Human bladder cancer invasion model using rat bladder in vitro and its use to test mechanisms and therapeutic inhibitors of invasion

As well as being a passive support, the extracellular matrix also regulates key biological processes such as invasion, differentiation and angiogenesis. We have therefore developed an in vitro model of bladder cancer invasion using de-epithelialized rat bladder to allow for tumour cell–extracellular matrix interactions. Onto this we have seeded a panel of human bladder cancer cell lines (RT4, RT112, 253J and EJ28 (T24)) representing progression from well to poorly differentiated phenotypes and used as models of superficial to invasive bladder cancer. The better differentiated cell lines RT4 and RT112 reproducibly grew as stratified epithelium, whereas poorly differentiated EJ28 cells invaded across a broad front. Invasion was not simply related to proliferation rate, measured either as doubling time on plastic (non-invasive 253J and invasive EJ28 having the same doubling time) or by Ki-67 proliferation index within the model. We used the model to test the ability of 4 compounds that interfere with tumour cell–extracellular matrix interactions (suramin, N-acetylcysteine and the urokinase plasminogen activator pathway antagonists Å5 compound and monoclonal antibody Mab 3936) to inhibit invasion. At non-toxic concentrations, all significantly inhibited invasion (P< 0.05), although to varying degrees, suramin and Å5 almost completely and N-acetylcysteine the least. In conclusion, this model shows the urokinase system is important for bladder invasion and can be used to investigate other mechanisms of bladder cancer invasion and also for the testing of intravesical drugs. © 2001 Cancer Research Campaign http://www.bjcancer.co

High performance structural laminate composite material for use to 1000.degree. F. and above, apparatus for and method of manufacturing same, and articles made with same

A novel materials technology has been developed and demonstrated for providing a high modulus composite material for use to 1000.degree. F. and above. This material can be produced at 5-20% of the cost of refractory materials, and has higher structural properties. This technology successfully resolves the problem of thermal shock or ply lift, which limits traditional high temperature laminates (such as graphite/polyimide and graphite/phenolic) to temperatures of 550-650.degree. F. in thicker (0.25 and above) laminates. The technology disclosed herein is an enabling technology for the nose for the External Tank (ET) of the Space Shuttle, and has been shown to be capable of withstanding the severe environments encountered by the nose cone through wind tunnel testing, high temperature subcomponent testing, and full scale structural, dynamic, acoustic, and damage tolerance testing

Predicting sexual problems in women: The relevance of sexual excitation and sexual inhibition

This is the post-print version of the article. The official published version can be obtained from the link below.Data from a non-clinical sample of 540 heterosexual women were used to examine the relationships between scores on the Sexual Excitation/Sexual Inhibition Inventory for Women (SESII-W) and ratings of current sexual problems, lifetime arousal difficulty, lifetime orgasm difficulty, and lifetime problems with low sexual interest. Multiple regression analyses also included several demographic/background variables as predictors: age, full-time employment, completed college, children in household, married, health ratings, importance of sex, and whether the woman was in a sexual relationship. The strongest statistical predictors of both current and lifetime sexual problems were the SESII-W inhibition factors Arousal Contingency and Concerns about Sexual Function. Demographic factors did not feature largely in any of the models predicting sexual problems even when statistically significant relationships were found. If future research supports the predictive utility of the SESII-W in identifying women who are more likely to experience sexual difficulties, these scales may be used as prognostic factors in treatment studies.This study was funded, in part, by a grant from the Lilly Centre for Women's Health

Hypoxia regulates FGFR3 expression via HIF-1α and miR-100 and contributes to cell survival in non-muscle invasive bladder cancer

Background: Non-muscle invasive (NMI) bladder cancer is characterised by increased expression and activating mutations of FGFR3. We have previously investigated the role of microRNAs in bladder cancer and have shown that FGFR3 is a target of miR-100. In this study, we investigated the effects of hypoxia on miR-100 and FGFR3 expression, and the link between miR-100 and FGFR3 in hypoxia. Methods: Bladder cancer cell lines were exposed to normoxic or hypoxic conditions and examined for the expression of FGFR3 by quantitative PCR (qPCR) and western blotting, and miR-100 by qPCR. The effect of FGFR3 and miR-100 on cell viability in twodimensional (2-D) and three-dimensional (3-D) was examined by transfecting siRNA or mimic-100, respectively. Results: In NMI bladder cancer cell lines, FGFR3 expression was induced by hypoxia in a transcriptional and HIF-1a-dependent manner. Increased FGFR3 was also in part dependent on miR-100 levels, which decreased in hypoxia. Knockdown of FGFR3 led to a decrease in phosphorylation of the downstream kinases mitogen-activated protein kinase (MAPK) and protein kinase B (PKB), which was more pronounced under hypoxic conditions. Furthermore, transfection of mimic-100 also decreased phosphorylation of MAPK and PKB. Finally, knocking down FGFR3 profoundly decreased 2-D and 3-D cell growth, whereas introduction of mimic-100 decreased 3-D growth of cells. Conclusion: Hypoxia, in part via suppression of miR-100, induces FGFR3 expression in bladder cancer, both of which have an important role in maintaining cell viability under conditions of stress

The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer

Regulation by hypoxia may underlie the expression of vascular endothelial growth factor in bladder cancer. We have compared the distribution of vascular endothelial growth factor mRNA with a hypoxia marker, carbonic anhydrase 9 (CA IX). vascular endothelial growth factor mRNA was analysed by in situ hybridisation and CA IX by immunochemistry in 22 cases of bladder cancer. The relationship of microvessels to the distribution of CA IX was determined. In a separate series of 49 superficial tumours, CA IX immunostaining was compared with clinico-pathological outcome. In superficial and invasive disease there was overlap in the expression of vascular endothelial growth factor and CA IX, CA IX being more widespread. Both were expressed predominantly on the luminal surface, and surrounding areas of necrosis (invasive tumours). Expression of both factors was greater in superficial disease. Expression was absent within ∼80 μm of microvessels. Unlike vascular endothelial growth factor, CA IX did not predict outcome in superficial disease. Differential responses to reoxygenation provide one explanation: vascular endothelial growth factor mRNA declined rapidly, while CA IX expression was sustained for >72 h. Expression of vascular endothelial growth factor mRNA in bladder tumours is consistent with hypoxic regulation and suggests differential regulation in superficial vs invasive disease. The expression of CA IX on the luminal surface justifies investigation of its utility as a therapeutic target/prognostic indicator

Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study

Design: Phase 1, randomized, two-site (US), double-blind, placebo-controlled study of sexually-abstinent males and females

Trouble in Paradise - A disabled person's right to the satisfaction of a self-defined need:Some conceptual and practical problems

This paper questions the usefulness of the rights-based approach to ameliorating the social situation of disabled people in Britain and advances two criticisms. First, that rights and self-de? ned needs have been under-theorised by disability theorists to the extent that they have insuf? ciently appreciated the problems that these approaches pose. The paper suggests that rights to appropriate resources to satisfy self-de? ned needs will generate vast numbers of competing rights claims and that the resulting tendency of rights to con? ict has been under-appreciated. Secondly, that there has been little consideration of how these con? icts might be reconciled. The ? rst two sections of the paper look at the concepts of ascribed and self-de? ned needs, respectively, whilst the ? nal one looks at some of the problems of the rights approach and some of the dif? culties of making self-de? ned need the basis of rights claims

Sustainability in Turbulent Times: Lessons from the Nexus Network for supporting transdisciplinary research

This is the final version. Available from the Nexus Network via the link in this recordEconomic and Social Research Council (ESRC

Measurement of neutron capture on 48^{48}Ca at thermal and thermonuclear energies

At the Karlsruhe pulsed 3.75\,MV Van de Graaff accelerator the thermonuclear $^{48}$Ca(n,$\gamma$)$^{49}$Ca(8.72\,min) cross section was measured by the fast cyclic activation technique via the 3084.5\,keV $\gamma$-ray line of the $^{49}$Ca-decay. Samples of CaCO$_3$ enriched in $^{48}$Ca by 77.87\,\% were irradiated between two gold foils which served as capture standards. The capture cross-section was measured at the neutron energies 25, 151, 176, and 218\,keV, respectively. Additionally, the thermal capture cross-section was measured at the reactor BR1 in Mol, Belgium, via the prompt and decay $\gamma$-ray lines using the same target material. The $^{48}$Ca(n,$\gamma$)$^{49}$Ca cross-section in the thermonuclear and thermal energy range has been calculated using the direct-capture model combined with folding potentials. The potential strengths are adjusted to the scattering length and the binding energies of the final states in $^{49}$Ca. The small coherent elastic cross section of $^{48}$Ca+n is explained through the nuclear Ramsauer effect. Spectroscopic factors of $^{49}$Ca have been extracted from the thermal capture cross-section with better accuracy than from a recent (d,p) experiment. Within the uncertainties both results are in agreement. The non-resonant thermal and thermonuclear experimental data for this reaction can be reproduced using the direct-capture model. A possible interference with a resonant contribution is discussed. The neutron spectroscopic factors of $^{49}$Ca determined from shell-model calculations are compared with the values extracted from the experimental cross sections for $^{48}$Ca(d,p)$^{49}$Ca and $^{48}$Ca(n,$\gamma$)$^{49}$Ca.Comment: 15 pages (uses Revtex), 7 postscript figures (uses psfig), accepted for publication in PRC, uuencoded tex-files and postscript-files also available at ftp://is1.kph.tuwien.ac.at/pub/ohu/Ca.u