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15. ročník kongresu s medzinárodnou účasťou
Slovenská spoločnosť pre laboratórnu medicínu Slovenská zdravotnícka univerzita Slovenská lekárska spoločnosť Slovenská komora iných zdravotníckych pracovníkov LABORATÓRNA MEDICÍNA 2014 15. ročník kongresu s medzinárodnou účasťou Kongres konaný pod záštitou EUMS – European Union of Medical Specialists Možnosti bunkovej terapie u pacientov s ischemickou chorobou srdca Ján Kyselovič, Peter Musil Katedra farmakológie a toxikológie, Farmaceutická fakulta Ústav farmakológie a klinickej farmakológie, Lekárska fakulta Univerzita Komenského v Bratislave Martin 29. novembra 2014
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Background Regenerative Medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects. Medicine Bioengineering Chemical Engineering Developmental Biology Molecular Biology Drug Delivery Physiology Biochemistry Genomics Proteomics Nanotechnology Regenerative Medicine Materials Science Stem cells are the seeds of tissue repair and regeneration and a promising source for novel therapies.
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Introduction Elena Matsa & Chris Denning, J. of Cardiovasc. Trans. Res. (2012) 5:581–592
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Intramyocardial CD133+ Cell Therapy
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Introduction
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Introduction CABG CABG +CD133+
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Stem Cell CD133+ preparation and transplamtation
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Stem Cell CD133+ preparation and transplamtation
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Meta/analysis of Cell Therapy Clincial Trails
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Ten years of Cardiac Regeneration
Perception of the General Cardiology Community
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Mechanisms of cardiac regeneration after cell therapy
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Ten years of Cardiac Regeneration
Current status Ten years of Cardiac Regeneration Perception of the General Cardiology Community Clinical trials demonstrate excellent safety profile Yet, Efficacy is modest and inconsistent across the trials with inter-trial heterogeneity Promise remains controversial and does not meet clinical expectations
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Pluripotency of Hematopoietic and Stromal Adult Stem Cell
Trans-differentiation or plasticity of adult stem cells Specific induction
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Regulation of cardiac differentiation
Jonathan A. Epstein N A T U R E | V O L | 1 9 M A Y Michael A. Laflamme1 & Charles E. Murry
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Regulation of differentiation
Cells can interact with each other and with their environment This interaction turns specific signaling paths ON or OFF At the present time we do not fully understand the mechanisms by which any mammalian gene is switched on and off during differentiation and development. This involves the interaction of key cis-elements e.g. enhancers, promoters and silencers with trans-acting proteins (e.g. transcription factors, coactivators, adaptors and chromatin modifiers) that give rise to changes in gene expression, It is associated with changes in epigenetic modification - methylation, replication, histone acetylation and nuclear position. The multiple growth factors and chemokines that have been shown to promote endogenous stem cell mobilization, proliferation, and homing to the injured myocardium, the development of growth factor/chemokine “cocktails” seems an attractive therapeutic approach for enhancing cardiac regeneration.
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Regulation of differentiation endogenic factors
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Open questions of cell therapy
However, apart from hematopoietic stem cell (HSC) transplantation, essentially all other stem cell treatments remain experimental. Numerous challenges, technical and clinical barriers must be overcome before novel stem cell therapies can achieve meaningful clinical impact. In recent years, unproven therapies have been widely practiced outside the standard clinical trial network, threatening the cause of legitimate clinical investigation. High hopes have inspired numerous clinical trials, but it has been difficult to obtain unequivocal evidence for robust clinical benefit. When clinical investigation proceeds largely empirically, and without a deeper understanding therapeutic mechanisms, it is difficult to reformulate therapeutic strategies after clinical failures.
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Molekulárna farmakológia Ca antagonistov
SHRSP NaCl + lacidipine NaCl 0, mg/kg/day 140 160 180 200 220 240 260 BP mmHg ns SHR-SP + Lacidipine H2O * Tlak krvi 7 8 9 10 11 12 SHRSP NaCl 25 50 75 100 % prežívanie potkanov týždne liečby Hmotnosť srdca NaCl 0, mg/kg/day 3,0 3,2 3,4 3,6 3,8 4,0 4,2 Heart/body * SHR-SP + Lacidipine H2O
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Pharmacological intervention to gene expression
DFT CU Bratislava Kyselovic et al. J Hypertension, 1998 Krenek, Kyselovic et al., Hyperten 2001
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Isoproterenol-induced heart failure – Growth factors
IL-1b Cardiotropin -1 TNFa HGF LIF VEGF SDF-1a
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Isoproterenol-induced heart failure – Transcription factors
c-fos STAT 3 Krenek, et al., Eur J Heart Failure. 2009, (11), 140 DPT FaF UK Bratislava
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Pharmacological intervention to gene expression
Bcl-2 Bax 8h control ISO 2days 8 days Masart et al. Hypertension Kyselovic et al, J Hyperten. 2004 Simko et al. Pharmazie. 1999a, b, Kyselovic et al. JPEP. 2005 Krenek et al. Hypertension Cagalinec et al. JCP. 2006 Kyselovic et al. Br. J. Pharmacol Krenek et al.Cnd J Physiol. 2006 Bacharova et al. Clin. Exp. Hyperten.2004, Bacharova et al.Electrocardioly 2008 Mackovičová et a.l- Can.J. Pharmacol Krenek et al. EU J Hert failure, 2009 Klimas et al., Basic Clin Pharmacol , 2012 Jankyova et. al., Pathol Res Prac. 2012
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Results – Human Explanted Heart
Hierarchical clustering: Spearman’s correlation matrix of all data (before selection)
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Regulation of differentiation – small molecules
Qian et al,. Neth Heart J, 2008; 16:
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Open questions of genomics
6th September The ENCODE (Encyclopedia of DNA Elements) Numerous challenges and technical barriers must be overcome before novel stem cell therapies can achieve meaningful clinical impact
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Summary of Pharmacological intervention
Stem cells: the modification of the multiple growth factors and chemokines that have been shown to promote endogenous stem cell mobilization, proliferation, and homing to the injured myocardium the interaction with gene expression via enhancers, promoters and silencers, transcription factors, coactivators, adaptors and chromatin modifiers the association with changes in epigenetic modification - methylation, replication, histone acetylation and nuclear position. Myocardium: pharmacological treatments target disease mechanisms at the molecular/cellular and whole-organ level. it is also complex of genetic, neurohumoral, immunological a metabolic changes modify function of cardiomyocytes, fibroblast or interstitium. Patient: Therapeutic, adverse and unwanted effects organs systems and whole body
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Co authors Department of Pharmacology and Toxicology, Faculty of Pharmacy Comenius University Bratislava, Slovakia Associate professors: Peter Krenek PharmD, PhD Peter Ochodnicky PharmD, PhD Jan Klimas, PharmD, PhD Adriana Adameova PharmD, PhD Anna Hrabovská, PharmD, PhD Marek Matus, PharmD, PhD Assistant of professors Peter Musil, PhD Adrea Gazova PharmD, PhD Ondrej Sprušansky , PhD Adela Čorejová, Pharm, PhD. Dana Kučerová, PhD Miriam Verčinská, PharmD. PhD PhD students Lenka Pivackova Hanka Cernecka Lucia Mesarosova Lea Dugovicova Katarina Tucekova Kristina Stahlova Bea Gajdacova Jana Mlynarova Matej Kucera Gabriel Doka Lucia Mensikova DPT FaF UK Bratislava MUDr. Michal Hulman doc. MUDr.. Eva Goncalvesova
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