral Cavity UrinaryBladderUterine CervixRelative Survival Rate (%)LocalRegionalDistantCell 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.pdf21.8180.748.1586.8193.957.5194.4245.80100200300400500600HeartDiseasesCerebrovascularDiseasesPneumonia/InfluenzaCancer19502001Rate Per 100,000Molecular basis of cancerCell physiologyFrancis Crick, Nobel Prize in Medicine 1962“ The central dogma of molecular biologydeals 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 CodeGGU (Gly/G)GlycineGGC (Gly/G)GlycineGGA (Gly/G)GlycineGGG (Gly/G)GlycineGAU (Asp/D)Aspartic acidGAC (Asp/D)Aspartic acidGAA (Glu/E)Glutamic acidGAG (Glu/E)Glutamic acidGCU (Ala/A)AlanineGCC (Ala/A)AlanineGCA (Ala/A)AlanineGCG (Ala/A)AlanineGUU (Val/V)ValineGUC (Val/V)ValineGUA (Val/V)ValineGUG (Val/V)ValineGAGU (Ser/S)SerineAGC (Ser/S)SerineAGA (Arg/R)ArginineAGG (Arg/R)ArginineAAU (Asn/N)AsparagineAAC (Asn/N)AsparagineAAA (Lys/K)LysineAAG (Lys/K)LysineACU (Thr/T)ThreonineACC (Thr/T)ThreonineACA (Thr/T)ThreonineACG (Thr/T)ThreonineAUU (Ile/I)IsoleucineAUC (Ile/I)IsoleucineAUA (Ile/I)IsoleucineAUG (Met/M)Methionine, Start[1]ACGU (Arg/R)ArginineCGC (Arg/R)ArginineCGA (Arg/R)ArginineCGG (Arg/R)ArginineCAU (His/H)HistidineCAC (His/H)HistidineCAA (Gln/Q)GlutamineCAG (Gln/Q)GlutamineCCU (Pro/P)ProlineCCC (Pro/P)ProlineCCA (Pro/P)ProlineCCG (Pro/P)ProlineCUU (Leu/L)LeucineCUC (Leu/L)LeucineCUA (Leu/L)LeucineCUG (Leu/L)LeucineCUGU (Cys/C)CysteineUGC (Cys/C)CysteineUGA Opal (Stop)UGG (Trp/W)TryptophanUAU (Tyr/Y)TyrosineUAC (Tyr/Y)TyrosineUAA Ochre (Stop)UAG Amber (Stop)UCU (Ser/S)SerineUCC (Ser/S)SerineUCA (Ser/S)SerineUCG (Ser/S)SerineUUU (Phe/F)PhenylalanineUUC (Phe/F)PhenylalanineUUA (Leu/L)LeucineUUG (Leu/L)LeucineU1stbaseGACU2nd baseMolecular 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 Studies Cervical Cancer Prostate Cancer Ovarian and Lung Cancer American Cancer Society (cancer.org) National Cancer Institute (cancer.gov)Dr. KoopBioengineering and Cervical CancerStatistics on cervical cancerUS data (2007) Incidence: 11,150 Mortality: 3,670World data (2004) Incidence: 510,000 (80% developing world) Mortality 288,000 deaths per year worldwideGlobal Burden of Cervical CancerHighest incidence in:Central and South America, Southern Afica, AsiaRisk factors HPV infection HPV infection is the central causative factor in squamous cell carcinoma of the cervix Sexual behaviors Sex at an early age Multiple sexual partners Cigarette smokingHuman papilloma virus (HPV) Most common STD >70 subtypes Asymptomatic infections in 5-40% of women of reproductive age HPV 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 US not effective to women already exposed to HPV Effective on 4 HPV isotypes Recombinant technology Alternative prevention technique to screening?How Do We Detect Early Cervical Cancer?Pap Smear 50,000-300,000 cells/per slide Cytotechnologists review slides (<100/day) Se = 62% 3% Sp = 78% $6BColposcopy and BiopsySe = 95%Sp = 44%ColposcopeBiopsy sectionsColposcopy and TreatmentCIN 1/LGSILCIN 1/LGSILCIN 2/HGSILCIN 2/HGSILCIN 3/HGSILCIN 3/HGSILMicroinvasive CAMicroinvasive CAInvasive CAInvasive CAInvasive CAInvasive CADetection and Treatment Screening: Pap smear Diagnosis: Colposcopy + biopsy Treatment: Surgery, radiotherapy, chemotherapy 5 year survival Localized disease: 92% (56%
View Full Document
Unlocking...