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1. Poster session 2Morphogenetic mechanisms290MiR-133 regulates retinoic acid pathway during early cardiac chamber specification291Bmp2 regulates atrial differentiation through miR-130 during early heart looping formationDevelopmental genetics294Association of deletion allele of insertion/deletion polymorphism in alpha 2B adrenoceptor gene and hypertension with or without type 2 diabetes mellitus295Association of G1359A polymorphism of the endocannabinoid type 1 receptor (CNR1) with coronary artery disease (CAD) with type 2 diabetes mellitusCell growth, differentiation and stem cells - Vascular298Gamma-secretase inhibitor prevents proliferation and migration of ductus arteriosus smooth muscle cells: a role of Notch signaling in postnatal closure of ductus arteriosus299Mesenchymal stromal-like cells (MLCs) derived from induced pluripotent stem (iPS) cells: a promising therapeutic option to promote neovascularization300Sonic Hedgehog promotes mesenchymal stem cell differentiation to vascular smooth muscle cells in cardiovacsular disease301Proinflammatory cytokine secretion and epigenetic modification in endothelial cells treated LPS-GinfivalisCell death and apoptosis - Vascular304Mitophagy acts as a safeguard mechanism against human vascular smooth muscle cell apoptosis induced by atherogenic lipidsTranscriptional control and RNA species - Vascular307MicroRNA-34a role in vascular calcification308Local delivery of a miR-146a inhibitor utilizing a clinically applicable approach attenuates neointima formation after vascular injury309Long noncoding RNA landscape of hypoxic endothelial cells310Specific circulating microRNAs levels associate with hypertension, hyperglycemia and dysfunctional HDL in acute coronary syndrome patientsCytokines and cellular inflammation - Vascular313Phosphodiesterase5A up-regulation in vascular endothelium under pro-inflammatory conditions: a newly disclosed anti-inflammatory activity for the omega-3polyunsaturated aatty acid docosahexaenoic acid314Cardiovascular risk modifying with extra-low dose anticytokine drugs in rhematoid arthritis315Conversion of human M-CSF macrophages into foam cells reduces their proinflammatory responses to classical M1-polarizing activation316Lymphocytic myocarditis coincides with increased plaque inflammation and plaque hemorrhage in coronary arteries, facilitating myocardial infarction317Serum osteoprotegerin level predictsdeclined numerous of circulating endothelial- derived and mononuclear-derived progenitor cells in patients with metabolic syndromeGrowth factors and neurohormones - Vascular320Effect of gastrin-releasing peptide (GRP) on vascular inflammationSignal transduction - Heart323A new synthetic peptide regulates hypertrophy in vitro through means of the inhibition of nfkb324Inducible fibroblast-specific knockout of p38 alpha map kinase is cardioprotective in a mouse model of isoproterenol-induced cardiac hypertrophy325Regulation of beta-adrenoceptor-evoked inotropic responses by inhibitory G protein, adenylyl cyclase isoforms 5 and 6 and phosphodiesterases326Binding to RGS3 and stimulation of M2 muscarinic acetylcholine receptors modulates the substrate specificity of p190RhoGAP in cardiac myocytes327Cardiac regulation of post-translational modifications, parylation and deacetylation in LMNA dilated cardiomyopathy mouse model328Beta-adrenergic regulation of the b56delta/pp2a holoenzyme in cardiac myocytes through b56delta phosphorylation at serine 573Nitric oxide and reactive oxygen species - Vascular331Oxidative stress-induced miR-200c disrupts the regulatory loop among SIRT1, FOXO1 and eNOS332Antioxidant therapy prevents oxidative stress-induced endothelial dysfunction and Enhances Wound Healing333Morphological and biochemical characterization of red blood cell in coronary artery diseaseCytoskeleton and mechanotransduction - Heart336Novel myosin activator, JSH compounds, increased myocardial contractility without chronotropic effect in ratsExtracellular matrix and fibrosis - Vascular339Ablation of Toll-like receptor 9 causes cardiac rupture after myocardial infarction by attenuating proliferation and differentiation of cardiac fibroblasts340Altered vascular remodeling in the mouse hind limb ischemia model in Factor VII activating protease (FSAP) deficiencyVasculogenesis, angiogenesis and arteriogenesis343Pro-angiogenic effects of proly-hydroxylase inhibitors and their potential for use in a novel strategy of therapeutic angiogenesis for coronary total occlusion344Nrf2 drives angiogenesis in transcription-independent manner: new function of the master regulator of oxidative stress response345Angiogenic gene therapy, despite efficient vascular growth, is not able to improve muscle function in normoxic or chronically ischemic rabbit hindlimbs -role of capillary arterialization and shunting346Effect of PAR-1 inhibition on collateral vessel growth in the murine hind limb model347Quaking is a key regulator of endothelial cell differentiation, neovascularization and angiogenesis348'Emerging angiogenesis' in the chick chorioallantoic membrane (CAM). An in vivo study349Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis in vitro and in vivo via EMMPRINEndothelium352Reciprocal regulation of GRK2 and bradykinin receptor stimulation modulate Ca2+ intracellular level in endothelial cells353The roles of bone morphogenetic proteins 9 and 10 in endothelial inflammation and atherosclerosis354The contribution of GPR55 to the L-alpha-lysophosphatidylinositol-induced vasorelaxation in isolated human pulmonary arteries355The endothelial protective ACE inhibitor Zofenoprilat exerts anti-inflammatory activities through H2S production356A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction357Endothelial progenitor cells to apoptotic endothelial cell-derived microparticles ration differentiatesas preserved from reduced ejection fractionheart failure358Proosteogenic genes are activated in endothelial cells of patients with thoracic aortic aneurysm359Endothelin ETB receptors mediate relaxing responses to insulin in pericardial resistance arteries from patients with cardiovascular disease (CVD)Smooth muscle and pericytes362CX3CR1 positive myeloid cells regulate vascular smooth muscle tone by inducing calcium oscillations via activation of IP3 receptors363A novel function of PI3Kg on cAMP regulation, role in arterial wall hyperplasia through modulation of smooth muscle cells proliferation364NRP1 and NRP2 play important roles in the development of neointimal hyperplasia in vivo365Azithromycin induces autophagy in aortic smooth muscle cellsCoagulation, thrombosis and platelets368The real time in vivo evaluation of platelet-dependent aldosterone prothrombotic action in mice369Development of a method for in vivo detection of active thrombi in mice370The antiplatelet effects of structural analogs of the taurine chloramine371The influence of heparin anticoagulant drugs on functional state of human platelets372Regulation of platelet aggregation and adenosine diphosphate release by d dimer in acute coronary syndrome (in vitro study)Oxygen sensing, ischaemia and reperfusion375Sirtuin 5 mediates brain injury in a mouse model of cerebral ischemia-reperfusion376Abscisic acid: a new player in cardiomyocyte protection from ischaemia?377Protective effects of ultramicronized palmitoylethanolamide (PEA-um) in myocardial ischaemia and reperfusion injury in vivo378Identification of stem cell-derived cardiomyocytes using cardiac specific markers and additional testing of these cells in simulated ischemia/reperfusion system379Single-dose intravenous metformin treatment could afford significant protection of the injured rat kidney in an experimental model of ischemia-reperfusion380Cardiotoxicity of long acting muscarinic receptor antagonists used for chronic obstructive pulmonary disease381Dependence antioxidant potential on the concentration of amino acids382The impact of ischemia-reperfusion on physiological parameters,apoptosis and ultrastructure of rabbit myocardium with experimental aterosclerosisMitochondria and energetics385MicroRNA-1 dependent regulation of mitochondrial calcium uniporter (MCU) in normal and hypertrophied hearts386Mitochondrial homeostasis and cardioprotection: common targets for desmin and aB-crystallin387Overexpression of mitofusin-2 (Mfn2) and associated mitochondrial dysfunction in the diabetic heart388NO-dependent prevention of permeability transition pore (MPTP) opening by H2S and its regulation of Ca2+ accumulation in rat heart mitochondria389G protein coupled receptor kinase 2 (GRK2) is fundamental in recovering mitochondrial morphology and function after exposure to ionizing radiation (IR)Gender issues392Sex differences in pulmonary vascular control; focus on the nitric oxide pathwayAging395Heart failure with preserved ejection fraction develops when feeding western diet to senescence-accelerated mice396Cardiovascular markers as predictors of cognitive decline in elderly hypertensive patients397Changes in connexin43 in old rats with volume overload chronic heart failureGenetics and epigenetics400Calcium content in the aortic valve is associated with 1G>2G matrix metalloproteinase 1 polymorphism401Neuropeptide receptor gene s (NPSR1) polymorphism and sleep disturbances402Endothelin-1 gene Lys198Asn polymorphism in men with essential hypertension complicated and uncomplicated with chronic heart failure403Association of common polymorphisms of the lipoprotein lipase and pon1 genes with the metabolic syndrome in a sample of community participantsGenomics, proteomics, metabolomics, lipidomics and glycomics405Gene expression quantification using multiplexed color-coded probe pairs to determine RNA content in sporadic cardiac myxoma406Large-scale phosphorylation study of the type 2 diabetic heart subjected to ischemia / reperfusion injury407Transcriptome-based identification of new anti-inflammatory properties of the olive oil hydroxytyrosol in vascular endothelial cell under basal and proinflammatory conditions408Gene polymorphisms combinations and risk of myocardial infarctionComputer modelling, bioinformatics and big data411Comparison of the repolarization reserve in three state-of-the-art models of the human ventricular action potentialMetabolism, diabetes mellitus and obesity414Endothelial monocyte-activating polypeptide-II improves heart function in type -I Diabetes mellitus415Admission glucose level is independent predictor of impaired left ventricular function in patients with acute myocardial infarction: a two dimensional speckle-tracking echocardiography study416Association between biochemical markers of lipid profile and inflammatory reaction and stiffness of the vascular wall in hypertensive patients with abdominal obesity417Multiple common co-morbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress and myocardial stiffening418Investigating the cardiovascular effects of antiretroviral drugs in a lean and high fat/sucrose diet rat model of obesity419Statins in the treatment of non-alcoholic steatohepatitis (NASH). Our experience from a 2-year prospective study in Constanta County, Romania420Epicardial adipose tissue as a predictor of cardiovascular outcome in patients with ACS undergoing PCI?Arterial and pulmonary hypertension423Dependence between heart rhythm disorers and ID polymorphism of ACE gene in hypertensive patients424Molecular mechanisms underlying the beneficial effects of Urocortin 2 in pulmonary arterial hypertension425Inhibition of TGf-b axis and action of renin-angiotensin system in human ascending aorta aneurysms426Early signs of microcirculation and macrocirculation abnormalities in prehypertension427Vascular smooth muscle cell-expressed Tie-2 controls vascular tone428Cardiac and vascular remodelling in the development of chronic thrombo-embolic pulmonary hypertension in a novel swine modelBiomarkers431Arrhythmogenic cardiomyopathy: a new, non invasive biomarker432Can circulating microRNAs distinguish type 1 and type 2 myocardial infarction?433Design of a high-throughput multiplex proteomics assay to identify left ventricular diastolic dysfunction in diabetes434Monocyte-derived and P-selectin-carrying microparticles are differently modified by a low fat diet in patients with cardiovascular risk factors who will and who will not develop a cardiovascular event435Red blood cell distribution width assessment by polychromatic interference microscopy of thin films in chronic heart failure436Invasive and noninvasive evaluation of quality of radiofrequency-induced cardiac denervation in patients with atrial fibrillation437The effect of therapeutic hypothermia on the level of brain derived neurotrophic factor (BDNF) in sera following cardiopulmonary resustitation438Novel biomarkers to predict outcome in patients with heart failure and severe aortic stenosis439Biological factors linking depression and anxiety to cardiovascular disease440Troponins and myoglobin dynamic at coronary arteries graftingInvasive, non-invasive and molecular imaging443Diet composition effects on the genetic typing of the mouse ob mutation: a micro-ultrasound characterization of cardiac function, macro and micro circulation and liver steatosis444Characterization of pig coronary and rabbit aortic lesions using IV-OCT quantitative analysis: correlations with histologyGene therapy and cell therapy447Enhancing the survival and angiogenic potential of mouse atrial mesenchymal cells448VCAM-1 expression in experimental myocardial infarction and its relation to bone marrow-derived mononuclear cell retentionTissue engineering451Advanced multi layered scaffold that increases the maturity of stem cell-derived human cardiomyocytes452Response of engineered heart tissue to simulated ischemia/reperfusion in the presence of acute hyperglycemic conditions453Serum albumin hydrogels prevent de-differentiation of neonatal cardiomyocytes454A novel paintbrush technique for transfer of low viscosity ultraviolet light curable cyan methacrylate on saline immersed in-vitro sheep heart

Author

MC Arokiaraj, E J Humphrey, E Ruivo, P Benzoni, A Uitterdijk, S Malandraki-Miller, SJ Tarvainen, N Di Lascio, MA Charnaia, T Gegenava, N Sunderland, J Skopal, A Evtushenko, L Malinova, G Chiva-Blanch, J O'reilly, S Stojkovic, E Sommariva, K Stam, SS Kapel, M L Sasonko, L Borges, C Maia-Rocha, MV Krestjyaninov, M Tscharre, I R Parepa, A Genis, O Sorop, TI Petelina, CH Chimed, N A Dorofeyeva, M Paci, Y Timasheva, MA Carluccio, LE Smith, E L Stepien, R Prakaschandra, VM Zhebel, V Gafarov, GSB Guillermo Solache Berrocal, J Benes, A Noriega De La Colina, AB Gevaert, DPM De Wijs-Meijler, A Fiordelisi, A Budko, L Murfitt, A Diokmetzidou, G Borile, C R Revnic, A Korda, S Cassambai, B Medic, A Szantai, S Cuzzocrea, T Vigliarolo, C Diaz-Canestro, YM Roka-Moiia, M Murina, A Dickhout, A Gromotowicz, R Stamatiou, C Pellet-Many, A Lupieri, A Kumar, J G R De Mey, AS Kostina, A Berezin, FL Wilkinson, L Morbidelli, O Karpinska, CG Mitrofan, J Gambardella, JA Maring, W Rong, A Margariti, C Deffge, P Korpisalo, A Grochot-Przeczek, G A Barnett, J Herold, Y Omori, E-S Jeon, B Porro, A Orlandi, A Magenta, A Ranieri, N Vignier, M Levay, K Krobert, S A Bageghni, C Del Giudice, MK Bae, L Woudstra, F Da Silva, AR Babaeva, M Massaro, L S Niculescu, C Voellenkle, L Korte, I Badi, C Vindis, J Pizzicannella, Maryam Alshamrani, R Ferrer-Lorente, JH Hsu, W Hamed, C Lopez Sanchez, V Garcia-Martinez, D Franco, V Garcia-Lopez, A Aranega, C Lopez-Sanchez, S Tayel, H Khader, N El-Helbawy, A Alrefai, H El-Barbary, JR Wu, ZK Dai, JL Yeh, C Sanjurjo-Rodriguez, Y Richaud-Patin, FJ Blanco, L Badimon, A Raya, Paul A Cahill, F Diomede, I Merciaro, O Trubiani, H Nahapetyan, A Swiader, J Faccini, P Boya, M Elbaz, F Zeni, I Burba, M Bertolotti, MC Capogrossi, G Pompilio, A Raucci, R Widmer-Teske, J Dutzmann, J Bauersachs, K Donde, JM Daniel, DG Sedding, N Simionescu, GM Sanda, MG Carnuta, CS Stancu, AC Popescu, MR Popescu, A Vlad, DR Dimulescu, AV Sima, E Scoditti, M Pellegrino, N Calabriso, C Storelli, R De Caterina, KS Solodenkova, EV Kalinina, MN Usachiova, J Lappalainen, M DE C Lee-Rueckert, PT Kovanen, PS Biesbroek, RWE Emmens, AC Van Rossum, LJM Juffermans, JWM Niessen, PAJ Krijnen, A Kremzer, T Samura, T Berezina, E Gronenko, MK Kim, HJ Park, SK Bae, D Sorriento, M Ciccarelli, E Vernieri, P Campiglia, B Trimarco, G Iaccarino, K E Hemmings, K E Porter, J F Ainscough, M J Drinkhill, N A Turner, HG Hiis, MV Cosson, FO Levy, T Wieland, C Macquart, M Chatzifrangkeskou, A Evans, G Bonne, A Muchir, E Kemp, M Avkiran, F Carlomosti, M D'agostino, S Beji, G Zaccagnini, B Maimone, V Di Stefano, F De Santa, S Cordisco, A Antonini, R Ciarapica, E Dellambra, F Martelli, D Avitabile, MG Scioli, A Bielli, S Agostinelli, C Tarquini, V Tarallo, S De Falco, A Zaninoni, S Fiorelli, P Bianchi, G Teruzzi, I Squellerio, L Turnu, A Lualdi, E Tremoli, V Cavalca, YJ Lee, ES Ju, JO Choi, GY Lee, BK Lim, MANOJ Manickam, S-H Jung, S Omiya, K Otsu, S Nowak, M Wagner, RC Braun-Dullaeus, S Kostin, A Francke, S Subramaniam, SM Kanse, K Al-Lamee, CJ Schofield, S Egginton, AH Gershlick, D Kloska, A Kopacz, A Augustyniak, J Dulak, A Jozkowicz, J Hytonen, P Halonen, J Taavitsainen, S Tarvainen, T Hiltunen, T Liimatainen, K Kalliokoski, J Knuuti, S Yla-Herttuala, S Weinert, B Isermann, J Lee, A Cochrane, S Kelaini, J Bojdo, M Vila Gonzalez, Y Hu, D Grieve, A W Stitt, L Zeng, Q Xu, B Reglin, W Xiang, B Nitzsche, M Maibier, AR Pries, KR Vrijsen, SAJ Chamuleau, V Verhage, CHG Metz, K Lodder, ECM Van Eeuwijk, SM Van Dommelen, PA Doevendans, AM Smits, MJ Goumans, JPG Sluijter, M Bova, S Loffredo, S Appleby, N Morrell, M Baranowska-Kuczko, M Kloza, E Ambrozewicz, M Kozlowski, B Malinowska, H Kozlowska, M Monti, E Terzuoli, M Ziche, AM Mahmoud, AM Jones, JA Wilkinson, M Romero, J Duarte, MY Alexander, G Faggian, AA Kostareva, AB Malashicheva, TM Leurgans, TN Nguyen, A Irmukhamedov, LP Riber, R Mcgeogh, S Comer, A Blanco Fernandez, A Ghigo, R Blaise, NF Smirnova, N Malet, P Vincent, I Limon, S Gayral, E Hirsch, M Laffargue, V Mehta, I Zachary, I Aidonidis, K Kramkowski, W Miltyk, P Kolodziejczyk, A Gradzka, J Szemraj, E Chabielska, I Dijkgraaf, N Bitsch, S Van Hoof, F Verhaegen, R Koenen, TM Hackeng, D I Roshchupkin, K V Buravleva, VI Sergienko, DD Zhernossekov, VM Rybachuk, TV Grinenko, N Furman, P Dolotovskaya, M Shamyunov, T Denisova, M Reiner, A Akhmedov, S Keller, M Miranda, S Briand, L Barile, G Kullak-Ublick, T Luscher, G Camici, L Guida, M Magnone, P Ameri, E Lazzarini, C Fresia, S Bruzzone, E Zocchi, R Di Paola, M Cordaro, R Crupi, R Siracusa, M Campolo, G Bruschetta, R Fusco, P Pugliatti, E Esposito, J Paloczi, R Gaspar, A Dinnyes, J Kobolak, P Ferdinandy, A Gorbe, Z Todorovic, D Krstic, K Savic Vujovic, D Jovicic, G Basta Jovanovic, S Radojevic Skodric, M Prostran, S Dean, CJ Mee, KL Harvey, A Hussain, C Pena, B Paltineanu, S Voinea, F Revnic, C Ginghina, T Zaglia, P Ceriotti, A Campo, P Carullo, A Armani, R Coppini, V Vida, I Olivotto, G Stellin, R Rizzuto, D De Stefani, M Sandri, D Catalucci, M Mongillo, E Soumaka, I Kloukina, M Tsikitis, M Makridakis, A Varela, C Davos, A Vlachou, Y Capetanaki, MM Iqbal, H Bennett, B Davenport, C Pinali, G Cooper, E Cartwright, A Kitmitto, NA Strutynska, LA Mys, VF Sagach, A Franco, A Verzijl, R Van Duin, IKM Reiss, DJ Duncker, D Merkus, H Shakeri, M Orije, AJ Leloup, CE Van Hove, EM Van Craenenbroeck, GRY De Meyer, CJ Vrints, K Lemmens, L Desjardins-Creapeau, R Wu, M Lamarre-Cliche, P Larochelle, L Bherer, H Girouard, M Melenovsky, A Kvasilova, K Ruskova, D Sedmera, ABV Ana Barral, M Martin Fernandez, PRG Pablo Roman Garcia, JCLL Juan Carlos Llosa, MND Manuel Naves Diaz, CM Cesar Moris, JBCA Jorge B Cannata-Andia, IR Isabel Rodriguez, M Voevoda, E Gromova, V Maximov, D Panov, I Gagulin, A Gafarova, H Palahniuk, IP Pashkova, NV Zhebel, OL Starzhynska, DP Naidoo, K Rawojc, F J Enguita, G Grudzien, SJ Cordwell, MY White, R Martinelli, V Gatta, TR Nasibullin, VV Erdman, IA Tuktarova, OE Mustafina, J Hyttinen, S Severi, GG Vorobyov, KH Batmyagmar, Z Lkhagvasuren, LI Gapon, NA Musikhina, KS Avdeeva, SM Dyachkov, I Heinonen, M Van Kranenburg, VJ De Beer, Y Octavia, RJ Van Geuns, AH Van Den Meiracker, J Van Der Velden, FP Everson, T Ogundipe, T Grandjean, P De Boever, N Goswami, H Strijdom, A I Suceveanu, A P Suceveanu, L Mazilu, D E Tofoleanu, D Catrinoiu, M Rohla, C Hauser, K Huber, H Wojta, TW Weiss, MA Melnikova, NV Olezov, RH Gimaev, H Khalaf, VI Ruzov, R Adao, P Mendes-Ferreira, D Santos-Ribeiro, M Rademaker, AF Leite-Moreira, C Bras-Silva, LAA Alvarenga, RSP Falcao, RR Dias, S Lacchini, PS Gutierrez, JB Michel, YU I Gurfinkel, O YU Atkov, M Teichert, C Korn, C Mogler, S Hertel, C Arnold, T Korff, HG Augustin, RWB Van Duin, Y D'alessandra, F M Farina, M Casella, V Catto, C Carbucicchio, A Dello Russso, I Stadiotti, S Brambilla, M Chiesa, M Giacca, G I Colombo, C Tondo, F Ahlin, T Andric, D Tihanyi, J Wojta, E O'connell, A Butt, L Murphy, S Pennington, M Ledwidge, K Mcdonald, J Baugh, C Watson, R Suades, J Crespo, R Estruch, A Dyachenko, V Ryabukho, V Evtushenko, YU Saushkina, YU Lishmanov, K Smyshlyaev, A Bykov, S Popov, E Pavlyukova, Y Anfinogenova, E Szigetfu, B Kapornai, E Forizs, ZS Jenei, Z Nagy, B Merkely, E Zima, A Cai, R Dworakowski, T Gibbs, S Piper, N Jegard, T Mcdonagh, M Gegenava, II Dementieva, YUA Morozov, C Barsanti, F Stea, F Lenzarini, C Kusmic, F Faita, PJ Halonen, PH Puhakka, JP Hytonen, JM Taavitsainen, E A Supit, C A Carr, BCW Groenendijk, C Gorsse-Bakker, A Panasewicz, S Sneep, D Tempel, WJ Van Der Giessen, J Rys, C Daraio, P Dell'era, J Pigler, A Eder, T Eschenhagen, M M Mazo, N Amdursky, N S Peters, M M Stevens, and C M Terracciano

Subjects
chemistry.chemical_classification, Physiology, business.industry, Fatty acid, 030204 cardiovascular system & hematology, Pharmacology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, chemistry, Glycomimetic, Physiology (medical), medicine, Endothelial dysfunction, Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease.

Published
2016

2. Poster session 1

Author

J. Schlueter, T. Brand, D. J. Henderson, V. Boczonadi, P. Humbert, B. Chaudhry, D. Sedmera, J. Svatunkova, R. Kockova, B. Sankova, C. Lopez Sanchez, D. Franco, A. Aranega, V. Garcia-Martinez, E. Demina, V. Miroshikova, A. Denisenko, A. Schwarzman, F. Sanchez-Cabo, C. Torroja, A. Benguria, R. Buchan, P. Srivastava, F. Martinez, P. Barton, S. Cook, A. Dopazo, E. Lara-Pezzi, H. Rai, S. Kumar, A. K. Sharma, S. Mastana, A. Kapoor, C. M. Pandey, S. Agrawal, N. Sinha, J. Lipkova, M. Goldbergova, J. Parenica, J. Bienertova Vasku, A. Vasku, P. Kala, J. Spinar, L. Perez-Cabornero, D. Cantalapiedra, A. Forteza, R. Saez-Villaverde, J. Zumalde, V. Fernandez-Pedrosa, S. Zuniga-Trejos, M. Gil-Borja, M. Lazaro, S. Santillan, M. Costa, N. Cortez-Dias, P. Carrilho-Ferreira, D. Silva, C. Jorge, R. Placido, C. Calisto, M. Fiuza, A. Nunes Diogo, F. J. Enguita, H. H. W. Sillje, B. Lu, H. Yu, M. Zwartbol, W. P. Ruifrok, W. H. Van Gilst, R. A. De Boer, D. Zaliaduonyte-Peksiene, S. Simonyte, V. Lesauskaite, J. Vaskelyte, V. Mizariene, R. Zaliunas, W. Tigchelaar, E. Barlaka, A. Lazou, C. Del Giudice, E. Cipolletta, A. Anastasio, G. Santulli, M. Rusciano, A. S. Maione, P. Campiglia, M. Illario, B. Trimarco, G. Iaccarino, G. A. Frentzou, M. J. Drinkhill, N. A. Turner, S. G. Ball, J. F. X. Ainscough, L. Bertrand, F. Mailleux, J. Hammond, A. Ginion, L. Hue, J. L. Balligand, S. Horman, J. L. Vanoverschelde, C. Beauloye, B. Demeulder, S. L. Puhl, A. Mueller, Y. Devaux, D. R. Wagner, K. Roemer, M. Boehm, C. Maack, D. Miranda-Silva, I. Falcao-Pires, N. Goncalves, D. Moreira-Goncalves, A. F. Leite-Moreira, F. Mraiche, L. Fliegel, J. Xue, G. G. Haddad, L. C. Hsiao, C. Carr, Z. F. Cui, K. Clarke, M. A. D'amico, P. Izzicupo, A. Di Fonso, A. Bascelli, S. Gallina, A. Di Baldassarre, C. Silvestre, P. Fernandez, O. M. Pello, C. Indolfi, F. Civeira, R. Hutter, B. Ibanez, J. Chaves, J. Martinez-Gonzalez, V. Andres Garcia, A. Zabirnik, N. Smolina, A. Malashicheva, E. Omelchenko, T. Sejersen, A. Kostareva, C. Noack, M. P. Zafiriou, A. Renger, R. Dietz, H. J. Schaeffer, M. B. Bergmann, C. Zelarayan, S. Van Linthout, K. Miteva, M. P. Becher, M. Haag, J. Ringe, H.-P. schultheiss, M. Sittinger, C. Tschoepe, T. Kakuchaya, L. Bockeria, E. Golukhova, M. Eremeeva, N. Chigogidze, I. Aslanidi, I. Shurupova, A. Svobodov, A. A. Ramkisoensing, D. A. Pijnappels, J. Swildens, M. J. Goumans, M. J. Schalij, A. A. F. De Vries, D. E. Atsma, A. Gomes, G. M. Costa, C. A. Cordeiro, A. Matsuada, L. B. Rosario, A. P. Freire, M. Bousquenaud, M. Rolland-Turner, F. Maskali, L. Zhang, P. Y. Marie, F. Azuaje, A. J. Smith, G. M. Ellison, C. D. Waring, S. Purushothaman, D. Torella, B. Nadal-Ginard, M. H. Van Marion, D. W. J. Van Der Schaft, M.-J. Goumans, F. P. T. Baaijens, C. V. C. Bouten, N. Kraenkel, K. Kuschnerus, M. Mueller, T. Speer, S. Briand, M. Bader, P. Madeddu, T. F. Luescher, U. Landmesser, A. Papalamprou, C. Vicinanza, D. F. Goldspink, M. Noseda, S. J. Mcsweeney, T. Leja, E. Belian, I. Macaulay, F. Al-Beidh, S. Koenemann, M. S. Abreu Pavia, S. E. Jacobsen, M. D. Schneider, G. Foldes, Z. Bagyura, Z. Lendvai, D. Mathe, T. Nemeth, J. Skopal, I. Foldes, B. Merkely, S. E. Harding, A. J. Candasamy, R. S. Haworth, A. Boguslavsky, F. Cuello, M. J. Shattock, M. Mayr, M. Gautel, M. Avkiran, P. Leszek, B. Sochanowicz, M. Szperl, P. Kolsut, K. Brzoska, W. Piotrowski, T. Rywik, B. Danko, J. Rozanski, M. Kruszewski, N. Bouteldja, R. J. Woodman, C. L. Hewitson, E. Domingo, J. A. Barbara, A. A. Mangoni, R. Carnicer Hijazo, A. B. Hale, X. Liu, S. Suffredini, J. K. Bendall, G. B. S. Lim, N. J. Alp, K. M. Channon, B. Casadei, L. R. Moltzau, J. M. Aronsen, S. Meier, I. Sjaastad, T. Skomedal, J.-B. Osnes, F. O. Levy, E. Qvigstad, P. T. Wright, L. M. K. Pannell, A. R. Lyon, J. Gorelik, A. Guellich, S. F. Vatner, R. Fischmeister, B. Manoury, E. Dubois, J. Hamelet, A. Vanderper, P. Herijgers, D. Langin, F. Gartner, J. Gummert, H. Milting, G. Euler, M. Priess, J. Heger, T. Noll, R. Schulz, T. Doi, T. Akagami, T. Naka, T. Masuyama, M. Ohyanagi, M. Massaro, E. Scoditti, M. Pellegrino, M. A. Carluccio, C. Martines, C. Storelli, R. De Caterina, M. Falck-Hansen, M. E. Goddard, J. E. Cole, N. Astola, A. J. Cross, R. Krams, C. Monaco, M. F. Corsten, W. Verhesen, A. P. Papageorgiou, P. Carai, M. Lindow, S. Obad, G. Summer, L. De Rijck, S. Coort, M. Hazebroek, R. Van Leeuwen, M. Gijbels, M. P. J. De Winther, F. R. M. Stassen, S. Kauppinen, B. Schroen, S. Heymans, Z. Husti, V. Juhasz, L. Virag, A. Kristof, I. Koncz, T. Szel, I. Baczko, N. Jost, J. G. Y. Papp, A. Varro, A. Ghigo, A. Perino, F. Damilano, J. Leroy, V. O. Nikolaev, W. Richter, M. Conti, G. Vandecasteele, E. Hirsch, R. Ang, S. Sebastian, A. Ludwig, L. Birnbaumer, A. Tinker, E. A. Ertel, R. Sube, A. Opel, C. L-H Huang, A. Grace, N. Tribulova, J. Radosinska, B. Bacova, T. Benova, V. Knezl, J. Slezak, T. A. Matsuyama, T. Tanaka, T. Adachi, Y. Jiang, H. Ishibashi-Ueda, T. Takamatsu, J. Kornej, C. Reihardt, J. Kosiuk, A. Arya, G. Hindricks, V. Adams, D. Husser, A. Bollmann, S. Severi, M. Fantini, E. Ravagli, L. A. Charawi, D. Difrancesco, C. Poulet, L. Lu, U. R. Ravens, M. Hoch, T. Koenig, A. Gardiwal, B. Stapel, S. Erschow, A. Froese, B. Weinhold, R. Gerardy-Schahn, G. Klein, D. Hilfiker-Kleiner, K. Chinda, S. Palee, S. Surinkaew, M. Phornphutkul, S. Chattipakorn, N. Chattipakorn, B. Tuana, Z. Kohajda, A. A. Kristof, C. Corici, F. Fulop, N. L. Jost, V. Szuts, D. Menesi, G. L. Puskas, A. Zvara, N. Houshmand, J. G. Papp, N. Al-Shanti, M. Hancock, A. Venturini, C. Stewart, R. Ascione, G. Angelini, M.-S. Suleiman, A. Gonzalez-Tendero, I. Torre, F. Crispi, E. Gratacos, T. Tzanavari, E. Varela, A. Economides, S. Theocharis, C. Pantos, D. V. Cokkinos, A. Karalis, P. Hecker, V. Lionetti, W. C. Stanley, C. Ferrara, N. Piroddi, B. Scellini, C. Ferrantini, V. Sequiera, C. Remedios, L. Carrier, C. Tesi, J. Van Der Velden, C. Poggesi, V. Kooij, G. J. M. Stienen, D. Dooijes, s. Marston, C. Redwood, C. Dos Remedios, I. Diakonov, S. Tokar, M. Sikkel, S. Schlossarek, M. Sauer, A. Papageorgiou, S. Velthuis, E. Lutgens, M. Swinnen, N. Van Rooijen, J. Kzhyshkowska, P. Carmeliet, P. Garcia-Canadilla, F. Garcia-Garcia, I. Iruretagoiena, J. Dopazo, I. Amat-Roldan, M. H. Zhang, Y. H. Zhang, C. E. Sears, B. Wojtas, A. Llach, L. Hove-Madsen, V. Spinelli, L. Sartiani, M. Bucciantini, R. Coppini, E. Russo, A. Mugelli, E. Cerbai, M. Stefani, M. Ibrahim, P. Kukadia, M. Navaratnarajah, U. Siedlecka, C. Van Doorn, M. Yacoub, C. Terracciano, W. Song, N. Curtin, R. Woledge, S. Marston, M. Balteau, N. Tajeddine, G. Behets-Wydemans, C. Dessy, P. Gailly, W. J. Van Der Laarse, S. J. P. Bogaards, D. Van Groen, Y. Y. Wong, I. Schalij, A. Vonk Noordegraaf, F. M. Faz, B. Littlejohns, P. Pasdois, A. P. Halestrap, G. D. Angelini, S. Lemoine, V. Jaspard-Vinassa, F. Vigneron, P. Dos Santos, M. Popescu, A. Vlad, G. Isvoranu, L. Suciu, B. Marinescu, D. Dimulescu, L. Zagrean, P. W. M. Kleikers, K. Wingler, K. Radermacher, A. Sydykov, H. A. Ghofrani, N. Weissmann, H. H. W. Schmidt, A. Poddubnaya, K. E. M. Khurs, S. O. G. Smolenskaya, G. Szucs, Z. Murlasits, S. Torok, G. F. Kocsis, T. Csont, C. Csonka, P. Ferdinandy, R. Dongworth, D. M. Yellon, D. J. Hausenloy, Y. Y. Chen, W. S. Lian, C. F. Cheng, K. H. Khoo, T. C. Meng, G. Youcef, E. Belaidi, L. Fazal, M. P. Vinvent, D. De Paulis, G. Zadigue, C. Richer-Giudicelli, F. Alhenc-Gelas, M. Ovize, A. Pizard, R. Cal, J. Castellano, J. Farre, G. Vilahur, L. Badimon, V. Llorente-Cortes, H. Naz, M. Gharanei, C. Mee, H. Maddock, A. Hussain, O. Pisarenko, V. Shulzhenko, L. Serebryakova, I. Studneva, Y. Pelogeykina, D. Khatri, O. Tskitishvili, E. Barnucz, G. Veres, P. Hegedus, T. Radovits, S. Korkmaz, S. Klein, R. Zoller, M. Karck, G. Szabo, S. Morel, M. A. Frias, C. Rosker, R. W. James, S. Rohr, B. R. Kwak, V. Braunersreuther, B. Foglia, F. Mach, E. Shantsila, S. Montoro-Garcia, L. D. Tapp, S. Apostolakis, B. J. Wrigley, G. Y. H. Lip, E. Sokolowska, K. Przyborowski, K. Kramkowski, W. Buczko, A. Mogielnicki, U. Simonsen, E. R. Hedegaard, B. D. Nielsen, A. Kun, A. Hughes, C. Kroigaard, S. Mogensen, O. Frobert, K. Ait Aissa, J. P. Max, D. Wahl, T. Lecompte, P. Lacolley, V. Regnault, A. Novakovic, M. Pavlovic, A. Vranic, P. Milojevic, I. Stojanovic, M. Jovic, D. Nenezic, N. Ugresic, Q. Yang, G. W. He, L. Calvier, P. Reboul, B. Martin-Fernandez, V. Lahera, F. Zannad, V. Cachofeiro, P. Rossignol, N. Lopez-Andres, V. K. Pulakazhi Venu, R. Baetta, A. Bonomo, A. F. Muro, A. Corsini, A. L. Catapano, G. D. Norata, L. E. Viiri, L. E. Full, T. J. Navin, A. Didangelos, I. Seppala, T. Lehtimaki, A. H. Davies, R. Wait, D. Sedding, P. Stieger, C. Thoelen, S. Fischer, J. M. Daniel, R. Widmer-Teske, K. T. Preissner, N. Alenina, L. A. Rabelo, M. Todiras, V. N. Souza, J. M. Penninger, R. A. Santos, I. A. Leonova, S. A. Boldueva, V. S. Feoktistova, O. V. Sirotkina, M. G. Kolesnichenko, Z. Springo, P. Toth, P. Cseplo, G. Szijjarto, A. Koller, S. Puthenkalam, M. K. Frey, I. M. Lang, R. Madonna, H. Shelat, Y. J. Geng, T. Ziegler, V. Pfetsch, J. Horstkotte, C. Schwab, I. Rohwedde, R. Hinkel, Q. Di, S. Dietzel, U. Deutsch, C. Kupatt, I. Ernens, B. Lenoir, O. Fortunato, A. Caporali, E. Sangalli, D. Cordella, M. Marchetti, G. Spinetti, C. Emanueli, G. Arderiu, E. Pena, M. J. Forteza, V. Bodi, S. Novella, C. Alguero, I. Trapero, I. Benet, C. Hermenegildo, J. Sanchis, F. J. Chorro, A. Nemeth, S. Szabados, A. Cziraki, E. Sulyok, I. G. Horvath, M. Rauh, W. Rascher, I. Sikharulidze, I. B. Bakhlishvili, J. T. T. Laitinen, J. P. Hytonen, O. Leppanen, J. Taavitsainen, A. Partanen, P. Korpisalo, S. Yla-Herttuala, J. Lonn, J. Hallstrom, T. Bengtsson, M. C. Guisasola, E. Dulin, S. Stojkovic, C. Kaun, G. Maurer, K. Huber, J. Wojta, S. Demyanets, T. B. Opstad, A. Pettersen, S. Aakra, H. Arnesen, I. Seljeflot, M. Borrell-Pages, C. Romero, A. Toso, M. Leoncini, L. Tanini, T. Pizzetti, F. Tropeano, M. Maioli, P. Casprini, F. Bellandi, R. F. Antunes, J. C. Kaski, I. E. Dumitriu, E. Wu, A. A. L. Tareen, M. Udovychenko, I. Rudyk, K. Riches, L. Franklin, A. Maqbool, J. Bond, M. L. Koschinsky, D. J. O'regan, K. E. Porter, I. R. Parepa, A. I. Suceveanu, A. Suceveanu, L. Mazilu, L. Cojocaru, A. Rusali, L. A. Tuta, E. Craiu, D. Lindner, C. Zietsch, H.-P. Schultheiss, C. Tschope, D. Westermann, M. Miana, E. Martinez, R. Jurado, C. Delgado, N. Gomez-Hurtado, A. Briones, J. Young, T. J. Geng, A. Brodehl, T. Schmidt, O. Smolenskaya, C. Stegemann, D. Byzov, I. Mikhaylova, N. Chizh, E. Pushkova, O. Synchykova, B. Sandomirsky, O. Freylikhman, O. Rotar, N. Chromova, E. Moguchaya, V. Ivanenko, E. Kolesova, A. Erina, M. Boyarinova, A. Konradi, S. D. Preston, D. Baskaran, A. M. Plonczak, K. Norita, S. V. De Noronha, M. N. Sheppard, A. Haghikia, S. F. Hill, M. Hoepfner, B. Nitzsche, M. Schrader, F. Zengerling, B. Hoffmann, A. Pries, S. Gao, J. T. Laitinen, S. Laidinen, H. Markkanen, H. Karvinen, V. Marjomaki, I. Vajanto, T. T. Rissanen, K. Alitalo, P. Mello Ferrao, M. C. Waghabi, L. R. Garzoni, J. Ritterhoff, C. Weidenhammer, M. Voelkers, W. H. Zimmermann, J. Rabinowitz, P. Most, S. C. Gordts, I. Muthuramu, F. Jacobs, E. Van Craeyveld, E. Nefyodova, B. De Geest, D. R. Tribuddharat, D. R. Sathitkarnmanee, M. R. Buddhisa, M. S. Suwannasaen, D. R. Silarat, D. R. Ngamsangsirisup, D. R. Hawrylowicz, D. R. Lertmemongkolchai, S. Rain, M. L. Handoko, N. Westerhof, A. Vonk-Noordegraaf, F. S. De Man, A. S. Iakovleva, O. A. Mirolyubova, A. Berezin, T. A. Samura, Suwannasaen, Tippayawat, Ngamsangsirisup, D. R. Sutra, Hawrylowicz, Lertmemongkolchai, L. M. Lima, M. G. Carvalho, D. R. G. Junqueira, M. O. Sousa, A. Zampetaki, P. Willeit, L. Tilling, I. Drozdov, M. Prokopi, A. Shah, C. Boulanger, P. Chowienczyk, S. Kiechl, S. H. V. Oliveira, V. Kirillova, E. Prosviryakov, C. T. M. Van Der Pouw Kraan, F. J. P. Bernink, J. M. Baggen, L. Timmers, A. M. Beek, M. Diamant, A. C. Van Rossum, N. Van Royen, A. J. G. Horrevoets, J. E. A. Appelman, A. Zyatenkov, L. S. Kokov, Y. U. D. Volynskiy, M. Krestjyaninov, V. I. Ruzov, A. V. Villar, E. Martinez-Laorden, A. Almela, M. A. Hurle, M. L. Laorden, N. Apaijai, M. K. Mcmullen, J. M. Whitehouse, G. Shine, and A. Towell

Subjects
Gerontology, Physiology, business.industry, Physiology (medical), Cancer research, Medicine, SCRIB gene, Cardiology and Cardiovascular Medicine, business
Published
2012

4. Alpha-methyl CoA racemase (AMACR) reactivity across the spectrum of clear cell renal cell neoplasms.

Author

Rotterova P, Alaghehbandan R, Skopal J, Rogala J, Slisarenko M, Strakova Peterikova A, Michalova K, Montiel DP, Farcas M, Ulamec M, Stransky P Jr, Fiala O, Pitra T, Hora M, Michal M, Pivovarcikova K, and Hes O

Subjects
Humans, Immunohistochemistry methods, Male, Female, Middle Aged, Aged, Racemases and Epimerases metabolism, Carcinoma, Renal Cell pathology, Carcinoma, Renal Cell metabolism, Carcinoma, Renal Cell diagnosis, Kidney Neoplasms pathology, Kidney Neoplasms metabolism, Kidney Neoplasms diagnosis, Biomarkers, Tumor metabolism
Abstract

a-Methylacyl coenzyme A racemase (AMACR) is traditionally considered to be a marker of papillary renal cell carcinoma. However, AMACR expression can be seen in other renal tumors. The aim of this study was to investigate AMACR immunoreactivity within the spectrum of clear cell renal cell neoplasms. Fifty-three clear cell renal epithelial tumors were used in assembling the following four cohorts: low grade (LG) clear cell renal cell carcinoma (CCRCC), high grade (HG) CCRCC, CCRCC with cystic changes, and multilocular cystic renal neoplasm of low malignant potential (MCRNLMP). Representative blocks were stained for AMACR, using two different clones (SP52 and OV-TL12/30). There were at least some AMACR immunoreactivity in 77.8 % and 68.9 % of CCRCCs (using SP52 and OV-TL12/30 clone, respectively). Moderate to strong positivity, or positivity in more than one third of the tumor (even weak in intensity) was detected in 46.7 % of CCRCCs using SP52 and in 48.9 % of CCRCC using OV-TL12/30 clone. The highest AMACR reactivity was observed in HG CCRCC (60 % by SP52 and 66.7 % by OV-TL12/30). Strong and diffuse AMACR positivity was detected in 8.9 % of all CCRCCs. AMACR immunoreactivity in MCRNLMP was 37.5 % (SP52 clone) and 25 % (OV-TL12/30 clone). We demonstrated relatively high expression rate of AMACR in CCRCC, while very variable in intensity and distribution. This finding may have diagnostic implications especially in limited samples (i.e., core biopsies), as AMACR positivity does not exclude the diagnosis of CCRCC., Competing Interests: Declaration of competing interest The authors declare no financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ondrej Fiala received honoraria from Novartis, Janssen, Merck and Pfizer for consultations and lectures unrelated to this project., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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5. Familial syndromes associated with testicular and paratesticular neoplasms: a comprehensive review.

Author

Strakova-Peterikova A, Slisarenko M, Skopal J, Pivovarcikova K, Pitra T, Farcas M, Michal M, Michal M, and Michalova K

Subjects
Humans, Male, Genetic Predisposition to Disease, Genital Neoplasms, Male pathology, Genital Neoplasms, Male genetics, Testicular Neoplasms genetics, Testicular Neoplasms pathology, Neoplastic Syndromes, Hereditary pathology, Neoplastic Syndromes, Hereditary genetics
Abstract

A syndromic association between a subset of testicular/paratesticular neoplasms is well established. Such examples include Carney complex and large cell calcifying Sertoli cell tumor, Peutz-Jeghers syndrome and intratubular large cell hyalinizing Sertoli cell neoplasia, and VHL syndrome and clear cell papillary cystadenoma of the epididymis.However, recent studies proposed potential novel links between some testicular and paratesticular neoplasms with certain tumor syndromes. While more studies are still needed to solidify these associations, recent research suggests that a subset of Leydig cell tumors may arise in patients with hereditary leiomyomatosis and renal cell carcinoma syndrome or that some seminomas may occur in Lynch syndrome patients. Additionally, an association between testicular sex cord stromal tumors and paratesticular sarcomas with Familial adenomatous polyposis syndrome and DICER1 syndrome, respectively, has been proposed as well. This review provides a comprehensive overview of the intricate relationship between familial syndromes and associated testicular and paratesticular tumors, shedding light on their clinicopathological and molecular characteristics., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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6. Lynch syndrome-associated upper tract urothelial carcinoma frequently occurs in patients older than 60 years: an opportunity to revisit urology clinical guidelines.

Author

Pivovarcikova K, Pitra T, Alaghehbandan R, Buchova K, Steiner P, Hajkova V, Ptakova N, Subrt I, Skopal J, Svajdler P, Farcas M, Slisarenko M, Michalova K, Strakova Peterikova A, Hora M, Michal M, Daum O, Svajdler M, and Hes O

Subjects
Male, Female, Humans, Middle Aged, Aged, MutL Protein Homolog 1 genetics, Mismatch Repair Endonuclease PMS2 genetics, Germ-Line Mutation, DNA Mismatch Repair, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, Carcinoma, Transitional Cell genetics, Urinary Bladder Neoplasms, Urology
Abstract

Upper tract urothelial carcinoma (UTUC) is the third most common malignancy associated with Lynch syndrome (LS). The current European urology guidelines recommend screening for LS in patients with UTUC up to the age of 60 years. In this study, we examined a cohort of patients with UTUC for potential association with LS in order to establish the sensitivity of current guidelines in detecting LS. A total of 180 patients with confirmed diagnosis of UTUC were enrolled in the study during a 12-year period (2010-2022). Loss of DNA-mismatch repair proteins (MMRp) expression was identified in 15/180 patients (8.3%). Germline analysis was eventually performed in 8 patients confirming LS in 5 patients (2.8%), including 4 germline mutations in MSH6 and 1 germline mutation in MSH2. LS-related UTUC included 3 females and 2 males, with a mean age of 66.2 years (median 71 years, range 46-75 years). Four of five LS patients (all with MSH6 mutation) were older than 65 years (mean age 71.3, median 72 years). Our findings indicate that LS-associated UTUCs can occur in patients with LS older than 60 years. In contrast to previous studies which used mainly highly pre-selected populations with already diagnosed LS, the most frequent mutation in our cohort involved MSH6 gene. All MSH6 mutation carriers were > 65 years, and UTUC was the first LS manifestation in 2/4 patients. Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2023
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7. Significance of extended sports cardiology screening of elite handball referees.

Author

Kiss O, Babity M, Kovacs A, Skopal J, Vago H, Lakatos BK, Bognar C, Rakoczi R, Zamodics M, Frivaldszky L, Menyhart-Hetenyi A, Dohy Z, Czimbalmos C, Szabo L, and Merkely B

Subjects
Adolescent, Adult, Blood Pressure, Cardiovascular Diseases physiopathology, Creatine Kinase blood, Electrocardiography, Exercise Test, Female, Heart diagnostic imaging, Humans, Life Style, Magnetic Resonance Imaging, Male, Middle Aged, Myocardial Contraction physiology, Risk Factors, Stress, Physiological, Stress, Psychological, Young Adult, Cardiovascular Diseases diagnosis, Heart physiology, Sports
Abstract

The significance of cardiology screening of referees is not well established. Cardiovascular risk factors and diseases were examined in asymptomatic Hungarian elite handball referees undergoing extended screening: personal/family history, physical examination, 12-lead ECG, laboratory tests, body-composition analysis, echocardiography, and cardiopulmonary exercise testing. Holter-ECG (n = 8), blood pressure monitorization (n = 10), cardiac magnetic resonance imaging (CMR; n = 27) and computer tomography (CCT; n = 4) were also carried out if needed. We examined 100 referees (age: 29.6±7.9years, male: 64, training: 4.3±2.0 hours/week), cardiovascular risk factors were: positive medical history: 24%, overweight: 10%, obesity: 3%, dyslipidaemia: 41%. Elevated resting blood pressure was measured in 38%. Stress-ECG was positive due to ECG-changes in 16%, due to elevated exercise blood pressure in 8%. Echocardiography and/or CMR identified abnormalities in 19%. A significant number of premature ventricular contractions was found on the Holter-ECG in two cases. The CCT showed myocardial bridge or coronary plaques in one-one case. We recommended lifestyle changes in 58%, new/modified antihypertensive or lipid-lowering therapy in 5%, iron-supplementation in 22%. By our results, a high percentage of elite Hungarian handball referees had cardiovascular risk factors or diseases, which, combined with physical and psychological stress, could increase the possibility of cardiovascular events. Our study draws attention to the importance of cardiac screening in elite handball referees., Competing Interests: The authors have declared that no competing interests exist.

Published
2021
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8. Circulating Relaxin-1 Level Is a Surrogate Marker of Myocardial Fibrosis in HFrEF.

Author

Simon J, Nemeth E, Nemes A, Husveth-Toth M, Radovits T, Foldes G, Kiss L, Bagyura Z, Skopal J, Merkely B, and Gara E

Abstract

Introduction: Relaxin-1 (RLN1) has emerged as a possible therapeutic target in myocardial fibrosis due to its anti-fibrotic effects. Previous randomized clinical trials investigated therapeutic role of exogenous relaxin in patients with acute-on-chronic heart failure (HF) and failed to meet clinical endpoints. Here, we aimed to assess endogenous, circulating RLN1 levels in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic origin. Furthermore, we analyzed relation of RLN1 and left ventricular diastolic function, left and right ventricular fibrosis, and invasive hemodynamic measurements. Unique feature of our study is the availability of ex vivo human myocardial tissue. Methods: Human myocardial samples were available from the Transplantation Biobank of the Heart and Vascular Center at Semmelweis University after local ethical approval and informed consent of all participants ( n = 47). Tissue was collected immediately after heart explantations; peripheral blood was collected before induction of anesthesia. Myocardial sections were stained for Masson's trichrome and Picrosirius red staining to quantify fibrosis. Medical records were analyzed (ECG, anthropometry, blood tests, medication, echocardiography, and invasive hemodynamic measurements). Results: Average RLN1 levels in HFrEF population were significantly higher than measured in age and gender matched healthy control human subjects (702 ± 283 pg/ml in HFrEF vs. 44 ± 27 pg/ml in control n = 47). We found a moderate inverse correlation between RLN1 levels and degree of myocardial fibrosis in both ventricles ( r = -0.357, p = 0.014 in the right ventricle vs. r = -0.321, p = 0.028 in the left ventricle with Masson's trichrome staining). Parallel, a moderate positive correlation was found in left ventricular diastolic function (echocardiography, E/A wave values) and RLN1 levels ( r = 0.456, p = 0.003); a negative correlation with RLN1 levels and left ventricular end-systolic diameter ( r = -0.373, p = 0.023), and diastolic pulmonary artery pressure ( r = -0.894, p < 0.001). RLN1 levels showed moderate correlation with RLN2 levels ( r = 0.453, p = 0.0003). Conclusion: Increased RLN1 levels were accompanied by lower myocardial fibrosis rate, which is a novel finding in our patient population with coronary artery disease and HFrEF. RLN1 can have a biomarker role in ventricular fibrosis; furthermore, it may influence hemodynamic and vasomotor activity via neurohormonal mechanisms of action. Given these valuable findings, RLN1 may be targeted in anti-fibrotic therapeutics and in perioperative care of heart transplantation.

Published
2019
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9. Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs.

Author

Hruby M, Agrawal K, Policianova O, Brus J, Skopal J, Svec P, Otmar M, Dzubak P, Stepanek P, and Hajduch M

Subjects
Absorbable Implants, Antimetabolites, Antineoplastic pharmacology, Azacitidine pharmacology, Cells, Cultured, Decitabine, Humans, Infusion Pumps, Implantable, Magnetic Resonance Spectroscopy, Microspheres, Polymers chemistry, Antimetabolites, Antineoplastic administration & dosage, Azacitidine administration & dosage, Azacitidine analogs & derivatives
Abstract

Background: The archetypal DNA methyltransferase inhibitors, 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) are potent antineoplastic agents used in the treatment of mainly, blood malignancies. However, the administration of these drugs is confounded by their hydrolytic lability which decreases plasma circulation time. Here, we describe a new biodegradable, polyanhydride formulation for drug delivery that circumvents this drawback., Methods: Injectable/implantable polymeric microbeads containing dispersed microcrystals of hydrophilic AZA or DAC packed in a dry environment are protected from hydrolysis, until the hydrolytic zone reaches the core. Diclofenac is embedded into the formulation to decrease any local inflammation. The efficacy of the formulations was confirmed by monitoring the induced demethylation, and cytostatic/cytotoxic effects of continuous drug release from the time-course dissolution of the microbeads, using an in vitro developed cell based reporter system., Results: Poly(sebaccic acid-co-1,4-cyclohexanedicarboxylic acid) containing 30 wt. % drug showed zero-order release (R(2) = 0.984 for linear regression), and release rate of 10.0 %/h within the first 5 h, and subsequent slower release of the remaining drug, thus maintaining the level of drugs in the outer environment considerably longer than the typical plasma half-life of free azanucleosides. At lower concentrations, the differences between powder drug formulations and microbeads were very low or negligible, however, at higher concentrations, we discovered equivalent or increasing effects of the drugs loaded in microbeads., Conclusions: The study provides evidence that microbead formulations of the hydrolytically labile azanucleoside drugs could prevent their chemical decomposition in aqueous solution, and effectively increase plasma circulation time.

Published
2016
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10. Pathogen sensing pathways in human embryonic stem cell derived-endothelial cells: role of NOD1 receptors.

Author

Reed DM, Foldes G, Gatheral T, Paschalaki KE, Lendvai Z, Bagyura Z, Nemeth T, Skopal J, Merkely B, Telcian AG, Gogsadze L, Edwards MR, Gough PJ, Bertin J, Johnston SL, Harding SE, and Mitchell JA

Subjects
Animals, Endothelial Cells cytology, Gene Knockdown Techniques, Haemophilus Infections microbiology, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells microbiology, Humans, Induced Pluripotent Stem Cells metabolism, RNA, Small Interfering metabolism, Rats, Nude, Receptor-Interacting Protein Serine-Threonine Kinase 2 metabolism, Stem Cell Transplantation, Toll-Like Receptor 4 metabolism, Endothelial Cells metabolism, Endothelial Cells microbiology, Haemophilus influenzae physiology, Human Embryonic Stem Cells cytology, Human Embryonic Stem Cells microbiology, Nod1 Signaling Adaptor Protein metabolism
Abstract

Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage.

Published
2014
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11. Bcl-2 or bcl-XL gene therapy increases neural plasticity proteins nestin and c-fos expression in PC12 cells.

Author

Gal A, Pentelenyi K, Remenyi V, Wappler EA, Safrany G, Skopal J, and Nagy Z

Subjects
Animals, Apoptosis genetics, Nestin, PC12 Cells, RNA, Messenger genetics, Rats, Reverse Transcriptase Polymerase Chain Reaction, Transduction, Genetic, Genes, fos, Genetic Therapy, Intermediate Filament Proteins genetics, Nerve Tissue Proteins genetics, Neuronal Plasticity, Proto-Oncogene Proteins c-bcl-2 genetics, bcl-X Protein genetics
Abstract

The anti-apoptotic gene replacements could be an option in preventing hypoxia-induced neuronal loss. In this paper we tested the effect of anti-apoptosis (bcl-2 and bcl-XL) gene transfer on cell plasticity. Nestin, synapsin-1 and c-fos genes and proteins expression were measured in PC12 cells in normal condition, and after hypoxia/re-oxygenation. Gene delivery results a significant increase in both bcl-2 and bcl-XL gene expression. Hypoxia (1h)/re-oxygenation (24h) have a detrimental effect upon cultured cells by increasing the pro-apoptotic, bax gene and protein expression. Bcl-2 or bcl-XL gene delivery resulted in a significant increase in and the cellular levels of the corresponding mRNAs and proteins. Bcl-2 gene augmented the nestin gene and protein expression which has been compromised previously by the hypoxic event. Similarly c-fos mRNA and protein expression decreased significantly after hypoxia, while the anti-apoptotic gene treatment normalized c-fos expression. Synapsin-1 gene or protein expression remained about on the same level under normoxic conditions or following hypoxia after gene treatment. We can conclude that anti-apoptotic gene transfers activate neuronal plasticity proteins nestin and c-fos. This link on anti-apoptotic proteins and cell plasticity is a new finding.

Published
2009
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12. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.

Author

Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, and Wolff AA

Subjects
Acetanilides, Aged, Chronic Disease, Double-Blind Method, Drug Therapy, Combination, Electrocardiography, Exercise Test, Female, Hemodynamics, Humans, Male, Middle Aged, Myocardial Ischemia, Nitroglycerin therapeutic use, Physical Exertion physiology, Ranolazine, Survival Analysis, Adrenergic beta-Antagonists therapeutic use, Amlodipine therapeutic use, Angina Pectoris drug therapy, Angina Pectoris physiopathology, Atenolol therapeutic use, Calcium Channel Blockers therapeutic use, Cardiovascular Agents therapeutic use, Diltiazem therapeutic use, Physical Exertion drug effects, Piperazines therapeutic use
Abstract

Context: Many patients with chronic angina experience anginal episodes despite revascularization and antianginal medications. In a previous trial, antianginal monotherapy with ranolazine, a drug believed to partially inhibit fatty acid oxidation, increased treadmill exercise performance; however, its long-term efficacy and safety have not been studied in combination with beta-blockers or calcium antagonists in a large patient population with severe chronic angina., Objectives: To determine whether, at trough levels, ranolazine improves the total exercise time of patients who have symptoms of chronic angina and who experience angina and ischemia at low workloads despite taking standard doses of atenolol, amlodipine, or diltiazem and to determine times to angina onset and to electrocardiographic evidence of myocardial ischemia, effect on angina attacks and nitroglycerin use, and effect on long-term survival in an open-label observational study extension., Design, Setting, and Patients: A randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were randomly assigned to receive placebo or 1 of 2 doses of ranolazine. Patients treated at the 118 participating ambulatory outpatient settings in several countries were enrolled in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial from July 1999 to August 2001 and followed up through October 31, 2002., Intervention: Patients received twice-daily placebo or 750 mg or 1000 mg of ranolazine. Treadmill exercise 12 hours (trough) and 4 hours (peak) after dosing was assessed after 2, 6 (trough only), and 12 weeks of treatment., Main Outcome Measures: Change in exercise duration, time to onset of angina, time to onset of ischemia, nitroglycerin use, and number of angina attacks., Results: Trough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P =.01). The times to angina and to electrocardiographic ischemia also increased in the ranolazine groups, at peak more than at trough. The increases did not depend on changes in blood pressure, heart rate, or background antianginal therapy and persisted throughout 12 weeks. Ranolazine reduced angina attacks and nitroglycerin use by about 1 per week vs placebo (P<.02). Survival of 750 patients taking ranolazine during the CARISA trial or its associated long-term open-label study was 98.4% in the first year and 95.9% in the second year., Conclusion: Twice-daily doses of ranolazine increased exercise capacity and provided additional antianginal relief to symptomatic patients with severe chronic angina taking standard doses of atenolol, amlodipine, or diltiazem, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.

Published
2004
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