Prognostic and predictive markers in colorectal cancer - The role of new genomic technologies

Colorectal cancer (CRC) is one of the most frequently occurring malignancies worldwide, and the second leading cause of cancer related death in the Western World. Although early stage disease is curable by surgical resection alone, one half of patients with CRC will present with metastatic disease at some stage in the course of their disease. The most active drug in the treatment of CRC is 5-fluorouracil (5-FU) which is used in both the adjuvant and advanced settings. The use of adjuvant therapy is of proven benefit in Stage III CRC, however, its role in Stage II disease is less clear. There is therefore a need to identify those patients with early stage disease who will develop recurrent disease, and who would therefore benefit most from adjuvant treatment. In the advanced setting, the use of irinotecan and oxaliplatin in combination with 5-FU has proven beneficial, with yet further improvements in survival reported with the addition of new targeted agents such as bevacizamab. Despite this, a significant number of patients with advanced disease do not derive any benefit from the chemotherapy they receive, highlighting a need for the development of molecular or genomic markers predictive of response to these chemotherapeutic agents. This review will evaluate the recent advances in pharmacogenomics in CRC, in particular the development of predictive markers of response to chemotherapy. The successful identification of these markers of response will herald an era of personalised treatment, reducing treatment-related toxicity and improving outcome of patients with CRC. -cr 2007 Bentham Science Publishers Ltd.

Expression of proteins associated with hypoxia and Wnt pathway activation is of prognostic significance in hepatocellular carcinoma

In the development and progression of hepatocellular carcinoma, tumor hypoxia plays an important role, as does activation of the Wnt pathway. The aim of this study was to characterize the expression and interrelationship between hypoxia and Wnt-pathway-associated proteins as prognostic factors for hepatocellular carcinoma. Expression of HIF-1α, CA-IX, E-cadherin, β-catenin, and Ki-67 was assessed by immunohistochemistry in 179 primary hepatocellular carcinoma cases. Univariate and multivariate analyses were performed to assess the relationship between the clinicopathological factors, protein expression, overall survival (OS), and recurrence-free survival (RFS). By univariate analysis, tumor stage, size, satellitosis, and vascular invasion were confirmed as prognostic factors for worse OS and RFS. High expression of HIF-1α, CA-IX, β-catenin, Ki-67, and E-cadherin was observed in 60, 15, 64, 8, and 64 % of tumors, respectively, and this was significantly associated with poor OS. CA-IX, HIF-1α, and E-cadherin were independent predictors of poor prognosis. We stratified 169 patients into four groups according to the expression level of hypoxia and Wnt pathway markers. The group with high expression of both hypoxia and Wnt-pathway-associated proteins showed worst OS. The poor survival of this group was also significant in patients with early stage disease and tumor size of less than 5 cm (p < 0.05). We identified a subgroup of hepatocellular carcinoma patients with high expression of both hypoxia and Wnt pathway proteins and found this predictive of poor survival. The therapeutic options for this group might need to be revisited.

Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer

The Colorectal Cancer (CRC) Subtyping Consortium (CRCSC) recently published four consensus molecular subtypes (CMS’s) representing the underlying biology in CRC. The Microsatellite Instable (MSI) immune group, CMS1, has a favorable prognosis in early stage disease, but paradoxically has the worst prognosis following relapse, suggesting the presence of factors enabling neoplastic cells to circumvent this immune response. To identify the genes influencing subsequent poor prognosis in CMS1, we analyzed this subtype, centered on risk of relapse.
In a cohort of early stage colon cancer (n=460), we examined, in silico, changes in gene expression within the CMS1 subtype and demonstrated for the first time the favorable prognostic value of chemokine-like factor (CKLF) gene expression in the adjuvant disease setting [HR=0.18, CI=0.04-0.89]. In addition, using transcription profiles originating from cell sorted CRC tumors, we delineated the source of CKLF transcription within the colorectal tumor microenvironment to the leukocyte component of these tumors. Further to this, we confirmed that CKLF gene expression is confined to distinct immune subsets in whole blood samples and primary cell lines, highlighting CKLF as a potential immune cell-derived factor promoting tumor immune-surveillance of nascent neoplastic cells, particularly in CMS1 tumors. Building on the recently reported CRCSC data, we provide compelling evidence that leukocyte-infiltrate derived CKLF expression is a candidate biomarker of favorable prognosis, specifically in MSI-immune stage II/III disease.

Embryonic and larval ecology and biochemistry of offshore decapods

Understanding the biology of offshore species is hardened by the difficulties of sampling in the deep-sea environment. Additionally, due to the vastness of the open ocean, knowledge of early life histories of pelagic larvae is still relatively scarce. In decapod species with bentho-pelagic lifestyle, the transition from life in the seafloor to the water column not only is associated with drastic morphological metamorphosis, but also with changes in behavior and feeding ecology. The purpose of the present thesis was to investigate physiological, biochemical and behavioral adaptation occurring during early development of such species. The Norway lobster, Nephrops norvegicus, and the crab Monodaeus couchi were used as a model as these two species are encountered off the NE Atlantic shelf at depth greater than 300 m. Chapter 1 introduces the challenges faced by both adult and larvae inhabiting such remote habitats, including the effect of food availability on development and oceanographic processes on dispersal and recruitment. The thesis follows early life histories, starting with within-brood variability in the fatty acid (FA) profile displayed by developing N. norvegicus embryos. There were no differences in the FA composition of embryos sampled from both sides of the brooding chamber in most females. However, all females exhibited significant differences in the FA profiles of embryos sampled from different pleopods. Potential causes for the variations recorded may be differential female investment during oocyte production or shifts in FA catabolism during the incubation period promoted by embryo’s location within the brooding chamber. Next, feeding rates and digestive enzymes activity of the early stage larvae was investigated in N. norvegicus. Both stages were able to maximize food intake when larvae were scarce and showed increased feeding rate following periods of starvation. Amylase activity indicated that carbohydrates are not the primary energy reserve and that feeding may be required soon after hatching to trigger amylase activity. Protease activity indicated that protein reserves are catabolized under starvation. These results indicate that larvae may maximize prey ingestion in the presence of plankton patches with higher food abundance and minimize the deleterious effects induced by previous periods of intermittent starvation or unsuitable prey densities/types. Additionally, changes in enzymatic activity may allow newly hatched N. norvegicus larvae to metabolize protein reserves to overcome short-term starvation. Vertical migration behavior and the influence of oceanographic properties were studied next. All zoeal stages of M. couchi displayed reverse diel vertical migration. Abundance of early stages was correlated with chlorophyll a levels. An ontogenic shift in vertical distribution explained the results; earlier zoeal stages remain in the food-rich upper water column while later stages migrate to the bottom for settlement. This vertical migration behavior is likely to affect horizontal distribution of larvae. Indeed, global current patterns will result in low inter-annual variations in decapod larvae recruitment, but short term variations such as upwelling events will cause deviation from the expected dispersal pattern. Throughout development, from the embryo to metamorphosis into benthic juvenile, offshore decapods face many challenges. For the developing individual survivorship will depend heavily on food availability but also on the reserves passed on by the mother. Even though vertical migration behavior can allow the larvae to take advantage of depth varying currents for transport, the effect of general circulation pattern will superimpose local current and influence feeding conditions and affect dispersal and recruitment.

Caracterização e modificação de heteroestruturas de nitretos do grupo III

Os nitretos binários semicondutores do grupo III, e respetivos compostos, são vastamente estudados devido à sua possível aplicabilidade em dispositivos optoeletrónicos, tais como díodos emissores de luz (LEDs) e LASERs, assim como dispositivos para a eletrónica de elevadas temperatura, potência e frequência. Enquanto se concretizou a comercialização na última década de LEDs e LASERs recorrendo ao ternário In1-yGayN, estudos das propriedades fundamentais estruturais e óticas, assim como de técnicas de processamento no desenvolvimento de novas aplicações de outros ternários do grupo III-N encontram-se na sua fase inicial. Esta tese apresenta a investigação experimental de filmes finos epitaxiais de Al1-xInxN crescidos sobre camadas tampão de GaN e de Al1-yGayN e o estudo do recozimento e implantação de super-redes (SL) compostas por pontos quânticos de GaN (QD) envolvidos por camadas de AlN. Apesar do hiato energético do Al1-xInxN poder variar entre os 0,7 eV e os 6,2 eV e, por isso, numa gama, consideravelmente superior à dos ternários Al1-yGayN e InyGa1-yN, o primeiro é o menos estudado devido a dificuldades no crescimento de filmes com elevada qualidade cristalina. É efetuada, nesta tese, uma caracterização estrutural e composicional de filmes finos de Al1-xInxN crescidos sobre camadas tampão de GaN e de Al1-yGayN usando técnicas de raios-X, feixe de iões e de microscopia. Mostra-se que o Al1-xInxN pode ser crescido com elevada qualidade cristalina quando a epitaxia do crescimento se aproxima da condição de rede combinada do Al1-xInxN e da camada tampão (GaN ou Al1-yGayN), isto é, com conteúdo de InN de ~18%, quando crescido sobre uma camada de GaN. Quando o conteúdo de InN é inferior/superior à condição de rede combinada, fenómenos de relaxação de tensão e deterioração do cristal tais como o aumento da rugosidade de superfície prejudicam a qualidade cristalina do filme de Al1-xInxN. Observou-se que a qualidade dos filmes de Al1-xInxN depende fortemente da qualidade cristalina da camada tampão e, em particular, da sua morfologia e densidade de deslocações. Verificou-se que, dentro da exatidão experimental, os parâmetros de rede do ternário seguem a lei empírica de Vegard, ou seja, variam linearmente com o conteúdo de InN. Contudo, em algumas amostras, a composição determinada via espetrometria de retrodispersão de Rutherford e difração e raios-X mostra valores discrepantes. Esta discrepância pode ser atribuída a defeitos ou impurezas capazes de alterar os parâmetros de rede do ternário. No que diz respeito às SL dos QD e camadas de AlN, estudos de recozimento mostraram elevada estabilidade térmica dos QD de GaN quando estes se encontram inseridos numa matriz de AlN. Por implantação iónica, incorporou-se európio nestas estruturas e, promoveu-se a ativação ótica dos iões de Eu3+ através de tratamentos térmicos. Foram investigados os efeitos da intermistura e da relaxação da tensão ocorridos durante o recozimento e implantação nas propriedades estruturais e óticas. Verificou-se que para fluências elevadas os defeitos gerados por implantação são de difícil remoção. Contudo, a implantação com baixa fluência de Eu, seguida de tratamento térmico, promove uma elevada eficiência e estabilidade térmica da emissão vermelha do ião lantanídeo incorporado nos QD de GaN. Estes resultados são, particularmente relevantes, pois, na região espetral indicada, a eficiência quântica dos LEDs convencionais de InGaN é baixa.

Tourism in Timor Leste: contributions to a sustainable development

The main goal of this thesis is to analyse tourism as a contributor to sustainable development, from a supply and demand perspective, in Timor-Leste, a destination not only “young” but also framed in an early stage of touristic development. From the supply side, studies 1 and 2 present a literature review on the concept of sustainable development, in small islands destinations, its weaknesses and vulnerabilities, and whose attractiveness lies in an integrated set of natural resources (attractive beaches, biodiversity, the coral triangle, a rich fauna and flora), its geographic location, tropical climate, socio cultural tradition and a Luso-Timorense cultural mix, that can meet the needs of important segments of the tourist demand. In these studies, the focus is on the residents’ attitudes in relation to sustainable development and, in particular, on the perceptions of local leaders about the importance of the operationalization of the concept. As Timor-Leste is a “young” destination, it is travel industry is still faced with several problems in order to be able to satisfy the demand and to meet the tourists’ motivations, preferences and requirements. In this perspective, the study 3 examines diaspora tourism, while a niche market, allowing for not only the entry of Timor-Leste in the international tourism market, but also an articulation between the people of Timor-Leste in the diasporas and the development of sustainable tourism . In general, the results show that the development of sustainable tourism cannot be successfully implemented without the involvement of all stakeholders such as residents, public sector (local government, policy makers, planners), private sector (tourism operators), and non-governmental organizations (NGOs) that include civil society, religious institutions, the academic community (the supply side), and Timorese diasporas tourists as consumers (the demand side).

Nuclear and mitochondrial control of the apoptosis machinery regulates neural stem cell fate

Tese de doutoramento, Farmácia (Bioquímica), Universidade de Lisboa, Faculdade de Farmácia, 2014

Identification of the cellular and molecular mechanism by which CD2AP, a regulator of neuronal intracellular transport contributes to the development of Alzheimer’s disease

Tese de mestrado. Biologia (Biologia Molecular e Genética). Universidade de Lisboa, Faculdade de Ciências,2014

Research into the Impact of School Leadership on Pupil Outcomes: Policy and Research Contexts

This paper extends the introduction to the authors’ study of successful school leadership and how it influences pupil outcomes begun in the Editorial introduction. Critical to an appreciation especially of the external validity of their results is an understanding of the policy context in which the English leaders in their study found themselves; this is a policy context dominated by concerns for external accountability and increases in the academic performance of pupils. In addition to describing this context, the paper summarises the conceptual and methodological framework that guided the early stage of their research and outlines their mixed-methods research design.

e-poltergeist

E-poltergeist takes over the user’s internet browser, automatically initiating Web searches without their permission. Web-based artwork which explores issues of user control when confronted with complex technological systems, questioning the limits of digital interactive arts as consensual reciprocal systems. e-poltergeist was a major web commission that marked an early stage of research in a larger enquiry by Craighead and Thomson into the relationship between live virtual data, global communications networks and instruction-based art, exploring how such systems can be re-contextualised within gallery environments. e-poltergeist presented the 'viewer' with a singular narrative by using live internet search-engine data that aimed to create a perpetual and virtually unstoppable cycle of search engine results, banner ads and moving windows as an interruption into the normal use of an internet browser. The work also addressed the ‘de-personalisation’ of internet use by sending a series of messages from the live search engine data that seemed to address the user directly: 'Is anyone there?'; 'Can anyone hear me?', 'Please help me!'; 'Nobody cares!' e-poltergeist makes a significant contribution to the taxonomy of new media art by dealing with the way that new media art can re-address notions of existing traditions in art such as appropriation and manipulation, instruction-based art and conceptual art. e-poltergeist was commissioned ($12,000) for 010101: Art in Technological Times, a landmark international exhibition presented by the San Francisco Museum of Modern Art, which bought together leading international practitioners working with emergent technologies, including Tatsuo Miyajima, Janet Cardiff, Brian Eno. Peer recognition of the project in the form of reviews include: Curating New Media. Gateshead: Baltic Centre for Contemporary Art. Cook, Sarah, Beryl Graham and Sarah Martin ISBN: 1093655064; The Wire; http://www.wired.com/culture/lifestyle/news/2000/12/40464 (review by Reena Jana); Leonardo (review Barbara Lee Williams and Sonya Rapoport) http://www.leonardo.info/reviews/feb2001/ex_010101_willrapop.html All the work is developed jointly and equally between Craighead and her collaborator, Jon Thomson, Slade School of Fine Art.

Governing through community? A comparative study of changing management practices in mixed tenure housing development

An important feature of UK housing policy has been the promotion of consortia between local authorities, private developers and housing associations in order to develop mixed tenure estates to meet a wide range of housing needs. Central to this approach has been a focus on the management of neighbourhoods, based on the assumption that high densities and the inter-mixing of tenure exacerbates the potential for incivility and anti-social behaviour and exerts a disproportionate impact on residents' quality of life. Landlord strategies are therefore based on a need to address such issues at an early stage in the development. In some cases community-based, third sector organisations are established in order to manage community assets and to provide a community development service to residents. In others, a common response is to appoint caretakers and wardens to tackle social and environmental problems before they escalate and undermine residents’ quality of life. A number of innovative developments have promoted such neighbourhood governance approaches to housing practice by applying community development methods to address potential management problems. In the process, there is an increasing trend towards strategies that shape behaviour, govern ethical conduct, promote aesthetic standards and determine resident and landlord expectations. These processes can be related to the wider concept of governmentality whereby residents are encouraged to become actively engaged in managing their own environments, based on the assumption that this produces more cohesive, integrated communities and projects positive images. Evidence is emerging from a number of countries that increasingly integrated and mutually supportive roles and relationships between public, private and third sector agencies are transforming neighbourhood governance in similar ways. This paper will review the evidence for this trend towards community governance in mixed housing developments by drawing on a series of UK case studies prepared for two national agencies in 2007. It will review in particular the contractual arrangements with different tenures, identify codes and guidelines promoting 'good neighbour' behaviour and discuss the role of community development trusts and other neighbourhood organisations in providing facilities and services, designed to generate a well integrated community. The second part of the paper will review evidence from the USA and Australia to see how far there is a convergence in this respect in advanced economies. The paper will conclude by discussing the extent to which housing management practice is changing, particularly in areas of mixed development, whether there is a convergence in practice between different countries and how far these trends are supported by theories of governmentality.

Networked learning ten years on: the rise of the virtual graduate school

The aim of this paper is to reflect on how conceptions of networked learning have changed, particularly in relation to educational practices and uses of technology, that can nurture new ideas of networked learning to sustain multiple and diverse communities of practice in institutional settings. Our work is framed using two theoretical frameworks: Giddens's (1984) structuration theory and Callon & Latour's (1981) Actor Network Theory as critiqued by Fox (2005) in relation to networked learning. We use these frameworks to analyse and critique ideas of networked learning embodied in both cases. We investigate three questions: (a) the role of individual agency in the development of networked learning; (b) the impact of technological developments on approaches to supporting students within institutional infrastructures; and (c) designing networked learning to incorporate Web 2.0 practices that sustain multiple communities and foster engagement with knowledge in new ways. We use an interpretivist approach by drawing on experiential knowledge of the Masters programme in Networked Collaborative Learning and the decision making process of designing the virtual graduate schools. At this early stage, we have limited empirical data related to the student experience of networked learning in current and earlier projects. Our findings indicate that the use of two different theoretical frameworks provided an essential tool in illuminating, situating and informing the process of designing networked learning that involves supporting multiple and diverse communities of practice in institutional settings. These theoretical frameworks have also helped us to analyze our existing projects as case studies and to problematize and begin to understand the challenges we face in facilitating the participation of research students in networked learning communities of practice and the barriers to that participation. We have also found that this process of theorizing has given us a way of reconceptualizing communities of practice within research settings that have the potential to lead to new ideas of networked learning.

E-learners’ experiences of time

This paper explores the experiences of e-learners participating in continuing professional development programmes in three UK universities. Data was collected using questionnaires, discussion group postings and informal telephone interviews. These were analysed using two approaches to content analysis: a coding scheme and metaphors. Findings indicated that: e-learners reconstruct their approaches to time management at an early stage in their programme; the e-learners developed different time management strategies (planned, opportunistic, planned/opportunistic); and metaphors illustrated their underlying experiences of time. These provide the basis of recommendations for e-tutors. Finally, the paper explores methodological issues and outlines some implications for practice.

Diagnóstico de avarias em motores elétricos

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Mecânica

Estratégias e internacionalização na manutenção e produção

Trabalho Final de Mestrado para obtenção do grau de Mestre em Engenharia Mecânica