Sphingosine-1-phosphate, a novel second messenger involved in cell growth regulation and signal transduction, affects growth and invasiveness of human breast cancer cells

This review will focus on the role of sphingosine and its phosphorylated derivative sphingosine-1-phosphate (SPP) in cell growth regulation and signal transduction. We will show that many of the effects attributed to sphingosine in quiescent Swiss 3T3 fibroblasts are mediated via its conversion to SPP. We propose that SPP has appropriate properties to function as an intracellular second messenger based on the following: it elicits diverse cellular responses; it is rapidly produced from sphingosine by a specific kinase and rapidly degraded by a specific lyase; its concentration is low in quiescent cells but increases rapidly and transiently in response to the growth factors, fetal calf serum (FCS) and platelet derived growth factor (PDGF); it releases Ca2+ from internal sources in an InsP3-independent manner; and finally, it may link sphingolipid signaling pathways to cellular ras-mediated signaling pathways by elevating phosphatidic acid levels. The effects of this novel second messenger on growth, differentiation and invasion of human breast cancer cells will be discussed. © 1994 Kluwer Academic Publishers.

Default judgment - whether irregular - whether court has residual discretion not to set aside default judgment irregularly entered

In CB Richard Ellis (C) Pty Ltd v Wingate Properties Pty Ltd [2005] QDC 399 McGill DCJ examined whether the court now has a discretion to set aside an irregularly entered default judgment.

Computation of ECG signal features using MCMC modelling in software and FPGA reconfigurable hardware

Computational optimisation of clinically important electrocardiogram signal features, within a single heart beat, using a Markov-chain Monte Carlo (MCMC) method is undertaken. A detailed, efficient data-driven software implementation of an MCMC algorithm has been shown. Initially software parallelisation is explored and has been shown that despite the large amount of model parameter inter-dependency that parallelisation is possible. Also, an initial reconfigurable hardware approach is explored for future applicability to real-time computation on a portable ECG device, under continuous extended use.

From short pulses to short breaks : exotic plasma bullets via residual electron control

Plasma plumes with exotically segmented channel structure and plasma bullet propagation are produced in atmospheric plasma jets. This is achieved by tailoring interruptions of a continuous DC power supply over the time scales of lifetimes of residual electrons produced by the preceding discharge phase. These phenomena are explained by studying the plasma dynamics using nanosecond-precision imaging. One of the plumes is produced using 2-10μs interruptions in the 8kV DC voltage and features a still bright channel from which a propagating bullet detaches. A shorter interruption of 900ns produces a plume with the additional long conducting dark channel between the jet nozzle and the bright area. The bullet size, formation dynamics, and propagation speed and distance can be effectively controlled. This may lead to micrometer-and nanosecond-precision delivery of quantized plasma bits, warranted for next-generation health, materials, and device technologies.

Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

Background Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. Methods The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Results Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts. Conclusions This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies. Keywords: Ovarian carcinoma, Cancer stem cell, Metastasis, Ascites, Chemoresistance, Recurrence, JAK2/STAT3 pathway

Catalytic probes with nanostructured surface for gas/discharge diagnostics : a study of a probe signal behaviour

Catalytic probes are used for plasma diagnostics in order to quantify the density of neutral atoms. The probe response primarily depends on the probe material and its surface morphology. Here we report on the design, operation and modelling of the response of niobium pentoxide sensors with a flat and nanowire (NW) surfaces. These sensors were used to detect neutral oxygen atoms in the afterglow region of an inductively coupled rf discharge in oxygen. A very different response of the flat-surface and NW probes to the varying densities of oxygen atoms was explained by modelling heat conduction and taking into account the associated temperature gradients. It was found that the nanostructure probe can measure in a broader range than the flat oxide probe due to an increase in the surface to volume ratio, and the presence of nanostructures which act as a thermal barrier against sensor overheating. These results can be used for the development of the new generation of catalytic probes for gas/discharge diagnostics in a range of industrial and environmental applications.

Stop-signal task difficulty and the right inferior frontal gyrus

The stop-signal paradigm is increasingly being used as a probe of response inhibition in basic and clinical neuroimaging research. The critical feature of this task is that a cued response is countermanded by a secondary ‘stop-signal’ stimulus offset from the first by a ‘stop-signal delay’. Here we explored the role of task difficulty in the stop-signal task with the hypothesis that what is critical for successful inhibition is the time available for stopping, that we define as the difference between stop-signal onset and the expected response time (approximated by reaction time from previous trial). We also used functional magnetic resonance imaging (fMRI) to examine how the time available for stopping affects activity in the putative right inferior frontal gyrus and presupplementary motor area (right IFG-preSMA) network that is known to support stopping. While undergoing fMRI scanning, participants performed a stop-signal variant where the time available for stopping was kept approximately constant across participants, which enabled us to compare how the time available for stopping affected stop-signal task difficulty both within and between subjects. Importantly, all behavioural and neuroimaging data were consistent with previous findings. We found that the time available for stopping distinguished successful from unsuccessful inhibition trials, was independent of stop-signal delay, and affected successful inhibition depending upon individual SSRT. We also found that right IFG and adjacent anterior insula were more strongly activated during more difficult stopping. These findings may have critical implications for stop-signal studies that compare different patient or other groups using fixed stop-signal delays.

Stop-signal response inhibition in schizophrenia : Behavioural, event-related potential and functional neuroimaging data

Inhibitory control deficits are well documented in schizophrenia, supported by impairment in an established measure of response inhibition, the stop-signal reaction time (SSRT). We investigated the neural basis of this impairment by comparing schizophrenia patients and controls matched for age, sex and education on behavioural, functional magnetic resonance imaging (fMRI) and event-related potential (ERP) indices of stop-signal task performance. Compared to controls, patients exhibited slower SSRT and reduced right inferior frontal gyrus (rIFG) activation, but rIFG activation correlated with SSRT in both groups. Go stimulus and stop-signal ERP components (N1/P3) were smaller in patients, but the peak latencies of stop-signal N1 and P3 were also delayed in patients, indicating impairment early in stop-signal processing. Additionally, response-locked lateralised readiness potentials indicated response preparation was prolonged in patients. An inability to engage rIFG may predicate slowed inhibition in patients, however multiple spatiotemporal irregularities in the networks underpinning stop-signal task performance may contribute to this deficit.

Electrochemical current rectification – a novel signal amplification strategy for highly sensitive and selective aptamer-based biosensor

Electrochemical aptamer-based (E-AB) sensors represent an emerging class of recently developed sensors. However, numerous of these sensors are limited by a low surface density of electrode-bound redox-oligonucleotides which are used as probe. Here we propose to use the concept of electrochemical current rectification (ECR) for the enhancement of the redox signal of E-AB sensors. Commonly, the probe-DNA performs a change in conformation during target binding and enables a nonrecurring charge transfer between redox-tag and electrode. In our system, the redox-tag of the probe-DNA is continuously replenished by solution-phase redox molecules. A unidirectional electron transfer from electrode via surface-linked redox-tag to the solution-phase redox molecules arises that efficiently amplifies the current response. Using this robust and straight-forward strategy, the developed sensor showed a substantial signal amplification and consequently improved sensitivity with a calculated detection limit of 114 nM for ATP, which was improved by one order of magnitude compared with the amplification-free detection and superior to other previous detection results using enzymes or nanomaterials-based signal amplification. To the best of our knowledge, this is the first demonstration of an aptamer-based electrochemical biosensor involving electrochemical rectification, which can be presumably transferred to other biomedical sensor systems.

Enhancing Raman signal sufficiently for practical sensing applications

Techniques are presented for enhancing weak Raman scattering signals for rapid yet accurate substance detection. Novel surfaces that allow signal enhancement quantification are described as are eye-safe methodologies that maximize the stand-off Raman detection range.

Confidence measurement in the light of signal detection theory

We compare three alternative methods for eliciting retrospective confidence in the context of a simple perceptual task: the Simple Confidence Rating (a direct report on a numerical scale), the Quadratic Scoring Rule (a post-wagering procedure), and the Matching Probability (MP; a generalization of the no-loss gambling method). We systematically compare the results obtained with these three rules to the theoretical confidence levels that can be inferred from performance in the perceptual task using Signal Detection Theory (SDT). We find that the MP provides better results in that respect. We conclude that MP is particularly well suited for studies of confidence that use SDT as a theoretical framework.

Spatial and temporal variability in a residual soil profile

It is well understood that that there is variation inherent in all testing techniques, and that all soil and rock materials also contain some degree of natural variability. Less consideration is normally given to variation associated with natural material heterogeneity within a site, or the relative condition of the material at the time of testing. This paper assesses the impact of spatial and temporal variability upon repeated insitu testing of a residual soil and rock profile present within a single residential site over a full calendar year, and thus range of seasonal conditions. From this repeated testing, the magnitude of spatial and temporal variation due to seasonal conditions has demonstrated that, depending on the selected location and moisture content of the subsurface at the time of testing, up to a 35% variation within the test results can be expected. The results have also demonstrated that the completed insitu test technique has a similarly large measurement and inherent variability error and, for the investigated site, up to a 60% variation in normalised results was observed. From these results, it is recommended that the frequency and timing of insitu tests should be considered when deriving geotechnical design parameters from a limited data set.