The purpose of this communication is to argue that the existence of a Portuguese-speaking cultural heritage can contribute to tourism development of rural areas of the Member States of the CPLP. This claim is based on the assumption that tourism activities can become an engine of economic activity, in general, helping to reduce the existing asymmetries of development, phenomenon that reaches Portugal and other Member States of the CPLP. The results of a study developed in Portugal reveal that the touristic commercialization of Portuguese-speaking cultural heritage cancontribute to the development of tourism in rural areas. Though, the relationship of Portuguese-speaking cultural heritage with the direct investment abroad and migration flows also enable to argue for its contribution to the development of tourism in theneediest areas of the CPLP.

Prostate cancer (PCa) is a hormone-dependent cancer whose development and progression are strongly influenced by the tumour microenvironment and exogenous factors, such as environmental influences. The periprostatic adipose tissue (PPAT), by its anatomical proximity and functional crosstalk with prostate cells, emerged as a key driver of tumour growth, particularly in obesity, with the secretome of “obese” PPAT being associated with enhanced tumour aggressiveness. On the other hand, epidemiological and experimental studies have implicated endocrine-disrupting chemicals (EDCs) as environmental risk factors for PCa. Given the hormone dependency of PCa, it is predictable that it is a cancer highly susceptible to the influence of environmental exposures, namely EDCs and specifically those with obesogenic properties (i.e. obesogens), which are capable of disrupting both endocrine and metabolic pathways. Notably, based on their mechanisms of action and the cellular and molecular alterations they induce, obesogens may promote tumorigenesis either directly by acting on prostate cells or indirectly by inducing adipose tissue dysfunction. However, the extent to which obesogenic compounds drive these alterations and the consequent impact on prostate tumorigenesis remain largely unknown. Moreover, despite the well-established effects of obesogens on adipose tissue, no study has characterised their actions on PPAT. Addressing these gaps is critical to understanding how environmental factors intersect with adipose tissue biology, influencing interorgan communication between the prostate and adipose tissue and PCa development. Based on this scientific rationale, this doctoral thesis hypothesises that obesogen-induced PPAT dysfunction represents a driving force in the initiation and progression of PCa. Tributyltin (TBT) is a well-characterised obesogenic EDC and a potent regulator of adipogenesis, widely used in experimental settings to investigate the effects of obesogens. Therefore, using the obesogen model TBT this thesis aimed to: (i) characterise the morphological and secretory alterations of PPAT following TBT exposure; (ii) assess the impact of TBT-induced PPAT dysregulation on prostate cell fate, metabolism, oxidative and inflammatory status, and response to chemotherapeutic drugs; and (iii) identify the molecular targets and signalling pathways mediating the crosstalk between dysregulated PPAT and prostate cells. First, it was demonstrated that in vivo exposure to TBT (50 μg/kg) besides increasing rat body weight, enhanced PPAT somatic index and altered its functional phenotype. TBT treatment promoted a shift in rat prostate cells toward a glycolytic and lipogenic metabolic profile and stimulated oncogenic signalling pathways, including increased phosphorylated/total protein kinase B (pAKT/AKT) ratio and androgen receptor expression. Moreover, macrophage infiltration and a shift in macrophage polarisation towards a pro-inflammatory phenotype were observed both in the prostate and PPAT of TBT-exposed animals, suggesting that TBT can perturb the local prostate-PPAT immune status, contributing to an environment permissive to prostate carcinogenesis. These findings confirmed the effects of TBT on prostate cells, supporting the hypothesis and the investigation into the contribution of PPAT-mediated effects in altering prostate cell behaviour. Culture of the PPAT from rats exposed to TBT clearly demonstrated that TBT induced a dysregulation of the PPAT secretome. TBT-treated PPAT (TBT-PPAT) displayed increased leptin/adiponectin ratio and C-C motif chemokine ligand 7 (CCL7) levels. This adipokine/chemokine profile induced by TBT mimics that observed in obesity and is concurrent with a metabolic reprogramming associated with enhanced glucose, free fatty acids, and lipid peroxidation. Importantly, ex vivo exposure of rat PPAT to TBT (100 nM) recapitulated the findings obtained in vivo concerning the features of its secretome, which are capable of having an impact on prostate cell fate. The results obtained in the subsequent preclinical approaches using co-cultures and conditioned media (CM) assays confirmed the ability of TBT-PPAT enhance the viability, proliferation and migration, as well as apoptosis resistance, in all the studied prostate cell line models, namely non-neoplastic prostate epithelial cells (PNT1A), and androgen-sensitive (22Rv1) and androgen-insensitive (DU145 and PC3) PCa cells. Notably, the TBT-PPAT secretome increased the expression of CCL7 receptor, the C-C motif receptor 3 (CCR3), in prostate cells, which, together with the enhanced CCL7 secretion observed in our experimental setting, raised curiosity about the role of the CCL7-CCR3 axis underlying the pro-tumorigenic effects of TBT-PPAT. The use of a CCR3 antagonist significantly reduced TBT-PPAT induced migration across all cell lines, allowing to implicate the CCL7 and CCR3 in the observed responses of prostate cells. Other molecular targets beyond the CCL7-CCR3 axis were also highlighted. It is the case of tribbles homolog 1 (TRIB1), a pseudokinase involved in tumorigenesis and lipid homeostasis that was overexpressed across all studied cell models exposed to TBT-PPAT-CM. Cell fate alterations observed upon TBT treatment were accompanied by metabolic changes with distinct outcomes in non-neoplastic and neoplastic cell lines: in PNT1A, enhanced fatty acid β-oxidation and synthesis indicate a plausible shift toward a cancer-like metabolic profile; in 22Rv1, the unaltered metabolic and oxidative status suggests the activation of alternative signalling pathways sustaining TBT-PPAT effects; in DU145 and PC3, the distinct metabolic responses observed underscore the differential responsiveness of androgen-insensitive PCa cell subtypes to adipose-derived cues. The investigation in the present thesis was extended to a clinically relevant setting. Human PPAT obtained from patients submitted to radical prostatectomy or prostatic adenomectomy (Millin’s procedure) was treated ex vivo with TBT (100 nM) to confirm if the human tissues resemble the pro-tumorigenic cues identified in controlled experimental models. This approach demonstrated that human PPAT is a target of obesogenic dysregulation and showed that the secretome of obesogen-dysregulated PPAT can significantly enhance the viability of prostate cells. Moreover, the presence of human TBT-PPAT reduced the sensitivity of PCa cells to docetaxel and cabazitaxel, suggesting that obesogenic dysregulation contributes to PCa resistance to taxane-based chemotherapy. Overall, the scientific evidence gathered in this thesis identifies PPAT as a key target of obesogenic EDCs, which disrupt PPAT function and its crosstalk with prostate cells, thereby contributing to the initiation and progression of PCa. These findings open new avenues for developing interventions aimed at modulating PPAT activity to counteract its tumour-promoting effects and emphasise obesity as a critical modulator of PCa aggressiveness.

The thesis titled "Emergency Healthcare Response in Settings of Forcibly Displaced People: A Review" focuses on the analysis of the published literature on emergency healthcare response in settings where people have been forcibly displaced. The research explores the challenges and barriers to accessing healthcare services in these contexts and the difficulties faced by healthcare workers and humanitarian organisations operating in such situations. Additionally, the thesis reviews the effectiveness of healthcare interventions and clinical practices for forcibly displaced populations and examines strategies for disease prevention and health promotion in displacement settings. The primary objective is to discern the challenges and opportunities intrinsic to efficient healthcare responses in these environments, thereby providing nuanced insights to enhance emergency healthcare provisions for forcibly displaced populations. The potential implications and contributions of this thesis to the field of emergency healthcare response in settings of forcibly displaced people include the identification of key challenges and opportunities for effective healthcare response, the evaluation of existing healthcare programs, and insights for improving emergency healthcare response for forcibly displaced populations. Furthermore, the thesis identifies promising areas for future research, emphasising the need to develop innovative models that consider the social, political, and environmental determinants of health in emergency healthcare response in forcibly displaced settings. Additionally, it suggests exploring the impact of these determinants on healthcare accessibility and availability. The provided guidance has the potential to be valuable not only for professionals and policymakers involved in the field of emergency healthcare in situations of forced displacement but also for shaping effective interventions and policies aimed at improving equitable access and healthcare quality for forcibly displaced populations.

Genes in human leucocyte antigens (HLA) System are important in the study of autoimmune diseases and responsible for the rejection of transplants of organs and tissues. HLA genes are part of the human major histocompatibility complex (MHC) which is characterized by the presence of several multigene families, extensive polymorphism at many loci and significant linkage disequilibrium between alleles at particular loci. We analysed HLA-A,-B,-DRB1 locus phenotypes through a sample of 1,021 subjects that were randomly selected among the volunteers recruited by the Portuguese Bone Marrow Donors Registry (Cedace) in order to evaluate allele, gene, haplotype and phenotype frequencies. Allelic frequencies in each of the studied locus were obtained by direct counting. Maximum-likelihood haplotype frequencies were estimated using an expectation-maximization (EM) algorithm [2]. Locus phenotype and gene relative frequencies were estimated according to Baur and Danilov [1]. Hardy–Weinberg equilibrium were tested. The data presented is a definition of HLA genetic repertoire of Cedace with relevance on the strategic management for the increase of a more diverse register with clinical utility.

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