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- Effects of physical exercise concomitant with chemotherapy on cardiac functionality of women with breast cancerPublication . Antunes, Pedro Miguel da Silva; Esteves, Maria Dulce Leal; Ascensão, António Alexandre Moreira Ribeiro de; Sampaio, Francisco Pedro Morais Dias de AlmeidaAnthracycline-containing chemotherapy is commonly used in the treatment of hematologic cancers and solid tumors, including breast cancer. Despite its wellrecognized clinical efficacy, the use of anthracyclines is limited by dose-dependent and cumulative cardiotoxic risk. Additionally, breast cancer treatment is often multimodal, which can further increase the cardiac damage. The cardiac toxicity poses significant challenges, influencing therapeutic decision-making and exacerbate patients’ morbidity and mortality. Longitudinal studies have shown that cardiovascular diseases are one of the leading causes of death among women with breast cancer. As a result, various international agencies, such as the American Society of Clinical Oncology and the European Society of Cardiology, emphasize the importance of implementing primary prevention interventions. Exercise training is an accessible and cost-effective intervention with well-documented benefits for overall health. Preclinical studies have shown promising results in mitigating the cardiotoxic impact of anthracyclines. However, whether this potential cardioprotective effect translates to humans is a question that remains to be clarified. The objectives of this thesis were to conduct a literature review on this topic (Study 1 and 2) and, as the core of this doctoral program, to design a single-center, randomized controlled trial with two arms (exercise group vs. usual care group) (Study 3). The main objective of this trial was to analyze the impact of a supervised exercise training program on established markers of cardiac toxicity (i.e., left ventricular ejection fraction, global longitudinal strain, and cardiac biomarkers) in women with breast cancer undergoing curative anthracycline-containing chemotherapy. Secondary objectives included analyzing the safety of exercise training and its effect on cardiorespiratory fitness, physical functionality, and health-related quality of life. The program consisted of three sessions per week of combined training (i.e., aerobic and resistance training) during each participant's chemotherapy length (approximately 5- months). Through the literature review, supported by a systematic review with metaanalysis of randomized controlled trials (Study 2), we found that evidence on the effect of physical exercise on established parameters of cardiac toxicity was limited, as only four eligible studies were identified. Most of these studies had significant limitations, including designs not specifically aimed at evaluating the efficacy of physical exercise on the parameters of interest, small sample sizes, short training programs, and brief followup periods. The results of the meta-analysis did not show a significant effect of exercise training compared to non-exercise. However, an exploratory analysis, which included studies with training programs consisting of at least 36 sessions (n=3), revealed a superior effect of exercise training on resting left ventricular ejection fraction. This suggests that the length of the exercise training programs might be associated with the effect of exercise training on cardiac function. The results of the randomized controlled trial demonstrated that exercise training did not significantly prevent the decline in established markers of cardiac toxicity compared to control (Study 4). However, it was found that exercising was safe—no serious adverse events were reported during the exercise training sessions—and it significantly prevented the decline in cardiorespiratory fitness, physical functionality, and health-related quality of life (Study 4 and 6). Additionally, we found that the response of cardiorespiratory fitness among participants randomized to the exercise group was heterogeneous, which justified the analysis of potential predictors through an exploratory study (Study 5). The results revealed that the parameters associated with the response in cardiorespiratory fitness to training were baseline body mass index and total aerobic training metabolic equivalent of task per hour (MET-hour). In summary, the results of this thesis suggest that adding exercise training to standard breast cancer care does not provide benefits on established markers of cardiac toxicity in women undergoing anthracycline-containing chemotherapy. However, the findings of experimental works indicate that implementing a supervised exercise training program during chemotherapy is safe and can be a viable and effective approach for improving cardiorespiratory fitness, preventing the decline in physical functionality and healthrelated quality of life in this challenging patient population. Additionally, our study suggests that the total energy expenditure of aerobic exercise (i.e., MET-hour) may be a predictor of cardiorespiratory response.
- Fatores de risco genético para adenomas hipofisários: Uma análise nacional, multicêntrica, genética e clínicaPublication . Gaspar, Leonor Isabel Mesquita ; Lemos, Manuel Carlos Loureiro de; Gonçalves, Catarina Inês Nunes PiresOs adenomas hipofisários representam, aproximadamente, 10-15% do total dos tumores intracranianos. A prevalência destes tumores foi estimada em 1:1000 na população geral, sendo mais frequentemente diagnosticados entre os 40-60 anos de idade. Estes tumores são monoclonais, tipicamente benignos e de crescimento lento, no entanto podem estar associados a um aumento da morbilidade e mortalidade através da sobreprodução hormonal e dos efeitos de massa resultantes da compressão das estruturas adjacentes ao tumor. Os tumores hipofisários mais frequentes são os prolactinomas, seguido pelos adenomas hipofisários não funcionantes. Os mecanismos subjacentes à tumorigénese hipofisária não são ainda totalmente conhecidos, pelo que uma melhor compreensão desta questão ajudará a gerir a doença. O aumento do risco associado a mutações em genes como o AIP, MEN1, CDKN1B e PRKAR1A, fornece evidências de uma predisposição genética para adenomas hipofisários familiares. A grande maioria dos adenomas hipofisários (cerca de 95%) ocorre num contexto esporádico e na ausência de predisposição genética conhecida. No entanto, três polimorfismos (rs2359536, rs10763170 e rs17083838) foram significativamente associados a adenomas hipofisários esporádicos na população Chinesa Han. O objetivo geral desta tese foi realizar um estudo de âmbito multicêntrico nacional, acerca dos fatores de risco genético para o desenvolvimento de adenomas hipofisários familiares e esporádicos, de forma a ampliar o conhecimento sobre a tumorigénese hipofisária. Numa primeira fase desta tese, foi construída uma base de dados com todas as variantes germinativas identificadas no gene AIP publicadas em casos esporádicos e familiares de adenomas hipofisários, até à data, a nível mundial. Nesta revisão, foram identificadas e avaliadas, ao nível da sua patogenicidade, um total de 158 mutações germinativas entre 562 doentes com adenomas hipofisários esporádicos ou familiares. Estas variantes estavam localizadas em toda a região codificadora e nas regiões de splicing do gene AIP. A patogenicidade de todas as variantes germinativas publicadas foi categorizada de acordo com os critérios da American College of Medical Genetic and Genomics (ACMG), utilizando todos os dados disponíveis. Do número total de doentes, 35,4% apresentavam variantes patogénicas e 24,0% apresentavam variantes provavelmente patogénicas. Na segunda fase desta tese foi determinada a frequência de mutações germinativas do gene AIP em doentes portugueses com macroadenomas hipofisários esporádicos de início precoce. Para isso, foi sequenciado o gene AIP em 218 doentes com macroadenomas hipofisários esporádicos diagnosticados antes dos 40 anos. Foram identificadas variantes raras em heterozigotia neste gene em 18 (8,3%) doentes. No entanto, apenas quatro (1,8%) doentes apresentavam variantes patogénicas. Estas variantes compreendiam duas mutações já conhecidas (p.Arg81* e p.Leu115Trpfs*41) e duas mutações novas (p.Ser53Thrfs*36, e p.Glu246*). Estes quatro doentes tinham sido diagnosticados com somatotrofinoma em idades compreendidas entre os 14 e os 25 anos. A frequência de variantes patogénicas no gene AIP em doentes com idade inferior a 30 anos foi de 3,4% e com idade inferior a 18 anos foi de 5%, respetivamente. A frequência de mutações no gene AIP nesta coorte de doentes portugueses foi inferior à de outros estudos. A identificação de novas variantes no gene AIP expande o espetro das causas genéticas dos adenomas hipofisários e pode ajudar a compreender o papel das mutações neste gene nos mecanismos moleculares subjacentes à tumorigénese hipofisária. A terceira fase desta tese consistiu em identificar mutações germinativas num conjunto específico de 29 genes, descritos na literatura como tendo mutações germinativas em doentes com adenomas hipofisários, numa coorte de doentes portugueses diagnosticados com adenomas hipofisários esporádicos de início precoce. Para isso, foi feita a sequenciação completa do exoma em 225 doentes com macroadenomas hipofisários esporádicos diagnosticados até aos 40 anos de idade. Foram identificadas 154 variantes raras em 25 dos 29 genes. Destas foram identificadas três variantes patogénicas e 13 variantes provavelmente patogénicas, nos genes AIP, CDH23, MEN1, MSH2, PMS2, SDHB, TP53 e VHL, em 7,1% dos doentes. Nos doentes diagnosticados com idades inferiores a 30 e 18 anos, a frequência de mutações foi de 9,0% e 12%, respectivamente. Esta é, até à data, a maior análise multigénica de doentes com macroadenomas hipofisários esporádicos de início jovem. Confirmámos que o AIP é o gene mais frequentemente envolvido, mas também descobrimos causas genéticas mais raras de adenomas hipofisários, incluindo a primeira confirmação independente de um papel do gene CDH23. Na última fase desta tese foi avaliada a associação de três polimorfismos comuns próximos dos genes NEBL (rs2359536), PCDH15 (rs10763170) e CDK8 (rs17083838) à suscetibilidade a adenomas hipofisários esporádicos na população portuguesa. Foram determinadas as frequências genotípicas e alélicas de 570 casos e 546 controlos. O alelo minor CDK8 rs17083838 (alelo A) foi significativamente associado a adenomas hipofisários esporádicos. As variantes NEBL rs2359536 e PCDH15 rs10763170 não foram associadas a risco geral para a doença, embora tenha sido observada uma associação significativa entre o alelo minor PCDH15 rs10763170 (alelo T) e somatotrofinomas. Estes resultados sugerem que a variante CDK8 rs17083838, e possivelmente a variante PCDH15 rs10763170, podem aumentar a suscetibilidade a adenomas hipofisários esporádicos na população portuguesa. Concluindo, diferentes estratégias foram desenvolvidas e implementadas, ao longo desta tese, de forma a determinar quais os fatores de risco genético mais associados ao desenvolvimento de adenomas hipofisários esporádicos e familiares. Estes resultados são importantes sob o ponto de vista científico não só para uma melhor compreensão do panorama genético dos adenomas hipofisários, como também abrem portas para novas estratégias de rastreio genético direcionadas, oferecendo conhecimentos fundamentais para a gestão personalizada dos macroadenomas hipofisários de início precoce.
- Characterization and evaluation of Achillea erba-rotta subsp. moschata (Wulfen) I. Richardson and Achillea millefolium L. as potential ingredients for skin applicationsPublication . Marengo, Arianna; Cagliero, Cecilia; Sgorbini, Barbara; Menzio, Giulia ; Fusani, Pietro; Duarte, Ana Paula; Luís, Ângelo Filipe Santos ; Fonseca, Lara R. S.; Feijó, Mariana Pombal ; Socorro, Sílvia; Bertea, Cinzia Margherita; Rubiolo, PatriziaEthnopharmacological relevance: Despite their different geographical distribution Achillea millefolium L. and Achillea erba-rotta subsp. moschata (Wulfen) I. Richardson are characterized by a consolidated traditional knowledge. Although this is not their first traditional use, they have also long been used as ingredients for skin healing and skin care. Aim of the study: The aim of this work was to characterize the two Achillea species from a chemical and biomolecular point of view in order to find a simple tool for their discrimination. At the same time, the biological activity of the extracts as inhibitors of the enzymes tyrosinase and elastase and as antimicrobial agents was evaluated. Materials and methods: The biomolecular analysis was performed on the DNA region trnL-F. The hydroalcholic (EtOH50 %) extracts were quali-quantitatively characterized by HPLC-PDA-MS/MS and tested for their inhibitory effect on the enzymes tyrosinase and elastase as well as for their antimicrobial activity. Cytotoxicity towards human fibroblasts was tested to evaluate their safety for potential applications. Results: Restriction Fragment Length Polymorphism (RFLP) analysis of the trnL-F DNA region was a useful tool for species discrimination. Both extracts are rich in polyphenols and showed moderate tyrosinase (26-5 %) and elastase (22-14 %) inhibitory activity at 17 μg/mL. They were also able to inhibit the growth of the bacteria and yeasts studied, generally exhibiting cytotoxicity to human fibroblasts at concentrations of 500 μg/mL or higher. Conclusions: The hydroalcoholic extracts from the aerial parts of A. millefolium and A. erba-rotta subsp. moschata can be considered good candidates for the cosmetic and health sectors, also supporting the traditional use of these species in the treatment of skin diseases.
- Driving Healthcare Monitoring with IoT and Wearable Devices: A Systematic ReviewPublication . João Pedro da Silva Baiense; Zdravevski, Eftim; Coelho, Paulo Jorge Simões; Serrano Pires, Ivan Miguel; Velez, Fernando J.Wearable technologies have become a significant part of the healthcare industry, collecting personal health data and extracting valuable information for real-time assistance. This review article analyzes 35 scientific publications on driving healthcare monitoring with IoT and wearable device applications. These articles were considered in a quantitative and qualitative analysis using the Natural Language Processing framework and the PRISMA methodology to filter the search results. The selected articles were published between January 2010 and May 2024 in one of the following scientific databases: IEEE Xplore, Springer, ScienceDirect (i.e., El- sevier), Association for Computing Machinery (ACM), Multidisciplinary Digital Publishing Institute (MDPI), or PubMed Central. The analysis considers population, methods, hardware, features, and communications. The research highlights that data collected from one or numerous sensors is processed and accessible in a database server for various uses, such as informing professional careers or assisting users. The review sug- gests that robust and efficient driving healthcare monitoring with IoT and wearable devices applications can be designed considering the valuable principles presented in this review.
- Os Efeitos do Treino da Condição Física em Contexto MilitarPublication . Coge, Manuel; Esteves, Maria Dulce Leal; Neiva, Henrique PereiraO campo de batalha moderno impõe tarefas quotidianas fisicamente exigentes, pelo que o condicionamento físico dos militares é um elemento crucial e o treino físico um dos elementos fundamentais da preparação de cadetes. Esta tese teve como objetivos caracterizar a composição corporal e os níveis de desempenho físico dos cadetes militares de Angola, bem como avaliar os efeitos de um programa de treino físico de 34 semanas na sua aptidão física. Foram analisadas variáveis de força muscular dos membros superiores e inferiores, aptidão cardiorrespiratória e a composição corporal de 90 cadetes da academia militar (48 homens e 42 mulheres), com idades entre 18 e 24 anos. Os valores do índice de massa corporal situaram-se dentro da faixa normal tanto para homens quanto para mulheres, assim como os níveis de gordura corporal. No entanto, o desempenho físico foi inferior nas mulheres, com valores mais baixos em indicadores como flexões, abdominais e o lançamento da bola medicinal. O salto com contramovimento, a corrida de 80 metros e a aptidão cardiorrespiratória também apresentaram resultados significativamente mais baixos entre as mulheres. Num seguinte estudo, foram analisados os efeitos de um programa de treino militar em 74 cadetes (40 homens e 37 mulheres), com idades entre os 18 e 26 anos. Os participantes foram sujeitos a um programa de treino de treino de força e de resistência por 34 semanas (realizado duas vezes por semana, 90 min/sessão). Antes e após o período de treino foi avaliada a força muscular dos membros superiores e inferiores, a aptidão cardiorrespiratória e a composição corporal. Os resultados obtidos mostram uma melhoria significativa em todas as variáveis avaliadas após o programa de treino. Os maiores efeitos foram notados na massa corporal, no salto com contramovimento, no lançamento de bola medicinal e nas flexões. Curiosamente, os homens apresentaram uma maior redução de massa corporal e maior melhoria no lançamento de bola medicinal, enquanto as mulheres mostraram uma maior redução de massa gorda. Estes resultados sublinham a necessidade de programas de treino físico específicos para melhorar a composição corporal e o condicionamento físico dos cadetes militares do ISTM, especialmente nas mulheres, que apresentaram valores mais baixos de massa livre de gordura, aptidão cardiorrespiratória e desempenho neuromuscular. A inclusão de protocolos de treino adaptados ao sexo poderá maximizar a eficácia do treino e otimizar o desempenho nas tarefas físicas de alta relevância militar. Embora o estudo tenha limitações, os resultados oferecem uma contribuição significativa para o desenvolvimento de estratégias de treino mais eficazes na preparação de cadetes militares em Angola.
- Water-Emulsified Diesel Fuel in a CI Engine Tested for Aeronautical ApplicationsPublication . Oliveira, Pedro Manuel Pimenta da Silva ; Brójo, Francisco Miguel Ribeiro Proença; Serôdio, Rogério Pedro FernandesWater-in-diesel emulsions as an alternative fuel are emerging as a viable option to fight global fossil fuel consumption and emissions restrictions without the need for engine modifications. In an emulsion, two immiscible liquids are mixed with the help of surfactants, where droplets of one liquid are dispersed in a continuous flow. This thesis aims to compare water-emulsified diesel fuel with European commercially available diesel (EN590) when it comes to engine performance and emissions. The tests were performed in a single-cylinder, direct injection diesel engine (Hatz 1B40) using an eddy current dynamometer, an exhaust gas analyser, and an opacimeter. With the objective of testing the engine and the alternative fuels for operating conditions often found in aerial vehicles equipped with diesel engines (same operating principles), the tests were performed for idle settings (simulating the taxiing movement of an aircraft), 100% engine load (simulating the take-off and climbing manoeuvres), 50% engine load (representing the descent, approach, and landing phases), and 75% engine load (representing the cruise component of an aircraft's flight profile) at different engine speeds. Mixtures of EN590 diesel fuel, deionised water, and surfactants were performed in laboratory by mechanical homogenization to obtain the ideal concentrations of the different reagents to be later replicated on a bigger scale using a low-energy mixing method. The emulsions were developed to be optimised at the engine’s operating temperature and heated above the diesel fuel operating temperature to reach similar viscosities during the test procedures. The results suggest that adding water as a dispersed phase in the fuel allows to obtain overall better thermal efficiency and lower emissions of nitrogen oxides and smoke in some conditions when compared to traditional diesel. On the other hand, carbon monoxide, hydrocarbons, and carbon dioxide emissions have increased, possibly due to differences in the injection delay between the fuels. By focusing on performance over stability through the adoption of a hydrophilic emulsion formulation in line with the difficulty of further optimisation in general aviation gasoline engines and the widespread availability of diesel fuel, it can be concluded that water-in-diesel emulsions can be a viable alternative towards the goal of improving fuel consumption rates, lowering emissions, and reducing costs when optimised for specific operating conditions of diesel-powered aerial vehicles.
- Carbon leakage and energy transition: essays on foreign direct investment, sustainable development, and international tradePublication . Caetano, Rafaela Vital ; Marques, António Manuel Cardoso; Afonso, Tiago Jorge LopesThe ever-pressing quest for climate action and the consequent enlargement of environmental restrictions is reshaping current Global Value Chains (GVCs) and international trade patterns. As economic integration continues to evolve, there is evidence of international movements (investment and goods) towards the development of trade blocs with a concentration of pollution-intensive industries in developing countries, alongside significant deindustrialisation processes in many developed countries. As integration into GVCs has progressed, developing countries have found themselves further upstream, hosting polluting industries from developed countries (mainly through Foreign Direct Investment (FDI)), with the latter leading the way in climate action. But at what cost? In fact, the cost advantages emerging in developing countries are apparently coming at the expense of environmental quality. In addition, these movements have increased the external dependence of developed countries. Unprecedented global health and geopolitical crises have revealed the drawbacks of being highly integrated into GVCs. These drawbacks include the perceived concerns about countries’ sovereignty, undermined international competitiveness, and threatened fulfilment of consumer needs owing to potential supply shortages. These issues motivated the development of this thesis, which aims to gain a deeper understanding of what underpins the external dependence of developed countries and how it can be eased. To this end, seven empirical essays were developed. Environmental regulation is a widely recognised driver in the relocation of polluting industries. Why, then, does some literature support the unlikely transfer of polluting industries to developed countries? In fact, such transfers have been sustained solely based on the polluting effect of FDI in recipient countries. This thesis provides empirical evidence indicating that the pollutant impact of FDI in recipient countries is generally accompanied by an increase in the overall energy demand, predominantly supplied by non-renewable sources. Hence, to accurately evaluate the environmental impacts of FDI, an analysis of the recipient countries’ energy mix diversification should be undertaken before endorsing the transfer of industries. This thesis also sheds light on the vital role of the energy transition in recipient countries in softening the polluting impact of FDI. It should be pointed out, however, that the results reveal a potential lack of energy infrastructure in developing countries, which makes it more challenging for these countries to benefit from the energy transition.In this regard, the main findings of this thesis indicate that private participation in energy infrastructure investment encourages the energy transition in developing countries and mitigates the pollution associated with FDI. The downstream production of “environmentally friendly goods” in developed countries appears to rely on the upstream production of intermediate goods in developing countries. Additionally, the imports of intermediate goods from developing countries seem strongly encouraged by outward FDI from developed countries. These facts underline the relevance of assessing the overall environmental impact of goods from their early production (including pollution embodied in imports of intermediate goods) until their consumption. In fact, by resorting to carbon leakage, developed countries can maintain their position as leaders in climate action by polluting considerably less through production while polluting through consumption. Hence, environmental performance should cease to be exclusively measured through production-based environmental indicators. This thesis, therefore, provides empirical evidence that the external dependence of developed countries is rooted in the carbon leakage phenomenon by assessing the overall environmental impacts that might underlie the carbon leakage phenomenon, namely from the moment the investment flows out of developed countries until the moment the manufactured goods return to those economies. The energy transition has proved to have a fundamental role not only in mitigating the polluting impact of FDI in recipient countries (first, second, third, and fourth essays), but also in determining international investment and trade flows (fifth, sixth, and seventh essays). Although it may be driving carbon leakage, environmental regulation has proven to effectively reduce the external dependence of developed countries. Even though it can be considered a non-tariff barrier, enforcing environmental restrictions poses considerably low risks of trade retaliation compared to import tariffs, which are more likely to inhibit the benefits of competition. Notwithstanding, this strategy should not be exclusive; the energy transition must be pursued in parallel. The energy transition should no longer be seen merely as the substitution of fossil-fuel energy sources for renewable ones. In fact, the energy transition can trigger and entail considerable structural changes, reversing the deindustrialisation trajectory of developed countries, thus contributing to the development of robust GVCs.