Percorrer por autor "Soares, Paula"
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- Alterações do equilíbrio em indivíduos com ou sem síndrome de Down em repouso e durante a execução de uma tarefaPublication . Soares, Paula; Santos, Rubim; Cardoso, JoanaO equilíbrio é fundamental para o desempenho de Actividades de Vida Diária e de Vida Diária Instrumentais que permitem aos indivíduos com Síndrome de Down manter a sua autonomia. O objectivo principal deste estudo foi verificar as características do estado de equilíbrio em indivíduos com e sem Síndrome de Down, em repouso e durante a execução de uma tarefa, de modo a compreender as implicações da alteração do estado de equilíbrio no desempenho de actividades. Neste estudo, foram seleccionadas duas amostras, de forma probabilística por conveniência, com indivíduos de ambos os sexos. A amostra do grupo experimental foi constituída por oito indivíduos com diagnóstico de Síndrome de Down, com idades compreendidas entre os 17 e os 39 anos de idade. A amostra do grupo de controlo foi constituída por doze indivíduos sem patologia, com idades compreendidas entre os 21 e os 37 anos. O equilíbrio foi avaliado com recurso a uma Plataforma de Forças (Bertec Corporation FP4060-10) para medir a deslocação do centro de pressão (CP) dos indivíduos. A avaliação do equilíbrio decorreu em dois momentos, na posição de pé: em repouso e no desempenho da tarefa segurar um saco de compras. Os resultados diferem entre os dois grupos em repouso e durante a execução da tarefa (segurar no saco). Os valores das variáveis área e distância de deslocação do CP e oscilações corporais, antero-posterior e médio-lateralmente apresentam resultados significativos, o que sugere diferenças do estado de equilíbrio entre as amostras.
- Assessing the antitumor potential of variants of the extracellular carbohydrate polymer from synechocystis ΔsigF mutantPublication . Mota, Rita; Lima, Raquel T.; Flores, Carlos; Silva, Juliana F.; Cruz, Beatriz; Alves, Bárbara; Pinto, Marta T.; Adessi, Alessandra; Pereira, Sara B.; De Philippis, Roberto; Soares, Paula; Tamagnini, PaulaCancer is a leading cause of death worldwide with a huge societal and economic impact. Clinically effective and less expensive anticancer agents derived from natural sources can help to overcome limitations and negative side effects of chemotherapy and radiotherapy. Previously, we showed that the extracellular carbohydrate polymer of a Synechocystis ΔsigF overproducing mutant displayed a strong antitumor activity towards several human tumor cell lines, by inducing high levels of apoptosis through p53 and caspase-3 activation. Here, the ΔsigF polymer was manipulated to obtain variants that were tested in a human melanoma (Mewo) cell line. Our results demonstrated that high molecular mass fractions were important for the polymer bioactivity, and that the reduction of the peptide content generated a variant with enhanced in vitro antitumor activity. This variant, and the original ΔsigF polymer, were further tested in vivo using the chick chorioallantoic membrane (CAM) assay. Both polymers significantly decreased xenografted CAM tumor growth and affected tumor morphology, by promoting less compact tumors, validating their antitumor potential in vivo. This work contributes with strategies for the design and testing tailored cyanobacterial extracellular polymers and further strengths the relevance of evaluating this type of polymers for biotechnological/biomedical applications.
- Comprehensive Assessment of TERT mRNA Expression across a Large Cohort of Benign and Malignant Thyroid TumoursPublication . Pestana, Ana; Batista, Rui; Celestino, Ricardo; Canberk, Sule; Sobrinho-Simões, Manuel; Soares, PaulaThe presence of TERT promoter (TERTp) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of TERT in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of TERTp mutations and TERT mRNA expression in these settings. In this series, TERTp mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. TERT mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, TERT mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. TERTp mutations and TERT mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas TERT mRNA expression in the benign tumours is associated with the presence of thyroiditis.
- CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extensionPublication . Celestino, Ricardo; Nome, Torfinn; Pestana, Ana; Hoff, Andreas M.; Gonçalves, A. Pedro; Pereira, Luísa; Cavadas, Bruno; Eloy, Catarina; Bjøro, Trine; Sobrinho-Simões, Manuel; Skotheim, Rolf I.; Soares, PaulaBackground: The prognostic variability of thyroid carcinomas has led to the search for accurate biomarkers at the molecular level. Follicular thyroid carcinoma (FTC) is a typical example of differentiated thyroid carcinomas (DTC) in which challenges are faced in the differential diagnosis. Methods: We used high-throughput paired-end RNA sequencing technology to study four cases of FTC with different degree of capsular invasion: two minimally invasive (mFTC) and two widely invasive FTC (wFTC). We searched by genes differentially expressed between mFTC and wFTC, in an attempt to find biomarkers of thyroid cancer diagnosis and/or progression. Selected biomarkers were validated by real-time quantitative PCR in 137 frozen thyroid samples and in an independent dataset (TCGA), evaluating the diagnostic and the prognostic performance of the candidate biomarkers. Results: We identified 17 genes significantly differentially expressed between mFTC and wFTC. C1QL1, LCN2, CRABP1 and CILP were differentially expressed in DTC in comparison with normal thyroid tissues. LCN2 and CRABP1 were also differentially expressed in DTC when compared with follicular thyroid adenoma. Additionally, overexpression of LCN2 and C1QL1 were found to be independent predictors of extrathyroidal extension in DTC. Conclusions: We conclude that the underexpression of CRABP1 and the overexpression of LCN2 may be useful diagnostic biomarkers in thyroid tumours with questionable malignity, and the overexpression of LCN2 and C1QL1 maybe useful for prognostic purposes.
- DGCR8 microprocessor subunit mutation and expression deregulation in thyroid lesionsPublication . Rodrigues, Lia; Canberk, Sule; Macedo, Sofia; Soares, Paula; Vinagre, JoãoDeregulation of microRNA (miRNA) processing is a driver event in several tumours including thyroid cancer. DiGeorge Critical Region 8 (DGCR8) gene holds a critical role in miRNA biogenesis, as a microprocessor complex component, and in the development of the thyroid. Previous studies identified a DGCR8 mutation – the variant c.1552G>A p.(E518K) – in cases of thyroid cancer and proposed to cause a familial syndrome characterized by multinodular goitre (MNG) and schwannomatosis. The goal of this study was to characterize the variant p.(E518K) of DGCR8 in thyroid lesions and evaluate its expression.
- DICER1 and DGCR8 in thyroid tumorigenesis: miRNA biogenesis and histopathologic diversityPublication . Rodrigues, Lia; Martins, Rui Sousa; Máximo, Valdemar; Soares, Paula; Vinagre, João; Nosé, Vânia; Canberk, Sule; Rodrigues, LiaThis review examines the emerging roles of DICER1 and DGCR8, key components of the miRNA biogenesis pathway, in thyroid pathogenesis, with a particular focus on their association with oncocytic morphology. Recent findings have expanded our understanding of DICER1 syndrome and DGCR8-related thyroid disorders, revealing a broader spectrum of thyroid lesions associated with mutations in these genes than previously recognised. We analyse the current literature on DICER1 and DGCR8 mutations in thyroid pathology, synthesising data from both basic science and pathological studies. The review explores recent findings on oncocytic features in some DICER1-mutated thyroid lesions, acknowledging that this association remains under investigation. The manuscript details the molecular mechanisms underlying DICER1 and DGCR8 mutations, including their impact on miRNA processing and subsequent effects on gene expression and cellular function. We discuss the diverse range of thyroid lesions associated with these mutations, from benign follicular nodular disease to aggressive carcinomas. The clinical implications of these findings are significant, as recognising DICER1 and DGCR8-related thyroid lesions can lead to improved patient management, including genetic counselling and surveillance for other associated malignancies. We propose an algorithm for identifying DICER1-related thyroid lesions, with a focus on oncocytic tumours, to aid clinicians and pathologists in recognising these entities. This emerging field promises to refine the diagnosis, management, and treatment of thyroid disorders associated with miRNA biogenesis pathway alterations, potentially leading to novel diagnostic and therapeutic approaches.
- Evaluation of RRAS2 and TTP1 promoter mutations in thyroid tumoursPublication . Leite, Rúben; Dias, Carolina; Soares, Paula; Vinagre, JoãoThyroid cancer is the most frequent endocrine neoplasm, being the tenth most prevalent in both genders and it presenting an overall good prognosis [1]. Ras related 2 (R-Ras2), also known as TC21, is a GTP-binding protein that together with R-Ras1 and R-Ras3, is part of the R-Ras GTPase subfamily. Mutations in RRAS2 gene in the long-tailed hotspot Q72L/H block the hydrolysis of guanosine triphosphate (GTP) in Ras superfamily proteins, generating constitutively active proteins that will preferentially bound to GTP [2]. This gene is composed by five exons encoding a member of the Ras superfamily that participates in the RAS-MAPK pathway [3]. The tripeptidyl peptidase 1 promoter (TPP1p) encodes the telomere-binding protein TPP1 that recruits telomerase to the telomeres. This process plays a key role in the telomere stability and length regulation. Mutations in this promoter were reported to create novel transcription factor binding sites as previously presented for telomerase promoter (TERTp) [4]. Co-expression of these two promoters lead to telomere elongation, indicating that mutations in the TPP1 and TERT promoter cooperate for the immortalisation of cancer cells [5]. Our project aimed to evaluate mutations in the Q72L hotspot of the RRAS2 gene and in the TPP1p in thyroid tumours. Upon genotyping of RRas2 and TPP1p, we conclude that the presence of mutations in the Q72L hotspot may not represent an oncogenic event, as we did not detect them. For TPP1p, still under study, although already presented in the literature, at the moment we have not detected them in our series, pointing that they may be a rare event in thyroid tumours.
- Exploring the genetic links between voltage-gated potassium channels and familial non-medullary thyroid carcinoma: a family studyPublication . Teixeira, Elisabete; Rodrigues, Lia; Cardoso, Marta; Fernandes, Cláudia; Paula, Arnaud da Cruz; Lima, Raquel; Ferreira, Marta; Martins, Teresa; Fernandes, Andreia; Rodrigues, Fernando; Prazeres, Hugo; Soares, Paula; Rodrigues, LiaOur team identified a family where 5 elements developed thyroid cancer between the ages of 26 and 38. Since no syndromic form of the disease was found, the diagnosis was of familial non-medullary thyroid carcinoma (FNMTC). Our team employed Whole-Exome Sequencing (WES) and identified a new potentially pathogenic germline mutation in the KCNB2 gene [ p.(Gly106Arg)]. KCNB2 encodes a voltage-gated potassium channel (vgKCN), and the detected missense mutation is localized in the tetramerization domain of the protein, possibly affecting its assembly and KC efflux. Since KC efflux by the cell is a necessary condition for cellular homeostasis, channel disruption can impact the function of other ion channels nearby. Mice studies showed that KCNE2 disruption indirectly impairs sodium-iodide symporter (NIS) function, and therefore iodide uptake by the cell, resulting in hypothyroidism or follicular nodular disease. Hypothesis By indirect effect on NIS function vgKCN mutations may increase predisposition to thyroid cancer and interfere with radioiodine (RAI) therapy response. We conducted in silico studies using two different NGS databases, TCGA and one in-house oncocytic tumors database (513 and 18 patients, respectively). Alterations in 59 genes were searched for copy-number variation, point mutations and other genetic alterations. in vitro assays using the FRTL-5 cell line are being performed. FRTL-5 cells were transfected with overexpression vectors containing either KCNB2 wild-type or KCNB2 mutated sequences, and the empty vector (EV) as a negative control. Expression of thyroid markers (e.g. NIS, TSH receptor, Thyroglobulin and TPO) was evaluated by qPCR and cell viability by PrestoBlue assay. Protein expression of thyroid markers will be assessed by Western blot. Cell cycle and apoptosis through flow cytometry, cell morphology by phalloidin assay, and cell colony formation by crystal violet. Transformed cells will further be treated with Guangxitoxin-1E, a potent KCNB1 / KCNB2 inhibitor. Our in silico results show that vgKCN mutations are rare events in thyroid cancer [19/488 (4%) in TCGA; 3/18 (17%) in our in-house database]. BRAF and NRAS alterations are frequent events in vgKCN altered tumors (58% and 16%, respectively). No KCNB2 pathogenic mutations were observed. vgKCN mutations were not correlated with patient prognosis. Our in vitro preliminary results show that KCNB2 mutated cells present higher expression of the channel than KCNB2 wild-type cells. No differences in cell viability were found between KCNB2 wild-type and mutated cells. If confirmed, vgKCN mutations may identify patients with altered RAI response, serving as thyroid cancer markers and potential pharmacological targets.
- Frequency of TERT promoter mutations in human cancersPublication . Vinagre, João; Almeida, Ana; Pópulo, Helena; Batista, Rui; Lyra, Joana; Pinto, Vasco; Coelho, Ricardo; Celestino, Ricardo; Prazeres, Hugo; Lima, Luís; Melo, Miguel; Rocha, Adriana Gaspar; Preto, Ana; Castro, Patrícia; Castro, Ligia; Pardal, Fernando; Lopes, José Manuel; Santos, Lúcio; Reis, Rui Manuel; Cameselle-Teijeiro, José; Sobrinho-Simões, Manuel; Lima, Jorge; Máximo, Valdemar; Soares, PaulaReactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.
- Generation of an obese diabetic mouse model upon conditional Atrx disruptionPublication . Gaspar, Tiago Bordeira; Jesus, Tito Teles; Azevedo, Maria Teresa; Macedo, Sofia; Soares, Mariana Alves; Martins, Rui Sousa; Leite, Rúben; Rodrigues, Lia; Rodrigues, Daniela Ferreira; Cardoso, Luís; Borges, Inês; Canberk, Sule; Gärtner, Fátima; Miranda-Alves, Leandro; Lopes, José Manuel; Soares, Paula; Vinagre, JoãoATRX mutations occur in up to 17% of human pancreatic neuroendocrine tumours (PanNETs), and recent evidence points towards its inability to drive PanNET formation in mouse pancreas while predisposing individuals to inflammageing. Aiming to explore the additional non-tumourigenic consequences of Atrx deletion, we characterised an aged series of Atrx conditional disruption in β cells using the Pdx1 promoter. Homozygous mice (P.AtrxHOM) exhibited obesity, diabetes, glucose intolerance, and pancreatic adiposity at a higher extent than age- and sex-matched controls (P.AtrxWT).