Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.

Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.

WFF-WFFP-ICSF-CIC: national workshop on capacity-building for the implementation of the voluntary guidelines for securing sustainable small-scale fisheries (SSF guidelines) - report, 21 and 22 March 2016 Multi-Purpose Hall, India International Centre, New Delhi, India

The report of the proceedings of the New Delhi workshop on the SSF Guidelines (Voluntary Guidelines for Securing Sustainable Small-scale Fisheries in the Context of Food Security and Poverty Eradication). The workshop brought together 95 participants from 13 states representing civil society organizations. governments, FAO, and fishworker organizations from both the marine and inland fisheries sectors. This report will be found useful for fishworker organizations, researchers, policy makers, members of civil society and anyone interested in small-scale fisheries, tenure rights, social development, livelihoods, post harvest and trade and disasters and climate change.

Multi-purpose adaptable business tier components based on Call Level Interfaces

Call Level Interfaces (CLI) play a key role in business tiers of relational and on some NoSQL database applications whenever a fine tune control between application tiers and the host databases is a key requirement. Unfortunately, in spite of this significant advantage, CLI are low level API, this way not addressing high level architectural requirements. Among the examples we emphasize two situations: a) the need to decouple or not to decouple the development process of business tiers from the development process of application tiers and b) the need to automatically adapt business tiers to new business and/or security needs at runtime. To tackle these CLI drawbacks, and simultaneously keep their advantages, this paper proposes an architecture relying on CLI from which multi-purpose business tiers components are built, herein referred to as Adaptable Business Tier Components (ABTC). Beyond the reference architecture, this paper presents a proof of concept based on Java and Java Database Connectivity (an example of CLI).

ABTC: multi-purpose adaptable business tier components based on Call Level Interfaces

Call Level Interfaces (CLI) are low level API that play a key role in database applications whenever a fine tune control between application tiers and the host databases is a key requirement. Unfortunately, in spite of this significant advantage, CLI were not designed to address organizational requirements and contextual runtime requirements. Among the examples we emphasize the need to decouple or not to decouple the development process of business tiers from the development process of application tiers and also the need to automatically adapt to new business and/or security needs at runtime. To tackle these CLI drawbacks, and simultaneously keep their advantages, this paper proposes an architecture relying on CLI from which multi-purpose business tiers components are built, herein referred to as Adaptable Business Tier Components (ABTC). This paper presents the reference architecture for those components and a proof of concept based on Java and Java Database Connectivity (an example of CLI).

Erikoiskalustetuotannon työprojektin hallinta

Tutkimuksessa on selvitetty erikoiskalustevalmistuksen projektinhallinnan suunnittelun toteutusta, tukiprosesseja sekä projektien seurantaa. Tutkimuksessa verrataan teoreettista projektinhallintaa ja käytännön toteutusta erikoiskalusteita valmistavassa yrityksessä. Osa-alueina ovat projektisuunnitelma, suunnitelman seuranta, asiakastyytyväisyys ja laatu sekä työprosessin vaihtelut ja riskit. Tutkimusaineisto on koottu kyselyin, seurannalla ja haastatteluin kohdeyrityksessä. Tutkimuksessa on käytetty tilastollisia ja analyyttisen hierarkian (AHP) sekä monitavoiteoptimoinnin menetelmiä. Tuloksissa esitetään työprojektin hallinnan eri osa-alueet mukaan lukien projektin laatu sekä työprosessin vaihtelun ja riskien kannattavat hallintamahdollisuudet. Suosituksena kalustevalmistuksen työprojektien kehittämiseksi tutkimuksessa esitetään toimintaperiaatteet projektinhallintaohjelmistojen käyttöönotolle.

A multi-objective genetic algorithm optimisation using variable speed pumps in water distribution systems

Due to its practical importance and inherent complexity, the optimisation of distribution networks for supplying drinking water has been the subject of extensive study for the past 30 years. The optimization is governed by sizing the pipes in the water distribution network (WDN) and / or optimises specific parts of the network such as pumps, tanks etc. or try to analyse and optimise the reliability of a WDN. In this thesis, the author has analysed two different WDNs (Anytown City and Cabrera city networks), trying to solve and optimise a multi-objective optimisation problem (MOOP). The main two objectives in both cases were the minimisation of Energy Cost (€) or Energy consumption (kWh), along with the total Number of pump switches (TNps) during a day. For this purpose, a decision support system generator for Multi-objective optimisation used. Its name is GANetXL and has been developed by the Center of Water System in the University of Exeter. GANetXL, works by calling the EPANET hydraulic solver, each time a hydraulic analysis has been fulfilled. The main algorithm used, was a second-generation algorithm for multi-objective optimisation called NSGA_II that gave us the Pareto fronts of each configuration. The first experiment that has been carried out was the network of Anytown city. It is a big network with a pump station of four fixed speed parallel pumps that are boosting the water dynamics. The main intervention was to change these pumps to new Variable speed driven pumps (VSDPs), by installing inverters capable to diverse their velocity during the day. Hence, it’s been achieved great Energy and cost savings along with minimisation in the number of pump switches. The results of the research are thoroughly illustrated in chapter 7, with comments and a variety of graphs and different configurations. The second experiment was about the network of Cabrera city. The smaller WDN had a unique FS pump in the system. The problem was the same as far as the optimisation process was concerned, thus, the minimisation of the energy consumption and in parallel the minimisation of TNps. The same optimisation tool has been used (GANetXL).The main scope was to carry out several and different experiments regarding a vast variety of configurations, using different pump (but this time keeping the FS mode), different tank levels, different pipe diameters and different emitters coefficient. All these different modes came up with a large number of results that were compared in the chapter 8. Concluding, it should be said that the optimisation of WDNs is a very interested field that has a vast space of options to deal with. This includes a large number of algorithms to choose from, different techniques and configurations to be made and different support system generators. The researcher has to be ready to “roam” between these choices, till a satisfactory result will convince him/her that has reached a good optimisation point.

Using Multi-Objective Optimization To Maximize Multiple Benefits For Sustainable Drainage Design

For many years, drainage design was mainly about providing sufficient network capacity. This traditional approach had been successful with the aid of computer software and technical guidance. However, the drainage design criteria had been evolving due to rapid population growth, urbanisation, climate change and increasing sustainability awareness. Sustainable drainage systems that bring benefits in addition to water management have been recommended as better alternatives to conventional pipes and storages. Although the concepts and good practice guidance had already been communicated to decision makers and public for years, network capacity still remains a key design focus in many circumstances while the additional benefits are generally considered secondary only. Yet, the picture is changing. The industry begins to realise that delivering multiple benefits should be given the top priority while the drainage service can be considered a secondary benefit instead. The shift in focus means the industry has to adapt to new design challenges. New guidance and computer software are needed to assist decision makers. For this purpose, we developed a new decision support system. The system consists of two main components – a multi-criteria evaluation framework for drainage systems and a multi-objective optimisation tool. Users can systematically quantify the performance, life-cycle costs and benefits of different drainage systems using the evaluation framework. The optimisation tool can assist users to determine combinations of design parameters such as the sizes, order and type of drainage components that maximise multiple benefits. In this paper, we will focus on the optimisation component of the decision support framework. The optimisation problem formation, parameters and general configuration will be discussed. We will also look at the sensitivity of individual variables and the benchmark results obtained using common multi-objective optimisation algorithms. The work described here is the output of an EngD project funded by EPSRC and XP Solutions.

Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MUSIASEM): an outline of rationale and theory

This paper presents an outline of rationale and theory of the MuSIASEM scheme (Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism). First, three points of the rationale behind our MuSIASEM scheme are discussed: (i) endosomatic and exosomatic metabolism in relation to Georgescu-Roegen’s flow-fund scheme; (2) the bioeconomic analogy of hypercycle and dissipative parts in ecosystems; (3) the dramatic reallocation of human time and land use patterns in various sectors of modern economy. Next, a flow-fund representation of the MUSIASEM scheme on three levels (the whole national level, the paid work sectors level, and the agricultural sector level) is illustrated to look at the structure of the human economy in relation to two primary factors: (i) human time - a fund; and (ii) exosomatic energy - a flow. The three levels representation uses extensive and intensive variables simultaneously. Key conceptual tools of the MuSIASEM scheme - mosaic effects and impredicative loop analysis - are explained using the three level flow-fund representation. Finally, we claim that the MuSIASEM scheme can be seen as a multi-purpose grammar useful to deal with sustainability issues.

Performance of a New One-step Multi-mode Adhesive on Etched vs Non-etched Enamel on Bond Strength and Interfacial Morphology

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Multi-step adhesive cementation versus one-step adhesive cementation: push-out bond strength between fiber post and root dentin before and after mechanical cycling

This study evaluated the effects of mechanical cycling on resin push-out bond strength to root dentin, using two strategies for fiber post cementation. Forty bovine roots were embedded in acrylic resin after root canal preparation using a custom drill of the fiber post system. The fiber posts were cemented into root canals using two different strategies (N = 20): a conventional adhesive approach using a three-step etch-and-rinse adhesive system combined with a conventional resin cement (ScotchBond Multi Purpose Plus + RelyX ARC ), or a simplified adhesive approach using a self-adhesive resin cement (RelyX U100). The core was built up with composite resin and half of the specimens from each cementation strategy were submitted to mechanical cycling (45 degree angle; 37 degrees C; 88 N; 4 Hz; 700,000 cycles). Each specimen was cross-sectioned and the disk specimens were pushed-out. The means from every group (n = 10) were statistically analyzed using a two-way ANOVA and a Tukey test (P = 0.05). The cementation strategy affected the push-out results (P < 0.001), while mechanical cycling did not (P = 0.3716). The simplified approach (a self-adhesive resin cement) had better bond performance despite the conditioning. The self-adhesive resin cement appears to be a good option for post cementation. Further trials are needed to confirm these results.

Adesivos multi-uso-avaliação da resistência adesiva a dentina frente a teste de cisalhamento, estereomicroscopia e microscopia eletrônica de varredura

Recent bonding systems have been advocated as multi-purpose bonding agents. The aim of this study was to determine if some of these bonding systems could be associated to composite resins from different manufacturers. This investigation was conducted to test lhe shear bond strength of three bonding systems: Scotchbond Multi-Purpose (3M Dental Products), Optibond Light Cure (Kerr) and Optibond Dual Cure (Kerr), when each of them was associated to lhe composite resins: Z1 00 (3M Dental Products), Prisma - APH (Dentsply) and Herculite XRV (Kerr). Seventy-two flat dentin bonding sites were prepared to 600 grit on human premolars mounted using acrilic resins. The teeth were assigned at random to 9 groups of 8 samples each. A split die with a 3mm diameter was placed over lhe surface of lhe dentin treated with one of lhe adhesive systems, and lhe selected composite resin was inserted and light cured. The split mold was removed and all samples were termocycled and stored in 37ºC water for 24 hours before testing. Shear bond strength was determined using an lnstron Universal testing machine. Some failures were examined under lhe S.E.M. Data was analysed by one-way analysis of variance, that demonstrated a significant difference (p<0,05) in the mean shear bond strength among Optibond Light Cure (15,446 MPa), Scotchbond Multi-Purpose (13,339 MPa) and Optibond Dual Cure (10,019 MPa). These values did not depend on the composite resin used. The association between bonding system/composite resin was statistycally significant (p<0,05) and the best results were obtained when the composite resins Z100 and Herculite were used with the adhesive system Optibond Light Cure, and when the composite resin APH was used with the adhesive system Scotchbond Multi-Purpose

Exposing market mechanism design trade-offs via multi-objective evolutionary search

Market mechanisms are a means by which resources in contention can be allocated between contending parties, both in human economies and those populated by software agents. Designing such mechanisms has traditionally been carried out by hand, and more recently by automation. Assessing these mechanisms typically involves them being evaluated with respect to multiple conflicting objectives, which can often be nonlinear, noisy, and expensive to compute. For typical performance objectives, it is known that designed mechanisms often fall short on being optimal across all objectives simultaneously. However, in all previous automated approaches, either only a single objective is considered, or else the multiple performance objectives are combined into a single objective. In this paper we do not aggregate objectives, instead considering a direct, novel application of multi-objective evolutionary algorithms (MOEAs) to the problem of automated mechanism design. This allows the automatic discovery of trade-offs that such objectives impose on mechanisms. We pose the problem of mechanism design, specifically for the class of linear redistribution mechanisms, as a naturally existing multi-objective optimisation problem. We apply a modified version of NSGA-II in order to design mechanisms within this class, given economically relevant objectives such as welfare and fairness. This application of NSGA-II exposes tradeoffs between objectives, revealing relationships between them that were otherwise unknown for this mechanism class. The understanding of the trade-off gained from the application of MOEAs can thus help practitioners with an insightful application of discovered mechanisms in their respective real/artificial markets.

Design of experiment in drug development: optimal allocations in multi-arm clinical trials and design space for multi-step processes

In this thesis, we deal with the design of experiments in the drug development process, focusing on the design of clinical trials for treatment comparisons (Part I) and the design of preclinical laboratory experiments for proteins development and manufacturing (Part II). In Part I we propose a multi-purpose design methodology for sequential clinical trials. We derived optimal allocations of patients to treatments for testing the efficacy of several experimental groups by also taking into account ethical considerations. We first consider exponential responses for survival trials and we then present a unified framework for heteroscedastic experimental groups that encompasses the general ANOVA set-up. The very good performance of the suggested optimal allocations, in terms of both inferential and ethical characteristics, are illustrated analytically and through several numerical examples, also performing comparisons with other designs proposed in the literature. Part II concerns the planning of experiments for processes composed of multiple steps in the context of preclinical drug development and manufacturing. Following the Quality by Design paradigm, the objective of the multi-step design strategy is the definition of the manufacturing design space of the whole process and, as we consider the interactions among the subsequent steps, our proposal ensures the quality and the safety of the final product, by enabling more flexibility and process robustness in the manufacturing.

Influence of different adhesive systems on the pull-out bond strength of glass fiber posts

This in vitro study evaluated the tensile bond strength of glass fiber posts (Reforpost - Angelus-Brazil) cemented to root dentin with a resin cement (RelyX ARC - 3M/ESPE) associated with two different adhesive systems (Adper Single Bond - 3M/ESPE and Adper Scotchbond Multi Purpose (MP) Plus - 3M/ESPE), using the pull-out test. Twenty single-rooted human teeth with standardized root canals were randomly assigned to 2 groups (n=10): G1- etching with 37% phosphoric acid gel (3M/ESPE) + Adper Single Bond + #1 post (Reforpost - Angelus) + four #1 accessory posts (Reforpin - Angelus) + resin cement; G2- etching with 37% phosphoric acid gel + Adper Scotchbond MP Plus + #1 post + four #1 accessory posts + resin cement. The specimens were stored in distilled water at 37°C for 7 days and submitted to the pull-out test in a universal testing machine (EMIC) at a crosshead speed of 0.5 mm/min. The mean values of bond strength (kgf) and standard deviation were: G1- 29.163 ± 7.123; G2- 37.752 ±13.054. Statistical analysis (Student's t-test; a=0.05 showed no statistically significant difference (p<0.05) between the groups. Adhesive bonding failures between resin cement and root canal dentin surface were observed in both groups, with non-polymerized resin cement in the apical portion of the post space when Single Bond was used (G1). The type of adhesive system employed on the fiber post cementation did not influence the pull-out bond strength.