Risk management of new product development process

Dissertation submitted to Faculdade de Ciências e Tecnologia of Universidade Nova de Lisboa for the achievement of Integrated Master´s degree in Industrial Management Engineering

Bone anabolic potential of soy isoflavones and plant extracts and genomic changes during differentiation of hPOB-tert osteoblast-like cells

Summary For the nutritional management of bone health and the prevention of osteoporosis it is important to identify nutrients that positively influence the bone remodeling process at the cellular level. Soy isoflavones show promising osteoprotective effects in animals and humans but their mechanism of action in bone cells is yet poorly understood. Firstly, soy tissue cultures were characterized as a new and optimized source of isoflavones. A large variability in the isoflavone content was observed and high-producing strains (46.3 mg/g dry wt isoflavones) were identified. In the Ishikawa cells bioassay, the estrogenicity of isoflavones was confirmed to be 1000 to 10000 less than 17Mestradiol and that of the malonyl forms was shown for the first time (EC50 of 350 nM and 1880 nM for malonylgenistin and malonyldaidzin, respectively). The estrogenic activity of soya tissue culture extracts correlated to their isoflavone content. Secondly, the effects of phytonutrients on BMP-2 gene expression and on the mevalonate synthesis pathway, as key mediators of bone formation, were investigated. Dietary achievable concentrations of genistein and daidzein (10vM), and statins (4xM) but not 17M estradiol (10nM), induced BMP-2 gene expression (by up to 3-fold) and inhibited the cholesterol biosynthetic pathway (by up to 50%) in the human osteoblastic cell line hP0B¬tert. In addition, several plant extracts (Cyperus rotundus, Lindera benzoin and Cnidium monnieri) induced BMP-2 gene expression but this induction was not restricted to the inhibition of the cholesterol synthesis pathway neither to the estrogenicity. Finally, the gene expression profiles during hP0B-tert differentiation induced by vitamin D and dexamethasone were analyzed with the Affymetrix human GeneChip. 1665 different genes and 98 ESTs were significantly regulated. The expression profiles of bone-related genes was largely in agreement with previously documented patterns, supporting the physiological relevance of the genomic results and the hP0B-tert cell line as a valid model of human osteoblast differentiation. The expression of alternative differentiation markers during the osteogenic treatment of hP0B-tert cells indicated that the adipocyte and myoblast differentiation pathways were repressed, confirming that these culture conditions allowed only osteoblast differentiation. The gene ontology analysis identified further sub-groups of genes that may be involved in the bone formation process. Aims of the thesis In order to define new strategies for the nutritional management of bone health and for the prevention of osteoporosis the major goal of the present work was to investigate the potential of phytonutrients to positively modulate the bone formation process at the cellular level and, in particular: 1.To select and optimise alternative plant sources containing high levels of isoflavones with estrogenic activity (Chapter 3). 2.To compare the effects of statins and phytonutrients on BMP-2 gene expression and on the mevalonate synthesis pathway and to select new plant extracts with a bone anabolic potential (Chapter 4). 3.To further characterize the new human periosteal cell line, hP0B-tert, as a bone- formation model, by elucidating its gene expression profile during differentiation induced by vitamin D and dexamethasone (Chapter 5).

Management of nanomaterials safety in research environment

Despite numerous discussions, workshops, reviews and reports about responsible development of nanotechnology, information describing health and environmental risk of engineered nanoparticles or nanomaterials is severely lacking and thus insufficient for completing rigorous risk assessment on their use. However, since preliminary scientific evaluations indicate that there are reasonable suspicions that activities involving nanomaterials might have damaging effects on human health; the precautionary principle must be applied. Public and private institutions as well as industries have the duty to adopt preventive and protective measures proportionate to the risk intensity and the desired level of protection. In this work, we present a practical, 'user-friendly' procedure for a university-wide safety and health management of nanomaterials, developed as a multi-stakeholder effort (government, accident insurance, researchers and experts for occupational safety and health). The process starts using a schematic decision tree that allows classifying the nano laboratory into three hazard classes similar to a control banding approach (from Nano 3 - highest hazard to Nano1 - lowest hazard). Classifying laboratories into risk classes would require considering actual or potential exposure to the nanomaterial as well as statistical data on health effects of exposure. Due to the fact that these data (as well as exposure limits for each individual material) are not available, risk classes could not be determined. For each hazard level we then provide a list of required risk mitigation measures (technical, organizational and personal). The target 'users' of this safety and health methodology are researchers and safety officers. They can rapidly access the precautionary hazard class of their activities and the corresponding adequate safety and health measures. We succeed in convincing scientist dealing with nano-activities that adequate safety measures and management are promoting innovation and discoveries by ensuring them a safe environment even in the case of very novel products. The proposed measures are not considered as constraints but as a support to their research. This methodology is being implemented at the Ecole Polytechnique de Lausanne in over 100 research labs dealing with nanomaterials. It is our opinion that it would be useful to other research and academia institutions as well. [Authors]

Prise en charge des facteurs de risque des maladies cardiovasculaires: qu'est-ce qui a vraiment changé en 15 ans [Management of cardiovascular diseases in adults from 1999 to 2014: what has really changed?].

Every year, a considerable number of clinical guidelines for the management of cardiovascular risk factors are issued. It may give the idea that this area is constantly evolving with regular changes for ambulatory clinical practice, including family medicine. Sometimes important differences between the various recommendations are observed. This led us to wonder about the evolution of recommendations for the management of diabetes, dyslipidemia and high blood pressure over time. This article presents a historical review of US and European recommendations between 1999 and 2014 to highlight what has actually changed.

Enhancement of viability of radiosensitive (PBMC) and resistant (MDA-MB-231) clones in low-dose-rate cobalt-60 radiation therapy

AbstractObjective:In the present study, the authors investigated the in vitrobehavior of radio-resistant breast adenocarcinoma (MDA-MB-231) cells line and radiosensitive peripheral blood mononuclear cells (PBMC), as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy.Materials and Methods:The cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min–1 and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed.Results:Radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB- 231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48–72 hours post-radiation.Conclusion:Low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer.

Urban retrofitting: identifying disruptive and sustaining technologies using performative and foresight techniques

Cities, which are now inhabited by a majority of the world's population, are not only an important source of global environmental and resource depletion problems, but can also act as important centres of technological innovation and social learning in the continuing quest for a low carbon future. Planning and managing large-scale transitions in cities to deal with these pressures require an understanding of urban retrofitting at city scale. In this context performative techniques (such as backcasting and roadmapping) can provide valuable tools for helping cities develop a strategic view of the future. However, it is also important to identify ‘disruptive’ and ‘sustaining’ technologies which may contribute to city-based sustainability transitions. This paper presents research findings from the EPSRC Retrofit 2050 project, and explores the relationship between technology roadmaps and transition theory literature, highlighting the research gaps at urban/city level. The paper develops a research methodology to describe the development of three guiding visions for city-regional retrofit futures, and identifies key sustaining and disruptive technologies at city scale within these visions using foresight (horizon scanning) techniques. The implications of the research for city-based transition studies and related methodologies are discussed.

Diet and herding strategies in a changing environment: stable isotope analysis of Bronze Age and Late Antique skeletal remains from Ya'amūn, Jordan

Carbon and nitrogen stable isotope ratios of 45 human and 23 faunal bone collagen samples were measured to study human diet and the management of domestic herbivores in past Jordan, contrasting skeletal remains from the Middle and Late Bronze Age and the Late Roman and Byzantine periods from the site of Ya'amūn near Irbid. The isotope data demonstrate that the management of the sheep and goats changed over time, with the earlier animals consuming more plants from semi-arid habitats, possibly because of transhumant herding strategies. The isotope data for fish presented here are the first from archaeological contexts from the Southern Levant. Although fish of diverse provenance was available at the site, human diet was predominately based on terrestrial resources and there was little dietary variability within each time-period. Isotopic variation between humans from different time-periods can mostly be explained by ‘baseline shifts’ in the available food sources; however, it is suggested that legumes may have played a more significant role in Middle and Late Bronze Age diet than later on.

The impact of European legislative and technology measures to reduce air pollutants on air quality, human health and climate

European air quality legislation has reduced emissions of air pollutants across Europe since the 1970s, affecting air quality, human health and regional climate. We used a coupled composition-climate model to simulate the impacts of European air quality legislation and technology measures implemented between 1970 and 2010. We contrast simulations using two emission scenarios; one with actual emissions in 2010 and the other with emissions that would have occurred in 2010 in the absence of technological improvements and end-of-pipe treatment measures in the energy, industrial and road transport sectors. European emissions of sulphur dioxide, black carbon (BC) and organic carbon in 2010 are 53%, 59% and 32% lower respectively compared to emissions that would have occurred in 2010 in the absence of legislative and technology measures. These emission reductions decreased simulated European annual mean concentrations of fine particulate matter(PM2.5) by 35%, sulphate by 44%, BC by 56% and particulate organic matter by 23%. The reduction in PM2.5 concentrations is calculated to have prevented 80 000 (37 000–116 000, at 95% confidence intervals) premature deaths annually across the European Union, resulting in a perceived financial benefit to society of US$232 billion annually (1.4% of 2010 EU GDP). The reduction in aerosol concentrations due to legislative and technology measures caused a positive change in the aerosol radiative effect at the top of atmosphere, reduced atmospheric absorption and also increased the amount of solar radiation incident at the surface over Europe. We used an energy budget approximation to estimate that these changes in the radiative balance have increased European annual mean surface temperatures and precipitation by 0.45 ± 0.11 °C and by 13 ± 0.8 mm yr−1 respectively. Our results show that the implementation of European legislation and technological improvements to reduce the emission of air pollutants has improved air quality and human health over Europe, as well as having an unintended impact on the regional radiative balance and climate.

A Law and Economics Analysis of Trade Secrets: Optimal Scope of Law, Misappropriation and Alternative Damages Regimes

This thesis is primarily based on three core chapters, focused on the fundamental issues of trade secrets law. The goal of this thesis is to come up with policy recommendations to improve legal structure governing trade secrets. The focal points of this research are the following. What is the optimal scope of trade secrets law? How does it depend on the market characteristics such as degree of product differentiation between competing products? What factors need to be considered to balance the contradicting objectives of promoting innovation and knowledge diffusion? The second strand of this research focuses on the desirability of lost profits or unjust enrichment damage regimes in case of misappropriation of a trade secret. A comparison between these regimes is made and simple policy implications are extracted from the analysis. The last part of this research is an empirical analysis of a possible relationship between trade secrets sharing and misappropriation instances faced by firms.

Guidance and counseling in Latin America : General considerations about the criteria of coherence, cooperation and quality

La Orientación en América Latina, como campo de formación profesional y en comparación con Europa y Estados Unidos, es una actividad de reciente aceptación en los medios académicos. La misma se ha caracterizado por una constante evolución en su afán de adaptarse a los nuevos cambios y transformaciones sociales, políticas y económicas que se suceden en el continente latinoamericano. En esta ponencia se presenta un panorama general acerca de la Orientación en América Latina. Las principales consideraciones formuladas se relacionan con cuatro dimensiones: a) la dimensión política pública, donde se presentan la situación actual y las propuestas al respecto; b) la dimensión contextual que hace referencia a la formación del orientador y los diferentes escenarios de acción; c) la dimensión organizacional que se relaciona con la provisión de este servicio, y d) la dimensión metodológica donde se desarrollan los principales aspectos relacionados con la práctica de la Orientación.

Guidance and counseling in Latin America : General considerations about the criteria of coherence, cooperation and quality

La Orientación en América Latina, como campo de formación profesional y en comparación con Europa y Estados Unidos, es una actividad de reciente aceptación en los medios académicos. La misma se ha caracterizado por una constante evolución en su afán de adaptarse a los nuevos cambios y transformaciones sociales, políticas y económicas que se suceden en el continente latinoamericano. En esta ponencia se presenta un panorama general acerca de la Orientación en América Latina. Las principales consideraciones formuladas se relacionan con cuatro dimensiones: a) la dimensión política pública, donde se presentan la situación actual y las propuestas al respecto; b) la dimensión contextual que hace referencia a la formación del orientador y los diferentes escenarios de acción; c) la dimensión organizacional que se relaciona con la provisión de este servicio, y d) la dimensión metodológica donde se desarrollan los principales aspectos relacionados con la práctica de la Orientación.

Guidance and counseling in Latin America : General considerations about the criteria of coherence, cooperation and quality

La Orientación en América Latina, como campo de formación profesional y en comparación con Europa y Estados Unidos, es una actividad de reciente aceptación en los medios académicos. La misma se ha caracterizado por una constante evolución en su afán de adaptarse a los nuevos cambios y transformaciones sociales, políticas y económicas que se suceden en el continente latinoamericano. En esta ponencia se presenta un panorama general acerca de la Orientación en América Latina. Las principales consideraciones formuladas se relacionan con cuatro dimensiones: a) la dimensión política pública, donde se presentan la situación actual y las propuestas al respecto; b) la dimensión contextual que hace referencia a la formación del orientador y los diferentes escenarios de acción; c) la dimensión organizacional que se relaciona con la provisión de este servicio, y d) la dimensión metodológica donde se desarrollan los principales aspectos relacionados con la práctica de la Orientación.

Selection of species and provenances for low-rainfall areas: physiological responses of Eucalyptus cloeziana and Eucalyptus argophloia to seasonal conditions in subtropical Queensland

Responses of stomatal conductance (g(s)) and net photosynthesis (A) to changes in soil water availability, photosynthetic photon flux density (Q), air temperature (1) and leaf-to-air vapour pressure deficit (D) were investigated in 4-year-old trees of a dry inland provenance of Eucalyptus argophloia Blakely, and two dry inland provenances (Coominglah and Hungry Hills) and a humid coastal provenance (Wolvi) of Eucalyptus cloeziana F. Muell. between April 2001 and April 2002 in southeast Queensland, Australia. There were minimal differences in A, g, and water relations variables among the coastal and inland provenances of E. cloeziana but large differences between E. argophloia and E. cloeziana. E. argophloia and to a lesser extent the Hungry Hills (inland) provenance of E. cloeziana maintained relatively higher pre-dawn water potential (psi(pd)) during the dry season suggesting possible access to water at depth. Simple phenomenological models of stomatal conductance as a function of Q, T and D explained 60% of variation in gs in E. cloeziana and more than 75% in E. argophloia, when seasonal effect was incorporated in the model. A Ball-Berry model for net photosynthesis explained between 70 and 80% of observed variation in A in both species. These results have implications in matching the dry and humid provenances of E. cloeziana and E. argophloia to suitable sites in subtropical environments. (C) 2004 Elsevier B.V. All rights reserved.

Water quality in the Great Barrier Reef region: responses of mangrove, seagrass and macroalgal communities

Marine plants colonise several interconnected ecosystems in the Great Barrier Reef region including tidal wetlands, seagrass meadows and coral reefs. Water quality in some coastal areas is declining from human activities. Losses of mangrove and other tidal wetland communities are mostly the result of reclamation for coastal development of estuaries, e.g. for residential use, port infrastructure or marina development, and result in river bank destabilisation, deterioration of water clarity and loss of key coastal marine habitat. Coastal seagrass meadows are characterized by small ephemeral species. They are disturbed by increased turbidity after extreme flood events, but generally recover. There is no evidence of an overall seagrass decline or expansion. High nutrient and substrate availability and low grazing pressure on nearshore reefs have lead to changed benthic communities with high macroalgal abundance. Conservation and management of GBR macrophytes and their ecosystems is hampered by scarce ecological knowledge across macrophyte community types. (c) 2004 Elsevier Ltd. All rights reserved.

Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant

Mutations in the ATM gene (mutated in ataxia telangiectasia) in both humans and mice predispose to lymphoid tumors. A defect in this gene also causes neurodegeneration in humans and a less severe neurological phenotype in mice. There is some evidence that oxidative stress contributes to these defects, suggesting that antioxidants could alleviate the phenotype. We demonstrate here that the antioxidant 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO) dramatically delays the onset of thymic lymphomas in Atm(-/-) mice which is not due to an enhancement of apoptosis by CTMIO. We also show that this compound corrects neurobehavioral deficits in these mice and reduces oxidative damage to Purkinje cells. The likely mechanism of action of CTMIO is due to a reduction in oxidative stress, which is protective against both the tumor progression and the development of neurological abnormalities. These data suggest that antioxidant therapy has considerable potential in the management of ataxia telangiectasia and possibly other neurodegenerative disorders where oxidative stress is implicated. (c) 2006 Elsevier Inc. All rights reserved.