Dose-response relationship in phase 1 clinical trials: a European Drug Development Network (EDDN) Collaboration Study

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.

Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).

Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD)

A pilot study to develop an assessment tool for sheep welfare after long journey transport

Sheep transport within Europe involves 9.5 million animals yearly, 63% of which travel over longjourneys (> 8 h). Livestock transport, particularly over long journeys, gives rise to concern about the welfare of transported animals. The European Commission stimulates the development of market-oriented animal welfare standards for all phases of livestock production, providing an alternative to the 'regulatory approach'. This study aimed to develop and test a new sheep welfare assessment protocol to be used following transport, irrespective of the journey purpose. The protocol included outcome (animal-based measures) and input variables (resource-based and management-based measures), being welfare-relevant aspects of both transport and unloading procedures. Weighted Cohen's Kappa and Heiss' Kappa index of agreement were calculated to evaluate the raters accuracy and the inter-observer reliability.Overall, good agreement levels were found. The protocol was tested on 40 commercial transports arriving at previously selected assembly centres and slaughterhouses in Italy and Greece. The protocol was found to be feasible when applied to commercial transports, allowing for a comprehensive and quick sheep welfare assessment during unloading, without impairing stockman work. Univariate analysis was carried out to evaluate associations between outcome and input variables. In this study, significant association between outcome measures and risk factors were identified when associated to unloading procedures but not to travel conditions. In collaboration with the relevant stakeholders, this protocol might be developed into a tool for routine checks for certification purposes and could provide direct feedback to all professionals involved in animal transportation on the weaknesses and strengths of their work.

The analysis of political will and its role in leadership: a study of portuguese mayors

This thesis analyses the concept of Political Will, suggests its operationalization and establishes a typological theory that provides the necessary support for the diverse strategies of action of a leader. It claims that political leadership styles articulate a choice of action that results from the Political Will of a leader, which is determined by his intention and his discerned possibilities to act. One main research question guided our research: How does a political leader select and change his leadership style? The most illustrative literature on political leadership is reviewed and the characteristics of democratic governance are analyzed. This is followed by an overview of the most noteworthy theories on the theme and a claim for the need of concept coherence, given the multiplicity of the existent standpoints. After that, we concentrate on leadership styles, with a focus on the local governance context. Human action and intentionality are addressed with particular attention, as well as the motivational drivers for action, in order to advance a conceptualization of Political Will through two dimensions: intention and possibility. This analysis led to a number of relevant propositions: (1) Political Will ‘exists’ when the agent has the intent and the possibility to act; (2) these two dimensions ‘translate’ simultaneously what the agent believes he must do and can do; (3) Intention and possibility reflect diverse but limited worldviews; (4) political leadership styles result from the agent’s Political Will; (5) different combinations of the expected and actual worldviews result in different leadership styles; and (6) political leadership styles can change accordingly to several strategies which allow conformity or reflect reaction to worldviews. We suggested the operationalization of the two dimensions of Political Will through the analytical tool of Grid-group Theory, which provided the identification of the heuristic devices that allowed further comprehension on the subjectivity of the agent’s choice. Four standard property spaces – representing four types of leadership styles – result from a preliminary approach to this process. Afterwards, and because these dimensions operate simultaneously, we advance on the analysis and suggest some plausible heuristical conflicts to happen and describe which consequences, strategies and type migrations are conceivable. An inclusive and more complete set of resulting property spaces renders fourteen different types of leadership styles and sixty different predictable causal paths that result from the expected migration strategies. Case-studies were conducted as plausibility probes designed to provide improvements to our theoretical claims and addressed the cases we selected for research purposes: Portuguese Mayors. The findings from five case studies are discussed and the probable impact and congruence of each with the theoretical claims are assessed. The communalities of the causal mechanisms related to the function of intention and possibility as the dimensions of Political Will and their role in explaining different leadership styles are, finally, addressed. To conclude, we advance some repercussions, mainly in the public policies field of research, and suggest a number of different and necessary paths for further work.

Study of the Cd complexation mechanism by glutathione in Rhizobium leguminosarum

A associação simbiótica de plantas leguminosas com bactérias do género Rhizobium é o maior e mais eficiente contribuinte de azoto fixado biologicamente (Somasegaran e Hoben, 1994; Zahran, 1999). No entanto, o constante aumento da poluição em solos agrícolas, nomeadamente a contaminação por metais devido à aplicação de fertilizantes e de lamas, está a tornar-se um problema ambiental cada vez mais preocupante (Alloway, 1995a; Giller et al., 1998; Permina et al., 2006; Thorsen et al., 2009; Wani et al., 2008), influenciando de forma negativa a persistência destas bactérias nos solos agrícolas, assim como a sua eficácia de nodulação (Broos et al., 2005; Wani et al., 2008;. Zhengwei et al., 2005). Desta forma, o estudo dos mecanismos de tolerância de Rhizobium a metais tornou-se uma área de investigação de elevada importância. Com o trabalho apresentado nesta tese pretendeu-se perceber melhor a tolerância Rhizobium leguminosarum ao cádmio (Cd), dando particular atenção a um mecanismo de tolerância previamente descrito em R. leguminosarum (Lima et al., 2006): a complexação intracelular de Cd pelo tripéptido glutationa (GSH). Assim, o principal objectivo deste trabalho foi perceber melhor qual a importância deste mecanismo nos níveis de tolerância de rizóbio ao Cd. Como já tinha sido descrito em trabalhos anteriores (Figueira et al., 2005; Lima et al., 2006), foi possível verificar que a estirpe mais tolerante ao metal apresenta níveis mais elevados de Cd e GSH intracelulares. Demonstrou-se ainda que a tolerância ao Cd está dependente da maior eficiência no mecanismo de complexação observada na estirpe tolerante, logo durante as primeiras 12 h de crescimento. Gomes et al. (2002) verificou que a acumulação de complexos GSH-Cd no citoplasma inibe a entrada de metal na célula. Como neste trabalho se observou um aumento nos níveis de Cd intracelular na estirpe tolerante ao longo do tempo, surgiu a hipótese dos complexos serem excretados para o espaço periplasmático. Os elevados níveis de GSH e de Cd determinados no espaço periplasmático corroboraram esta hipótese. Neste trabalho demonstrou-se ainda que a eficácia do mecanismo de complexação, depende da actividade enzimática de uma isoforma específica de GST, que apresentou um elevado acréscimo de actividade na presença do metal. Desta forma, os resultados desta tese indicam que, a maior tolerância de R. leguminosarum ao Cd, depende da capacidade das estirpes para induzir a síntese de GSH na presença de Cd e, simultaneamente aumentar a actividade enzimática da GST específica, optimizando assim o mecanismo de complexação de Cd intracelular.

Effects of Prochlorperazine on Normal Vestibular Ocular and Perceptual Responses: A Randomised, Double-Blind, Crossover, Placebo-Controlled Study

Background: The present study investigated whether prochlorperazine affects vestibular-ocular reflex (VOR) and vestibulo-perceptual function. Methods: We studied 12 healthy naïve subjects 3 hours after a single dose of oral prochlorperazine 5mg in a randomised, placebo-controlled, double-blind, cross-over study in healthy young subjects. Two rotational tests in yaw were used: 1) a Threshold task investigating perceptual motion detection and nystagmic thresholds (acceleration steps of 0.5deg/s/s) and 2) Suprathreshold responses to velocity steps of 90deg/s in which vestibulo-ocular (VO) and vestibulo-perceptual (VP) time constants of decay, as well as VOR gain, were measured. Results: Prochlorperazine had no effect upon any measure of nystagmic or perceptual vestibular function compared to placebo. This lack of effects on vestibular-mediated motion perception suggests that the drug is likely to act more as an antiemetic than as an anti-vertiginous agent.

A pyrophosphate-responsive gadolinium(III) MRI contrast agent

This study shows that the relaxivity and optical properties of functionalised lanthanide-DTPA-bis-amide complexes (lanthanide=Gd3+ and Eu3+, DTPA=diethylene triamine pentaacetic acid) can be successfully modulated by addition of specific anions, without direct Ln3+/anion coordination. Zinc(II)-dipicolylamine moieties, which are known to bind strongly to phosphates, were introduced in the amide “arms” of these ligands, and the interaction of the resulting Gd–Zn2 complexes with a range of anions was screened by using indicator displacement assays (IDAs). Considerable selectivity for polyphosphorylated species (such as pyrophosphate and adenosine-5′-triphosphate (ATP)) over a range of other anions (including monophosphorylated anions) was apparent. In addition, we show that pyrophosphate modulates the relaxivity of the gadolinium(III) complex, this modulation being sufficiently large to be observed in imaging experiments. To establish the binding mode of the pyrophosphate and gain insight into the origin of the relaxometric modulation, a series of studies including UV/Vis and emission spectroscopy, luminescence lifetime measurements in H2O and D2O, 17O and 31P NMR spectroscopy and nuclear magnetic resonance dispersion (NMRD) studies were carried out.

Agent-Based Modeling of Deshopping Behaviour: A Single Shop Model with Multiple Deshoppers

Deshopping is rapidly turning into a modern day scourge for the retailers worldwide due to its prevalence and regularity. The presence of flexible return policies have made retail return management a real challenging issue for both the present and the future. In this study, we propose and develop a multi-agent simulation model for deshopper behavior in a single shop context. The background, theoretical underpinning, logical and computational model, experiment design and simulation results are reported and discussed in the paper.

A multi-agent based approach for intelligent smart grid management

The spread and globalization of distributed generation (DG) in recent years has should highly influence the changes that occur in Electricity Markets (EMs). DG has brought a large number of new players to take action in the EMs, therefore increasing the complexity of these markets. Simulation based on multi-agent systems appears as a good way of analyzing players’ behavior and interactions, especially in a coalition perspective, and the effects these players have on the markets. MASCEM – Multi-Agent System for Competitive Electricity Markets was created to permit the study of the market operation with several different players and market mechanisms. MASGriP – Multi-Agent Smart Grid Platform is being developed to facilitate the simulation of micro grid (MG) and smart grid (SG) concepts with multiple different scenarios. This paper presents an intelligent management method for MG and SG. The simulation of different methods of control provides an advantage in comparing different possible approaches to respond to market events. Players utilize electric vehicles’ batteries and participate in Demand Response (DR) contracts, taking advantage on the best opportunities brought by the use of all resources, to improve their actions in response to MG and/or SG requests.

Multi-agent electricity market simulation with dynamic strategies & virtual power producers

Distributed energy resources will provide a significant amount of the electricity generation and will be a normal profitable business. In the new decentralized grid, customers will be among the many decentralized players and may even help to co-produce the required energy services such as demand-side management and load shedding. So, they will gain the opportunity to be more active market players. The aggregation of DG plants gives place to a new concept: the Virtual Power Producer (VPP). VPPs can reinforce the importance of these generation technologies making them valuable in electricity markets. In this paper we propose the improvement of MASCEM, a multi-agent simulation tool to study negotiations in electricity spot markets based on different market mechanisms and behavior strategies, in order to take account of decentralized players such as VPP.

A new approach for multi-agent coalition formation and management in the scope of electricity markets

This paper presents a new methodology for the creation and management of coalitions in Electricity Markets. This approach is tested using the multi-agent market simulator MASCEM, taking advantage of its ability to provide the means to model and simulate VPP (Virtual Power Producers). VPPs are represented as coalitions of agents, with the capability of negotiating both in the market, and internally, with their members, in order to combine and manage their individual specific characteristics and goals, with the strategy and objectives of the VPP itself. The new features include the development of particular individual facilitators to manage the communications amongst the members of each coalition independently from the rest of the simulation, and also the mechanisms for the classification of the agents that are candidates to join the coalition. In addition, a global study on the results of the Iberian Electricity Market is performed, to compare and analyze different approaches for defining consistent and adequate strategies to integrate into the agents of MASCEM. This, combined with the application of learning and prediction techniques provide the agents with the ability to learn and adapt themselves, by adjusting their actions to the continued evolving states of the world they are playing in.

Multi-apprentice learning for meta-heuristics parameter tuning in a multi agent scheduling system

The scheduling problem is considered in complexity theory as a NP-hard combinatorial optimization problem. Meta-heuristics proved to be very useful in the resolution of this class of problems. However, these techniques require parameter tuning which is a very hard task to perform. A Case-based Reasoning module is proposed in order to solve the parameter tuning problem in a Multi-Agent Scheduling System. A computational study is performed in order to evaluate the proposed CBR module performance.

Re-use assessment of thermoset composite wastes as aggregate and filler replacement for concrete-polymer composite materials: a case study regarding GFRP pultrusion wastes

Glass fibre-reinforced plastics (GFRP), nowadays commonly used in the construction, transportation and automobile sectors, have been considered inherently difficult to recycle due to both the cross-linked nature of thermoset resins, which cannot be remoulded, and the complex composition of the composite itself, which includes glass fibres, polymer matrix and different types of inorganic fillers. Hence, to date, most of the thermoset based GFRP waste is being incinerated or landfilled leading to negative environmental impacts and additional costs to producers and suppliers. With an increasing awareness of environmental matters and the subsequent desire to save resources, recycling would convert an expensive waste disposal into a profitable reusable material. In this study, the effect of the incorporation of mechanically recycled GFRP pultrusion wastes on flexural and compressive behaviour of polyester polymer mortars (PM) was assessed. For this purpose, different contents of GFRP recyclates (0%, 4%, 8% and 12%, w/w), with distinct size grades (coarse fibrous mixture and fine powdered mixture), were incorporated into polyester PM as sand aggregates and filler replacements. The effect of the incorporation of a silane coupling agent was also assessed. Experimental results revealed that GFRP waste filled polymer mortars show improved mechanical behaviour over unmodified polyester based mortars, thus indicating the feasibility of GFRP waste reuse as raw material in concrete-polymer composites.

Implementação de uma marca de produção e distribuição de citrinos biológicos: Orange made in Algarve

Trabalho de projeto apresentado à Escola Superior de Comunicação Social como parte dos requisitos para obtenção de grau de mestre em Publicidade e Marketing.