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Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver
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Diseased Genome Hospital http:// blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg
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http://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpg
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http://img.quamut.com/chart/9471/02_healthy_sick_x-ray.jpg
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http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y
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What Is Lung Cancer? Types Risks PredispositionMutations EGFR Other proteins Angiogenesis VEGF Your Treatment Plan http://www.freefoto.com/images/21/16/21_16_2---Single-Carriageway-Road_web.jpg
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http://www.odec.ca/projects/2005/thog5n0/public_html/Tumour.gif
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http://www.icowman.com/uploadfiles/2007072409225175.jpg
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NON SMALL CELL Squamous cell carcinoma Adenocarcinoma Large-cell carcinoma SMALL CELL Bronchi Grows rapidly Spreads quickly http://images.google.com/imgres?imgurl=http://www.dkimages.com/discover/previews/852/202230 38.JPG http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/ Lynch et al., (2004)
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http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
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This year approximately 200,000 people will be diagnosed with lung cancer NSCLC accounts for 80% of all lung cancers http://www.cdc.gov/cancer/lung/statistics/ http://seo2.0.onreact.com/wp-content/uploads/2008/09/you-re-not-alone.jpg
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http://medicineworld.org/cancer/lung/http://images.google.com/
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While there is no known cure as of right now, there ARE options! http://dspace.mit.edu Imatinib Gefinitib Cisplatin http://dspace.mit.edu
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CisplatinImatinib Gefitinib EGF ERBB2 EGFR Nucleus P Protein Cascade
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P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade
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http://rosenblumtv.files.wordpress.com http://www.pharmgkb.org http://academic.evergreen.edu
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Compact structures of DNA Contains thousands of genes Centromere Chromatid Genes http://staff.jccc.net/PDECELL/celldivision/chromosome1.gif
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Single variation in nucleotide base pairs Alleles are a result of SNPs within gene sequence SNP’s are the basis for lung cancer susceptibility http://www.dnalandmarks.com/english/pictures/what_are_snps.jpg
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Variation across genomes Genotype cases along with controls Find roles that genes play in disease Large sample sizes http://www.blog.speculist.com/archives/dna2two
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Centromere p-arm q-arm 6 Regions Away Region 5q6 5 http://images.google.com/
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http://upload.wikimedia.org/
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Nicotine binds and stimulates acetylcholine ion channel-linked in neurons http://www.jyi.org/articleimages/88/originals/img0.jpg
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(Hung et al., 2008)
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(Thorgeirson et al., 2008)
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Cancerous Growth http://images.google.com/i
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(McKay et al., 2008)
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P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade
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How Do Cells Proliferate?
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EGFR P EGF Proliferation Survival Apoptosis ERBB2 Nucleus EGFR P Protein Cascade ERBB2
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How Can This Lead to Cancer?
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ERBB2 EGFR Nucleus Proliferation P Protein Cascade
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(Chen et al., 2006)
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EGFR ATPTKI ATP binding cleft on the kinase Tyrosine Kinase domain
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(Chen et al., 2006)
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What About the Proteins in the Signaling Pathway?
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(Pedersen et al., 2005)
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(Chen et al., 2006)
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P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade
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What Are the Roles of Proteins Associated with Lung Cancer? http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
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Recap Nucleus N-terminus C-terminus P Serine P Threonine Tyrosine P Leucine Lysine Alanine
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ERBB2 P PI3KSH2 Nucleus P Protein Cascade Change in Gene Expression
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(Rikova et al. 2007)
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Green and Blue circles =Proteins involved in cascade Red lines = Interactions Red circles =EGFR Receptor (Jones et al. 2006)
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No. protein receptors Affinity Threshold (nM) Affinity Threshold (nM) Affinity Threshold (nM)
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http://en.wikipedia.org/wiki/Proteins
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(Rikova et al. 2007)
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Chart configured from Table1 of Rikova et al. 2007 A mount of overphosphorylated protein in samples
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(Engelman et al., 2007)
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P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade
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http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg
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http://www.researchvegf.com/researchvegf/multimedia/index.m#type-slides
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VEGF-A VEGFR Angiogenesis Tumors PDGF-β PDGFR-β
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P85-α PIP 2 P P PTEN P PIP 3 P P P P110-α PI3K AKT SH2 P P Endothelial Cell
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AKT P P P BAD MDM2 mTOR Growth, Translation Apoptosis p53 P Nucleus
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Cancer Cell Proto-Oncogene Oncogene
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(Chen et al., 2009)
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Giemsa-Stained Cells
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P85-α PIP 2 P P PTEN P PIP 3 P P P P110-α PI3K AKT SH2 P P VEGF-A VEGFR FLJ10540 Endothelial Cell
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http://www.medicinescomplete.com/mc/martindale/2007/images/MRT9229C001.gif Binds to ATP binding site of many enzymes: p-PDGFR-β Inhibitor Reduced IFP, Hypoxia Decreased VEGF Expression
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http://www.medscape.com/pi/editorial/clinupdates/2000/583/art-tu02.fig04.jpg http://www.nature.com/nm/journal/v7/n9/images/nm0901-987-F1.gif Normal Tumor
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(Vlahovic et al. 2007)
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Vlahovic et al. 2007
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http://onctalk.com/wp-content/uploads/2008/01/angiogenesis-summary.jpg Imatinib
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P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Protein Cascade PDGFR Protein Cascade Nucleus
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Dr. Vildaver Imatinib Dr. Ross Gefinitib
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(Rosenberg et al., 1969)
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Cisplatin Nucleus Simple Diffusion Pt NH 3 GG P73 C-Abl Cell Cycle Arrest & Apoptosis P53 HMG1 ? ?
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nucleus Pt Transporter protein Transporter protein Pt (Hall et al., 2007)
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crosslink nucleus Pt NH 3 Cell Cycle Arrest & Apoptosis G G 1,2-intrastrand d(GpG)adduct (Ohndorf et al., 1999)
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http://www.unc.edu/~shantanu/images/bkstcg_aacr07.png
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Pt-DNA Adduct Apoptosis HMGB P73P53 (Stross et al., 2002)
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(Ohndorf et al., 1999) * Nucleotides crosslinked Bold- nucleotides contacted by the protein
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(Ohndorf et al., 1999)
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Cisplatin Nucleus ? Simple Diffusion Pt NH 3 GG P73 C-Abl Cell Cycle Arrest & Apoptosis P53 HMG1 ? ?
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tyrosine kinase mismatch repair protein cisplatin homologue of p53 Tumor suppresor (Gong et al., 1999)
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P53 knockout= less sensitive to CDDP, survived better than wild type in lower concentrations of CDDP MLH1-/- & Abl= less sensitive to CDDP, survived better than wild type in lower concentrations of CDDP (Gong et al., 1999)
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Cisplatin Nucleus Simple Diffusion Pt NH 3 GG P73 Cell Cycle Arrest & Apoptosis P53 HMG1 ATM Transporter Proteins C-Abl P
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CisplatinImatinib Gefitinib EGF ERBB2 EGFR Nucleus P Protein Cascade
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P P EGF ERBB2 EGFR PI3K AKT P P MET P VEGF-A CisplatinImatinib Gefitinib Nucleus Protein Cascade PDGFR Protein Cascade
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http://immunodefence.com/ii/gefitinib.gif http://www.themesotheliomalibrary.com/cisplatin.jpg http://www.specialityformulations.com/pcat-gifs/products-small/imatinib.jpg
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New plasma membrane proteins have unique mechanisms and effects on NSCLC Gefitinib effectively inhibits particular EGFR mutants SiRNA could be used as a possible treatment for various mutated proteins
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How does cisplatin enter the nucleus? Roles and mechanisms behind the various mutated proteins involved in lung cancer New drugs, secondary mutations
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Professor Sleiter Schmooing yeast!!!
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Dr. DebBurman
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Mike Fiske
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Abid MR, Guo S, Minami T, Spokes KC, Ueki K, et al. (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 24: 294-300. Agami, R., Blandino, G., Oren, M., and Shaul, Y. (1999). Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399, 809-813. Alberg AJ, Ford JG, Samet JM; American College of Chest Physicins. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2 nd edition). Chest. 2007; 132:29S-55S. Alberts, B., Bray, D., Hopkin, K., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. 2004. Essential Cell Biology. Garland Science. New York, pp740. Chanock, Stephen J., Hunter, David J. 2008. When the smoke clears. Nature. 452: 537-538. Chen, C.H., Lai, J.M., Chou, T.Y., Chen, C.Y., Su, L.J., Lee, Y.C., Cheng, T.S., Hong, Y.R., Chou, C.K., Whang-Peng, J., Wu, Y.C., and Huang, C.Y. (2009). VEGFA upregulates FLJ10540 and modulates migration and invasion of lung cancer via PI3K/AKT pathway. PLoS ONE 4, e5052. Chen, Y.R., Fu, Y.N., Lin, C.H., Yang, S.T., Hu, S.F., Chen, Y.T., Tsai, S.F., and Huang, S.F. (2006). Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants. Oncogene 25, 1205-1215. Engelman, J.A., Janne, P.A., Mermel, C., Pearlberg, J., Mukohara, T., Fleet, C., Cichowski, K., Johnson, B.E., and Cantley, L.C. (2005). ErbB-3 mediates phosphoinositide 3- kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl. Acad. Sci. U. S. A. 102, 3788-3793. Ferrara, N. and Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature 438, 967. Franks, L.M. and Teich, N. (1986). Introduction to the Cellular and Molecular Biology of Cancer (New York:Oxford University Press). Gao, B., Lee, S.M., and Fang, D. (2006). The tyrosine kinase c-Abl protects c-Jun from ubiquitination-mediated degradation in T cells. J. Biol. Chem. 281, 29711-29718. Hall, M.D., Okabe, M., Shen, D.W., Liang, X.J., and Gottesman, M.M. (2008). The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu. Rev. Pharmacol. Toxicol. 48, 495-535. Helotera, H. and Alitalo, K. (2007). The VEGF Family, the Inside Story. Cell 130:591-592 Hung, Rayjean J. et al. 2008. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 452: 633-637. Huang, J.C., Zamble, D.B., Reardon, J.T., Lippard, S.J., and Sancar, A. (1994). HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. Proc. Natl. Acad. Sci. U. S. A. 91, 10394-10398. Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. (2008) Cancer statistics, 2008. CA Cancer J Clin 58: 71-96.
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