The broad-spectrum anti-DNA virus agent cidofovir inhibits lung metastasis of virus-independent, FGF2-driven tumors.

The FDA-approved anti-DNA virus agent cidofovir (CDV) is being evaluated in phase II/III clinical trials for the treatment of human papillomavirus (HPV)-associated tumors. However, previous observations had shown that CDV also inhibits the growth of vascular tumors induced by fibroblast growth factor-2 (FGF2)-transformed FGF2-T-MAE cells. Here, we demonstrate that CDV inhibits metastasis induced by FGF2-driven, virus-independent tumor cells. Pre-treatment of luciferase-expressing FGF2-T-MAE cells with CDV reduced single cell survival and anchorage-independent growth in vitro and lung metastasis formation upon intravenous inoculation into SCID mice. This occurred in the absence of any effect on homing of FGF2-T-MAE cells to the lungs and on the growth of subconfluent cell cultures or subcutaneous tumors in mice. Accordingly, CDV protected against lung metastasis when given systemically after tumor cell injection. Lung metastases in CDV-treated mice showed reduced Ki67 expression and increased nuclear accumulation of p53, indicating that CDV inhibits metastasis by affecting single cell survival properties. The anti-metastatic potential of CDV was confirmed on B16-F10 melanoma cells, both in zebrafish embryos and mice. These findings suggest that CDV may have therapeutic potential as an anti-metastatic agent and warrants further study to select those tumor types that are most likely to benefit from CDV therapy

Proof-of-concept: neonatal intravenous injection of adeno-associated virus vectors results in successful transduction of myenteric and submucosal neurons in the mouse small and large intestine

BACKGROUND: Despite the success of viral vector technology in the transduction of the central nervous system in both preclinical research and gene therapy, its potential in neurogastroenterological research remains largely unexploited. This study asked whether and to what extent myenteric and submucosal neurons in the ileum and distal colon of the mouse were transduced after neonatal systemic delivery of recombinant adeno-associated viral vectors (AAVs). METHODS: Mice were intravenously injected at postnatal day one with AAV pseudotypes AAV8 or AAV9 carrying a cassette encoding enhanced green fluorescent protein (eGFP) as a reporter under the control of a cytomegalovirus promoter. At postnatal day 35, transduction of the myenteric and submucosal plexuses of the ileum and distal colon was evaluated in whole-mount preparations, using immunohistochemistry to neurochemically identify transduced enteric neurons. KEY RESULTS: The pseudotypes AAV8 and AAV9 showed equal potential in transducing the enteric nervous system (ENS), with 25-30% of the neurons expressing eGFP. However, the percentage of eGFP-expressing colonic submucosal neurons was significantly lower. Neurochemical analysis showed that all enteric neuron subtypes, but not glia, expressed the reporter protein. Intrinsic sensory neurons were most efficiently transduced as nearly 80% of calcitonin gene-related peptide-positive neurons expressed the transgene. CONCLUSIONS & INFERENCES: The pseudotypes AAV8 and AAV9 can be employed for gene delivery to both the myenteric and the submucosal plexus, although the transduction efficiency in the latter is region-dependent. These findings open perspectives for novel preclinical applications aimed at manipulating and imaging the ENS in the short term, and in gene therapy in the longer term

Aanpasbaarheid van de draagstructuur I: Slim en flexibel bouwen

Aan de TU Eindhoven is de afgelopen jaren onderzocht op welke wijze flexibiliteit en aanpasbaarheid doelgericht geïntegreerd kunnen worden in de bouwtechniek. In het onderzoek is speciale aandacht voor de draagstructuur, die in grote mate bepalend is voor de ruimtelijke kwaliteit van het gebouw, maar ook voor de economische en milieutechnische consequenties van ontwerpkeuzes. In twee artikelen worden de belangrijkste bevindingen uit het onderzoek uiteengezet. Een herbezinning op flexibel bouwen wordt in dit artikel gepresenteerd

Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice.

BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of chronic morbidity and mortality in muscular dystrophy (MD) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. MicroRNAs have been implicated as fine regulators of cardiomyopathic progression. Previously, miR-669a downregulation has been linked to the severe DCM progression displayed by Sgcb-null dystrophic mice. However, the impact of long-term overexpression of miR-669a on muscle structure and functionality of the dystrophic heart is yet unknown. METHODS AND RESULTS: Here, we demonstrate that intraventricular delivery of adeno-associated viral (AAV) vectors induces long-term (18 months) miR-669a overexpression and improves survival of Sgcb-null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR-669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/miRNA profile of DCM markers. Furthermore, long-term miR-669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. CONCLUSIONS: Our findings provide the first evidence of long-term beneficial impact of AAV-mediated miRNA therapy in a transgenic model of severe, chronic MD-associated DCM

Comparison of adaptability measures in building design - CSA Method: Functionally effective and technically efficient design founded on (future) user demands

Most buildings are hardly technically equipped to fulfil the ever changing user requirements. Stimulation of flexible use of buildings is a strategy that aims at extending the functional lifespan of buildings. Adaptability of building components is an important technical aid to facilitate flexible use. Due to the large number of variables and the many dependencies and uncertainties in the translation of (changing) user requirements into technical solutions, a methodical approach is indispensible. Therefore the CSA method is developed. The method is designed to impartially select and compare a number of adaptability measures. The degree of efficiency of the chosen measure is assessed by quantifying the required effort for an adaptation, costs and environmental impact. The initial (single) effects for these criteria are distinguished from the more often occurring effects that come with each adaptation. The uniqueness of the CSA method is that a best fit is sought from both the user point of view and the effects on/of the applied building technology. Operation of the CSA method proved to be valid by performing three case studies. In current building the initial phase is decisive for decision making. However, the case studies show that solutions with a high degree of adaptability are the most efficient for the long term, when adaptation occurs several times during the lifespan of a building

Building the future

De eerste week van 2014 is een ideale gelegenheid om de strategie voor het komende jaar te bepalen. Het bestuur van de faculteit Bouwkunde is zelfs nog vooruitstrevender en kijkt zelfs tot 2020 vooruit met het nieuwe strategiedocument ‘Building the Future’

Noodzaak van flexibel bouwen

No abstract

Verwijderingsbijdrage

Een paar jaar geleden stelden een aantal partijen een verwijderingsbijdrage voor nieuwe kantoren voor. Dit werd niet direct met gejubel ontvangen. Het legt echter wel de vinger op de zere plek