SCOTROC 2A: Carboplatin followed by docetaxel or docetaxel gemcitabine as first-line chemotherapy for ovarian cancer

The feasibility of sequential carboplatin followed by docetaxel-based therapy for untreated ovarian cancer was determined. Patients received four q3w cycles of carboplatin AUC 7, then four q3w cycles of either docetaxel 100 mg m(-2) (day 1) (arm A); docetaxel 75 mg m(-2) (day 8) and gemcitabine 1250 mg m(-2) (days 1,8) (arm B) or docetaxel 25 mg m(-2) and gemcitabine 800 mg m(-2) (both given weekly (days 1,8,15)) (arm C). A total of 44 patients were randomised to each treatment arm. None of the arms demonstrated an eight cycle completion rate (70.5/72.7/45.5% in arms A/B/C, respectively), which was statistically greater than 60% (P = 0.102, P = 0.056, P = 0.982) which was our formal feasibility criteria, although only the completion rate in arm C was clearly worse than this level. The overall response rate (ORR) after carboplatin was 65.7% in 70 evaluable patients. In evaluable patients, ORRs after docetaxel-based cycles were: arm A 84.0% (21 out of 25); arm B 77.3% (17 out of 22); arm C 69.6% (16 out of 23). At follow-up (median 30 months), median progression-free survival times were: arm A 15.5 months (95% Cl: 10.5 - 20.6); arm B 18.1 months (95% Cl: 15.9 - 20.3); arm C, 13.7 months (95% Cl: 12.8 - 14.6). Neutropenia was the predominant grade 3 - 4 haematological toxicity: 77.8/85.7/54.4% in arms A/B/C, respectively. Dyspnoea was markedly increased in both gemcitabine-containing arms (P = 0.001) but was worse in arm C. Although just failing to rule out eight cycle completion rates less than 60%, within the statistical limitations of these small cohorts, the overall results for arms A and B are encouraging. Larger phase III studies are required to test these combinations.

Inhibition of interferon signaling by the New York 99 strain and Kunjin subtype of West Nile virus involves blockage of STAT1 and STAT2 activation by nonstructural proteins

The interferon (IFN) response is the first line of defense against viral infections, and the majority of viruses have developed different strategies to counteract IFN responses in order to ensure their survival in an infected host. In this study, the abilities to inhibit IFN signaling of two closely related West Nile viruses, the New York 99 strain (NY99) and Kunjin virus (KUN), strain MRM61C, were analyzed using reporter plasmid assays, as well as immunofluorescence and Western blot analyses. We have demonstrated that infections with both NY99 and KUN, as well as transient or stable transfections with their replicon RNAs, inhibited the signaling of both alpha/beta IFN (IFN-alpha/beta) and gamma IFN (IFN-gamma) by blocking the phosphorylation of STAT1 and its translocation to the nucleus. In addition, the phosphorylation of STAT2 and its translocation to the nucleus were also blocked by KUN, NY99, and their replicons in response to treatment with IFN-alpha. IFN-alpha signaling and STAT2 translocation to the nucleus was inhibited when the KUN nonstructural proteins NS2A, NS2B, NS3, NS4A, and NS4B, but not NS1 and NS5, were expressed individually from the pcDNA3 vector. The results clearly demonstrate that both NY99 and KUN inhibit IFN signaling by preventing STAT1 and STAT2 phosphorylation and identify nonstructural proteins. responsible for this inhibition.

A refined solution to the first terrestrial Pb-isotope paradox

The first terrestrial Pb-isotope paradox refers to the fact that on average, rocks from the Earth's surface (i.e. the accessible Earth) plot significantly to the right of the meteorite isochron in a common Pb-isotope diagram. The Earth as a whole, however, should plot close to the meteorite isochron, implying the existence of at least one terrestrial reservoir that plots to the left of the meteorite isochron. The core and the lower continental crust are the two candidates that have been widely discussed in the past. Here we propose that subducted oceanic crust and associated continental sediment stored as garnetite slabs in the mantle Transition Zone or mid-lower mantle are an additional potential reservoir that requires consideration. We present evidence from the literature that indicates that neither the core nor the lower crust contains sufficient unradiogenic Pb to balance the accessible Earth. Of all mantle magmas, only rare alkaline melts plot significantly to the left of the meteorite isochron. We interpret these melts to be derived from the missing mantle reservoir that plots to the left of the meteorite isochron but, significantly, above the mid-ocean ridge basalt (MORB)-source mantle evolution line. Our solution to the paradox predicts the bulk silicate Earth to be more radiogenic in Pb-207/Pb-204 than present-day MORB-source mantle, which opens the possibility that undegassed primitive mantle might be the source of certain ocean island basalts (OIB). Further implications for mantle dynamics and oceanic magmatism are discussed based on a previously justified proposal that lamproites and associated rocks could derive from the Transition Zone.

A review of the first year's experience with an automatic message-routing system for low-cost telemedicine

The Swinfen Charitable Trust has used email for some years as a low-cost telemedicine medium to provide consultant support for doctors in developing countries. A scalable, automatic message-routing system was constructed which automates many of the tasks involved in message handling. During the first 12 months of its use, 1510 messages were processed automatically. There were 128 referrals from 18 hospitals in nine countries. Of these 128 queries, 89 (70%) were replied to within 72 h; the median delay was 1.1 day. The 39 unanswered queries were sent to backup specialists for reply and 36 of them (92%) were replied to within 72 h. In the remaining three cases, a second-line (backup) specialist was required. The referrals were handled by 54 volunteer specialists from a panel of over 70. Two system operators, located 10 time zones apart, managed the system. The median time from receipt of a new referral to its allocation to a specialist was 0.2 days (interquartile range, IQR, 0.1-0.8). The median interval between receipt of a new referral and first reply was 2.6 days (IQR 0.8-5.9). Automatic message handling solves many of the problems of manual email telemedicine systems and represents a potentially scalable way of doing low-cost telemedicine in the developing world.

The BeWo choriocarcinoma cell line as a model of iodide transport by placenta

Cultured human choriocarcinoma cells of the BeWo line exhibited saturable accumulation of radioiodide. Inhibition by competing anions followed the affinity series perchlorate >= iodide >= thiocyanate, consistent with uptake through the thyroid iodide transporter, NIS, whose messenger RNA was found in BeWo cells, and whose protein was distributed towards the apical pole of the cells. Efflux obeyed first order kinetics and was inhibited by DIDS, an antagonist of anion exchangers including pendrin, whose messenger RNA was also present. In cultures where iodide uptake through NIS was blocked with excess perchlorate, radiolodide accumulation was stimulated by exposure to medium in which physiological anions were replaced by 2-morpholinoethanesulfonic acid (MES), consistent with the operation of an anion exchange mechanism taking up iodide. Chloride in the medium was more effective than sulfate at inhibiting this uptake, matching the ionic specificity of pendrin. These studies provide evidence that the trophoblast accumulates iodide through NIS and releases it to the fetal compartment through pendrin. (c) 2004 Elsevier Ltd. All rights reserved.

Expression analysis of a human hepatic cell line in response to palmitate

Saturated fat plays a role in common debilitating diseases such as obesity, type 2 diabetes, and coronary heart disease. It is also clear that certain fatty acids act as regulators of metabolism via both direct and indirect signalling of target tissues. As the molecular mechanisms of saturated fatty acid signalling in the liver are poorly defined, hepatic gene expression analysis was undertaken in a human hepatocyte cell line after incubation with palmitate. Profiling of mRNA expression using cDNA microarray analysis revealed that 162 of approximately 18,000 genes tested were differentially expressed after incubation with palmitate for 48 h. Altered transcription profiles were observed in a wide variety of genes, including genes involved in lipid and cholesterol transport, cholesterol catabolism, cell growth and proliferation, cell signalling, P-oxidation, and oxidative stress response. While palinitate signalling has been examined in pancreatic beta-cells, this is the first report showing that palmitate regulates expression of numerous genes via direct molecular signalling mechanisms in liver cells. (C) 2005 Elsevier Inc. All rights reserved.

Modelling knowledge production performance of research centres with a focus on triple bottom line benchmarking

We demonstrate a portable process for developing a triple bottom line model to measure the knowledge production performance of individual research centres. For the first time, this study also empirically illustrates how a fully units-invariant model of Data Envelopment Analysis (DEA) can be used to measure the relative efficiency of research centres by capturing the interaction amongst a common set of multiple inputs and outputs. This study is particularly timely given the increasing transparency required by governments and industries that fund research activities. The process highlights the links between organisational objectives, desired outcomes and outputs while the emerging performance model represents an executive managerial view. This study brings consistency to current measures that often rely on ratios and univariate analyses that are not otherwise conducive to relative performance analysis.

Off-line signature verification and forgery detection using fuzzy modeling

Automatic signature verification is a well-established and an active area of research with numerous applications such as bank check verification, ATM access, etc. This paper proposes a novel approach to the problem of automatic off-line signature verification and forgery detection. The proposed approach is based on fuzzy modeling that employs the Takagi-Sugeno (TS) model. Signature verification and forgery detection are carried out using angle features extracted from box approach. Each feature corresponds to a fuzzy set. The features are fuzzified by an exponential membership function involved in the TS model, which is modified to include structural parameters. The structural parameters are devised to take account of possible variations due to handwriting styles and to reflect moods. The membership functions constitute weights in the TS model. The optimization of the output of the TS model with respect to the structural parameters yields the solution for the parameters. We have also derived two TS models by considering a rule for each input feature in the first formulation (Multiple rules) and by considering a single rule for all input features in the second formulation. In this work, we have found that TS model with multiple rules is better than TS model with single rule for detecting three types of forgeries; random, skilled and unskilled from a large database of sample signatures in addition to verifying genuine signatures. We have also devised three approaches, viz., an innovative approach and two intuitive approaches using the TS model with multiple rules for improved performance. (C) 2004 Pattern Recognition Society. Published by Elsevier Ltd. All rights reserved.