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Challenges of EU Social Issues in Medical Biotechnology Teaching

This study explores how the European Union's social challenges manifest in the teaching materials of Master's programs in Medical Biotechnology at the Universities of Pécs and Debrecen. The focus is on the implications of these challenges on tumor cells, immune system interactions, signaling pathways, and therapeutic targets. Key topics include immune escape mechanisms, cytokine signaling, growth factor receptors, and angiogenesis in cancer progression. The research also delves into HER gene family characteristics, anti-EGFR resistance mutations, VEGFR2 signaling in endothelial cells, and the kinase inhibitory profiles of anti-angiogenic agents. The overview of EGF signaling pathways and their impact on cellular functions are also discussed.

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Challenges of EU Social Issues in Medical Biotechnology Teaching

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Tímea Berki and Ferenc Boldizsár Signaltransduction Signallingin tumor cells

  3. Immuneselectioninthedevelopment of cancer: no twotumorsarealike Initiation, proliferation, diversification Microevolution, selection of immune resistance Immune escape and unchecked proliferation

  4. Tumor and activated T cells Activated T cell Immune escape Tumor cell Cytokines Cytokinereceptors RCAS1 TCR MHC I RCAS1R Growtharrest CTLA4 B7-1/2 CD28 Proliferation Cell death FasL Fas FasL DcR3 DF3/MUC1

  5. WhathappenswhenFas-stimulatedimmunecellsresistto die? Cytokines? FasL Fas Tissue environment? Immunecells Tumor cells

  6. TGF-bsignalingin tumor signaling and cancerprogression Stromalcell Tumor cell LatentTGF- Proteases Thrombospondin Integrins Decorin Betaglycan ActiveTGF- Effectson tumor cells Effectsontumor environment Stroma Endothelial cells Immune cells ↓Fas-Lactivity ↓ NK cells ↓ T cells ↓ B cells ↑Proteases ↑ECM production Growth inhibition (early) Invasion (late) ↑Angiogenesis

  7. Type II Type I Fassignal FasL TPA Fas FADD FADD CAP3 CAP3 PKC DISC MAPK c-FLIP Caspase-8 tBid Bcl-2 Bcl-xL Cytc Cytc Caspase-9 Apaf-1 AIF Caspase-3 Caspase-8 Deathsubstrates APOPTOSIS

  8. Growth factors (GFs) • Small molecular weight soluble mediators • They control: • 1 Proliferation • 2 Survival • 3 Metabolism • 4 Tissue differentiation • Important implication in tumors • Cytokines – growth factors

  9. Receptortyrosinekinase(RTK)families • 90 unique Tyr kinases in the human genome, 58 are RTKs • Growth factor, cytokine and hormone receptors • Classes:

  10. GF signalingpathways Ligand RTK Dimerization P P P P P P P P GRB2 SOS PI3K PDK1 JAK PLC Ras Akt PKC Src Raf STAT Erk Proliferation Survival Migration Cell cycle progression Transcription

  11. GF receptorsastherapeutictargets EGF TGF β-cellulin Amphiregulin HB-EGF PDGF-C β-cellulin NRG2 NRG3 No specific ligands PDGF-B PDGF-D Heregulins VEGF-B VEGF-A VEGF-C VEGF-D PDGF-A SCF P P P P P P P P EGFR Her2 Her3 Her4 VEGFR1 VEGFR2 VEGFR3 PDGFR-a PDGFR-b c-kit P P P P P P P P P P P P P P P P P P GRB2 SOS Ras Rac CDC42 Rho P P P P P P P P P P P P P P P P P P ERK pathway JNK pathway p38 pathway Raf MEKK Tak PI3K Sorafenib Sirolimus P P P P P P P P P P P P P P P P P P Panitumumab Temsirolimus Erlotinib Midostaurin MEK1/2 MKK4/7 MKK3/6 P P P P P P P P P P P P P P P P P P Akt Gefitinib Motesanib Lapatinib Pazopanib Erk JNK p38 mTor Leflunomide Enzastaurin Trastuzumab Sunitinib Imatinib Vandetanib Everolimus Bevacizumab Cellsurvival Proliferation Apoptosisresistance Cetuximab Metastasis Angiogenesis

  12. HER genefamily • HER1/EGFR(1): ligandsknown (TNFa, EGF etc), kinaseactivity • HER2/EGFR2: no ligand, kinaseactivity • HER3/EGFR3:ligandsknown (TNFa, EGF etc), no kinaseactivity • HER4/EGFR4: ligandsknown, kinaseactivity • Characteristic:co-operations

  13. HER2 geneticsincancer

  14. Anti-EGFRresistancein NSCLC • EGFR resistancemutation 790M • K-RAS mutation • C-MET amplification • EGFR negativity (protein?)

  15. Colorectalcancer and EGFR • EGFR expression (mRNS and protein): 75-80% • Intensityvariable (1-100% cell) • EGFR amplification: 0.6-15% • Chr. 7 polisomy: 30% • Chr.7 LOH: 8% (loss) • TK-mutation: 12% (onlyAsia) • EC-LD R497K polimorphism • SP1-216 promoter G/T polimorphism

  16. VEGFR2 receptor signalinginendothelialcells VEGF-B VEGF VEGF-E VEGF-C VEGF-D P P P P P P VEGFR1 VEGFR2 VEGFR3 P P P P P P TSAd P P P P P P PLC Src GRB2 P P P P P P PKC Angiogenesis Monocytemigration Lymphangiogenesis PI3K Ca2+ Akt Raf SOS Ras Cellmigration MEK Caspase-9 Erk Bad eNOS Cellsurvival Vascularpermeability Cellproliferation

  17. Kinaseinhibitoryprofiles of anti-angiogenicagents Döme, Tímár, AntiCancerAgents, 2007

  18. Overview of EGF signaling EGF Vav2 EGFR PTP + E2Ub - - STAT1 STAT3 PLC H2O2 GRB2 Cbl IP3 NADPH synthesis DAG Gab1 SOS Targetgenes Shc Ca2+ + - - Cdc42 /Rac PKC Rac PI3K Ras Src DOK Targets PIP3 - Raf MEKK MEKK4 Akt PDK1 ADAM Ras GAP MAPKK MKK2 MKK4 Nck + GRB2 - Targets HB-EGF FAK Bad FKHR MAPK MAPK p38 JNK Gab1 Src PAK1 Paxillin C-Fos MAPK Shp2 RSK2 p53 Jun CAS WASP Rac JNK AP1 Apoptosis CREB Cell cycle Cytoskeleton

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