Modulation of human apurinic/apyrimidinic endonuclease 1 (APE1) functions for breast cancer therapy

Tese de doutoramento, Farmácia (Toxicologia), Universidade de Lisboa, Faculdade de Farmácia, 2016DNA repair is required for the maintenance of genome stability. In the last years DNA repair pathways have emerged as important targets for cancer therapy. Since standard anticancer agents are mainly DNA-damaging drugs, its combination with DNA repair inhibitors may contribute to improve treatment outcomes. Among the multiple effectors involved in DNA repair, the multifunctional base excision repair (BER) protein apurinic/apyrimidinic endonuclease 1 (APE1) is one of the most attractive druggable targets in this field. APE1 is the major endonuclease in BER participating in the repair of different DNA lesions including toxic abasic sites. In addition to the DNA repair activity, APE1 also acts independently as a reduction/oxidation signalling protein modulating the activation and DNA binding ability of several transcription factors implicated in cell survival and tumour promotion and progression. In this context, this thesis is focused on the combination of APE1 pharmacological inhibitors with conventional anticancer agents in the highly aggressive human breast cancer MDA-MB-231 cell line. Endonuclease activity has been the most studied function of APE1 in cancer therapy. Methoxyamine (MX), a commercially available indirect inhibitor of APE1 DNA repair function, was evaluated in combination with doxorubicin (Dox) in MDA-MB-231 cells. The chemotherapeutic drug Dox is widely used in the treatment of advanced breast cancer and may act, in part, by inducing oxidative DNA damage. MX had little effects in viability and colony formation of MDA-MB-231 cells. However, a significant increase in the frequency of micronucleated cells and an alteration in the pattern of micronuclei distribution were observed suggesting an increase in Dox genotoxicity. The differential results obtained in terms of cytotoxicity and genotoxicity showed that a therapeutic strategy based on APE1 inhibition is likely to have no relevance for the improvement of outcomes of Dox treatment. Although several putative inhibitors of APE1 endonuclease activity have been reported they still lack potential to be translated to the clinical setting. Therefore, in this thesis a structure-based virtual screening (SBVS) study based on molecular docking analysis of National Cancer Institute (NCI) database of compounds was performed to identify novel small-molecule inhibitors of APE1. The evaluation of SBVS study most promising compounds in a fluorescence-based APE1 endonuclease activity assay revealed three APE1 inhibitors. Compound 22 was a potent APE1 inhibitor showing inhibitory effects at nanomolar concentrations, while compounds 37 and 41 inhibited the enzyme in the micromolar range. These novel scaffolds for the design of more potent APE1 inhibitors did not affect the viability of non-tumourigenic human breast epithelial MCF10A cell line highlighting their promising features. The importance of APE1 modulation is beyond its functions in DNA repair. Therefore, E3330, a commercially available inhibitor of APE1 redox function, was also evaluated as single agent and in combination with the taxane drug docetaxel (DTX) in MDA-MB- 231 cells. DTX has anti-migratory and anti-angiogenic effects and is frequently used in advanced breast cancer refractory to anthracycline-based regimens. Consequently, relevant endpoints of cell migration and invasion were studied in addition to cell viability, proliferation and cell cycle profile assessment. Minor effects were observed in cell proliferation. However, E3330 alone significantly reduced the collective cell migration evaluated by the wound-healing assay without affecting chemotaxis and chemoinvasion. The combination of E3330 with DTX significantly decreased invasion of MDA-MB-231 cells suggesting a potential therapeutic role in metastatic breast cancer. The results described in this work emphasise the importance of preclinical studies of APE1 functions in cancer therapy and highlight the potential of novel drug combinations based on APE1 inhibitors reinforcing the role of targeting DNA repair in cancer treatment

Are Yelp's tips helpful in building influential consumers?

In the cluttered environment of online reviews, consumers frequently have to choose the most trustworthy reviewers to help them in their purchasing decision. Such reviewers are influential in their community and co-create value among their peers. The current research note studies the antecedents of fandom, particularly if contents of the message written by the reviewers predict the number of fans they might have in the future. 27,097 tips written by 16,334 users of Yelp are structured using text mining and a support vector machine algorithm is used to study the accuracy of such relation. Results show that tips which may help consumers to avoid the service and tips that highlight the positive elements of the service are the most relevant in predicting the number of fans. Findings may help managers to understand which type of messages may increase the reviewer's number of fans, thus increasing their influence in the network.info:eu-repo/semantics/acceptedVersio

Cause-related marketing in the digital era: how enterprises can deal with international campaigns in individualist versus collectivist countries

The purpose of the paper is to (i) analyze how different users of social media (Twitter) interact and spread cause-related communication and (ii) explore how people search for cause-related marketing campaigns online, allowing a comparison between individualist and collectivist cultures. A social network analysis was used to map the different types of networks created by online users. A second in-depth study on how online users search for cause-related marketing campaigns used a 5-year analysis. Online users in individualist countries are more engaged with a broader community than those in collectivist countries who focus their attention on a narrower set of CRM messages. These findings are useful insights for companies and charities, which should adopt different strategies depending on the culture.info:eu-repo/semantics/acceptedVersio

Transforming housing typologies. Space syntax evaluation and shape grammar generation

This paper focuses on the transformation of housing typologies by using a grammar-based methodology assisted by the use of space syntax measures. In this paper we start by describing three different types of housing buildings regarding their functionality by using syntactic measures. The studied buildings were constructed in Lisbon from the 18th to the 20th century and are representative repetitive cases in the city. The buildings’ descriptions are then used as part of the systematization of rehabilitation principles for the transformation grammar. We concluded that the particular characteristics of those buildings enable specific rehabilitation strategies to be carried out and that those different strategies may be integrated in the general grammar framework but defining specific sub-grammars.info:eu-repo/semantics/publishedVersio

Belimumab in Systemic Lupus Erythematosus (SLE): Evidence-To-Date and Clinical Usefulness

Systemic lupus erythematosus (SLE) is a complex autoimmune rheumatic disease with multiple presentations, whose management presents many challenges. Many disease modifying or immunosuppressive drugs have been used with limited success, especially in patients with more severe disease activity. Belimumab is the first drug to be approved specifically for the treatment of SLE in more than 50 years. By blocking the B-cell activating factor, it interferes in B-cell differentiation and survival. Here we consider the results of the clinical trials that led to its approval, as well as the post-hoc analyses, follow-up studies and the current trials.info:eu-repo/semantics/publishedVersio

The Portuguese-speaking community in Lambeth: a scoping study

This report presents the findings from research with the Portuguese-speaking community in Lambeth commissioned by the London Community Foundation. It is designed to inform the work of the Lambeth Community Fund Grant Committee which makes decisions regarding the distribution the Portuguese Speakers Community Fund. Based mainly on semi-structured, face to face interviews with community representatives and local service providers, it provides a snapshot of the Portuguese-speaking community in Lambeth, its make-up, needs and support structure

Using mixed realities to explore consumers behaviors

The ongoing and future research focus on exploring how mixed realities, especially virtual reality, may be used for changing consumers’ behaviours in complement or substituting traditional advertising means. With this main aim the group of researchers submitted a research proposal for FCT (call May 2017), are co-advising a master thesis and have several targets for future research.info:eu-repo/semantics/publishedVersio

Impacto econômico de pesquisa da Embrapa no bioma caatinga com variedade de mandioca (Manihot esculenta Crantz) resistente à bacteriose.

Neste artigo é analisada a viabilidade econômica de investimento em pesquisa pública da Embrapa para o desenvolvimento de variedades de mandioca resistentes à bacteriose e adaptadas ao bioma caatinga. A bacteriose é a principal doença da mandiocultura na microrregião de Guanambi, no Estado da Bahia, e o estresse hídrico um dos grandes desafios ao incremento do rendimento e da produção na região Nordeste. Com base nesse conhecimento e com o objetivo de evitar o avanço da bacteriose e simultaneamente revitalizar a mandiocultura da microrregião de Guanambi, a Embrapa Mandioca e Fruticultura (CNPMF), com a colaboração da Embrapa Cerrados (CPAC) e agricultores familiares da microrregião, uniram esforços num programa participativo de seleção de variedades de mandioca resistentes à bacteriose e adaptadas às condições locais. O programa teve início em 1997; ano em que a doença foi identificada na microrregião por uma equipe de pesquisadores da Embrapa Mandioca e Fruticultura. Desse esforço conjunto foi selecionada a variedade de mandioca de nome BRS Formosa; que atualmente está sendo utilizada em escala comercial por agricultores familiares da microrregião de Guanambi

On IT risk management ontology using DEMO

Nowadays, organisations use and rely on Information Technology (IT) solutions. However, despite their benefits, IT solutions induct risks. Consequently, organisations implement Risk Management (RM), more specifically Information Technology Risk Management (IT RM), in order to maximize the effectiveness of IT usage while dealing with IT risks. Nevertheless, IT RM's implementation is not easy, since numerous standards and frameworks propose multiple RM processes to deal with IT risks. Moreover, these processes are composed of different activities causing confusion. In the end, organisations are not capable of managing risks successfully due to IT RM's complexity. To overcome IT RM diversity, a Systematic Literature Review (SLR) was conducted. The goal is to identify which are the most essential IT RM activities. The SLR results were then integrated with ISO 31000 and PMBOK standards in the form of an ontology using Design and Engineering Methodology Ontology (DEMO). The contributions of this study are: the aggregate analysis of IT RM activities through the SLR; the identification of reasons and benefits of using DEMO; a description of an IT RM's essential model designed as an ontology; and a critical view of the benefits of the ontological model proposed.info:eu-repo/semantics/acceptedVersio

I am attracted to my Cool Smart Assistant! Analyzing attachment-aversion in AI-human relationships

The conversation between humans and Artificial Intelligence (AI)-enabled intelligent voice assistants (IVA) can create bonds that go beyond a mere utilitarian purpose. The emotional cues in a Human-AI conversation can lead consumers to feel connected with the AI-agents and even consider such a relationship as cool. Although brand coolness is known to affect consumer behavior, little is known about how consumers perceive a close relationship with IVAs and what the drivers of their use or avoidance are. Therefore, the current paper adds to the literature by analyzing how AI-enabled voice assistant experience affects IVA coolness and customer-brand relationships using the attachment-aversion (A-A) theory. A total of 308 consumers showed that affective, behavioral, and intellectual experiences with the intelligent voice assistant affect IVA coolness. IVA coolness was also found to affect A-A relationships positively, influencing consumers’ motivational strength to adopt, maintain and enhance the relationship in the future.info:eu-repo/semantics/publishedVersio