Yu P.,Yale University |
Wilhelm K.,Max Planck Institute for Heart and Lung Research |
Dubrac A.,Yale University |
Tung J.K.,Yale University |
And 22 more authors.
Nature | Year: 2017
Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes1. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism2,3, little is understood about the role of fibroblast growth factors (FGFs) in this context4. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Osadnik T.,Silesian Center for Heart Diseases |
Osadnik T.,Genomics Laboratory |
Strzelczyk J.K.,University of Silesia |
Fronczek M.,University of Silesia |
And 14 more authors.
Advances in Medical Sciences | Year: 2016
Purpose The renin-angiotensin-aldosterone system may influence in-stent restenosis (ISR) via angiotensin II, which stimulates the production of growth factors for smooth muscle cells. The aim of this work is to assess the influence of the rs1799752 polymorphism of the angiotensin-converting enzyme (ACE) gene and the rs699 polymorphism of the angiotensinogen (AGT) gene on the ISR in Polish patients with stable coronary artery disease (SCAD) who underwent stent implantation. Material/methods Two hundred and sixty-five patients with SCAD were included in the study. All patients underwent stent implantation upon admission to the hospital and had subsequent coronary angiography performed. The patients were divided into two groups - those with significant ISR (n = 53) and those without ISR (n = 212). The ACE polymorphism was assessed using the classical PCR method and the AGT polymorphism was determined using the TaqMan method for SNP genotyping. Results No difference in the frequency of angiographically significant ISR occurrence associated with the different ACE and AGT gene polymorphisms was observed. In a multivariable analysis, after correction for clinical variables, the relationship between the ACE and AGT genotypes within the scope of the analyzed polymorphisms and the process of restenosis was not found using a dominant, recessive and log-additive model. Late lumen loss was also independent of the genotypes of the polymorphisms before and after correction with angiographic variables. Conclusions The rs1799752 polymorphism and the rs699 polymorphism had no relationship with the occurrence of angiographically significant ISR and late lumen loss in a group of Polish patients who underwent metal stent implantation. © 2016 Medical University of Bialystok. Published by Elsevier Sp. z o.o. All rights reserved.
Wasilewski J.,University of Silesia |
Pyka L.,University of Silesia |
Hawranek M.,University of Silesia |
Osadnik T.,University of Silesia |
And 9 more authors.
Polskie Archiwum Medycyny Wewnetrznej | Year: 2016
INTRODUCTION: Previous studies have shown that an elevated neutrophil-to-lymphocyte ratio (NLR) was associated with a poorer long-term prognosis in patients with heart failure (HF). Objectives We aimed to study the predictive value of the NLR in patients with left ventricular ejection fraction of 35% or lower. The second objective was to establish whether the NLR has the same prognostic value in patients with ischemic and nonischemic HF. PATIENTS AND METHODS: The study group consisted of a cohort of patients with HF (1387 men, 347 women; median age, 61 years) from the prospective COMMIT-HF registry. The primary endpoint was all-cause mortality. Patients were divided into tertiles based on the NLR values on admission. The first (low), second (medium), and third (high) tertiles were defined as NLR ≤2.04 (n = 578), NLR 2.05.3.1 (n = 578) and NLR >3.1 (n = 578), respectively. RESULTS: During long-term follow-up, 443 deaths were reported. The 12-month mortality in patients in the third NLR tertile was almost 3-fold higher compared with those in the first tertile (7.61% vs 20.07%; P <0.001). In a multivariate analysis, the NLR was an independent factor of mortality (hazard ratio [HR], 2.31; 95% confidence interval [CI], 188.8.131.52; P <0.0001). In addition, the multivariate analysis revealed that the third NLR tertile in the ischemic HF group was an independent factor related to longterm mortality (HR, 1.51; 95% CI, 1.11.2.04; P = 0.008). In the nonischemic HF group, the influence of the NLR on long-term survival was not confirmed. CONCLUSIONS: The association between the NLR and the risk of death in long-term follow-up was confirmed only in the subgroup of patients with ischemic HF. Copyright by Medycyna Praktyczna, Kraków 2016.
Osadnik T.,University of Silesia |
Osadnik T.,Genomics Laboratory |
Strzelczyk J.K.,University of Silesia |
Regula R.,University of Silesia |
And 15 more authors.
PLoS ONE | Year: 2016
Background Neointima forming after stent implantation consists of vascular smooth muscle cells (VSMCs) in 90%. Growth factors TGF-β1, PDGFB, EGF, bFGF and VEGF-A play an important role in VSMC proliferation and migration to the tunica intima after arterial wall injury. The aim of this paper was an analysis of functional polymorphisms in genes encoding TGF-β1, PDGFB, EGF, bFGF and VEGF-A in relation to in-stent restenosis (ISR). Materials and Methods 265 patients with a stable coronary artery disease (SCAD) hospitalized in our center in the years 2007-2011 were included in the study. All patients underwent stent implantation at admission to the hospital and had another coronary angiography performed due to recurrence of the ailments or a positive result of the test assessing the coronary flow reserve. Angiographically significant ISR was defined as stenosis >50% in the stented coronary artery segment. The patients were divided into two groups-with angiographically significant ISR (n = 53) and without significant ISR (n = 212). Additionally, the assessment of late lumen loss (LLL) in vessel was performed. EGF rs4444903 polymorphism was genotyped using the PCR-RFLP method whilst rs1800470 (TGFB1), rs2285094 (PDGFB) rs308395 (bFGF) and rs699947 (VEGF-A) were determined using the TaqMan method. Results Angiographically significant ISR was significantly less frequently observed in the group of patients with the A/A genotype of rs1800470 polymorphism (TGFB1) versus patients with A/ G and G/G genotypes. In the multivariable analysis, LLL was significantly lower in patients with the A/A genotype of rs1800470 (TGFB1) versus those with the A/G and G/G genotypes and higher in patients with the A/A genotype of the VEGF-A polymorphism versus the A/C and C/C genotypes. The C/C genotype of rs2285094 (PDGFB) was associated with greater LLL compared to C/T heterozygotes and T/T homozygotes. Conclusions The polymorphisms rs1800470, rs2285094 and rs6999447 of the TGFB1, PDGFB and VEGF-A genes, respectively, are associated with LLL in patients with SCAD treated by PCI with a metal stent implantation. © 2016 Osadnik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PubMed | Medical University of Silesia, Katowice, University of Silesia, Silesian Center for Heart Diseases and Genomics Laboratory
Type: Journal Article | Journal: BMC cardiovascular disorders | Year: 2016
Despite the important roles of vascular smooth muscle cells and endothelial cells in atherosclerotic lesion formation, data regarding the associations of functional polymorphisms in the genes encoding growth factors with the severity of coronary artery disease (CAD) are lacking. The aim of the present study is to analyze the relationships between functional polymorphisms in genes encoding basic fibroblast growth factor (bFGF, FGF2), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), platelet derived growth factor-B (PDGFB), transforming growth factor-1 (TGF-1) and vascular endothelial growth factor A (VEGF-A) and the severity of coronary atherosclerosis in patients with stable CAD undergoing their first coronary angiography.In total, 319 patients with stable CAD who underwent their first coronary angiography at the Silesian Centre for Heart Diseases in Zabrze, Poland were included in the analysis. CAD burden was assessed using the Gensini score. The TaqMan method was used for genotyping of selected functional polymorphisms in the FGF2, PDGFB, TGFB1, IGF1 and VEGFA genes, while rs4444903 in the EGF gene was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The associations between the selected polymorphisms and the Gensini were calculated both for the whole cohort and for a subgroup of patients without previous myocardial infarction (MI).There were no differences in the distribution of the Gensini score between the genotypes of the analyzed polymorphisms in FGF2, EGF, IGF1, PDFGB, and TGFB1 in the whole cohort and in the subgroup of patients without previous MI. The Gensini score for VEGFA rs699947 single-nucleotide polymorphism (SNP) in patients without previous myocardial infarction, after correction for multiple testing, was highest in patients with the A/A genotype, lower in heterozygotes and lowest in patients with the C/C genotype, (p value for trend=0.013, false discovery rate (FDR)=0.02). After adjustment for clinical variables, and correction for multiple comparisons the association between the VEGFA genotype and Gensini score remained only nominally significant (p=0.04, FDR=0.19) under the dominant genetic model in patients without previous MI.We were unable to find strong association between analyzed polymorphisms in growth factors and the severity of coronary artery disease, although there was a trend toward association between rs699947 and the severity of CAD in patients without previous MI.
Carmen Carrascosa-Romero M.,Complejo Hospitalario Universitario Of Albacete |
Suela J.,Genomics Laboratory |
Alfaro-Ponce B.,Complejo Hospitalario Universitario Of Albacete |
Cepillo-Boluda A.J.,Complejo Hospitalario Universitario Of Albacete
Revista de Neurologia | Year: 2012
Summary. X-chromosome-linked ichthyosis is caused by mutation or deletion of the STS gene associated with a deficiency of the enzyme steroid sulphatase, located in the distal part of the short arm of the X chromosome (Xp22.3-pter), close to the pseudo-autosomal region. Depending on its size, it can present as an isolated entity or combined with a syndrome caused by neighbouring genes, thus associating itself with other monogenic diseases as well as other mental disorders. The most relevant findings from the literature review are the importance of the Xp22.3-pter region and the higher incidence of neurological disorders among males (attention deficit hyperactivity disorder, autism and X-linked mental retardation). The role and implication of these genes in the disease are discussed and the authors suggest a possible contribution of the gene PNPLA4, which was originally described as GS2 and codes for calcium-independent phospholipase A2 beta, involved in lipoprotein metabolism, as one of the causes of autism. Improvements have been observed following treatment with citicoline, thanks to the role this nootropic plays in the biosynthesis of structural phospholipids involved in the formation and repair of the neuronal membrane. © 2012 Revista de Neurología.
Magni P.,University of Pavia |
Simeone A.,TU Dresden |
Healy S.,National University of Ireland |
Isacchi A.,Genomics Laboratory |
Bosotti R.,Genomics Laboratory
IEEE/ACM Transactions on Computational Biology and Bioinformatics | Year: 2011
Microarray experiments are affected by several sources of variability. The paper demonstrates the major role of the day-to-day variability, it underlines the importance of a randomized block design when processing replicates over several days to avoid systematic biases and it proposes a simple algorithm that minimizes the day dependence. © 2006 IEEE.
Wasilewski J.,Medical University of Silesia, Katowice |
Desperak P.,Medical University of Silesia, Katowice |
Hawranek M.,Medical University of Silesia, Katowice |
Cislak A.,Medical University of Silesia, Katowice |
And 8 more authors.
Platelets | Year: 2016
Abstract: Background: Mean platelet volume (MPV) is a simple and reliable indicator of platelet size that correlates with platelet activation and their ability to aggregate. We studied the predictive value of MPV in patients with non-ST-segment elevation myocardial infarction (NSTEMI) treated with percutaneous coronary intervention (PCI). Methods: We analyzed the consecutive records of 1001 patients who were hospitalized due to NSTEMI at our center. The primary end point was a composite end point that included the rates of all-cause death, non-fatal myocardial infarction, and acute coronary syndrome (ACS) driven revascularization at 12 months. The enrolled patients were stratified according to the quartile of the MPV level at admission. Results: Along with the increasing quartile of MPV, the 12-month composite end point increased significantly (p = 0.010), and this association remained significant after the risk-adjusted analyses (per 1 fL higher MPV; adjusted hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.02–1.27; p = 0.026). In the multivariate analysis, the MPV was also an independent factor of all-cause mortality (per 1 fL increase; adjusted HR 1.34; 95% CI 1.12–1.61; p = 0.0014) and death or non-fatal myocardial infarction (per 1 fL increase; adjusted HR 1.16; 95% CI 1.03–1.31; p = 0.017). Conclusion: In patients with NSTEMI treated with PCI, a high MPV value was associated with a significantly increased incidence of long-term adverse events, particularly for all-cause mortality. © 2016 Taylor & Francis.