Desenvolvimento de novos micro- e nano-sistemas responsivos para entrega de drogas anti-tumorais

Cancer is a major health care problem with growing incidence, not only at a national level but also worldwide. Due to this urgency in reducing cancer prevalence, the scientific community has put forward a great attention in the search for novel anti-cancer treatments, particularly, in the development of nanocarriers capable to control and promote drug delivery to target cells. These drug delivery systems are capable to overcome the limitations presented by the conventional chemotherapeutic treatments. Among the various types of nanocarriers developed so far, mesoporous silica nanoparticles (MSNs) possess unique structural properties that make them highly suitable to encapsulate and deliver drugs to cancer cells. However, for these specialized nanocarriers to be applied in cancer therapies it is still of critical importance to control the time frame of drug release at the tumor microenvironment or inside cancer cells, in order to maximize the therapeutic effect and reduce unspecific cytotoxicity. One alternative to control drug release is to endow the nanocarriers with a pH responsive drug release that takes advantage of the naturally acidic tumor microenvironment and also of the acidic pH of lysosomes. In this thesis the development of dual drug loaded pH-responsive mesoporous silica nanoparticles (MSNs) with a calcium carbonate-based coating is presented as an effective alternative to deliver drugs to prostate cancer cells. This approach allowed the simultaneous co-encapsulation of a non-steroidal anti-inflammatory drug (Ibuprofen) and Doxorubicin (an anti-tumoral drug), with high efficiency. Furthermore, the idealized calcium carbonate coating successfully promoted a pH sensitive drug release from the MSNs matrix. The delivery systems proved to be capable of maintaining the drugs inside their mesoporous structure under physiological pH, and to prompt its release in acidic environments. The resulting dual loaded MSNs coated with calcium carbonate have spherical morphology and a mean size of 167 nm, presenting therefore, good characteristics to be applied as nanocarriers. Such, is supported by the cytotoxicity studies where the idealized MSNs produced a 93% higher anti-proliferative effect than the non-coated silica nanoparticles, being even more effective than the dual free drug administration, as well. Overall, the carbonate coating of MSNs showed to be a simple and cost-effective approach for cancer therapy, in particular for a pH-triggered drug delivery. Moreover, the versatile nature of these nanocarriers allows surface modifications that can improve the selectivity to target cells, allow imaging or even a combination of them both.O cancro é atualmente um dos maiores problemas que afeta a saúde pública, tanto ao nível nacional como mundial. Apesar de grande parte das terapias convencionais possuírem a potencialidade de eliminar a maioria das células cancerígenas, estas apresentam vários problemas associados. Um dos que mais se destaca é a falta de especificidade, o que se traduz frequentemente em danos de células e tecidos saudáveis, que constituem efeitos secundários nefastos. Aliado a este facto, normalmente, também se verifica uma baixa biodisponibilidade e, por isso, são muitas vezes utilizadas concentrações mais elevadas dos agentes terapêuticos na tentativa produzir algum efeito benéfico para o paciente. Estes aumentos nas concentrações administradas acarretam consigo um acréscimo dos efeitos nocivos. Como tal, esta doença tem atraído a atenção da comunidade científica para o desenvolvimento de novas terapias. Uma boa abordagem para ultrapassar estas desvantagens é a entrega combinada de diferentes agentes terapêuticos. Esta múltipla administração utiliza os compostos em quantidades inferiores à da sua aplicação isolada, tentando assim tirar partido de um possível efeito terapêutico sinérgico resultante da combinação do ataque a diferentes caraterísticas chave das células cancerígenas. Contudo, mesmo esta abordagem não tem conseguido ultrapassar os efeitos secundários produzidos nas células saudáveis. Nos últimos anos, uma estratégia que tem sobressaído é a utilização da Nanotecnologia para a administração destes agentes terapêuticos. A utilização de nanotransportadores concede a oportunidade de ultrapassar algumas das limitações apresentadas anteriormente. De fato, no geral os nanoveículos são capazes de aumentar a solubilidade dos agentes terapêuticos, protegê-los e transportá-los na circulação sanguínea. Simultaneamente, também podem controlar a libertação destes compostos bioativos, aumentando a seletividade e penetração/absorção dos mesmos no tecido alvo. Dentro dos diferentes tipos de nanopartículas que têm vindo a ser estudados as nanopartículas mesoporosas de sílica (MSNs) apresentam características estruturais que as tornam muito adequadas para esta aplicação. Estas partículas possuem uma estrutura porosa singular, com um grande número de poros que nunca se interconectam, aliada à capacidade de armazenarem uma grande quantidade de agentes terapêuticos. Além disso, as MSNs apresentam uma estrutura rígida muito resistente à temperatura, pH e stress mecânico o que lhes garante uma elevada estabilidade. Contudo, apesar das boas propriedades que as MSNs apresentam, é ainda necessário conferir-lhes a capacidade de libertarem a sua carga na presença de um determinado estímulo para que os agentes terapêuticos sejam apenas libertados quando cheguem a um ambiente que possua esses estímulos. O estímulo pode ter como origem alterações no pH, luz, enzimas, temperatura entre outros. A sensibilidade ao pH é um dos estímulos que melhor se adequa para ser utilizado na terapia do cancro, pois as diferenças de pH observadas no microambiente tumoral e também nas vias endocíticas no interior das células cancerígenas podem ser aproveitadas para desencadear a libertação dos agentes terapêuticos. Nas MSNs esta sensibilidade a estímulos é geralmente conseguida através da ligação de polímeros na sua superfície. Porém, esta estratégia apresenta algumas desvantagens como a necessidade de utilização de processos de purificação complexos, custos elevados e um potencial de aplicação clínica limitado. Assim sendo, o trabalho de investigação desenvolvido nesta tese descreve não só o desenvolvimento de nanopartículas de sílica mesoporosas carregadas com dois agentes terapêuticos, Doxorrubicina e Ibuprofeno mas, também a nova aplicação do carbonato de cálcio para tornar as MSNs sensíveis ao pH. O carbonato de cálcio forma-se preferencialmente nos poros das MSNs impedindo assim a libertação da sua carga, e quando em meio ácido este sofre uma rápida degradação desimpedindo os poros e permitindo a libertação da Doxorrubicina e do Ibuprofeno. Este sistema foi desenvolvido e testado para a entrega de agentes terapêuticos a células do cancro da próstata. As nanopartículas produzidas apresentaram um tamanho na ordem dos 160 nm e uma morfologia esférica uniforme. Além disto, os estudos efetuados demostraram que as partículas são capazes de armazenar grandes quantidades de Doxorrubicina e Ibuprofeno na sua matriz porosa. Por outro lado, apenas perdas residuais destes agentes terapêuticos foram detetadas nos passos subsequentes ao seu armazenamento nas MSNs. Os resultados obtidos demostraram também que o revestimento de carbonato de cálcio é sensível ao pH, visto que a um pH acídico (5,6) os agentes terapêuticos apresentaram uma rápida libertação e a um pH fisiológico (7,4) a libertação foi retardada. Os estudos realizados in vitro com células do cancro da próstata (PC-3) mostraram que estas partículas eram capazes de penetrar nas células e entregar os agentes terapêuticos no seu local de ação. Em particular, foi comprovado que uma quantidade substancial de Doxorrubicina se localizava no núcleo das células tumorais após administração. Estes resultados são essenciais para verificar a eficácia desta estratégia uma vez que este agente anti-tumoral atua no núcleo ao nível do ADN. Adicionalmente, as partículas de sílica revestidas com carbonato de cálcio contendo os fármacos apresentaram uma maior atividade citotóxica do que os agentes terapêuticos na forma livre e mesmo do que as nanopartículas não revestidas. Em geral, o revestimento de carbonato de cálcio mostrou-se capaz de imprimir um comportamento sensível ao pH por parte das nanopartículas de sílica, e futuramente permitir a sua utilização na terapia do cancro. Além disto, a versatilidade que este sistema apresenta, permite modificações futuras que podem melhorar a sua seletividade para as células de interesse ou mesmo adicionar funções permitindo por exemplo o diagnóstico e a terapia em simultâneo

Open-source software product line extraction processes: the ArgoUML-SPL and Phaser cases

Software Product Lines (SPLs) are rarely developed from scratch. Commonly, they emerge from one product when there is a need to create tailored variants, or from existing variants created in an ad-hoc way once their separated maintenance and evolution become challenging. Despite the vast literature about re-engineering systems into SPLs and related technical approaches, there is a lack of detailed analysis of the process itself and the effort involved. In this paper, we provide and analyze empirical data of the extraction processes of two open source case studies, namely ArgoUML and Phaser. Both cases emerged from the transition of a monolithic system into an SPL. The analysis relies on information mined from the version control history of their respective source-code repositories and the discussion with developers that took part in the process. Unlike previous works that focused mostly on the structural results of the final SPL, the contribution of this study is an in-depth characterization of the processes. With this work, we aimed at providing a deeper understanding of the strategies for SPL extraction and their implications. Our results indicate that the source code changes can range from almost a fourth to over half of the total lines of code. Developers may or may not use branching strategies for feature extraction. Additionally, the problems faced during the extraction process may be due to lack of tool support, complexity on managing feature dependencies and issues with feature constraints. We made publicly available the datasets and the analysis scripts of both case studies to be used as a baseline for extractive SPL adoption research and practice.This research was partially funded by CNPq, grant no. 408356/2018-9; FAPPR, grant no. 51435; and FAPERJ PDR-10 Fellowship 202073/2020. Open access funding provided by Johannes Kepler University Lin

Optimization of gold core-mesoporous silica shell functionalization with TPGS and PEI for cancer therapy

Photothermal therapy (PTT) has captured the attention of different researchers around the world, since the application of NIR light responsive-nanomaterials has shown promising results in cancer therapy. Gold-core mesoporous silica shell (Au-MSS) nanoparticles allow the combination of gold mediated PTT with the drug delivery in order to improve their therapeutic potential. In this study, two different methodologies, electrostatic or chemical linkage, were explored to functionalize Au-MSS nanorods with TPGS and PEI. For that purpose, the TPGS and PEI were chemically coupled to each other or modified with 3-(triethoxysilyl)propyl isocyanate. The produced Au-MSS nanorods display a uniform morphology and a well-defined gold nucleus and silica shell. Further, the particles surface charge was dependent on the synthesis methodology. The particles modified by electrostatic interactions (Au-MSS/TPGS-PEI) were slightly negative (−16.9 and −5.1 mV) whereas the formulations produced by chemical linkage (Au-MSS/TPGS/PEI) resulted in positively charged nanoparticles (30.9 and 6.8 mV). The successful incorporation of the polymers was confirmed by Fourier Transformed Infrared spectroscopy and thermogravimetric analysis. Moreover, the Au-MSS functionalization did not affect the particles PTT capacity. However, the Au-MSS/TPGS/PEI nanorods displayed a decreased drug encapsulation efficiency. In vitro assays demonstrated the cytocompatibility of Au-MSS up to concentrations of 200 μg/mL, however the positively charged formulations only remained biocompatible until 100 and 125 μg/mL. Overall, the attained data confirm the successful modification of Au-MSS nanorods with TPGS and PEI as well as their applicability as PTT and drug delivery agents.info:eu-repo/semantics/publishedVersio

La notion d'urbanisation

La notion d’urbanisatio

Lignin-enriched tricalcium phosphate/sodium alginate 3D scaffolds for application in bone tissue regeneration

The bone is a connective, vascularized, and mineralized tissue that confers protection to organs, and participates in the support and locomotion of the human body, maintenance of homeostasis, as well as in hematopoiesis. However, throughout the lifetime, bone defects may arise due to traumas (mechanical fractures), diseases, and/or aging, which when too extensive compromise the ability of the bone to self-regenerate. To surpass such clinical situation, different therapeutic approaches have been pursued. Rapid prototyping techniques using composite materials (consisting of ceramics and polymers) have been used to produce customized 3D structures with osteoinductive and osteoconductive properties. In order to reinforce the mechanical and osteogenic properties of these 3D structures, herein, a new 3D scaffold was produced through the layer-by-layer deposition of a tricalcium phosphate (TCP), sodium alginate (SA), and lignin (LG) mixture using the Fab@Home 3D-Plotter. Three different TCP/LG/SA formulations, LG/SA ratio 1:3, 1:2, or 1:1, were produced and subsequently evaluated to determine their suitability for bone regeneration. The physicochemical assays demonstrated that the LG inclusion improved the mechanical resistance of the scaffolds, particularly in the 1:2 ratio, since a 15 % increase in the mechanical strength was observed. Moreover, all TCP/LG/SA formulations showed an enhanced wettability and maintained their capacity to promote the osteoblasts' adhesion and proliferation as well as their bioactivity (formation of hydroxyapatite crystals). Such results support the LG inclusion and application in the development of 3D scaffolds aimed for bone regeneration.info:eu-repo/semantics/publishedVersio

O Conselho Municipal de Assistência Social de Palmas-TO: uma análise de sua atuação sob a perspectiva da Cidadania Deliberativa

O modelo democrático, deliberativo e participativo dos Conselhos Municipais no Brasil foi impulsionado com a promulgação da Constituição Federal de 1988. Tais ambientes tornaram-se campos de excelência para o exercício da cidadania e espaços legítimos de participação, com portas abertas para que a sociedade civil pudesse opinar, deliberar e ser parte ativa do processo de decisão e na construção de políticas públicas. Partindo-se deste contexto, objetivou-se neste estudo, realizar uma análise sobre a participação dos diferentes atores sociais – conselheiros – no Conselho Municipal de Assistência Social (CMAS) do município de Palmas, capital do Tocantins, à luz do conceito de Cidadania Deliberativa. Sendo o CMAS o palco do nosso objeto de estudo, tratou-se também de compreender a percepção dos Conselheiros (biênio 2016-2018) a respeito do funcionamento, dinâmica e objetivos do CMAS. Dentre os métodos investigativos, a pesquisa se valeu de observação direta não participante, aplicação de entrevistas semiestruturadas, questionários e análise documental. Os resultados da pesquisa apontam que alguns critérios de cidadania deliberativa foram identificados e bem atendidos; enquanto outros critérios carecem de reflexão no sentido de elevar os níveis de participação social no Conselho estudado

Challenges in characterization of GNSS precise positioning systems for automotive

Autonomous driving is currently one of the main focuses of attention in the automotive industry. A requirement for efficient and safe driving of autonomous vehicles is the ability to precisely pinpoint the location of the vehicle, in the decimeter- to centimeter-level on a global scale. GNSS is expected to play a major role in providing accurate absolute and global positioning, yet many challenges arise in dense urban environments due to lack of line-of-sight to satellites and multi-path, decreasing availability and accuracy. Also, the position accuracy announced by GNSS receiver manufacturers is rather optimistic, typically obtained in best-case scenarios. However, this is rarely encountered in real-world driving conditions, especially in urban areas, leading to a mismatch between receiver specification and real world performance. This paper provides a systematic study regarding the requirements, methods, and solutions available for the characterization/evaluation of a GNSS po- sitioning system in real world driving conditions. An architecture for a precise Automotive Global Reference System (centimeter-level), able to characterize a decimeter-level accuracy GNSS position- ing system in dynamic conditions, is proposed. To the best of authors’ knowledge, such a study is not available in the literature.This work has been supported by: European Structural and Investment Funds in the FEDER component, through the Operational Competitiveness and Internationalization Programme (COMPETE 2020) [Project no 037902; Funding Reference: POCI-01-0247-FEDER-037902]

Development of a poly(vinyl alcohol)/lysine electrospun membrane-based drug delivery system for improved skin regeneration

Nanofiber-based wound dressings are currently being explored as delivery systems of different biomolecules for avoiding skin infections as well as improve/accelerate the healing process. In the present work, a nanofibrous membrane composed of poly(vinyl alcohol) (PVA) and lysine (Lys) was produced by using the electrospinning technique. Further, anti-inflammatory (ibuprofen (IBP)) and antibacterial (lavender oil (LO)) agents were incorporated within the electrospun membrane through blend electrospinning and surface physical adsorption methods, respectively. The obtained results demonstrated that the PVA_Lys electrospun membranes incorporating IBP or LO displayed the suitable morphological, mechanical and biological properties for enhancing the wound healing process. Moreover, the controlled and sustained release profile attained for IBP was appropriate for the duration of the wound healing inflammatory phase, whereas the initial burst release of LO is crucial to prevent wound bacterial contamination. Indeed, the PVA_Lys_LO electrospun membranes were able to mediate a strong antibacterial activity against both S. aureus and P. aeruginosa, without compromising human fibroblasts viability. Overall, the gathered data emphasizes the potential of the PVA_Lys electrospun membranes-based drug delivery systems to be used as wound dressings.info:eu-repo/semantics/publishedVersio

Some statistical methods directed the information centers

Este estudo visa mostrar algumas técnicas estatísticas aplicadas na gestão informacional nas unidades de informação através da utilização de métodos de mensuração e métricas quantitativas atreladas a estudos relacionados à bibliometria, cienciometria, econometria entre outros. Os estudos envolvendo estatística podem ser descritivos, para construção de indicadores, inferencial através de modelos teóricos ou empíricos. As técnicas estatísticas permitem que de base de dados sejam extraídas informações relevantes à tomada de decisão.  Assim, será brevemente explanando sobre probabilidade, distribuição de frequência, séries estatísticas, covariância e correlação, regressão linear e números índices.Este estudio apunta a mostrar algunas técnicas estadísticas aplicadas en la gestión informacional en las unidades de información a través del uso de métodos de medición y métricas cuantitativas relacionadas a los estudios en bibliometria,  cienciometria, econometría entre otros. Los estudios que involucran estadística pueden ser descriptivos, para la construcción de indicadores, o inferenciales mediante modelos teóricos o empíricos. Las técnicas estadísticas permiten que desde las bases de datos se extraiga información relevante para la toma de decisiones. Así se expondrá brevemente sobre la probabilidad, la distribución de frecuencia, las series estadísticas, la covariancia y correlación, la regresión lineal y los números índices.This study aims to show some statistical techniques applied in information management in the units of information through the use of methods of measurement and quantitative metrics tied to studies related to bibliometrics, scientometrics, econometrics among others. The studies involving statistics can be descriptive, for construction of indicators, inferential models through theoretical or empirical. Statistical techniques allow the database to be extracted relevant information for decision making. This will briefly explaining about probability, frequency distribution, statistical series, covariance and correlation, linear regression and index numbers

Myocardial stretch-induced compliance is abrogated under ischemic conditions and restored by cGMP/PKG-related pathways

Introduction: Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI.Methods: We conducted experiments in ex vivo rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure–volume hemodynamic evaluations in experimental in vivo MI induced by left anterior descending artery ligation in rats.Results: Acutely stretching muscles ex vivo yielded increased compliance over the next 15 min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5i) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration. In vivo translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5i. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading.Discussion: Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5i. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia