Repositório RCAAP

Cancer disease is the second most common cause of death in the world, being responsible for more than 25.8% of the total number of deaths. Over the last decades, a considerable effort has been made to bring new therapeutic alternatives and consequently increase survival rates in oncological disease. Due to therapeutic innovation, various cancer types can be managed as chronic and complex diseases. In spite of positive prospects, more compelling and less harmful medicines are required. With the innovative advance of chemistry and biology, it has ended up conceivable to apply precision medicine’s basis to drug development. Targeted therapies are the expression of this paradigm-changing. Antibody drugs conjugate (ADC) consists of a biotherapeutic class that combines cytotoxic drugs and monoclonal antibodies, allying potent therapeutic activity with precision. The development of ADCs is complex and requires the correct tuning of its components – antibody, payload, linker and bioconjugation. Despite the challenging process, eleven ADCs are approved for clinical treatment. Linker chemistry plays an important role in ADC design and may compromise its pharmacokinetics and therapeutic effect. Boronic acid (BA) derivatives have been used to develop reversible chemistries with application in targeted technologies. Due to the reversible nature of boron, several boron-based scaffolds display selective cleavage in the presence of ROS, GSH levels or at acidic conditions. Considering the chemical features of tumour cells, we started to explore diazaborines (DABs) as ROS-responsive scaffolds. In this work, we developed a ROS-responsive linker based on DAB scaffold to construct ROS-responsive ADCs. In the chapter II, we describe a ROS-responsive linker-payload that proved to be stable in physiological conditions (half-life time of over 130 h). Besides, it was also efficiently activated (a half-life time of 8.1 h) to release the SN-38 payload under oxidative conditions. In the chapter III, these structures were used in the site-selective functionalization of a single-domain antibody fragment (sdAb) and we were able to construct a homogeneous ADC. The obtained ADC presented a high selectivity and potency (IC50=54.1 nM) against the B-cell lymphoma CLBL-1 cell line. In the chapter IV, we present the initial steps for developing other ROS-responsive scaffolds. Benzoxazaborines are boron-based scaffolds containing B-N-C-N, B-N-C-O and B-O-C=N linkages. We identify benzoxazaborines with potential application as stable ROS-responsive linkers during these studies. Overall, this PhD thesis gives valuable insights about ROS-responsive boron scaffolds. In particular, diazaborines prove useful for constructing ROS-responsive ADCs with potential biological application. Besides, ROS-responsive linkers can be applied to other cytotoxic payloads and targets, expanding the disease scope for ROS-responsive ADCs.

The worldwide social and economic impact of cancer keeps increasing and proper disease management is a critical step to reducing the cancer burden on society, where appropriate diagnosis, staging, and treatment are key factors. Concomitantly, the increasing prevalence of obesity brings forward its importance as a risk factor for cancer development but also allows to explore associated metabolites and signaling pathways as tools for cancer research. As such, the studies presented in this thesis aim to tackle two pillars in cancer research: early diagnosis and therapy resistance, by exploring metabolism-related hormones as disease biomarkers and their impact on resistance to chemoradiotherapy, as well as unraveling novel molecules targeting cancer stem cells as major culprits in refractory cancer. In our first study, we focused on nonalcoholic fatty liver disease (NAFLD) as a predisposing risk factor for the development of hepatocellular carcinoma. Our goal was to evaluate serum levels of metabolism hormones as non-invasive biomarkers aiming to produce diagnostic options alternative to liver biopsy. Using two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls, we measured adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) serum levels. Leptin serum levels were able to discriminate NAFLD with obesity posing as a potential confounding factor. Adiponectin serum levels combined with specific serum lipids composed a biomarker panel with good assay performance for the stratification of nonalcoholic steatohepatitis versus nonalcoholic fatty liver, however, it can be influenced by the presence of patatin-like phosphate domain-containing protein 3 (PNPLA3) genetic polymorphisms. In turn, IGF-1 levels combined with INR and ferritin were able to distinguish advanced liver fibrosis outranking other fibrosis evaluation scores used in the clinical practice. Next, we followed to evaluate how adiponectin and leptin modulated cell stemness and influenced resistance to chemoradiotherapy in rectal cancer patients, and ultimately providing novel biomarker candidates to identify patients not responding to neoadjuvant therapy. By evaluating serum and biopsy tissue from a cohort of locally advanced rectal cancer, we observed that leptin and adiponectin serum levels were not able to identify non-responder patients to chemoradiotherapy. Yet, high leptin and low adiponectin levels were associated with worsened clinical outcomes and unfavorable patient survival. At a molecular level, leptin serum profile was associated with increased expression of Yamanaka factors mRNA, particularly of octamer-binding transcription factor 4 (OCT4) and Kruppel-like factor 4 (KLF4), as well as signal transducer and activator of transcription 3 (STAT3) activation in the biopsy tissues, and all three parameters tended to increase in non-responders. Bringing together STAT3 activation, OCT4, and KLF4 mRNA expression with carcinoembryonic antigen levels – the only serological parameter that distinguished responders from non-responders – we were able to establish a high-performance biomarker panel to distinguish rectal cancer patient responders versus non-responders to chemoradiotherapy. In our third study, we focused on cancer stem cells as a cause of cancer relapse and resistance to therapy. Taking advantage of in vitro tumorsphere forming assays, we identified a curcumin analog that was able to reduce cellular viability of several colorectal cancer cell lines, by modulating stemness traits and inducing apoptosis. Importantly, this compound significantly reduced tumor burden in an in vivo xenograft mouse model following the same mechanisms of action. Moreover, in silico analysis identified nuclear factor kappa B (NF-ĸB) and STAT3 as putative molecular targets that were later confirmed both in vitro and in vivo. In conclusion, our studies highlight how hormones associated with obesity may pose as biomarkers in chronic disease diagnosis and valuable tools in cancer prognosis. Moreover, our results support the influence of obesity on cancer development and clinical outcome, and how its associated signaling pathways provide valuable targets for an innovative approach developed to treat cancer. Finally, we discovered a novel molecule that by targeting those signaling pathways could be a promising drug candidate for therapy insensitive tumors.

The timing and magnitude of Holocene glacial oscillations in most currently ice-free areas of Antarctica remain unknown. This work focuses on the recent deglaciation in the northern sector of the Fildes Peninsula, King George Island, northern Antarctic Peninsula. The ice cap covering ca. 90% of the island has receded since the Last Glacial Maximum and exposed ca. 29 km2 of ice-free land. We reconstruct its glacial history based on a dataset of 12 36Cl exposure ages obtained through cosmic-ray exposure (CRE) dating of moraine boulders, polished surfaces and erratic boulders surrounding the peninsula's northern plateau. Results reveal that the deglaciation of the northern Fildes Peninsula took place during the Holocene Thermal Maximum at 7–6 ka, when warm conditions promoted a massive glacial retreat. The present arrangement of ice-free areas was in place by 6 ka. Small cirque moraines suggest the subsequent occurrence of favourable climate conditions for glacial expansion fed by intense snow deflation at 4.6 and 1 ka at the foot of the northern plateau. The deglaciation pattern of the Fildes Peninsula resulted from the combined shrinkage of different ice masses, rather than of the long-term retreat of the King George Ice Cap. No evidence of glacier expansion during more recent cold periods (i.e. the Little Ice Age) was found. These results fit well with regional deglacial histories inferred from lacustrine sediments and raised beaches and complement the existing chronological framework to help better understand the peninsula's Holocene geoecological dynamics.

The perfect storm model that was elaborated for the HIV-1M pandemic has also been used to explain the emergence of HIV-2, a second human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) that became an epidemic in Guinea-Bissau, West Africa. The use of this model creates epidemiological generalizations, ecological oversimplifications and historical misunderstandings as its assumptions—an urban center with explosive population growth, a high level of commercial sex and a surge in STDs, a network of mechanical transport and country-wide, en masse mobile campaigns—are absent from the historical record. This model fails to explain how the HIV-2 epidemic actually came about. This is the first study to conduct an exhaustive examination of sociohistorical contextual developments and align them with environmental, virological and epidemiological data. The interdisciplinary dialogue indicates that the emergence of the HIV-2 epidemic piggybacked on local sociopolitical transformations. The war’s indirect effects on ecological relations, mobility and sociability were acute in rural areas and are a key to the HIV-2 epidemic. This setting had the natural host of the virus, the population numbers, the mobility trends and the use of technology on a scale needed to foster viral adaptation and amplification. The present analysis suggests new reflections on the processes of zoonotic spillovers and disease emergence.

O problema deste estudo consistiu em analisar se existe transferência de competências cognitivas (representação espacial e consciência situacional) do simulador não imersivo instalado num computador pessoal para o simulador semi-imersivo semelhante ao cockpit de um avião. Tentou-se resolver este problema, num quadro de quasi-transferência, através da constituição de um grupo experimental e de um grupo de controlo com o propósito de estudar a relação entre o treino em simulador não imersivo e o desempenho em simulador semi-imersivo, em termos de competências cognitivas de representação espacial e de consciência situacional. O grupo experimental participou numa simulação em um simulador não imersivo e de seguida participou numa simulação em um simulador semi-imersivo. O grupo de controlo apenas participou numa simulação em um simulador semi-imersivo. Foi utilizada uma prova colectiva de desenvolvimento lógico para controlar os resultados obtidos, aplicadas provas de navegação e de consciência situacional e analisados os dados através da aplicação de testes não paramétricos U de Mann Whitney ao nível de significância α= 0,05. Desta forma pretendia-se inferir que existem elementos comuns entre os simuladores que promovem uma transferência de aprendizagens. Não encontrámos valores estatísticos que sustentem as hipóteses do estudo. Sendo assim concluímos que não ocorre transferência entre os simuladores de voo não imersivo e semiimersivo, em termos de competências de navegação horizontal e vertical e em termos de competências de consciência situacional: percepção, compreensão e projecção. Os resultados encontrados sugerem a possibilidade da existência de uma transferência negativa em categorias em que ocorreu um decréscimo do desempenho: navegação vertical e compreensão.

Gully erosion has been identified in recent decades as a global threat to people and property. This problem also affects the socioeconomic stability of societies and therefore limits their sustainable development, as it impacts a nonrenewable resource on a human scale, namely, soil. The focus of this study is to evaluate the prediction performance of four machine learning (ML) models: Logistic Regression (LR), classification and regression tree (CART), Linear Discriminate Analysis (LDA), and the k-Nearest Neighbors (kNN), which are novel approaches in gully erosion modeling research, particularly in semi-arid regions with a mountainous character. 204 samples of erosion areas and 204 samples of non-erosion areas were collected through field surveys and high-resolution satellite images, and 17 significant factors were considered. The dataset cells of samples (70% for training and 30% for testing) were randomly prepared to assess the robustness of the different models. The functional relevance between soil erosion and effective factors was computed using the ML models. The ML models were evaluated using different metrics, including accuracy, the kappa coefficient. kNN is the ideal model for this study. The value of the AUC from ROC considering the testing datasets of KNN is 0.93; the remaining models are associated to ideal AUC and are similar to kNN in terms of values. The AUC values from ROC of GLM, LDA, and CART for testing datasets are 0.90, 0.91, and 0.84, respectively. The value of accuracy considering the validation datasets of LDA, CART, KNN, and GLM are 0.85, 0.82, 0.89, 0.84 respectively. The values of Kappa of LDA, CART, and GLM for testing datasets are 0.70, 0.65, and 0.68, respectively. ML models, in particular KNN, GLM, and LDA, have achieved outstanding results in terms of creating soil erosion susceptibility maps. The maps created with the most reliable models could be a useful tool for sustainable management, watershed conservation and prevention of soil and water losses.

Esta Newsletter (NL) resulta de uma parceria entre o Instituto de Saúde Baseada na Evidência e a Cochrane Portugal, e tem como objectivo disponibilizar informação sobre áreas importantes para a prática clínica, com base na melhor evidência científica disponível. São incluídos estudos relevantes, criticamente avaliados pela sua validade, importância dos resultados e aplicabilidade prática, resumidos numa óptica de suporte à decisão. É dada prioridade a estudos de causalidade incluindo-se ainda, quando justificado, estudos qualitativos e metodológicos, assim como revisões científicas. O conteúdo da NL é da exclusiva responsabilidade do(s) seu(s) autor(es).

Após um longo período de desinvestimento e declínio, nos últimos anos tem-se assistido a um crescente interesse na reabilitação dos mercados municipais em países europeus e sul-americanos, culminando frequentemente na gentrificação daqueles equipamentos comerciais. A nossa hipótese de trabalho é que alguns agentes na busca por boas práticas de planeamento urbano utilizam como referência certos mercados que, por via dos moldes usados para reabilitação, promovem processos de gentrificação. Face a uma aparente contradição entre os estudos académicos que confirmam a gentrificação dos mercados municipais reabilitados e a prática dos agentes políticos que encaram o atual molde de reabilitação como uma boa prática de planeamento urbano, temos como objectivo analisar e discutir no atual processo de reabilitação de mercados municipais em Portugal. Em termos metodológicos, este trabalho é suportado por uma abordagem qualitativa, baseando-se na análise teórica acerca da temática em causa e em entrevistas realizadas a responsáveis de três Câmaras Municipais portuguesas, assim como duas entrevistas a empresas de consultoria envolvidas no processo. Recorrendo ao quadro concetual da gentrificação para auxiliar na interpretação dos resultados, concluímos que a motivação para a reabilitação dos mercados é baseada numa leitura dos mercados em declínio e que os atuais moldes de intervenção se devem a estratégias de benchmarking e de transferências de modelos entendidos como sendo boas práticas, destacando-se, ainda, o papel das empresas de consultoria na sua disseminação.

Purpose This article poses the question on whether and how youth participation in environmental sustainability makes a difference within participatory budgets (PBs). This is a question worth asking because PBs have pursued, from the very beginning, goals of social sustainability through the inclusion of social groups that struggle to make their voices heard, as in the case of the youth. As young people show an increasing capacity to self-organise around environmental issues, a knowledge gap emerges as to the contribution that youth can give to environmental sustainability within PBs. >>> Design/methodology/approach The 2021 edition of the Lisbon PB (2021PB) has been analysed through desk research – document analysis using the city council's website as the main source of information, and fieldwork – an organisation of one two-day workshop with 20 young students through a partnership between the local authority and the Institute of Social Sciences at the University of Lisbon. Methods were applied to retrieve findings on youth participation in environmental sustainability in the 2021PB. >>> Findings The youth show a relative increase of participation in the 2021PB and emerge as a key target group in funded proposals. Convergence with student proposals suggest shared awareness on the role of youth in the pursuit of social sustainability. The success of health-related proposals confirms ownership of (young) citizens over the concept of environmental sustainability, which further relies on the various scopes of funded proposals at both city and neighbourhood levels. In the workshop, students did not stick to specific themes and struggled to connect present criticalities and future imaginaries. >>> Research limitations/implications Focus on one case study necessarily limits the generalisation of findings. Nevertheless, the 2021PB illuminates pathways of research on youth participation in environmental sustainability through participatory budgeting that are worth clearing in the future, such as the role of digital participation, dynamics induced by extreme events as the COVID-19 pandemic and PBs' capacity to intercept environmental activism. >>> Practical implications Decision-makers and practitioners can take advantage of findings to acknowledge the potential of youth participation in PBs to reframe the take of environmental sustainability. >>> Social implications The article provides new inputs for future developments in the operationalisation of social and environmental sustainability through participatory budgeting. >>> Originality/value This article examines original data retrieved from the 2021PB. Data analysis is backed by the literature review of key democratic challenges in social and environmental sustainability within participatory budgeting.

The conference “Film, Migration and the Archive” took place at the Institute of Social Science (ICS, University of Lisbon) and at the Cinemateca Portuguesa in June 2022. Organized by the Film Studies section of the European Communication and Research Association (ECREA), the event brought together over 40 panelists from around the world, including filmmakers, activists, and scholars. The conference approached the complex field of archiving moving images representing or originating from migration processes.

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Analisa-se historicamente uma instituição de ensino criada pelo rei D. Pedro V (1837-1861) – a Escola Real de Mafra. Por um lado, a narrativa procura apreender as linhas mestras da construção e afirmação da identidade da Escola e, por outro lado, salientar aspetos da sua organização pedagógica; estabelece-se, para o efeito, pontos de contacto com o panorama das escolas primárias públicas da segunda metade de Oitocentos. Um objetivo paralelo será o de perceber de que forma a Escola Real de Mafra, que veiculou um projeto pedagógico coerente e muito peculiar ao nível do ensino primário, abraçou uma dimensão de formação de docentes; ou, pelo menos, de encaminhamento para essa área profissional.

Este estudo articula-se em duas partes. Na primeira aproximámo-nos da obra de Eugénio de Andrade na perspectiva de uma análise da sua estética e poética, visando esclarecer as implicações com o tópos da infância, que se torna fonte de inovação da linguagem literária. Neste âmbito surgem também as questões relativas à prática literária como exemplo de rigor formal e, por conseguinte, do seu aporte ético no seio da sociedade. Para entrançar uma rede de correspondências textuais e iluminar aspectos da reflexão estética e da prática poética de Eugénio de Andrade são aqui convocados Martin Heidegger, Giambattista Vico e Giorgio Agamben. Na segunda parte aplicámos a metodologia da crítica genética para descrever os processos de formação de textos considerados exemplares. São analisadas todas as variantes dos poemas intitulados Todas as águas e Como pólen , documentos que se encontram no espólio de Eugénio de Andrade. Em seguida, a análise foca o conjunto dos Primeiros Poemas, fruto da reelaboração de textos juvenis primeiro renegados e depois passados mais de trinta anos sobre a sua primeira publicação , reacolhidos na obra canónica.

Esta tese descreve o projecto realizado no âmbito da disciplina Projecto em Engenharia Informática do Mestrado em Engenharia Informática da Faculdade de Ciências da Universidade de Lisboa. Desde o início da década de 90 que as tecnologias Data Warehouse estão amplamente disseminadas, ao nível das organizações. Estes sistemas emergiram, como solução, para sustentar estratégias de mercado e auxiliar o processo de suporte a decisões de uma área de negócios. O conceito de Reporting, tema fulcral neste projecto, traduz-se na restituição de informação aos clientes através da construção e entrega de relatórios com toda a informação por estes requisitada. Esta dissertação aborda o problema do crescimento exponencial da informação armazenada que é continuamente alterada, num ambiente Data Warehouse. Este processo de contínuo refrescamento da informação, pode colocar em risco o desempenho do sistema e a eficiência do Reporting. Para atenuar este problema, carece-se de um processo complexo de análise e gestão da informação. Neste trabalho, é proposto um conjunto de técnicas aplicadas à informação existente para que o desempenho do sistema e a eficiência do Reporting não fiquem comprometidos pela acumulação de informação obsoleta. Foi aplicada uma metodologia que combina técnicas de análise e gestão do conhecimento, exploração de informação e manutenção correctiva. Esta metodologia, visa dar resposta ao problema existente, num caso típico de Engenharia do Software. A viabilidade destas estratégias foi avaliada, quando aplicada a um caso de estudo bem definido, no sentido de verificar a precisão e abrangência dos resultados obtidos. O projecto descrito nesta tese foi concretizado no âmbito de uma instituição bancária e, consequentemente, a informação manipulada pelo sistema é de natureza financeira. O trabalho realizado, visa atingir um ambiente organizado, eficiente, reutilizável, mais robusto e caracterizado pela qualidade, contemplando também a redução do espaço físico, ocupado em memória, como um requisito aplicacional a alcançar.

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Pela teoria mimética, a democracia é um sistema sacrificial. Mantendo os seus cidadãos crentes em sua autonomia, a democracia garante diferenças, ritos e instituições, a conter e a canalizar decisão, culpa, desejo e violência. O Povo, herdando cristãs propriedades divinas e inocentárias, reina com materna democracia e sua ciclicidade imortalizante. O Estado, de paternidade menorizada em governo demiurgo, é periodicamente culpado, morto e ressuscitado: em fecundo caos culminado em sacrifício / sacramento eleitoral, em jogo sagrado contando votos em vez de baixas, regenera-se o cosmos, saem próximos decisores culpados. Complementam este pilar pagão do regime, o parlamento, a diferenciação entre poderes, a domesticação da rua em dita participação democrática. Mas o progredir do pilar cristão, a doce e igualizante maternização, ameaça a democracia: na exagerada fuga à decisão; no cair da crença; na ideia de democracia directa, no movimento correctivo, nas imperativas tolerâncias e transparências.