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- Avaliação da viabilidade de implementação da braquiterapia de alta taxa de dose para o cancro ginecológico no AlgarvePublication . Calapez, Cristina Isabel Duarte Fernandes; Coelho, Luís Miguel Serra; Peixinho, Rúben Miguel TorcatoO cancro é um dos maiores problemas de saúde pública mundial, com milhões de novos casos diagnosticados todos os anos e uma das principais causas de morte. Em particular, estima-se anualmente a incidência de mais de um milhão de novos casos de cancros ginecológicos no mundo. A braquiterapia surge como uma possível abordagem terapêutica para algumas localizações do cancro ginecológico. O presente estudo surge, assim, da necessidade de implementar valências adequadas que permitam proporcionar um cuidado de saúde mais próximo. Para tal, seguiu-se um método de investigação descritivo, quantitativo e retrospetivo. Por forma a entender a viabilidade de implementação da técnica considerou-se como população todas as mulheres residentes no Algarve diagnosticadas com neoplasias ginecológicas e como amostra aquelas em que a braquiterapia é eleita como terapêutica. Na pretensão de avaliar a viabilidade de um novo programa de braquiterapia, consideraram-se para a determinação dos custos duas realidades: aquisição dos recursos necessários para implementar a técnica na região versus a utilização de recursos existentes noutras instituições. Estima-se que se poderia evitar um excesso de cerca de 50,5 % no custo médio de cada tratamento, caso a região possuísse recursos próprios que permitissem tratar as doentes referenciadas.
- Epigenetic regulation of ZNF687 in bone cells: elucidation of its role in the progression of Paget’s disease of bonePublication . Domingos Varela, Débora Cristina; Cancela, Leonor; Conceição, NatérciaPaget’s disease of bone (PDB) is characterized by focal areas of intense bone resorption by hyperactive osteoclasts followed by excessive bone formation by osteoblasts. Mutations and increased expression of ZNF687 have been associated with PDB. However, the role of ZNF687 in bone metabolism is poorly understood, and the molecular mechanisms that regulate its expression remain unknow. Therefore, the main objective of this study was to investigate the regulation of ZNF687 in bone cells, focusing on epigenetic mechanisms, in order to elucidate its involvement in the pathophysiology of PDB. In addition, we performed a genetic analysis of ZNF687, along with other candidate genes, in a cohort from southern Portugal. First, we characterized the human ZNF687 promoter, evaluated the functionality of predicted binding sites for bone-related transcription factors, and assessed the impact of CpG methylation on its regulatory activity. Our results indicate that NFκB, PU.1, DLX5, and SOX9 act as transcriptional regulators of ZNF687, and that DNA methylation inhibits their regulatory activity. Next, we analyzed mice Zfp687 expression and epigenetic regulation in MC3T3-E1 osteoblast differentiation and in hindlimb bones throughout mice life stages. Our results suggest that miR-142a-3p targets Zfp687 3′UTR, contributing to its downregulation during osteoblastogenesis, while DNA methylation does not appear to regulate Zfp687. In the PDB genetic study of Portuguese population, we identified the ZNF687 c.2810C>A variant that was predicted in silico to be pathogenic and shown in vitro to enhance nuclear import. In addition, OPTN rs2234968 variant was significantly associated with PDB. Finally, we examined ZNF687 expression and CpG methylation during in vitro osteoclast differentiation. ZNF687 was upregulated during murine osteoclastogenesis and overexpressed in osteoclasts from PDB patients in comparison to those of healthy controls. Moreover, methylation levels in -506/-396 promoter region were significantly higher in osteoclasts from PDB patients compared to their undifferentiated precursors and healthy osteoclasts. In summary, this work evidences the involvement of epigenetic mechanisms in bone cells’ differentiation, particularly in the regulation of the ZNF687 gene during osteoclast and osteoblast differentiation. Furthermore, it suggests that DNA methylation may contribute to the upregulation of ZNF687 in PDB.