Dynamics of non-equilibrium membrane bud formation

The dynamical response of a lipid membrane to a local perturbation of its molecular symmetry is investigated theoretically. A density asymmetry between the two membrane leaflets is predominantly released by in-plane lipid diffusion or membrane curvature, depending upon the spatial extent of the perturbation. It may result in the formation of non-equilibrium structures (buds), for which a dynamical size selection is observed. A preferred size in the micrometer range is predicted, as a signature of the crossover between membrane and solvent dominated dynamical membrane response.Comment: 7 pages 3 figure

Methodiek arbeidsmarktprognoses en -indicatoren 2005-2010

De weergave van de methodiek in dit werkdocument heeft betrekking op het samenstellen van de arbeidsmarktinformatie over 34 bedrijfssectoren, 127 beroepsgroepen en 102 opleidingstypen die is gebruikt in het rapport De arbeidsmarkt naar opleiding en beroep tot 2010. Dit rapport is in november 2005 uitgebracht in het kader van het Project Onderwijs-Arbeidsmarkt (POA) van het ROA. Het rapport biedt een overzicht van de huidige en toekomstige ontwikkelingen op de Nederlandse arbeidsmarkt in de periode 2005-2010. Het gepresenteerde overzicht heeft als doel inzicht te verschaffen in de actuele situatie en de prognoses van beroepen en opleidingen op de arbeidsmarkt. De prognoses worden elke twee jaar herhaald voor een nieuwe periode van vijf jaar. De beschrijvingen en analyses in het rapport spitsen zich toe op de grote lijnen van de huidige en toekomstige arbeidsmarktontwikkelingen.In bijlage C van De arbeidsmarkt naar opleiding en beroep tot 2010 en op de website van het ROA (http://www.roa.unimaas.nl) wordt een overzicht van de beschikbare arbeidsmarktinformatie naar bedrijfssector, beroepsgroep en opleidingstype gegeven. Deze informatie is op aanvraag bij het ROA verkrijgbaar. Voor de financiers van POA is het zogenaamde ArbeidsmarktInformatieSysteem (AIS) beschikbaar, waarmee gebruikers zelf op eenvoudige wijze de gewenste tabellen kunnen samenstellen.Het Project Onderwijs-Arbeidsmarkt wordt gefinancierd door het Ministerie van Onderwijs, Cultuur en Wetenschap (OCW), het Centrum voor Werk en Inkomen (CWI), het Ministerie van Landbouw, Natuur en Voedselkwaliteit (LNV), de vereniging kenniscentra beroepsonderwijs bedrijfsleven COLO, Randstad Nederland en de Raad voor Werk en Inkomen (RWI).education, training and the labour market;

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of dipyrrolo[3,4-a:3,4-c]carbazole triones.

The syntheses of dipyrrolo[3,4-a:3,4-c]carbazole-1,4,6-triones and dipyrrolo[3,4-a:3,4-c]carbazole-3,4,6-triones are reported. These compounds can be considered as granulatimide analogues in which a maleimide replaces the imidazole moiety and a five-membered lactam ring replaces the upper maleimide. The Chk1 inhibitory properties of the more soluble compounds have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, and human colon carcinoma HT29 and HCT116. Due to their insolubility, the biological activities of the other compounds in this series could not be evaluated. All the tested compounds proved to be potent Chk1 inhibitor

Design of Cationic Multi-Walled Carbon Nanotubes as Efficient siRNA Vectors for Lung Cancer Xenograft Eradication

Polo-Like Kinase (PLK1) has been identified as a potential target in cancer gene therapy via chemical or genetic inhibitory approaches. The biomedical applications of chemically functionalized carbon nanotubes (f-CNTs) in cancer therapy have been studied due to their ability to efficiently deliver siRNA intracellularly. In this study, we established the capacity of cationic MWNT-NH3+ to deliver the apoptotic siRNA against PLK1 (siPLK1) in Calu6 tumor xenografts by direct intratumoural injections. A direct comparison with cationic liposomes was made. This study validates the PLK1 gene as a potential target in cancer gene therapy including lung cancer, as demonstrated by the therapeutic efficacy of siPLK1:MWNT-NH3+ complexes and their ability to significantly improve animal survival. Biological analysis of the siPLK1:MWNT-NH3+ treated tumors by RT-PCR and Western blot, in addition to TUNEL staining confirmed the biological functionality of the siRNA intratumourally, suggesting that tumor eradication was due to PLK1 knockdown. Furthermore, by using a fluorescently labelled, non-coding siRNA sequence complexed with MWNT-NH3+, we established for the first time that the improved therapeutic efficacy observed in f-CNT-based siRNA delivery is directly proportional to the enhanced siRNA retention in the solid tumor and subsequent uptake by tumor cells after local administration in vivo

Molecular analysis of ex-vivo CD133+ GBM cells revealed a common invasive and angiogenic profile but different proliferative signatures among high grade gliomas

<p>Abstract</p> <p>Background</p> <p>Gliomas are the most common type of primary brain tumours, and in this group glioblastomas (GBMs) are the higher-grade gliomas with fast progression and unfortunate prognosis. Two major aspects of glioma biology that contributes to its awful prognosis are the formation of new blood vessels through the process of angiogenesis and the invasion of glioma cells. Despite of advances, two-year survival for GBM patients with optimal therapy is less than 30%. Even in those patients with low-grade gliomas, that imply a moderately good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells with characteristics of neural stem cells which are able to grow <it>in vitro </it>forming neurospheres and that can be isolated <it>in vivo </it>using surface markers such as CD133. The aim of this study was to define the molecular signature of GBM cells expressing CD133 in comparison with non expressing CD133 cells. This molecular classification could lead to the finding of new potential therapeutic targets for the rationale treatment of high grade GBM.</p> <p>Methods</p> <p>Eight fresh, primary and non cultured GBMs were used in order to study the gene expression signatures from its CD133 positive and negative populations isolated by FACS-sorting. Dataset was generated with Affymetrix U133 Plus 2 arrays and analysed using the software of the Affymetrix Expression Console. In addition, genomic analysis of these tumours was carried out by CGH arrays, FISH studies and MLPA;</p> <p>Results</p> <p>Gene expression analysis of CD133+ vs. CD133- cell population from each tumour showed that CD133+ cells presented common characteristics in all glioblastoma samples (up-regulation of genes involved in angiogenesis, permeability and down-regulation of genes implicated in cell assembly, neural cell organization and neurological disorders). Furthermore, unsupervised clustering of gene expression led us to distinguish between two groups of samples: those discriminated by tumour location and, the most importantly, the group discriminated by their proliferative potential;</p> <p>Conclusions</p> <p>Primary glioblastomas could be sub-classified according to the properties of their CD133+ cells. The molecular characterization of these potential stem cell populations could be critical to find new therapeutic targets and to develop an effective therapy for these tumours with very dismal prognosis.</p

Activation of Cell Cycle Arrest and Apoptosis by the Proto-Oncogene Pim-2

Potent survival effects have been ascribed to the serine/threonine kinase proto-oncogene PIM-2. Elevated levels of PIM-2 are associated with various malignancies. In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites. In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function. To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells. These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform. The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2. By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73-dependent. These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well

Targeting the cell cycle for cancer therapy

Most if not all neoplasias show a directly or indirectly deregulated cell cycle. Targeting its regulatory molecules, the cyclin-dependent kinases, as a therapeutic mode to develop new anticancer drugs, is being currently explored in both academia and pharmaceutical companies. The development of new compounds is being focused on the many features of the cell cycle with promising preclinical data in most fields. Moreover, a few compounds have entered clinical trials with excellent results maintaining the high hopes. Thus, although too early to provide a cell cycle target based new commercial drug, there is no doubt that it will be an excellent source of new anticancer compounds