Faculdade de Medicina e Ciências Biomédicas
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Percorrer Faculdade de Medicina e Ciências Biomédicas por Objetivos de Desenvolvimento Sustentável (ODS) "17:Parcerias para a Implementação dos Objetivos"
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- Developing a toolkit for building a community hospital clinical research programPublication . Rego, Kian; Orlando, Elaina; Archambault, Patrick; Geagea, Anna; Mitra, Anish R.; Vazquez-Grande, Gloria; Marticorena, Rosa M.; Patterson, Lisa; DiDiodato, Giulio; Rewa, Oleksa G.; Senaratne, Janek; Law, Madelyn; Binnie, Alexandra; Tsang, JenniferPurpose Although health research in Canada is primarily conducted in academic hospitals, most patients receive their care in community hospitals. The benefits of increasing research capacity in community hospitals include improved study recruitment, increased generalizability of results, broader patient access to novel therapies, better patient outcomes, enhanced staff satisfaction, and improved organizational efficiency.
- Drug-related glomerular phenotypes: a global pharmacovigilance perspectivePublication . Baptista, Alexandre; Macedo, Ana; Marreiros, Ana; Coelho, André; Perazella, Mark A.Abstract: Introduction: Adverse drug reactions are a significant problem in modern society, stemming from the increase in prescribed medications, over-the-counter drugs, and overall polypharmacy. Glomerular disorders are one of the frequently reported renal conditions associated with medication use. VigiBase is a significant tool for evaluating events associated with drug use, and, to the authors’ knowledge, no study has yet assessed this database to identify the primary medications associated with glomerular disorders. Materials and Methods: We collected data from VigiBase for 54 years and evaluated data based on global frequencies, disproportionality (IC025 values), nephrotoxic potential, and physiopathological mechanisms. Results: Over the evaluation period, 33.932.051 spontaneous notifications of adverse drug reactions reported in VigiBase were assessed, from which 106.775 notifications of drug-associated glomerular disorders were extracted. The isolated medications were classified as ‘potential nephrotoxins’ (47.0%), with 40% of the medications lacking scientific references to report any association with the development of glomerular disorders. Among the evaluated medications, Inotersen (IC025 of 8.3), Penicillamine (IC025 6.8), Bevacizumab (IC025 5.9) and Lenvatinib (IC025 5.4) were identified as having the strongest association with these glomerular disorders. For medications classified as ‘non-nephrotoxic’, a high disproportionality index was observed, suggesting drugs that might be considered as new potential nephrotoxins. Conclusions: Drug-induced glomerular disorders were significantly associated with medications that had no established nephrotoxic role but demonstrated a high disproportionality index in VigiBase. These newly alleged nephrotoxic drugs warrant further evaluation in dedicated studies to assess their true nephrotoxic potential.
- 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.