National Koranyi Institute of Pulmonology

Budapest, Hungary

National Koranyi Institute of Pulmonology

Budapest, Hungary
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Mildner M.,Medical University of Vienna | Storka A.,Medical University of Vienna | Lichtenauer M.,Christian Doppler Laboratory | Mlitz V.,Medical University of Vienna | And 6 more authors.
Cardiovascular Research | Year: 2010

Aims Serum levels of the soluble growth stimulation gene-2 (sST2) are elevated in heart and pulmonary diseases. However, the relationship of the sST2/interleukin (IL)-33 axis and its triggers as well as its organ distribution is still not known. This study was thus designed to investigate the cellular origin and regulation of sST2 and IL-33 in vitro and in vivo. Methods and results sST2 and IL-33 gene expression and protein secretion were analysed in pooled organ-specific cDNAs and in primary cell cultures, respectively, by RT-PCR and ELISA technology. The strongest sST2 mRNA expression was detected in heart and lung tissues, which correlated with spontaneous secretion of sST2 protein in vitro. The inflammatory cytokines IL-1, IL-1, and tumour necrosis factor as well as supernatants of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells led to an enhanced secretion of sST2 in cultured cardiac myocytes and lung alveolar epithelial cells. These cytokines enhanced sST2 secretion via an NFκB-dependent mechanism. In addition, LPS stimulation in humans in vivo induced a short-term inflammatory response that was followed by a massive enhancement of sST2 secretion. Conclusion These results identify the primary sources and inflammatory triggers for the enhancement of sST2 secretion and demonstrate a relationship between inflammation and the secretion of a bioactive member of the IL-1R family, both in vitro and in vivo. © 2010 The Author.

Marko-Varga G.,Biomedical Imaging Center | Marko-Varga G.,Tokyo Medical University | Fehniger T.E.,Biomedical Imaging Center | Fehniger T.E.,Tallinn University of Technology | And 5 more authors.
Journal of Proteomics | Year: 2011

Lung cancer is a common cause of cancer mortality in the world, largely due to the risk factor of tobacco smoking. The drug therapy at the molecular level includes targeting the epidermal growth factor receptor (EGFR) tyrosine kinase activity by using inhibitors, such as erlotinib (Tarceva) and gefitinib (Iressa). The heterogeneity of disease phenotypes and the somatic mutations presented in patient populations have a great impact on the efficacy of treatments using targeted personalized medicine.In this study, we report on basic physical and chemical properties of erlotinib and gefitinib in three different lung cancer tumor phenotypes, using MALDI instrumentation in imaging mode, providing spatial localization of drugs without chemical labeling. Erlotinib and gefitinib were analyzed in i) planocellular lung carcinoma, ii) adenocarcinoma and iii) large cell lung carcinoma following their deposition on the tissue surfaces by piezo-dispensing, using a controlled procedure. The importance of high-resolution sampling was crucial in order to accurately localize the EGFR tyrosine kinase inhibitors deposited in heterogeneous cancer tissue compartments.This is the first report on personalized drug characterization with localizations at a lateral resolution of 30. μm, which allowed us to map these compounds at attomolar concentrations within the lung tumor tissue microenvironments. © 2011 Elsevier B.V.

Heller G.,Medical University of Vienna | Weinzierl M.,Medical University of Vienna | Noll C.,Medical University of Vienna | Babinsky V.,Medical University of Vienna | And 12 more authors.
Clinical Cancer Research | Year: 2012

Purpose: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on miRNA silencing in non-small cell lung cancers (NSCLC). Experimental Design: We conducted microarray expression analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. miRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding nonmalignant lung tissue samples of 101 patients with stage I-III NSCLC. Results: By comparing microarray data of untreated and drug-treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with aCpGisland. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analyzed. Moreover, miR-9-3 and miR-193a were found to be tumor specifically methylated in patients with NSCLC. We observed a shorter disease-free survival of patients with miR-9-3 methylated lung squamous cell carcinoma (LSCC) than patients with miR-9-3 unmethylated LSCC by multivariate analysis [HR = 3.8; 95% confidence interval (CI), 1.3-11.2, P = 0.017] and a shorter overall survival of patients with miR-9-3 methylated LSCC than patients with miR-9-3 unmethylated LSCC by univariate analysis (P = 0.013). Conclusions: Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in patients with LSCC. ©2012 AACR.

Dome P.,Semmelweis University | Dome P.,National Koranyi Institute of Pulmonology | Kapitany B.,Demographic Research Institute of the Hungarian Central Statistical Office | Ignits G.,University of Pécs | And 2 more authors.
Journal of Psychiatric Research | Year: 2011

The suicide rate of Hungary is the highest in the world averaged over the last century but it has shown a very pronounced decrease since 1987. To explore the background of this decrease we investigated the associations between some known suicide-related factors (i.e. tobacco use, antidepressant use and alcohol consumption at the population level) and the suicide rate between 1985 and 2008. The total number of man-hours worked per year by psychiatrists in the outpatient service system and real GDP growth were also monitored in our study. A time series analysis model was constructed to investigate the associations between the above variables and the suicide rate. In the unadjusted model annual tobacco consumption was significantly associated with the suicide rate in a positive manner, while antidepressant use and man-hours were significantly associated with the suicide rate in a negative manner. After adjustment, the associations remained significant only for tobacco consumption and antidepressant use. Neither alcohol consumption nor real GDP growth was associated with the suicide rate in any models. Our results from group-level data confirmed the role of smoking in suicidal behavior previously suggested mainly by studies using individual-level data and also corroborated the results of previous ecological studies concerning the inverse association between antidepressant use and suicide rate. These findings and the results of previous studies - investigating the relationship between smoking and the risk of suicidal behavior at the individual-level - may suggest that programs to prevent tobacco use or to address the widespread recognition and treatment of depression may also prevent suicidality. © 2010 Elsevier Ltd.

Dome P.,Semmelweis University | Dome P.,National Koranyi Institute of Pulmonology | Kapitany B.,Demographic Research Institute | Ignits G.,University of Pécs | Rihmer Z.,Semmelweis University
Biological Psychiatry | Year: 2010

Background: Previous studies have provided somewhat inconsistent results about the effects of season of birth on the risk of suicidal behavior. Therefore, we decided to investigate this question in a large sample of suicide completers. Methods: We determined the season of birth-associated risk of completed suicide between the years 1970 and 2008 among all individuals who were born in the area of todays Hungary between 1930 and 1939, 1941 and 1942, and 1944 and 1969. Results: The final sample of participants included around six and a half million people. About 80,000 completed suicides occurred among participants during the period investigated (the number of suicide completers in our study greatly exceeds the number of suicide completers in any previous studies). A significantly (p <.05) elevated risk of completed suicide was found among those individuals who were born in the high-risk period (spring and summer). Quantitatively, the biggest increase (7.6% [95% confidence interval: 5.4 9.9]) in suicide risk was detected among those who were born in July compared with the average risk of suicide in the population investigated. The associations between season of birth and the risk of completed suicide were stronger among male subjects than among female subjects and among those who committed suicide using violent methods than among those who chose nonviolent methods. Conclusions: Our results from a large sample of suicide completers from Hungarya country with one of the highest suicide rates in the world over the last centurystrongly support the concept that the season of birth is significantly associated with the risk of completed suicide. © 2010 Society of Biological Psychiatry.

Wegiel B.,Harvard University | Hedblom A.,Harvard University | Hedblom A.,Lund University | Li M.,Harvard University | And 9 more authors.
Cell Death and Disease | Year: 2014

Critical functions of the immune system are maintained by the ability of myeloid progenitors to differentiate and mature into macrophages. We hypothesized that the cytoprotective gas molecule carbon monoxide (CO), generated endogenously by heme oxygenases (HO), promotes differentiation of progenitors into functional macrophages. Deletion of HO-1, specifically in the myeloid lineage (Lyz-Cre:Hmox1flfl), attenuated the ability of myeloid progenitors to differentiate toward macrophages and decreased the expression of macrophage markers, CD14 and macrophage colony-stimulating factor receptor (MCSFR). We showed that HO-1 and CO induced CD14 expression and efficiently increased expansion and differentiation of myeloid cells into macrophages. Further, CO sensitized myeloid cells to treatment with MCSF at low doses by increasing MCSFR expression, mediated partially through a PI3K-Akt-dependent mechanism. Exposure of mice to CO in a model of marginal bone marrow transplantation significantly improved donor myeloid cell engraftment efficiency, expansion and differentiation, which corresponded to increased serum levels of GM-CSF, IL-1α and MCP-1. Collectively, we conclude that HO-1 and CO in part are critical for myeloid cell differentiation. CO may prove to be a novel therapeutic agent to improve functional recovery of bone marrow cells in patients undergoing irradiation, chemotherapy and/or bone marrow transplantation. © 2014 Macmillan Publishers Limited All rights reserved.

Douillard J.-Y.,Institute Of Cance Rologie Of Louest | Ostoros G.,National Koranyi Institute of Pulmonology | Cobo M.,Hospital Regional Universitario Carlos Haya | Ciuleanu T.,Institutul Oncologic Ion Chiricuta | And 3 more authors.
British Journal of Cancer | Year: 2014

Background:Phase-IV, open-label, single-arm study (NCT01203917) to assess efficacy and safety/tolerability of first-line gefitinib in Caucasian patients with stage IIIA/B/IV, epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC).Methods:Treatment: gefitinib 250 mg day-1 until progression. Primary endpoint: objective response rate (ORR). Secondary endpoints: disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objective: EGFR mutation analysis in matched tumour and plasma samples.Results:Of 1060 screened patients with NSCLC (859 known mutation status; 118 positive, mutation frequency 14%), 106 with EGFR sensitising mutations were enrolled (female 70.8%; adenocarcinoma 97.2%; never-smoker 64.2%). At data cutoff: ORR 69.8% (95% confidence interval (CI) 60.5-77.7), DCR 90.6% (95% CI 83.5-94.8), median PFS 9.7 months (95% CI 8.5-11.0), median OS 19.2 months (95% CI 17.0-NC; 27% maturity). Most common adverse events (AEs; any grade): rash (44.9%), diarrhoea (30.8%); CTC (Common Toxicity Criteria) grade 3/4 AEs: 15%; SAEs: 19%. Baseline plasma 1 samples were available in 803 patients (784 known mutation status; 82 positive; mutation frequency 10%). Plasma 1 EGFR mutation test sensitivity: 65.7% (95% CI 55.8-74.7).Conclusion:First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. Plasma samples could be considered for mutation analysis if tumour tissue is unavailable. © 2014 Cancer Research UK.

Douillard J.-Y.,Institute Of Cancerologie | Ostoros G.,National Koranyi Institute of Pulmonology | Cobo M.,Hospital Regional Universitario | Ciuleanu T.,University of Medicine and Pharmacy, Cluj-Napoca | And 7 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION: In the phase IV, open-label, single-arm study NCT01203917, first-line gefitinib 250 mg/d was effective and well tolerated in Caucasian patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (previously published). Here, we report EGFR mutation analyses of plasma-derived, circulating-free tumor DNA. METHODS: Mandatory tumor and duplicate plasma (1 and 2) baseline samples were collected (all screened patients; n = 1060). Preplanned, exploratory analyses included EGFR mutation (and subtype) status of tumor versus plasma and between plasma samples. Post hoc, exploratory analyses included efficacy by tumor and plasma EGFR mutation (and subtype) status. RESULTS: Available baseline tumor samples were 1033 of 1060 (118 positive of 859 mutation status known; mutation frequency, 13.7%). Available plasma 1 samples were 803 of 1060 (82 positive of 784 mutation status known; mutation frequency, 10.5%). Mutation status concordance between 652 matched tumor and plasma 1 samples was 94.3% (95% confidence interval [CI], 92.3-96.0) (comparable for mutation subtypes); test sensitivity was 65.7% (95% CI, 55.8-74.7); and test specificity was 99.8% (95% CI, 99.0-100.0). Twelve patients of unknown tumor mutation status were subsequently identified as plasma mutation-positive. Available plasma 2 samples were 803 of 1060 (65 positive of 224 mutation status-evaluable and -known). Mutation status concordance between 224 matched duplicate plasma 1 and 2 samples was 96.9% (95% CI, 93.7-98.7). Objective response rates are as follows: mutation-positive tumor, 70% (95% CI, 60.5-77.7); mutation-positive tumor and plasma 1, 76.9% (95% CI, 65.4-85.5); and mutation-positive tumor and mutation-negative plasma 1, 59.5% (95% CI, 43.5-73.7). Median progression-free survival (months) was 9.7 (95% CI, 8.5-11.0; 61 events) for mutation-positive tumor and 10.2 (95% CI, 8.5-12.5; 36 events) for mutation-positive tumor and plasma 1. CONCLUSION: The high concordance, specificity, and sensitivity demonstrate that EGFR mutation status can be accurately assessed using circulating-free tumor DNA. Although encouraging and suggesting that plasma is a suitable substitute for mutation analysis, tumor tissue should remain the preferred sample type when available. Copyright © 2014 by the International Association for the Study of Lung Cancer.

Paku S.,Semmelweis University | Dezs K.,Semmelweis University | Bugyik E.,Semmelweis University | Tovari J.,National Institute of Oncology | And 6 more authors.
American Journal of Pathology | Year: 2011

One of the hallmarks of intussusceptive angiogenesis is the development of intraluminal connective tissue pillars. The exact mechanism of pillar formation has not yet been elucidated. By using electron and confocal microscopy, we observed intraluminal nascent pillars that contain a collagen bundle covered by endothelial cells (ECs) in the vasculature of experimental tumors. We proposed a new mechanism for the development of these pillars. First, intraluminal endothelial bridges are formed. Second, localized dissolution of the basement membrane occurs and a bridging EC attaches to a collagen bundle in the underlying connective tissue. A pulling force is then exerted by the actin cytoskeleton of the ECs via specific attachment points, which contain vinculin, to the collagen bundle, resulting in suction and subsequent transport of the collagen bundle into and through the vessel lumen. Third, the pillar matures through the immigration of connective tissue cells and the deposition of new collagenous connective tissue. The proposed simple mechanism generates a connection between the processes of endothelial bridging and intussusceptive angiogenesis and identifies the source of the force behind pillar formation. Moreover, it ensures the rapid formation of pillars from pre-existing building blocks and the maintenance of EC polarity. To describe it, we coined the term inverse sprouting. © 2011 American Society for Investigative Pathology.

Wegiel B.,Harvard University | Nemeth Z.,Harvard University | Nemeth Z.,National Koranyi Institute of Pulmonology | Correa-Costa M.,Harvard University | And 2 more authors.
Antioxidants and Redox Signaling | Year: 2014

Significance: Heme degradation, which was described more than 30 years ago, is still very actively explored with many novel discoveries on its role in various disease models every year. Recent Advances: The heme oxygenases (HO) are metabolic enzymes that utilize NADPH and oxygen to break apart the heme moiety liberating biliverdin (BV), carbon monoxide (CO), and iron. Heme that is derived from hemoproteins can be toxic to the cells and if not removed immediately, it causes cell apoptosis and local inflammation. Elimination of heme from the milieu enables generation of three products that influences numerous metabolic changes in the cell. Critical Issues: CO has profound effects on mitochondria and cellular respiration and other hemoproteins to which it can bind and affect their function, while BV and bilirubin (BR), the substrate and product of BV, reductase, respectively, are potent antioxidants. Sequestration of iron into ferritin and its recycling in the tissues is a part of the homeodynamic processes that control oxidation-reduction in cellular metabolism. Further, heme is an important component of a number of metabolic enzymes, and, therefore, HO-1 plays an important role in the modulation of cellular bioenergetics. Future Directions: In this review, we describe the cross-talk between heme oxygenase-1 (HO-1) and its products with other metabolic pathways. HO-1, which we have labeled Nike, the goddess who personified victory, dictates triumph over pathophysiologic conditions, including diabetes, ischemia, and cancer. © Copyright 2014, Mary Ann Liebert, Inc. 2014.

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