A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer.

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2'-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer.

Methods: Patients progressing 6-12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma.

Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%).

Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

Testing Tidal Turbines - Part 1: Steady Towing Tests vs Tidal Moored Tests

Tidal turbines have been tested extensively at many scales in steady state flow. Testing medium- or full-scale devices in turbulent flow has been less thoroughly examined. The differences between turbine performances in these two different states are needed for testing method verification and numerical model validation. The work in this paper documents the performance of a 1/10 scale turbine in steady state pushing tests and tidal moored tests. The overall performance of the device appears to decrease with turbulent flow, though there is increased data scatter and therefore, reduced uncertainty. At maximum power performance, as velocity increases the mechanical power and electrical power reduction from steady to unsteady flow increases. The drive train conversion efficiency also decreases. This infers that the performance for this turbine design is affected by the presence of turbulent flow.

Towards Understanding Man-In-The-Middle Attacks on IEC 60870-5-104 SCADA Networks

This paper investigates cyber attacks on ICS which rely on IEC 60870-5-104 for telecontrol communications. The main focus of the paper is on man-in-the-middle attacks, covering modification and injection of commands, it also details capture and replay attacks. An initial set of attacks are preformed on a local software simulated laboratory. Final experiments and validation of a man-in-the-middle attack are performed in a comprehensive testbed environment in conjunction with an electricity distribution operator.

Bricks vs. clicks: Which is better for marketing remanufactured products?

The economical and environmental benefits are the central issues for remanufacturing. Whereas extant remanufacturing research focuses primarily on such issues in remanufacturing technologies, production planning, inventory control and competitive strategies, we provide an alternative yet somewhat complementary approach to consider both issues related to different channels structures for marketing remanufactured products. Specifically, based on observations from current practice, we consider a manufacturer sells new units through an independent retailer but with two options for marketing remanufactured products: (1) marketing through its own e-channel (Model M) or (2) subcontracting the marketing activity to a third party (Model 3P). A central result we obtain is that although Model M is always greener than Model 3P, firms have less incentive to adopt it because both the manufacturer and retailer may be worse off when the manufacturer sells remanufactured products through its own e-channel rather than subcontracting to a third party. Extending both models to cases in which the manufacturer interacts with multiple retailers further reveals that the more retailers in the market, the greener Model M relative to Model 3P.

Environmental filtering vs. resource-based niche partitioning in diverse soil animal assemblages

Terrestrial invertebrates constitute most of described animal biodiversity and soil is a major reservoir of this diversity. In the classical attempt to understand the processes supporting biodiversity, ecologists are currently seeking to unravel the differential roles of environmental filtering and competition for resources in niche partitioning processes: these processes are in principle distinct although they may act simultaneously, interact at multiple spatial and temporal scales, and are often confounded in studies of soil communities. We used a novel combination of methods based on stable isotopes and trait analysis to resolve these processes in diverse oribatid mite assemblages at spatial
scales at which competition for resources could in principle be a major driver. We also used a null model approach based on a general neutral model of beta diversity. A large and significant fraction of community variation was explainable in terms of linear and periodic spatial structures in the distribution of organic C, N and soil structure: species were clearly arranged along an environmental, spatially structured gradient. However, competition related trait differences did not map onto the distances separating species along the environmental gradient and neutral models provided a satisfying approximation of beta diversity patterns. The results represent the first robust evidence
that in very diverse soil arthropod assemblages resource-based niche partitioning plays a minor role while environmental filtering remains a fundamental driver of species distribution.

Stateful Intrusion Detection for IEC 60870-5-104 SCADA Security

Cyber threats in Supervisory Control and Data Acquisition (SCADA) systems have the potential to render physical damage and jeopardize power system operation, safety and stability. SCADA systems were originally designed with little consideration of escalating cyber threats and hence the problem of how to develop robust intrusion detection technologies to tailor the requirements of SCADA is an emerging topic and a big challenge. This paper proposes a stateful Intrusion Detection System (IDS) using a Deep Packet Inspection (DPI) method to improve the cyber-security of SCADA systems using the IEC 60870-5-104 protocol which is tailored for basic telecontrol communications. The proposed stateful protocol analysis approach is presented that is designed specifically for the IEC 60870-5-104 protocol. Finally, the novel intrusion detection approach are implemented and validated.

Reducing SCADA System Nuisance Alarms in the Water Industry in Northern Ireland

The advancement of telemetry control for the water industry has increased the difficulty of 14 managing large volumes of nuisance alarms (i.e. alarms that do not require a response). The aim 15 of this study was to identify and reduce the number of nuisance alarms that occur for Northern 16 Ireland (NI) Water by carrying-out alarm duration analysis to determine the appropriate length of 17 persistence (an advanced alarm management tool) that could be applied. All data was extracted 18 from TelemWeb (NI Water’s telemetry monitoring system) and analysed in Excel. Over a 6 19 week period, an average of 40,000 alarms occurred per week. The alarm duration analysis, which 20 has never been implemented before by NI Water, found that an average of 57% of NI Water 21 alarms had a duration of <5 minutes. Applying 5 minute persistence; therefore, could prevent an 22 average 26,816 nuisance alarms per week. Most of these alarms were from wastewater assets.

An Architecture of a Multi-Agent System for SCADA - Dealing With Uncertainty, Plans and Actions

This paper presents a multi-agent system approach to address the difficulties encountered in traditional SCADA systems deployed in critical environments such as electrical power generation, transmission and distribution. The approach models uncertainty and combines multiple sources of uncertain information to deliver robust plan selection. We examine the approach in the context of a simplified power supply/demand scenario using a residential grid connected solar system and consider the challenges of modelling and reasoning with
uncertain sensor information in this environment. We discuss examples of plans and actions required for sensing, establish and discuss the effect of uncertainty on such systems and investigate different uncertainty theories and how they can fuse uncertain information from multiple sources for effective decision making in
such a complex system.

A randomised comparison of daunorubicin 90mg/m2 vs 60mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients

Modifying induction therapy in AML may improve the remission rate and reduce the risk of relapse thereby improving survival. Escalation of the daunorubicin dose to 90mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45mg/m(2) and has been recommended as a standard of care. However 60mg/m(2) is widely used and has never been directly compared to 90mg/m(2). As part of the UK NCRI AML17 trial 1206 adults with untreated AML or high risk MDS, mostly under 60 years of age, were randomised to a first induction course of chemotherapy which delivered either 90mg/m(2) or 60mg/m(2) on days 1,3 and 5 combined with cytosine arabinoside. All patients then received a second course which included daunorubicin 50mg/m(2) on days 1,3 and 5. There was no overall difference in complete remission rate (CR) (73% vs 75%, OR1.07 (0.83-1.39), p=0.6) or in any recognised subgroup. The 60 day mortality was increased in the 90mg/m2 arm (10% vs 5% (HR 1.98(1.30-3.02) p=0.001)), which resulted in no difference in overall 2 year survival (59% vs 60%, HR 1.16(0.95-1.43), p=0.15). In exploratory subgroup analysis there was no subgroup which showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. The trial is registered to www.isrctn.com as ISRCTN55675535.

Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia

The development of new treatments for older patients with acute myeloid leukemia is an active area, but has met with limited success. Vosaroxin, a quinolone-derived intercalating agent has several properties that could prove beneficial. Initial clinical studies showed it to be well-tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with cytarabine (Ara-C). To evaluate vosaroxin, we performed 2 randomized comparisons within the "Pick a Winner" program. A total of 104 patients were randomized to vosaroxin vs low-dose Ara-C (LDAC) and 104 to vosaroxin + LDAC vs LDAC. When comparing vosaroxin with LDAC, neither response rate (complete recovery [CR]/complete recovery with incomplete count recovery [CRi], 26% vs 30%; odds ratio [OR], 1.16 (0.49-2.72); P = .7) nor 12-month survival (12% vs 31%; hazard ratio [HR], 1.94 [1.26-3.00]; P = .003) showed benefit for vosaroxin. Likewise, in the vosaroxin + LDAC vs LDAC comparison, neither response rate (CR/CRi, 38% vs 34%; OR, 0.83 [0.37-1.84]; P = .6) nor survival (33% vs 37%; HR, 1.30 [0.81-2.07]; P = .3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin + LDAC arm, most obviously in the second month following randomization. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms because a clinically relevant benefit was unlikely.