Cathepsin S expression: An independent prognostic factor in glioblastoma tumours - A pilot Study

Cysteine proteinases have been implicated in astrocytoma invasion. We recently demonstrated that cathepsin S (CatS) expression is up-regulated in astrocytomas and provided evidence for a potential role in astrocytoma invasion (Flannery et al., Am J Path 2003;163(1):175–82). We aimed to evaluate the significance of CatS in human astrocytoma progression and as a prognostic marker. Frozen tissue homogenates from 71 patients with astrocytomas and 3 normal brain specimens were subjected to ELISA analyses. Immunohistochemical analysis of CatS expression was performed on 126 paraffin-embedded tumour samples. Fifty-one astrocytoma cases were suitable for both frozen tissue and paraffin tissue analysis. ELISA revealed minimal expression of CatS in normal brain homogenates. CatS expression was increased in grade IV tumours whereas astrocytoma grades I–III exhibited lower values. Immunohistochemical analysis revealed a similar pattern of expression. Moreover, high-CatS immunohistochemical scores in glioblastomas were associated with significantly shorter survival (10 vs. 5 months, p = 0.014). With forced inclusion of patient age, radiation dose and Karnofsky score in the Cox multivariate model, CatS score was found to be an independent predictor of survival. CatS expression in astrocytomas is associated with tumour progression and poor outcome in glioblastomas. CatS may serve as a useful prognostic indicator and potential target for anti-invasive therapy.

Platform-Independent IP Transmission over Wireless Networks: The WINE Approach

First demonstration of a working dynamically configurable architecture for wireless IP networks. The programmable architecture was as result of a European collaboration between Industry and University and was applied to a range of IP wireless networks. The work laid the foundations for subsequent research initiatives (including the UK) into programmable wireless networks as well as influencing future wireless standards (e.g. ITU-T).EU project WINE (Wireless Internet NEtworking), -1999-10028.

Ca2+-independent phospholipase A2-dependent gating of TRPM8 by lysophospholipids

TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca(2+)-independent phospholipase A(2) (iPLA(2)) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA(2) resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA(2) stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland.

Comparing whole-link travel time models used in DTA

In a model commonly used in dynamic traffic assignment the link travel time for a vehicle entering a link at time t is taken as a function of the number of vehicles on the link at time t. In an alternative recently introduced model, the travel time for a vehicle entering a link at time t is taken as a function of an estimate of the flow in the immediate neighbourhood of the vehicle, averaged over the time the vehicle is traversing the link. Here we compare the solutions obtained from these two models when applied to various inflow profiles. We also divide the link into segments, apply each model sequentially to the segments and again compare the results. As the number of segments is increased, the discretisation refined to the continuous limit, the solutions from the two models converge to the same solution, which is the solution of the Lighthill, Whitham, Richards (LWR) model for traffic flow. We illustrate the results for different travel time functions and patterns of inflows to the link. In the numerical examples the solutions from the second of the two models are closer to the limit solutions. We also show that the models converge even when the link segments are not homogeneous, and introduce a correction scheme in the second model to compensate for an approximation error, hence improving the approximation to the LWR model.