Thomsen-Friedenreich antigens in bladder cancer: evaluation of their prognostic value

RESUMO: Introdução. O cancro de bexiga é uma patologia comum que representa o 6° e o 5° cancro mais incidente em Portugal e na Itália, respetivamente. Em mais de metade dos casos ocorre reincidência durante o primeiro ano, requerendo acompanhamento clínico ao longo da vida. A instilação intravesical de Bacillus Calmette-Guérin (BCG) (uma estirpe atenuada do Mycobacterium bovis) representa uma imunoterapia eficaz no combate ao cancro de bexiga, no entanto, muitos aspetos da interação de BCG com as células tumorais bem como com as células do sistema imunitário permanecem por desvendar. As células tumorais de bexiga expressam frequentemente as formas sialiladas dos antigénios de Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). Contudo ainda se desconhece o significado da sua expressão na malignidade tumoral e se afeta a eficácia da terapêutica BCG. Objetivo do estudo. Investigar o papel dos antigénios sT e sTn no fenótipo maligno de células de cancro de bexiga bem como na resposta mediada pelo sistema imunitário à terapia com BCG. Metodologia. Para tal, foram utilizadas as linhas celulares de cancro da bexiga HT1376 e MCR, geneticamente modificadas por transdução com vetores codificantes para as sialiltransferases ST3GAL1 ou ST6GALNAC1, de forma a expressar homogeneamente os antigénios sT ou sTn respetivamente. Estes modelos celulares foram estudados após confronto com BCG. O nível de BCG internalizado foi avaliado por citometria de fluxo. O perfil global de expressão genética dos modelos celulares antes e após incubação com BCG foi analisado pela tecnologia de microarray. O perfil de citocinas secretadas pelos modelos celulares após incubação com BCG, bem como de macrófagos estimulados pelo secretoma de células de cancro de bexiga que por sua vez foram estimuladas previamente por BCG, foi estudado pelo sistema multiplex de “imuno-esferas”. Resultados. A análise do transcritoma dos modelos celulares revelou que grupos de genes envolvidos em funções específicas foram modulados em paralelo nos dois modelos celulares, após transdução, independentemente da sialiltransferase expressa. Ou seja, em células que expressavam a sialiltransferase ST3GAL1 ou ST6GALNAC1, os genes envolvidos na regulação da segregação cromossómica e na reparação do DNA foram consistentemente regulados negativamente. Genes descritos na literatura como marcadores para o cancro de bexiga foram também modulados. A incubação com BCG resultou numa tendência ao aumento da expressão de genes relevantes na preservação e estabilidade genómica e menor malignidade, no entanto, apenas em células que expressavam sT ou sTn. Entre as dez citocinas testadas, apenas a IL-6 e IL-8 foram expressas pelas linhas celulares de cancro da bexiga, com indução destas após estimulação com BCG, e principalmente em células que expressavam ST3GAL1 ou ST6GALNAC1. Em macrófagos, citocinas inflamatórias, tais como IL-1β, IL-6 e TNFα, e a citocina anti-inflamatória IL-10, foram induzidas apenas pelo secretoma de células de cancro da bexiga confrontadas com BCG, com maior relevância quando estas expressavam ST3GAL1 ou ST6GALNAC1, prevendo a estimulação de macrófagos semelhantes aos de tipo M1 e uma melhor resposta à terapia com BCG. Conclusões. O efeito geral da expressão destas sialiltransferases e dos produtos enzimáticos sT ou sTn nas células de cancro de bexiga conduz a um fenótipo de maior malignidade. Contudo, a maior avidez de estas na produção de citocinas inflamatórias após confronto com BCG, bem como a maior capacidade de estimulação de macrófagos, predirá uma resposta à terapia com BCG mais eficaz em tumores que expressem os antigénios de TF sialilados. Tais conclusões são totalmente concordantes com os nossos mais recentes dados clínicos obtidos em colaboração, que mostram que em doentes com cancro de bexiga que expressam sTn respondem melhor a terapia BCG. ----------ABSTRACT: Background. Bladder cancer is a common malignancy representing the 6th and the 5th most incident cancer in Portugal and in Italy, respectively. More than half of the cases relapse within one year, requiring though a lifelong follow-up. Intravesical instillation of Bacillus Calmette-Guérin (BCG) (an attenuated strain of Mycobacterium bovis) represents an effective immunotherapy of bladder cancer, although many aspects of the interaction of BCG with cancer cells and host immune cells remain obscure. Bladder cancer cells often express the sialylated forms of the Thomsen-Friedenreich (TF), i.e., sialil-T (sT) e sialil-Tn (sTn). However, it’s still unknown the sense of such expression in tumour malignancy and in the BCG therapy efficacy. Aim of the study. To investigate the role of the sT and sTn antigens on the malignant phenotype of bladder cancer cells and the immune mediated response to BCG therapy. Experimental. We have utilized populations of the bladder cancer cell lines HT1376 and MCR, genetically modified by transduction with the sialyltransferases ST3GAL1 or ST6GALNAC1 to express homogeneously sT or sTn antigens. The level of BCG internalized was assessed by flow cytometry. The whole gene expression profile of BCG-challenged or unchallenged bladder cancer cell lines was studied by microarray technology. The profile of cytokines secreted by BCG-challenged bladder cancer cells and that of macrophages challenged by the secretome of BCG-challenged bladder cancer cells was studied by multiplex immune-beads assay. Results. Transcriptome analysis of the sialyltransferase-transduced cells revealed that groups of genes involved in specific functions were regulated in parallel in the two cell lines, regardless the sialyltransferase expressed. Namely, in sialyltransferase-expressing cells, genes involved in the proper chromosomal segregation and in the DNA repair were consistently down-regulated, while genes reported in literature as markers for bladder cancer were modulated. BCG-challenging induced a tendency to up-regulation of the genes preserving genomic stability and reducing malignancy, but only in cells expressing either sT or sTn. Among the ten cytokines tested, only IL-6 and IL-8 were expressed by bladder cancer cell lines and up-regulated by BCG-challenging, mainly in sialyltransferases-expressing cells. In macrophages, inflammatory cytokines, such as IL-1β, IL-6 and TNFα, and the antinflammatory IL-10 were induced only by the secretome of BCG-challenged bladder cancer cells, particularly when expressing either sialyltransferase, predicting the stimulation of M1-like macrophages and a better response to BCG therapy. Conclusions. The general effect of the expression of the two sialyltransferases and their products in the bladder cancer cells is toward a more malignant phenotype. However, the stronger ability of sialyltransferase expressing cells to produce inflammatory cytokines upon BCG-challenging and to stimulate macrophages predicts a more effective response to BCG in tumours expressing the sialylated TF antigens. This is fully consistent with our recent clinical data obtained in collaboration, showing that patients with bladder cancer expressing sTn respond better to BCG therapy.

Fair value measurement: Is the debate around level II and level III assets and liabilities relevant

Double Degree. A Work Project presented as part of the requirements for the Award of a Masters Degree in Finance from the NOVA- School of Business and Economics and a Masters Degree in Business Engineering from Louvain school of Management

Modeling and forecasting value-at-risk for the Portuguese stock market

The aim of this work project is to find a model that is able to accurately forecast the daily Value-at-Risk for PSI-20 Index, independently of the market conditions, in order to expand empirical literature for the Portuguese stock market. Hence, two subsamples, representing more and less volatile periods, were modeled through unconditional and conditional volatility models (because it is what drives returns). All models were evaluated through Kupiec’s and Christoffersen’s tests, by comparing forecasts with actual results. Using an out-of-sample of 204 observations, it was found that a GARCH(1,1) is an accurate model for our purposes.

Market value of corruption

This paper studies the impact of the Brazilian anticorruption legislation, PL 6826/2010, on stock returns. I show that, around the law approval date, the greater the link between the corporate and political worlds, the worse is the companies’ performance. Companies awarded with public contracts in 2012 suffer more with the new legislation approval. Firms with above median contract values have 2.9% lower returns than its peers. The negative effect is more pronounced for bigger and more complex entities, associated with higher levels of Corporate Responsibility and Governance and not subject to the US FCPA.

The accuracy of the escrowed dividend model on the value of European options on a stock paying discrete dividend

This project characterizes the accuracy of the escrowed dividend model on the value of European options on a stock paying discrete dividend. A description of the escrowed dividend model is provided, and a comparison between this model and the benchmark model is realized. It is concluded that options on stocks with either low volatility, low dividend yield, low ex-dividend to maturity ratio or that are deep in or out of the money are reasonably priced with the escrowed dividend model.

Evaluating the potential of yeast strains to produce added value products for the food and/or pharmaceutical industries

This study focus in the valorization of the apple pomace with the main goal of obtaining added value products. For that, hot compressed water technology was used for the extraction of phenolic compounds and hydrolysis of polysaccharides presents in the lignocellulosic structure of apple pomace to obtain simple sugars. The sugars have been utilized as alternative carbon source for growth, lipid accumulation and carotenoids production by five different yeast Yarrowia lipolytica, Rhodotorula mucilaginosa, Rhodotorula glutinis, Rhodosporidium babjevae and Rhodosporidium toruloides. Hydrolysis experiments were carried out with constant pressure of 100 bar, flow rate of 2mL/min and temperatures between 50°C and 250°C. The amount of total sugars present in apple pomace hydrolysates showed maximum values for the hydrolysis temperatures of 110°C and 190°C. In fact, these temperatures revealed the best results regarding the monosaccharides quantities. The amount of 5-HMF and furfural in each hydrolysate varied through the different temperatures. Maximum values for 5-HMF were obtained with 170°C, while furfural showed to be maximum at 210°C. Extraction of phenolic compounds were performed in simultaneously with hydrolysis reactions. Total phenolic compounds (TPC) increased along the temperature, however with small variations between 170°C and 250°C. Hydrolysates were then used as alternative carbon source to yeast growth. R. mucilaginosa shows the highest optical density, with the hydrolysate obtained at 130°C. Carotenoids produced by these yeast scored a total of 7.02μg carotenoids/g cell dry weight, while for the control assay, the same yeast scored 9.31μg caratonoides/g cell dry weight. β-carotene was quantified by HPLC, were 33% of the carotenoid production by R. mucilaginosa with hydrolysate as carbon source, corresponded to β-caroteno.

Comprehensive income: evidence from Portuguese listed companies on reporting choices and value relevance

This work project aims at analysing choices related to Comprehensive income (CI) of Portuguese listed firms and understanding the reasons behind them. Additionally, it studies the relevance of CI versus Net Income (NI). It was found that firm’s size and volume of Other comprehensive income (OCI) are positively related with the choice for separate statements while smaller firms with positive NI and negative OCI tend to disclose less information about taxes. The value relevance of CI proved to be superior to that of NI but OCI seems to have no incremental value relevance.

Lifetime-value creation through a customized offer adressed to diferent lifestyles

This paper purposes a method for marketing segmentation based on customers‟ lifestyle. A quantitative and qualitative segmentation established by the Whitaker Lifestyle™ Method was created in order to define a concrete and clear identification of the customer, by understanding the behavior, style and preferences of each segment. After conducting 18 in-depth interviews, it was concluded that four main personas characterize the customer base of the company. These four personas will be the support for the creation of „quick-wins‟ that address to the expectations of each lifestyle, projecting a significant impact on the lifetime-value of the company‟s customer base

Developing a gamification system to increase customer lifetime value at MyGon

There have never been so many touch points between companies and consumers as there are today, which paradoxically makes it very challenging for companies to be able to retain and engage customers. Gamification is a strategy used by a large number of companies to increase customer engagement and customer lifetime value. This work aims at developing a gamification system for MyGon, a Portuguese startup working in the market of discounts and experiences. In addition to examining the literature concerning gamification, its elements and characteristics, recommendations were developed for addressing MyGon’s business goals of increasing conversion and customer engagement. The gamification mechanisms suggested include badges, missions, points, leaderboards and levels.

Value creation in the nursing home real estate investment market - A case study

The underlying thesis examines the value drivers of direct investments in nursing home real estate in Germany. A survey among investors and operators is conducted in order to identify significant value drivers. Moreover, based on survey results, a framework for assessing German nursing home real estate is developed. This is applied in a case-study about the set-up of a nursing home value-add fund which will demonstrate the value creation process of redeveloping an existing nursing home real estate portfolio. Through a concluding analysis the sources of value creation, sensitivities and future prospects of direct investing into German nursing home real estate are concluded.

Future lending income and security value

I test the Duffie, Gârleanu, and Pedersen hypothesis that security prices incorporate expected future securities lending income. To determine whether institutional investors anticipate gains from future lending of securities, I examine their trading behavior around loan-fee increases. The evidence suggests that institutions buy shares in response to an increase in lending fees, and that this could explain the premium associated with high- lending-fee stocks. Expected future lending income affects stock prices, although the effect seems to be attenuated by the negative information that arises from short selling.

O âmbito de aplicação material da legislação de proteção de dados pessoais e o tratamento de imagem por pessoa singular

Images have gained a never before seen importance. Technological changes have given the Information Society extraordinary means to capture, treat and transmit images, wheter your own or those of others, with or without a commercial purpose, with no boundaries of time or country, without “any kind of eraser”. From the several different ways natural persons may engage in image processing with no commercial purpose, the cases of sharing pictures through social networks and video surveillance assume particular relevance. Consequently there are growing legitimate concerns with the protection of one's image, since its processing may sometimes generate situations of privacy invasion or put at risk other fundamental rights. With this in mind, the present thesis arises from the question: what are the existent legal instruments in Portuguese Law that enable citizens to protect themselves from the abusive usage of their own pictures, whether because that image have been captured by a smartphone or some video surveillance camera, whether because it was massively shared through a blog or some social network? There is no question the one's right to not having his or her image used in an abusive way is protected by the Portuguese constitution, through the article 26th CRP, as well as personally right, under the article 79th of the Civil Code, and finally through criminal law, articles 192nd and 193rd of the Criminal Code. The question arises in the personal data protection context, considering that one's picture, given certain conditions, is personal data. Both the Directive 95/46/CE dated from 1995 as well as the LPD from 1998 are applicable to the processing of personal data, but both exclude situations of natural persons doing so in the pursuit of activities strictly personal or family-related. These laws demand complex procedures to natural persons, such as the preemptive formal authorisation request to the Data Protection National Commission. Failing to do so a natural person may result in the application of fines as high as €2.500,00 or even criminal charges. Consequently, the present thesis aims to study if the image processing with no commercial purposes by a natural person in the context of social networks or through video surveillance belongs to the domain of the existent personal data protection law. To that effect, it was made general considerations regarding the concept of video surveillance, what is its regimen, in a way that it may be distinguishable from Steve Mann's definition of sousveillance, and what are the associated obligations in order to better understand the concept's essence. The application of the existent laws on personal data protection to images processing by natural persons has been analysed taking into account the Directive 95/46/CE, the LPD and the General Regulation. From this analysis it is concluded that the regimen from 1995 to 1998 is out of touch with reality creating an absence of legal shielding in the personal data protection law, a flaw that doesn't exist because compensated by the right to image as a right to personality, that anyway reveals the inability of the Portuguese legislator to face the new technological challenges. It is urgent to legislate. A contrary interpretation will evidence the unconstitutionality of several rules on the LPD due to the obligations natural persons are bound to that violate the right to the freedom of speech and information, which would be inadequate and disproportionate. Considering the recently approved General Regulation and in the case it becomes the final version, the use for natural person of video surveillance of private spaces, Google Glass (in public and private places) and other similar gadgets used to recreational purposes, as well as social networks are subject to its regulation only if the images are shared without limits or existing commercial purposes. Video surveillance of public spaces in all situations is subject to General Regulation provisions.

Dispondo de si : autonomia, género e envelhecimento nos quotidianos de saúde

Esta tese de doutoramento tem como objectivo geral compreender as experiências de autonomia individual na actual geração de adultos mais velhos, enquadrados pelas construções identitárias de género e assumindo como plataforma de observação as vivências quotidianas de saúde. Para tanto, justifica-se a centralidade do valor da autonomia individual na contemporaneidade, para depois se problematizar o conceito a partir de uma perspectiva feminista, com base na conceptualização proposta por este corpo teórico. O feminismo propõe a adopção do conceito de autonomia relacional, que ao reconhecer a natureza social do self e das identidades, é capaz de proporcionar uma leitura crítica e contextualizada da autonomia de cada sujeito, por integrar não só as especificidades, estímulos, oportunidades e contingências de um tempo e de um espaço social, como também o poder resolutivo, transformador e de resistência da agência individual. A vivência da velhice constitui, cada vez mais, um exercício de individualidade. No envelhecer, a vivência da saúde ganha especiais contornos. Não só porque o cuidar de si se tornou um aspecto biográfico de progressiva acentuação, como também por ser este um tempo da vida em que os dilemas, inquietações e exigências com o corpo se acentuam. A individualização dos trajectos biográficos que nas sociedades contemporâneas surge com cada vez maior expressão sugere a importância do estudo das diferentes ecologias sociais, com base na precisão e no detalhe. A tese adoptou uma estratégia metodológica de estudos de casos, concretizada num estudo de caso múltiplo, de tipo qualitativo. Os sentidos conferidos às experiências da autonomia individual pela actual geração de adultos mais velhos, nos seus quotidianos de saúde, mobilizam e matizam diferentes modelos culturais, iluminando a ideia de uma transição sociocultural que abandona parcialmente certos aspectos, mas que mantém tantos outros. No envelhecer, a vivência da autonomia individual é mediatizada por diferentes performatividades femininas e masculinas, tendo sido três os espaços principais de expressão social da autonomia, resultantes do seu cruzamento com o género, enquanto dimensão de análise principal. Tem-se que estas diferenças entre espaços factoriais vêm demonstrar o hibridismo dos posicionamentos resultante da crescente individualidade das trajectórias de vida. Face à saúde, a capacidade de adaptação e de auto-gestão mais positivos relacionam-se, face às mulheres, com a expressão singular de uma maior individualidade e, face aos homens, com o valor social conferido a diferentes masculinidades.

A type system for value-dependent information flow analysis

Information systems are widespread and used by anyone with computing devices as well as corporations and governments. It is often the case that security leaks are introduced during the development of an application. Reasons for these security bugs are multiple but among them one can easily identify that it is very hard to define and enforce relevant security policies in modern software. This is because modern applications often rely on container sharing and multi-tenancy where, for instance, data can be stored in the same physical space but is logically mapped into different security compartments or data structures. In turn, these security compartments, to which data is classified into in security policies, can also be dynamic and depend on runtime data. In this thesis we introduce and develop the novel notion of dependent information flow types, and focus on the problem of ensuring data confidentiality in data-centric software. Dependent information flow types fit within the standard framework of dependent type theory, but, unlike usual dependent types, crucially allow the security level of a type, rather than just the structural data type itself, to depend on runtime values. Our dependent function and dependent sum information flow types provide a direct, natural and elegant way to express and enforce fine grained security policies on programs. Namely programs that manipulate structured data types in which the security level of a structure field may depend on values dynamically stored in other fields The main contribution of this work is an efficient analysis that allows programmers to verify, during the development phase, whether programs have information leaks, that is, it verifies whether programs protect the confidentiality of the information they manipulate. As such, we also implemented a prototype typechecker that can be found at http://ctp.di.fct.unl.pt/DIFTprototype/.

How to increase brand value expanding the category and brand presence to the main meal occasion for Sumol- Compal

Having registered negative retail value growth of 4% in Portugal in 2014, the juice category is set to decline further by 5,5% until 2019. Manufacturers of juices and nectars are therefore increasingly looking for new categories in order to balance this negative forecast in their home territory. One apparent growth opportunity for Compal, the leading producer of juices and nectars, is to expand its commercial reach to new occasions of consumption. This report carefully analyzes the opportunities related to an expansion to the main meal occasion and introduces a complete marketing and communications plan for a possible new main meal juice, Compal à Mesa. The product concept represents a rather premium positioning for the main meal occasion, including new flavor mixes that are targeted at different occasions of meals. The justification of the introduced concept includes a discussion of the primary and secondary research that was performed