Alternatív sejtelhalási mechanizmusok, mint a tumor ellenes terápia célpontjai = Alternative mechanisms of the cell death as targets for anti-tumor therapy

A daganatellenes kemoterápiában alakalmazott vegyületek egyik fontos hatása az, hogy daganatsejtekben aktív sejtelhalást váltanak ki. Az alternatív sejtelhalási típusok közül legismeretebb az apoptotikus és a nekrotikus forma, amelyeknek eltérő immunológiai következménye is vélelmezhető. Az apoptotikus jelpálya centrális elemei a kaszpáz proteázok. Azonban kaszpázaktivitás hiányában is (génexpressziós eltérések, oxidatív környezet) indukálódhat aktív sejtelhalás és fordítva: a kaszpázaktivitás nem jár együtt mindig sejtelhalással. Kutatásaink célja az volt, hogy olyan, elsősorban proteolitikus aktivitásokat azonosítsunk daganatsejtekben, amelyek helyettesíthetik a kaszpázok hiányát, illetve kaszpáz aktiválódás mellett is befolyásolják a sejtelhalást. Távlati célunk az, hogy ezeket a proteolitikus aktivitásokat megcélozva hatékonyabb daganatellenes terápiák lehetőségét alapozzunk meg. Eredményeink azt mutatják, hogy a cisztein katepszinek nem helyettesítik a kaszpázok apoptótikus funkcióját az általunk kidolgozott leukémia modellekben, de befolyásolhatják a kialakuló sejtelhalás típusát (apoptózis-nekrózis váltás). A proteaszóma aktivitás pro- és antiapoptotikus hatású is lehet kaszpáz-mediálta sejtelhaláskor függően az indukáló szerektől és sejttípustól. Kidolgoztunk egy új eljárást nekrotikus sejtek detektálására áramlásos citométerrel. | Induction of active cell death is the main effect of therapeutic anticancer drugs. The most known alternative cell death forms are apoptosis and necrosis that have also alternative immunological consequences. Caspase proteases are the central elements of the apoptotic pathway. However, in the absence of caspase activity (change in gene expression, oxidative environment) cell death can proceed and vica versa: caspase activation is not always accompanied with cell death. The purpose of our project was to identify proteolytic activities that may replace caspases in apoptosis or modulate the outcome of apoptotic process in the presence of caspase activation in cancer cells. Taking a long view, our aim is to target these proteolytic activities to improve the anticancer activities of therapeutic drugs. Our resuls demonstrated that cystein cathepsins do not substitute caspase activity in our leukemic models, but influence the emerging mode of cell death (apoptosis-necrosis switch). Proteasome activity can promote both pro- and anti-apoptotic effects in caspase-mediated cell death depending on inducer drugs and cell types. We have developed a new method to detect necrotic cells by flow cytometry

Relationship of Tree Stand Heterogeneity and Forest Naturalness

The aim of our study was to investigate if compositional (tree species richness) andstructural (vertical structure, age-structure, patterns of canopy closure) heterogeneity of the canopylayer is related to individual naturalness criteria and to overall forest naturalness at the stand scale. Thenaturalness values of the assessed criteria (tree species composition, tree stand structure, speciescomposition and structure of shrub layer and forest floor vegetation, dead wood, effects of game, sitecharacteristics) showed similar behaviour when groups of stands with different heterogeneity werecompared, regardless of the studied aspect of canopy heterogeneity. The greatest difference was foundfor criteria describing the canopy layer. Composition and structure of canopy layer, dead wood andtotal naturalness of the stand differed significantly among the stand groups showing consistentlyhigher values from homogeneous to the most heterogeneous group. Naturalness of the compositionand structure of the shrub layer is slightly but significantly higher in stands with heterogeneous canopylayer. Regarding other criteria, significant differences were found only between the homogeneous andthe most heterogeneous groups, while groups with intermediate level of heterogeneity did not differsignificantly from one extreme. However, the criterion describing effects of game got lowernaturalness values in more heterogeneous stands. Naturalness of site characteristics did not differsignificantly among the groups except for when stands were grouped based on pattern of canopyclosure. From the practical viewpoint it is shown that purposeful forestry operations affecting thecanopy layer cause changes in compositional and structural characteristics of other layers as well as inoverall stand scale forest naturalness

Circulating endothelial cells, bone marrow-derived endothelial progenitor cells and proangiogenic haematopoietic cells in cancer: From biology to therapy

Vascularization, a hallmark of tumorigenesis, is classically thought to occur exclusively through angiogenesis (i.e. endothelial sprouting). However, there is a growing body of evidence that endothelial progenitor cells (EPCs) and proangiogenic hematopoietic cells (HCs) are able to support the vascularization of tumors and may therefore play a synergistic role with angiogenesis. An additional cell type being studied in the field of tumor vascularization is the circulating endothelial cell (CEC), whose presence in elevated numbers reflects vascular injury. Levels of EPCs and CECs are reported to correlate with tumor stage and have been evaluated as biomarkers of the efficacy of anticancer/antiangiogenic treatments. Furthermore, because EPCs and subtypes of proangiogenic HCs are actively participating in capillary growth, these cells are attractive potential vehicles for delivering therapeutic molecules. The current paper provides an update on the biology of CECs, EPCs and proangiogenic HCs, and explores the utility of these cell populations for clinical oncology

Szemelvények a Semmelweis Egyetem, az Országos Onkológiai Intézet és az Országos Korányi Tbc és Pulmonológiai Intézet együttműködésén alapuló tüdőrák-kutatási programból

Lung cancer places a significant socio-economic burden on the Hungarian population. This overview summarizes the findings of collaborative translational lung cancer research efforts of three Hungarian flagship academic institutions, the Semmelweis University, the National Institute of Oncology and the National Koranyi Institute of TB and Pulmonology. With regards to the molecular factors regulating tumor angiogenesis, we identified the prognostic significance of apelin and erythropoietin receptor (EPOR) expression in non-small cell lung cancer (NSCLC). Furthermore, the impact of KRAS mutation subtypes and ERCC1 (excision repair cross-complementation group 1) expression on the response to platinum-based chemotherapy have been studied. We also described the epidemiology and predictive power of rare EGFR (epidermal growth factor receptor) mutations in a large Hungarian patient cohort. Lastly, the expression of molecular factors associated with NSCLC progression was studied specifically in brain metastatic matched cases series. These preclinical and clinical studies provide clinically relevant information that hopefully will contribute to the improvement of lung cancer patient care

Vészkorszak. Magyar művészettörténészek, magyar művészettörténet a vészkorszakban.

A "Magyar művészettörténészek, magyar művészettörténet a vészkorszakban" című konferencia anyaga. Az ELTE, 2014. novemberi Holokauszt megemlékezésének keretében elhangzott előadások forrásközlésekkel kiegészített szövegei az Enigma folyóiratban

Antimigratory and antimetastatic effect of heparin-derived 4-18 unit oligosaccharides in a preclinical human melanoma metastasis model

Heparin and its derivatives have been shown to inhibit angiogenesis and metastasis formation. Accordingly, we investigated the effect of heparin fragments containing 4 to 22 monomers on human melanoma cell proliferation, migration and invasion in vitro as well as on the in vivo metastatic potential in a SCID mouse model. Only oligosaccharide dp18 had significant inhibitory effect on cell proliferation. In contrast, cell migration was inhibited by all oligosaccharides studied except dp8 and dp22. Anti-CD44v3 antibody stimulated cell migration and invasion, and this effect could be attenuated by oligosaccharides dp4 and dp18. These fragments also inhibited the catalytic activity of myosin light chain phosphatase as well. Moreover, oligosaccharides dp4 and dp18 reduced the number of lung colonies formed in SCID mice intravenously injected with human melanoma cells, while dp22 proved to be ineffective in this respect. These studies revealed that fragments of heparin have an antimigratory and antimetastatic potential. These fragments lack the haemostatic effect of heparin, suggesting that they are potential specific antimetastatic agents in anticancer therapy. © 2009 Schattauer GmbH

The evidence for and against different modes of tumour cell extravasation in the lung: diapedesis, capillary destruction, necroptosis and endothelialisation.

The development of lung metastasis is a significant negative prognostic factor for cancer patients. The extravasation phase of lung metastasis involves interactions of tumour cells with the pulmonary endothelium. These interactions may have broad biological and medical significance, with potential clinical implications ranging from the discovery of lung metastasis biomarkers to the identification of targets for intervention in preventing lung metastases. Because of the potential significance, the mechanisms of tumour cell extravasation require cautious, systematic studies. Here, we discuss the literature pertaining to the proposed mechanisms of extravasation and critically compare a recently proposed mechanism (tumour cell-induced endothelial necroptosis) with the already described extravasation mechanisms in the lung. We also provide novel data that may help to explain the underlying physiological basis for endothelialisation as a mechanism of tumour cell extravasation in the lung