RCAAP Repository

The global impact of cancer emphasizes the importance of developing innovative, effective and minimally invasive therapies. In the context of superficial cancers, the development of a multifunctional nanoparticle-based system and its in vitro and in vivo safety and efficacy characterization are, herein, proposed as a proof-of-concept. This multifunctional system consists of gold nanoparticles coated with hyaluronic and oleic acids, and functionalized with epidermal growth factor for greater specificity towards cutaneous melanoma cells. This nanoparticle system is activated by a near-infrared laser. The characterization of this nanoparticle system included several phases, with in vitro assays being firstly performed to assess the safety of gold nanoparticles without laser irradiation. Then, hairless immunocompromised mice were selected for a xenograft model upon inoculation of A375 human melanoma cells. Treatment with near-infrared laser irradiation for five minutes combined with in situ administration of the nanoparticles showed a tumor volume reduction of approximately 80% and, in some cases, led to the formation of several necrotic foci, observed histologically. No significant skin erythema at the irradiation zone was verified, nor other harmful effects on the excised organs. In conclusion, these assays suggest that this system is safe and shows promising results for the treatment of superficial melanoma.

This study aimed to examine the association between meeting 24-h movement guidelines and cardiometabolic health in Chilean adults. We used cross-sectional data of 2618 adults from the Chilean National Health Survey 2016-2017. Meeting the 24-h movement guidelines was defined as ≥ 600 MET-min/week of physical activity; ≤ 8 h/day of sitting time; and 7 to 9 h/day of sleep duration. Cardiometabolic health indicators were body mass index, waist circumference, high triglycerides, high blood pressure, type 2 diabetes, metabolic syndrome, and risk of cardiovascular disease in a 10-year period. Meeting none out of three 24-h movement guidelines (vs all three) was associated with higher odds of overweight/obesity (OR 1.67; 95%CI 1.45 to 1.89), high waist circumference (1.65; 1.40 to 1.90), hypertension (2.88; 2.23 to 3.53), type 2 diabetes (1.60; 1.26 to 1.94), metabolic syndrome (1.97; 1.54 to 2.40) and risk of cardiovascular disease (1.50; 1.20, 1.80). Meeting one guideline (vs three) was associated with higher odds of five of out seven cardiometabolic indicators. Our study found that the composition of movement behaviors within a 24-h period may have important implications for cardiometabolic health.

The properties of gold-based materials have been explored for centuries in several research fields, including medicine. Multiple published production methods for gold nanoparticles (AuNPs) have shown that the physicochemical and optical properties of AuNPs depend on the production method used. These different AuNP properties have allowed exploration of their usefulness in countless distinct biomedical applications over the last few years. Here we present an extensive overview of the most commonly used AuNP production methods, the resulting distinct properties of the AuNPs and the potential application of these AuNPs in diagnostic and therapeutic approaches in biomedicine.

Background: Predicting progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD) is an utmost open issue in AD-related research. Neuropsychological assessment has proven to be useful in identifying MCI patients who are likely to convert to dementia. However, the large battery of neuropsychological tests (NPTs) performed in clinical practice and the limited number of training examples are challenge to machine learning when learning prognostic models. In this context, it is paramount to pursue approaches that effectively seek for reduced sets of relevant features. Subsets of NPTs from which prognostic models can be learnt should not only be good predictors, but also stable, promoting generalizable and explainable models. Methods: We propose a feature selection (FS) ensemble combining stability and predictability to choose the most relevant NPTs for prognostic prediction in AD. First, we combine the outcome of multiple (filter and embedded) FS methods. Then, we use a wrapper-based approach optimizing both stability and predictability to compute the number of selected features. We use two large prospective studies (ADNI and the Portuguese Cognitive Complaints Cohort, CCC) to evaluate the approach and assess the predictive value of a large number of NPTs. Results: The best subsets of features include approximately 30 and 20 (from the original 79 and 40) features, for ADNI and CCC data, respectively, yielding stability above 0.89 and 0.95, and AUC above 0.87 and 0.82. Most NPTs learnt using the proposed feature selection ensemble have been identified in the literature as strong predictors of conversion from MCI to AD. Conclusions: The FS ensemble approach was able to 1) identify subsets of stable and relevant predictors from a consensus of multiple FS methods using baseline NPTs and 2) learn reliable prognostic models of conversion from MCI to AD using these subsets of features. The machine learning models learnt from these features outperformed the models trained without FS and achieved competitive results when compared to commonly used FS algorithms. Furthermore, the selected features are derived from a consensus of methods thus being more robust, while releasing users from choosing the most appropriate FS method to be used in their classification task.

Breast cancer is a high-burden malignancy for society, whose impact boosts a continuous search for novel diagnostic and therapeutic tools. Among the recent therapeutic approaches, photothermal therapy (PTT), which causes tumor cell death by hyperthermia after being irradiated with a light source, represents a high-potential strategy. Furthermore, the effectiveness of PTT can be improved by combining near infrared (NIR) irradiation with gold nanoparticles (AuNPs) as photothermal enhancers. Herein, an alternative synthetic method using rosmarinic acid (RA) for synthesizing AuNPs is reported. The RA concentration was varied and its impact on the AuNPs physicochemical and optical features was assessed. Results showed that RA concentration plays an active role on AuNPs features, allowing the optimization of mean size and maximum absorbance peak. Moreover, the synthetic method explored here allowed us to obtain negatively charged AuNPs with sizes favoring the local particle accumulation at tumor site and maximum absorbance peaks within the NIR region. In addition, AuNPs were safe both in vitro and in vivo. In conclusion, the synthesized AuNPs present favorable properties to be applied as part of a PTT system combining AuNPs with a NIR laser for the treatment of breast cancer.

Cancer like melanoma is a complex disease, for which standard therapies have significant adverse side effects that in most cases are ineffective and highly unspecific. Thus, a new paradigm has come with the need of achieving alternative (less invasive) and effective therapies. In this work, biocompatible gold nanoparticles (GNPs) coated with hyaluronic acid and oleic acid were prepared and characterized in terms of size, morphology and cytotoxicity in the presence of Saccharomyces cerevisiae, and two cell lines, the keratinocytes (healthy skin cells, HaCat) and the melanoma cells (B16F10). Results showed that these GNPs absorb within the near-infrared region (750–1400 nm), in the optical therapeutic window (from 650 to 1300 nm), in contrast to other commercial gold nanoparticles, which enables light to penetrate into deep skin layers. A laser emitting in this region was applied and its effect also analyzed. The coated GNPs showed a spherical morphology with a mean size of 297 nm without cytotoxic effects towards yeast and tested cell lines. Nevertheless, after laser irradiation, a reduction of 20% in B16F10 cell line viability was observed. In summary, this work appears to be a promising strategy for the treatment of non-metastatic melanoma or other superficial tumors.

Theranostics has emerged in recent years to provide an efficient and safer alternative in cancer management. This review presents an updated description of nanotheranostic formulations under development for skin cancer (including melanoma), head and neck, thyroid, breast, gynecologic, prostate, and colon cancers, brain-related cancer, and hepatocellular carcinoma. With this focus, we appraised the clinical advantages and drawbacks of metallic, polymeric, and lipid-based nanosystems, such as low invasiveness, low toxicity to the surrounding healthy tissues, high precision, deeper tissue penetration, and dosage adjustment in a real-time setting. Particularly recognizing the increased complexity and multimodality in this area, multifunctional hybrid nanoparticles, comprising different nanomaterials and functionalized with targeting moieties and/or anticancer drugs, present the best characteristics for theranostics. Several examples, focusing on their design, composition, imaging and treatment modalities, and in vitro and in vivo characterization, are detailed herein. Briefly, all studies followed a common trend in the design of these theranostics modalities, such as the use of materials and/or drugs that share both inherent imaging (e.g., contrast agents) and therapeutic properties (e.g., heating or production reactive oxygen species). This rationale allows one to apparently overcome the heterogeneity, complexity, and harsh conditions of tumor microenvironments, leading to the development of successful targeted therapies.

No summary/description provided

Apresenta-se o estudo de adaptação para Portugal da escala de autoconceito profissional dos professores, denominada “Teacher self-concept evaluation scale” (TSCES), de Villa e Calvete (2001). A amostra foi constituída por 251 professores de diferentes grupos disciplinares e níveis de ensino, diferenciados, ainda, quanto a variáveis pessoais, escolares e sociais. No estudo psicométrico da escala, recorreu-se à análise factorial de componentes principais com rotação varimax – que evidenciou os seis factores esperados (competência, relação com colegas, relação com os alunos, satisfação, aceitação de iniciativas, auto-aceitação); procedeu-se ainda à determinação dos coeficientes de fiabilidade, para diferentes grupos, sendo 57,59% a variância total explicada. Para o estudo da validade externa, considerou-se a relação entre os resultados na TSCES e os resultados na escala EAPP (Escala de Autoconceito Profissional dos Professores), de Veiga e outros (2003), observando-se significativas correlações. Os elementos apresentados mostraram-se consistentes e salientam as qualidades da “Teacher self-concept evaluation scale” em diferentes grupos, bem como a sua utilidade para a investigação com professores.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with short survival, mainly due to respiratory failure. A pathological repeat expansion in the C9orf72 gene is observed in about 10% of the European ALS population and is associated with a worse prognosis. Still, the exact function of this gene is unknown. To understand the role of the C9orf72 expansion in disease prognosis, we tested the impact of this mutation on the respiratory function in ALS.

The frequency and importance of Aspergillus infections is increasing worldwide. This study aimed to assess the occupational exposure of forklifts and taxi drivers to Aspergillus spp. Nineteen filters from air conditioning system of taxis, 17 from forklifts and 37 from personal vehicles were assessed. Filters extract were streaked onto MEA, DG18 and in azole-supplemented media. Real-time quantitative PCR amplification of selected Aspergillus species-complex was also performed. Forklifts filter samples presented higher median values. Aspergillus section Nigri was the most observed in forklifts filters in MEA (28.2%) and in azole-supplemented media. DNA from Aspergillus sections Fumigati and Versicolores was successfully amplified by qPCR. This study enlightens the added value of using filters from the air conditioning system to assess Aspergillus spp. occupational exposure. Aspergillus azole resistance screening should be included in future occupational exposure assessments.

Background: Perioperative complications can affect outcomes after gastrectomy for cancer, with high mortality and morbidity rates ranging between 10 and 40%. The absence of a standardized system for recording complications generates wide variation in evaluating their impacts on outcomes and hinders proposals of quality-improvement projects. The aim of this study was to provide a list of defined gastrectomy complications approved through international consensus. Methods: The Gastrectomy Complications Consensus Group consists of 34 European gastric cancer experts who are members of the International Gastric Cancer Association. A group meeting established the work plan for study implementation through Delphi surveys. A consensus was reached regarding a set of standardized methods to define gastrectomy complications. Results: A standardized list of 27 defined complications (grouped into 3 intraoperative, 14 postoperative general, and 10 postoperative surgical complications) was created to provide a simple but accurate template for recording individual gastrectomy complications. A consensus was reached for both the list of complications that should be considered major adverse events after gastrectomy for cancer and their specific definitions. The study group also agreed that an assessment of each surgical case should be completed at patient discharge and 90 days postoperatively using a Complication Recording Sheet. Conclusion: The list of defined complications (soon to be validated in an international multicenter study) and the ongoing development of an electronic datasheet app to record them provide the basic infrastructure to reach the ultimate goals of standardized international data collection, establishment of benchmark results, and fostering of quality-improvement projects.

Interleukin 7 (IL-7) and its receptor (IL-7R, a heterodimer of IL-7Rα and γc) are essential for normal lymphoid development. In their absence, severe combined immunodeficiency occurs. By contrast, excessive IL-7/IL-7R-mediated signaling can drive lymphoid leukemia development, disease acceleration and resistance to chemotherapy. IL-7 and IL-7R activate three main pathways: STAT5, PI3K/Akt/mTOR and MEK/Erk, ultimately leading to the promotion of leukemia cell viability, cell cycle progression and growth. However, the contribution of each of these pathways towards particular functional outcomes is still not completely known and appears to differ between normal and malignant states. For example, IL-7 upregulates Bcl-2 in a PI3K/Akt/mTOR-dependent and STAT5-independent manner in T-ALL cells. This is a 'symmetric image' of what apparently happens in normal lymphoid cells, where PI3K/Akt/mTOR does not impact on Bcl-2 and regulates proliferation rather than survival. In this review, we provide an updated summary of the knowledge on IL-7/IL-7R-mediated signaling in the context of cancer, focusing mainly on T-cell acute lymphoblastic leukemia, where this axis has been more extensively studied.

Objectives: To compare consecutive disease modifying antirheumatic drug (DMARD)-treatment regimes in daily practice in patients with rheumatoid arthritis (RA) who failed on initial methotrexate, while using a multiple propensity score (PS) method to control for the spurious effects of confounding by indication. Methods: Patients with newly diagnosed RA who had failed initial treatment with methotrexate were selected from METEOR, an international, observational registry. Subsequent DMARD-treatment regimens were categorised as: (1) conventional synthetic DMARD(s) (csDMARD(s)) only (143 patients), (2) csDMARD(s)+glucocorticoid (278 patients) and (3) biological DMARD (bDMARD)±csDMARD(s) (89 patients). Multiple PS that reflect the likelihood of treatment with each treatment-regime were estimated per patient using multinomial regression. Linear mixed model analyses were performed to analyse treatment responses per category (Disease Activity Score (DAS)) after a maximum follow-up duration of 6 and 12 months, and results were presented with adjustment for the multiple PS. Results: After 6 months, follow-up PS-adjusted treatment responses yielded a change in DAS per year (95% CI) of -2.00 (-2.65 to -1.36) if patients received a bDMARD; of -0.96 (-1.33 to -0.59) if patients received csDMARD(s)+glucocorticoids and of -0.73 (-1.21 to -0.25) if patients received csDMARDs only. These changes were -0.91 (-1.23 to -0.60); -0.43 (-0.62 to -0.23) and -0.39 (-0.66 to -0.13), respectively after 1 year of follow-up. Conclusions: In this analysis of worldwide common practice data with adjustment for multiple PS, patients with RA who had failed initial treatment with methotrexate monotherapy had a better DAS-response after a subsequent switch to a bDMARD-containing treatment regimen than to a regimen with csDMARD(s) only, with or without glucocorticoids.

The incidence of end-stage renal disease (ESRD) is increasing worldwide. When compared to dialysis, renal transplantation (RT) leads to a survival advantage and to an improvement in quality of life in most ESRD patients. Additionally, from a societal perspective, RT is the most cost-effective modality of renal replacement therapy (RRT) for eligible patients. In the last decades, RT has prolonged and improved the lives of hundreds of thousands of patients worldwide. Nevertheless, although the prevalence of ESRD is increasing in most countries, transplantation rates have not kept pace. In 2016, there were nearly 2000 patients waiting for RT in Portugal and only 500 kidney transplants were performed, illustrating the clear discrepancy between the number of transplants and the number of patients awaiting for transplantation.

A doença provocada pelo vírus Influenza é etiologia mundial de doença respiratória aguda que cursa com hospitalizações e mortes anualmente. Neste sentido, antivirais foram criados para melhorar o prognóstico dos doentes com patologia severa, no entanto, têm demonstrado reduzir os dias de doença em apenas 1 dia. Assim, a vacina é a único método que efetivamente reduz a morbimortalidade da doença, traduzindo-se numa diminuição do número de hospitalizações e mortes. O vírus Influenza tem duas glicoproteínas - Hemaglutinina (HA) e Neuramidase (NA) – cuja porção superior dos antigénios HA/NA mutam-se constantemente, reduzindo o reconhecimento imunitário e a neutralização viral. Historicamente, os vírus Influenza demonstraram capacidade para sofrer alterações significativas, mecanismo denominado de antigenic-shift, tendo cursado com pandemias e vulnerabilizado a população mundial. A sazonalidade do vírus Influenza deve-se a mutações minor constantes das glicoproteínas, mecanismo denominado de antigenic-drift, permitindo a recorrência de infeção pela Influenza. De modo que, a produção de vacinas atuais tem eficácia oscilante, é dependente da qualidade e quantidade de ovos disponíveis, é um método de produção moroso com fatores externos capazes de induzir mutação. Neste sentido, novas vacinas foram idealizadas por formar a contornar as fragilidades das vacinas atuais. Porventura, apenas recentemente, pela necessidade de produção de vacinas face à pressão que a pandemia pela COVID-19 exerceu, novos métodos de produção de vacinas têm surgido e demonstrado abrir portas a alternativas custo-eficazes para a vacinologia de várias doenças infecciosas. O objetivo desta Tese é fazer uma revisão narrativa sobre as fragilidades das vacinas atuais e avanços na vacina da Influenza. A metodologia baseia-se na pesquisa bibliográfica na PubMed, Centre for Disease control and Prevention (CDC), European Centre for disease prevention and Control (ECDC).

Introdução e objetivos: Craniectomia descompressiva (CD) é uma cirurgia utilizada nos casos de hipertensão intracraniana refratária, que envolve a remoção de uma parte do crânio para diminuir a pressão intracraniana. Está indicada posterior reconstrução (cranioplastia). Os objetivos são: a) caracterizar os doentes que realizaram estes procedimentos, b) avaliar os estados funcionais pós-CD, pós-cranioplastia e atual, c) avaliar a qualidade de vida relacionada com saúde (QVRS) pós-CD e pós-cranioplastia. Métodos: Estudo retrospetivo descritivo, unicêntrico, não controlado e não aleatorizado. Consulta dos processos dos doentes internados na UCIPed do HSM que realizaram CD entre Janeiro de 2011 e Junho de 2021. Para avaliar o estado funcional utilizou-se a escala PCPC/POPC, e para a QVRS utilizou-se o questionário KINDL®. Resultados: 35 doentes, 22 (62,9%) do sexo masculino, idade média de 10,6 anos. A indicação mais frequente para CD foi traumatismo crânio-encefálico. A duração média do internamento foi de 8,6 dias. A mediana do pior GCS pré-CD foi de 8. A probabilidade de morte média foi de 11,6%. 3 doentes (8,6%) faleceram. 29 doentes fizeram cranioplastia (intervalo médio CD-cranioplastia de 180 dias). A duração de seguimento média foi de 57,5 meses. 2 crianças faleceram pós-cranioplastia. Em relação ao PCPC, pré-CD 34 (97,1%) doentes tinham um bom outcome, pós-CD 8 (22,9%) tinham um bom outcome, atualmente 23 (65,7%) têm um bom outcome. Em relação ao POPC, pré-CD 32 (91,4%) doentes tinham um bom outcome, pós-CD 8 (22,9%) tinham um bom outcome, atualmente 23 (65,7%) têm um bom outcome. Em relação à QVRS, foi avaliada em 20 doentes. A QVRS média pós-CD foi 56,56 ±16,44 e pós-cranioplastia foi 63,59 ±15,74. Conclusão: A CD permitiu uma melhoria da sobrevida, verificando-se uma melhoria do outcome a longo prazo. A QVRS melhorou após a cranioplastia.

Introduction Non-healing wounds remain a major burden due to the lack of effective treatments. Mesenchymal stem cell-derived exosomes (MSC-Exo) have emerged as therapeutic options given their pro-regenerative and immunomodulatory features. Still, little is known on the exact mechanisms mediated by MSC-Exo. Importantly, modulation of their efficacy through 3D-physiologic cultures together with loading strategies continues underexplored. Objectives To uncover the MSC-Exo-mediated mechanism via proteomic analyses, and to use 3D-culture and loading technologies to expand MSC-Exo efficacy for cutaneous wound healing. Methods MSC-Exo were produced in either 3D or 2D cultures (Exo3D/Exo2D) and loaded with an exogenous immunosuppressive oligodeoxynucleotide (A151 ODN). Both, loaded and naïve exosomes were characterised regarding size, morphology and the presence of specific protein markers; while IPA analyses enabled to correlate their protein content with the effects observed in vitro and in vivo. The Exo3D/Exo2D regenerative potential was evaluated in vitro by assessing keratinocyte and fibroblast mitogenicity, motogenicity, and cytokine secretion as well as using an in vivo wound splinting model. Accordingly, the modulation of inflammatory and immune responses by A151-loaded Exo3D/Exo2D was also assessed. Results Exo3D stimulated mitogenically and motogenically keratinocytes and fibroblasts in vitro, with upregulation of IL-1α and VEGF-α or increased secretion of TGF-β, TNF-α and IL-10. In vivo, Exo3D reduced the granulation tissue area and promoted complete re-epithelization of the wound. These observations were sustained by the proteomic profiling of the Exo3D cargo that identified wound healing-related proteins, such as TGF-β, ITGA1-3/5, IL-6, CDC151, S100A10 and Wnt5α. Moreover, when loaded with A151 ODN, Exo3D differentially mediated wound healing-related trophic factors reducing the systemic levels of IL-6 and TNF-α at the late stage of wound healing in vivo. Conclusion Our results support the potential of A151-loaded Exo3D for the treatment of chronic wounds by promoting skin regeneration, while modulating the systemic levels of the pro-inflammatory cytokines

We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor βγc heterodimer (IL-2Rβγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rβγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rβγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.

Este estudo teve como objectivo analisar a relação entre as perspectivas de educação superior (aspirações escolares) e variáveis de natureza social (nacionalidade, nível de instrução familiar), e ainda estudar a relação entre a realização (escolar e pessoal) e as aspirações profissionais, ao longo da adolescência. A amostra foi constituída por 487 sujeitos de diferentes anos de escolaridade (7º, 9º e 11º anos), de escolas da Grande Lisboa e do Interior do país. A realização escolar foi avaliada através das notas escolares em disciplinas fundamentais, e a realização pessoal através do instrumento Children’s Rights Scale; os alunos foram questionados ainda acerca da profissão que gostariam de vir a ter e do nível de escolaridade que gostariam de atingir. A análise dos resultados permitiu observar diferenças significativas nas variáveis da realização, quer escolar quer pessoal, em função das perspectivas de educação superior (aspirações escolares e profissionais), apresentando-se tais diferenças favoráveis aos grupos de alunos com maiores aspirações a uma Educação Superior. Observou-se, ainda, que tais diferenças passaram por oscilações específicas ao longo dos anos de escolaridade. Os resultados foram interpretados num posicionamento cognitivo-social e desenvolvimentista, remetendo para a necessidade de pesquisas específicas e tomando como suporte de discussão a sua comparação com investigações algo similares.