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- Funcionalidade das pessoas centenáriasPublication . Panta, Ana Graça Carrasco; Afonso, Rosa Marina Lopes Brás MartinsOs centenários são o grupo etário onde se verifica o maior crescimento demográfico na maioria dos países desenvolvidos. Este aumento deve-se à melhoria das condições de vida e aos avanços dos cuidados médicos que permitiram às pessoas idosas a manutenção de uma boa condição física durante mais tempo e, consequentemente, uma maior longevidade. Esta investigação insere-se no âmbito do estudo PT 100 – Estudo dos centenários da Beira Interior, que deriva do PT 100 – Centenários do Porto, desenvolvido pela Unidade de Investigação e Formação sobre Adultos e Idosos (ICBAS _ UP). O PT 100 – Centenários do Porto insere-se num consórcio internacional com investigadores dos estudos de centenários de Heidelberg (Alemanha) e Fohrdam (Estados Unidos da América). A presente investigação tem como objetivo geral caracterizar a funcionalidade dos centenários residentes no concelho de Figueira de Castelo Rodrigo. A amostra do estudo é constituída por sete participantes com uma média de idade que ronda os 102 anos. São todas do sexo feminino, viúvas, reformadas e com baixa escolaridade. A maioria dedicou-se ao trabalho no campo e desempenhou atividades domésticas. Atualmente, quatro das participantes estão institucionalizadas e três vivem em casas unifamiliares ao cuidado das filhas. Os problemas de saúde que mais afetam as participantes neste estudo são problemas de visão e de audição. A maioria (n=5), sofreu quedas nos últimos cincos anos. Ao nível da funcionalidade, as participantes desempenham as funções inerentes às atividades básicas da vida diária com alguma autonomia, no entanto, quanto ao desempenho das atividades instrumentais da vida diária, as participantes revelaram incapacidade de realizar estas atividades de modo autónomo. A maioria das participantes necessita de ajudas técnicas na realização das atividades do quotidiano. Apesar das limitações físicas inerentes ao processo de envelhecimento, a maioria das participantes perceciona a sua saúde como aceitável. Os resultados sugerem, no entanto que estes resultados ao nível da funcionalidade poderiam ser mais favoráveis com a ativação de possíveis ajudas técnicas/apoio, atitudes e ambientes mais promotores de autonomia.
- Combinatorial delivery of Crizotinib–Palbociclib–Sildenafil using TPGS-PLA micelles for improved cancer treatmentPublication . Diogo, Duarte Miguel de Melo; Gaspar, Vítor Manuel Abreu; Costa, Elisabete C.; Moreira, André; Oppolzer, David; Gallardo, Eugenia; Correia, Ilídio Joaquim SobreiraThe co-delivery of multiple chemotherapeutics by micellar delivery systems is a valuable approach to improve cancer treatment since various disease hallmarks can be targeted simultaneously. However, the delivery of multiple drugs requires a nanocarrier structure that can encapsulate various bioactive molecules. In this study, we evaluate the simultaneous encapsulation of a novel triple drug combination in D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) (TPGS-PLA) amphiphilic micelles for cancer therapy. The drug mixture involves two anti-tumoral drugs, Crizotinib and Palbociclib combined with Sildenafil, a compound that is capable of increasing drug accumulation in the intracellular compartment. Such combination aims to achieve an enhanced cytotoxic effect in cancer cells. Our results demonstrated that TPGS-PLA copolymers self-assembled into stable nanosized micelles (158.3 nm) capable of co-encapsulating the three drugs with high loading efficiency. Triple drug loaded TPGS-PLA micelles were internalized in A549 non-small lung cancer cells and exhibited an improved cytotoxic effect in comparison with single (Crizotinib) or dual (Crizotinib–Palbociclib) drug loaded micelles, indicating the therapeutic potential of the triple co-delivery strategy. These findings demonstrate that TPGS-PLA micelles are suitable carriers for multiple drug delivery and also that this particular drug combination may have potential to improve cancer treatment.
- Estrogenic Regulation of the SCF/c-KIT System in Prostate Cells: a Relationship with Prostate Cancer?Publication . Figueira, Marília Isabel Neto; Batista, Cláudio Jorge Maia; Socorro, Sílvia Cristina da Cruz MarquesProstate cancer (PCa) is the most common type of oncological disorder in men, for which an increasing incidence has been reported. Development and progression of PCa have been highly related with the circulating and intraprostatic hormonal milieu. Despite the classical role of androgens as stimulating agents in PCa growth, currently, estrogens also have been implicated in the prostate carcinogenesis. However, a duality for the possible role of estrogens in prostate cells has been gaining consistency over the last years. If some studies defend that estrogens are potential causative agents of PCa, other strong evidences indicate that these steroids may be protective against PCa. The tyrosine kinase receptor c-KIT and its ligand, the Stem Cell Factor (SCF) are powerful agents stimulating cell proliferation in a broad range of tissues, and the SCF/c-KIT interaction seems to play a crucial role in carcinogenesis. Moreover, it has been shown that estrogens modulate the expression of SCF/c-KIT system in several tissues, except the prostate. The present work aims to evaluate the role of estrogens regulating the SCF/c-KIT expression in human prostate cell lines and in rat prostate in vivo. The consequent effects on proliferation and apoptosis of prostatic cells will also be determined. Neoplastic (LNCaP, DU145 and PC3) and non-neoplastic (PNT1A) human prostate cell lines were cultured in presence or absence of 100 nM 17b-estradiol (E2) for different time periods. Adult male Wistar rats were daily injected with vehicle (control) or E2 (250 mg/day/kg) for 5 days. After treatment, animals were euthanized under anesthesia and prostates were collected, weighted and either fixed in 4 % paraformaldehyde or snap frozen in liquid nitrogen. The expression analysis of SCF and c-KIT in response to E2 was performed by means of real-time PCR, Western Blot and immunocito/histochemistry. The proliferation in rat prostate cells was estimated via fluorescent immunohistochemistry of Ki67. The protein ratio of Bax (pro-apoptotic)/Bcl-2 (anti-apoptotic), the expression of caspase-9, Fas and Fas- L, the enzymatic activity of caspase-3 and a TUNEL assay were used to evaluate apoptosis. The results obtained showed a decreased expression of both SCF and c-KIT in response to E2-treatment either in human prostate cells or rat prostate in vivo, which suggested a restricted proliferation of prostate cells in response to estrogens. This fact was confirmed in vivo by the diminished prostate weight and reduced Ki67 proliferation index observed in the E2-treated group. In addition, the enzymatic activity of caspase-3 was increased in response to E2, which indicates that estrogens induced apoptosis in rat prostate. The enhanced expression of the Fas system in the prostate of E2-treated animals suggests the involvement of the extrinsic pathway in the estrogen-induced apoptosis. In conclusion, the present work demonstrated that estrogens down-regulate the SCF/c-KIT system in neoplastic and non-neoplastic human prostate cells and in rat prostate in vivo. Moreover, estrogens have anti-proliferative and apoptosis-inducer effects in prostate exerted likely through the down-regulation of the SCF/c-KIT system. These findings also provided a body of evidence supporting the protective role of estrogens against development of PCa.
- The SCF/c-KIT system and imatinib actions in prostate cancer: a cross-talk with RGN?Publication . Cardoso, Henrique José Matos Morão Mingote; Batista, Cláudio Jorge Maia; Socorro, Sílvia Cristina da Cruz MarquesThe progression of prostate cancer (PCa), from an early stage confined to prostate to a more aggressive form, is associated with loss of androgen responsiveness. At this stage, PCa cells proliferate independently of androgens actions (the so-called hormone refractory prostate cancer, HRPC), which cause the failure of classical androgen ablation therapies and restricts the therapeutic options for this usually lethal form of disease. Imatinib mesylate is a chemotherapeutic drug that inhibits the tyrosine kinase activity of c-KIT receptors among others, and has been successfully used to treat leukemias and gastrointestinal stromal tumors. However, its application for treatment of PCa has not been totally effective with preclinical models and clinical experimentation producing discordant results. On the other hand, regucalcin (RGN), a calcium (Ca2+)-binding protein that regulates intracellular Ca2+ homeostasis and the activity of several proteins involved in intracellular signaling pathways, namely, kinases and phosphatases, has been associated with suppression of cell proliferation in rat prostate. These raised the question whether RGN may regulate the expression of c-KIT and its ligand, the stem cell factor (SCF). Therefore, the present dissertation firstly aimed to analyze the cytotoxic effects of imatinib in two cell line models of HRPC, DU145 and PC3 cells. Moreover, the effect of RGN on the expression of SCF/c-KIT in rat prostate was evaluated by means of a transgenic animal model overexpressing RGN (Tg-RGN). Finally, the subcellular localization of RGN in HRPC cell lines and its association with a-tubulin was investigated. DU145 and PC3 cells were incubated with 20 µM imatinib for 48 and 72 hours. The MTS assay was used to assess cell viability in response to imatinib and the colorimetric measurement of the enzymatic activity of caspase-3 was included as an end-point of apoptosis. The expression of cell-cycle and apoptosis regulators in response to imatinib, and the expression of SCF/c-KIT in Tg-RGN vs. wild-type rats were determined by real-time PCR and Western Blot. The expression of RGN in HRPC cells lines in its association with a-tubulin were evaluated through fluorescent immunocytochemistry. Treatment with imatinib decreased the viability of DU145 cells at 48 and 72 hours. Although imatinib decreased the viability of PC3 cells upon 6 hours of treatment, thereafter cell viability significantly increased in relation to control. Accordingly, the enzymatic activity of caspase-3 was increased in DU145 cells whereas diminished activity of caspase-3 was observed in PC3 cells treated with imatinib for 48 and 72 hours. Moreover, DU145 cells displayed reduced expression of anti-apoptotic protein Bcl-2 and increased levels of the executioners of apoptosis caspase-8 and caspase-9. No differences were observed on the expression levels of these apoptosis related proteins in PC3 cells. The mRNA expression of cell cycle inhibitor p21 was increased in both DU145 and PC3 cells. Also, the mRNA levels of VEGF were decreased in DU145 cells in response to Imatinib but the opposite effect was seen in PC3 cells. To start explaining the differential response of DU145 and PC3 cells to imatinib, the expression of c- KIT receptor in these cell lines was characterized. Fluorescent immunocytochemistry and Western Blot analysis showed that the expression of the active membrane-bound c-KIT is decreased in PC3 cells relatively to DU145. In addition, PC3 cells presented increased expression of truncated isoforms of c-KIT. Relatively to RGN the results obtained showed that the expression of SCF/c-KIT system is diminished in the prostate of Tg-RGN animals, which is in accordance with the antiproliferative effects of RGN, and indicates that regulation of SCF/c-KIT system may be a mechanism by which RGN restricts proliferation. Moreover, it was confirmed the expression of RGN in HRPC cells and its co-localization with a-tubulin, a fundamental component of microtubules. The results presented in this dissertation indicated that Imatinib was effective inducing apoptosis of DU145 cells likely through the inactivation of c-KIT. On the other hand, the paradoxical effects of imatinib in PC3 cells may be associated with the presence of truncated isoforms of c-KIT for which no definitive role has been established. These findings also contributed to understand the inefficacy of imatinib as therapeutic option in PCa. Moreover, the role of RGN as an antiproliferative molecule controlling cell cycle was further highlighted by the observed decreased expression of SCF/c- KIT system with overexpression of RGN, as well as, by the association of RGN with components of the cell division machinery.
- New drug-eluting lenses to be applied as bandages after keratoprosthesis implantationPublication . Carreira, Ana; Ferreira, Paula; Ribeiro, MP.; Correia, Tiago R.; Coutinho, Paula Isabel Teixeira Gonçalves; Correia, Ilídio Joaquim Sobreira; Gil, MariaCorneal tissue is the most commonly transplanted tissue worldwide. This work aimed to develop a new drug-eluting contact lens that may be used as a bandage after keratoprosthesis. During this work, films were produced using poly(vinyl alcohol) (PVA) and chitosan (CS) crosslinked with glyoxal (GL). Vancomycin chlorhydrate (VA) was impregnated in these systems by soaking. Attenuated total reflectance – Fourier transform infrared spectroscopy was used to confirm crosslinking. The cytotoxic and drug release profile, hydrophilicity, thermal and biodegradation as well as swelling capacity of the samples were assessed through in vitro studies. PVA and PVA/CS films were obtained by crosslinking with GL. The films were transparent, flexible with smooth surfaces, hydrophilic and able to load and release vancomycin for more than 8 h. Biodegradation in artificial lachrymal fluid (ALF) with lysozyme at 37 °C showed that mass loss was higher for the samples containing CS. Also, the samples prepared with CS showed the formation of pores which were visualized by SEM. All samples revealed a biocompatible character after 24 h in contact with cornea endothelial cells. As a general conclusion it was possible to determine that the 70PVA/30CS film showed to combine the necessary features to prepare vancomycin-eluting contact lenses to prevent inflammation after corneal substitution.
- A liderança e o clima de escola na promoção de práticas pedagógicas supervisivasPublication . Monteiro, Olga dos Santos Moura; Monteiro, Samuel José FonsecaNos últimos anos, a preocupação com a qualidade do ensino e a eficácia da escola no desempenho da sua missão educativa tem estado no centro dos discursos sobre educação, pelo que se torna cada vez mais relevante refletir sobre as condicionantes que podem afetar o funcionamento e desempenho das escolas, procurando encontrar caminhos que permitam a sua melhoria. Partilhando do interesse por esta questão, o presente trabalho centrou-se em três aspetos da vida organizacional das escolas: a liderança, o clima e a supervisão, por quanto se considera que estes, potencialmente, têm impacto na vida das escolas e na qualidade do trabalho nelas realizado. Deste modo, considerando, por um lado, que “a capacidade de melhoraria de um estabelecimento escolar depende, de maneira relevante, de equipas diretivas com uma liderança que contribua ativamente para dinamizar, apoiar e animar o seu desenvolvimento, de maneira a que possa construir a sua capacidade interna de melhoria” (Bolívar-Botía, 2010, p.81), e por outro que, em contexto nacional, o atual enquadramento legal (DL 75/2008) prevê um reforço das responsabilidades e atribuições dos líderes, um dos objetivos estruturante do trabalho que aqui se apresenta é conhecer a percepção dos docentes sobre o desempenho das suas lideranças, identificando pontos fracos e fortes, nomeadamente na sua atuação enquanto supervisores em contexto escolar. De facto, numa escola que se pretende eficaz, o exercício da liderança tem de ir muito além das práticas de gestão, sendo necessário que os líderes centrem a sua atenção num conjunto de atividades relacionadas com os processos de ensino e aprendizagem, como é o caso da supervisão (Bolívar-Botía, 2010). O outro vetor desta investigação prende-se com a perceção dos professores sobre o clima da escola, de modo a caraterizá-lo e avaliar, em que medida, este pode ser promotor de práticas supervisivas, as quais apenas serão viáveis e eficazes num clima de reconhecimento do trabalho realizado, e que seja favorável à inovação, ao desenvolvimento do trabalho cooperativo, no qual a discussão e análise das questões pedagógicas se faça de forma aberta (Herdeiro & Silva, 2008; Boudrias et al. 2010; Sousa et al., 2011). Com vista a concretizar os objectivos empíricos desta dissertação foi realizado um estudo de natureza quantitativa e descritiva, com recurso a dois questionários, para recolha da informação junto dos docentes. Esta investigação contou com uma amostra de 50 participantes e incidiu em três escolas/agrupamentos escolares, um localizado na Beira Baixa e os outros no Alto Alentejo. A análise dos dados recolhidos apontou para a existência de uma perceção global positiva tanto da liderança como do clima de escola, o que indicia que os professores têm uma imagem positiva da organização a que pertencem. No entanto, no que se refere à promoção de condições favoráveis à prática da supervisão, verificou-se haver pontos a melhorar, pois, as questões que se prendem com a assunção por parte dos diretores do seu papel como supervisores, o reconhecimento do trabalho dos professores, a ampla discussão de questões pedagógicas e de abertura à inovação foram as áreas que apresentaram resultados inferiores.