DGH - Apresentações orais em encontros internacionais
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- Chemicals in food: from toxicological research to regulatory challengesPublication . Silva, Maria JoãoCommunication on toxicological research and regulatory challenges related to chemicals in food.
- FAIREHR: A Novel Online Research Registry PlatformPublication . Galea, Karen S.The FAIREHR (Findable, Accessible, Interoperable, Reusable Environmental and Health Registry) is a state-of-the-art online registry platform designed to enhance the transparency, reproducibility, and comparability of environmental health research, focusing on human biomonitoring (HBM) studies as a starting point. This platform is developed in response to the Europe Regional Chapter of the International Society of Exposure Science (ISES Europe) HBM working group strategic objectives to generate high quality HBM by harmonising the data life cycle and implementation of FAIR (findable, accessible, interoperable and reusable) guiding principles. The registry enables preregistration of studies, capturing key metadata on study design, data management, and planned methods before recruitment od the participants. FAIREHR is the first registry tailored for HBM studies and is also first registry promoting FAIR by design studies. Benefits of FAIREHR include increased research visibility, improved data comparability, enhanced collaboration, and better-informed decision-making. We will discuss the unique propositions of FAIREHR, emphasizing its role in enhancing the exchange of information, with its implementation expected to yield significant benefits for researchers, policymakers, and public health through effective utilization of HBM data.
- Generation of Cellular Models for Fabry Disease: Unlocking the Potential of iPSCs and Gene EditingPublication . Duarte, Ana Joana; Moreira, Luciana; Ribeiro, Diogo; Alves, Sandra; Gaspar, Paulo; Bragança, José; Amaral, OlgaIntroduction: Fabry Disease (FD) is a lysosomal storage disorder caused by mutations in the GLA gene, resulting in a defective α-GAL A enzyme. This deficiency leads to the accumulation of Gb3 and lyso-Gb3 within lysosomes, resulting in a multisystem disease. Through reprogramming, we obtained induced pluripotent stem cells (iPSCs) derived from fibroblasts of a patient with FD2 and from a wild-type (WT) control. We used CRISPR/Cas9 to correct the c.860G>A mutation present in the patient’s cells, as well as to generate a WT GLA knockout (KO). The resulting cells were then differentiated into cardiomyocytes, a cell type affected by this disease. Methods: We reprogrammed the fibroblasts into iPSCs using episomal vectors or Sendai virus. For gene editing, single-guide RNAs (sgRNAs) and Cas9 were nucleofected, and the editing was confirmed by Sanger sequencing. Following colony selection, isogenic cell lines were established. The FD iPSCs, the corrected FD iPSCs, and the WT iPSCs were then differentiated into iPSC-derived cardiomyocytes (iPSC-CMs). Results: Seven new cell models were generated. Functional studies of the FD iPSCs showed the maintenance of the molecular and biochemical characteristics and a normal karyotype. The KO cell line recapitulated the biological features observed in FD patient cells, with reduced GLA expression, lower α-Galactosidase A (α-Gal A) activity (1.5 nmol/h/mg protein), and Gb3 accumulation. The corrected cell line was generated with 75.8% efficiency and 69.6% on-target efficacy. Enzyme activity increased to 579 nmol/h/mg protein (vs. 0.78 nmol/h/mg protein in FD iPSCs), accompanied by a marked reduction in Gb3 levels. We successfully generated iPSC-CM lines, which were validated by qRT-PCR and immunofluorescence. Discussion: Cell modelling is essential for studying the pathophysiology of disease mechanisms. By retaining the characteristics of the original cells, iPSCs are a valuable biological resource for generating specific differentiated cell types affected by the disease, which would otherwise be difficult to access. This study also explored the therapeutic potential of gene editing as a promising approach to altering the course of rare diseases.
- Hemocromatose - causa genética ou adquirida?Publication . Faustino, PaulaNesta comunicação oral apresentam-se e discutem-se as possíveis causas responsáveis pela a hemocromatose adquirida e genética e os seus diversos tipos. Explicam-se os principias mecanismos de absorção e reciclagem do ferro no Homem e a atuação da principal hormona responsável pela regulação dos níveis de ferro no organismo. Apresentam-se os biomarcadores bioquímicos usados no diagnóstico da doença e os métodos moleculares usados para caracterizar os genótipos de risco. Debate-se a penetrância e elevada variabilidade da doença e os seus fatores modificadores. Apresenta-se trabalho de investigação realizado no Departamento de Genética Humana do INSA no âmbito destas patologias.
- Hemoglobinopatias - InvestigaçãoPublication . Faustino, PaulaNesta comunicação oral apresentam-se as recomendações da OMS para combater a drepanocitose nos países Africanos e o papel da investigação para compreender os mecanismos da doença e desenvolver estratégias terapêuticas para a combater. Apresentam-se os fatores genéticos modificadores da doença, nomeadamente o nível de hemoglobina fetal e como esta pode ser manipulada farmacologicamente para benefício do doente. Mostram-se e discutem-se os resultados dos trabalhos de investigação de âmbito colaborativo desenvolvidos entre o INSA e algumas Instituições de Saúde Angolanas na área dos fatores genéticos modificadores das manifestações da drepanocitose. Discutem-se os tratamentos sintomáticos e os curativos, incluindo a terapia génica, e os obstáculos às suas utilizações em África.
- Influência da genética do metabolismo do ferro nos fenótipos bioquímicos e hematológicos da insuficiência cardíacaPublication . Bicho, Manuel; Aguiar, Laura; Matias, Ana; Santos, Mafalda; Barbosa, Mário; Melício, Ana; Menezes Falcão, Luiz; Faustino, Paula; Inácio, ÂngelaIntrodução: A insuficiência cardíaca (IC) é uma síndrome que se caracteriza pela incapacidade do coração bombear sangue de forma eficiente para atender às necessidades metabólicas do organismo humano. Esta patologia multifatorial, frequentemente associada a deficiência de ferro e anemia, pode ser influenciada por diversos moduladores, entre estes, genes responsáveis pelo equilíbrio do metabolismo do ferro. Objetivos: O presente estudo teve como objetivo investigar a contribuição da variação genética em genes relacionados com o metabolismo do ferro, nomeadamente HFE, SLC40A1 e TMPRSS6, para os fenótipos bioquímicos e hematológicos relacionados com a cinética do ferro na IC no geral, na IC com fração de ejeção preservada (ICFEp) e na IC com fração de ejeção não preservada (ICFEnp), considerando as diferenças entre os sexos. Material e Métodos: O estudo englobou uma amostra populacional de 192 indivíduos com IC, com idades compreendidas entre os 35 e os 99 anos (mediana de 84 anos). A análise das variantes em estudo do gene HFE foi realizada através da técnica PCR-ARMS Multiplex. As análises dos restantes polimorfismos foram realizadas através da técnica Endpoint-Genotyping. Os parâmetros bioquímicos e hematológicos estudados (ferro sérico, ferritina, saturação da transferrina, hemoglobina, volume globular médio, Red Cell Distribution Width e capacidade total de fixação do ferro) foram recolhidos dos registos hospitalares dos doentes. A análise estatística foi realizada recorrendo ao software SPSS 28, sendo considerado o nível de significância estatística de p<0,05. Resultados: Neste estudo, a população com IC apresentou anemia ferropénica com baixos níveis de saturação de transferrina. Nos homens, o ferro sérico e o RDW também se apresentaram alterados. Diferenças significativas na presença do genótipo ou alelo variante foram encontradas para os parâmetros bioquímicos ou hematológicos estudados. Para os valores de ferro sérico foram encontradas diferenças significativas associadas a polimorfismos localizados nos três genes estudados. Quanto à ferritina, foram observadas diferenças significativas no HFE_H63D em mulheres e em homens e no SLC40A1_rs2304704 em mulheres, mais especificamente em mulheres com ICFEp. Para a saturação de transferrina, diferenças significativas foram encontradas no polimorfismo HFE_H63D em mulheres e no TMPRSS6_rs855791 em mulheres, particularmente em mulheres com ICFEnp e em homens com ICFEp. Em relação à hemoglobina, foram observadas diferenças significativas para o SLC40A1_rs1439816 em homens. Analisando o VGM, diferenças estatisticamente significativas foram observadas no SLC40A1_rs1439816 em homens com ICFEp e no SLC40A1_rs2304704 em mulheres, e em particular mulheres com ICFEp. Em relação ao RDW, diferenças significativas foram encontradas no polimorfismo C282Y em mulheres com ICFEnp e no polimorfismo H63D em mulheres com ICFEnp e em homens com ICFEp. Para a CTFF, diferenças significativas foram encontradas no rs855791 em mulheres com ICFEp. Conclusão: Este estudo confirmou a presença de indicadores de anemia ferropénica nesta população de indivíduos com IC, destacando a contribuição dos três genes analisados na modulação de fenótipos bioquímicos e hematológicos relacionados com o metabolismo do ferro. Observou-se que estas variantes genéticas têm impacto significativo tanto em homens quanto em mulheres, observando-se também diferenças nos subgrupos da IC com fração de ejeção preservada e não preservada.
- Interlaboratory Validation of the Cell Transformation Assay (CTA) for Carcinogenic Assessment of BPA AlternativesPublication . El Yamani, N.; Aimonen, K.; Dusinska, M.; Guichard, Y.; Honza, T.; Louro, H.; Pereira, M.J.; Rundén-Pran, E.; SenGupta, T.; Tavares, A.M.; Silva, M.J.Bisphenol A (BPA) has long been used in various plastic products, resins and coatings, making human exposure to this chemical inevitable. Due to its harmful health effects, including endocrine disruption, and immunotoxicity, BPA has been increasingly replaced by several alternative compounds. However, there are still significant gaps in research regarding the safety of these BPA alternatives, particularly concerning their potential carcinogenicity. One of the in vitro assays to assess carcinogenic potential of chemicals is the Bhas-42 cell transformation assay (CTA). The assay can detect both genotoxic and non-genotoxic carcinogens It is valuable in identifying potential cancer risks before widespread exposure occurs, contributing to the development of safer chemicals and products, as well as better regulatory standards while adhering to the 3R concept. The EU-Partnership for the Assessment of Risks from Chemicals (PARC) project is addressing these research gaps to enhance the risk assessment of BPA alternatives. BPA and some alternatives, including BPZ, BPE, BPAP, BPA-MAE, BPP, and TCBPA, were selected for evaluation of their carcinogenic potential using the in vitro 2-stage Bhas-42 CTA. A key objective of the project is to validate the CTA as a reliable in vitro method for assessing carcinogenicity. To ensure consistency and accuracy across participating labs, an interlaboratory comparison was initiated and a standardized SOP was developed, including concentration ranges for controls and BPA analogues, in alignment with OECD guidance document. The first results from the protocol harmonization, using the selected controls, were consistent across all participating labs. BPA and its analogues are being tested, and the results are under evaluation. The data generated will contribute to the overall weight of evidence on the hazards posed by these chemicals and, when combined with findings from other endpoints, will provide a solid basis for refining their regulation.
- MIR-HBM: The Minimum Information Requirements Guidance for Human Biomonitoring StudiesPublication . Hopf, Nancy B.Background To fully understand the context, methods, data, and interpretations of a human biomonitoring (HBM) study, access to comprehensive background information is essential. However, the diversity in HBM study designs, coupled with varying levels of detail in the data collected, often makes meaningful comparisons, data reuse, and interpretation across different studies challanging. Materials and methods To address this need, the Minimum Information Requirements for Human Biomonitoring (MIR-HBM) was developed by the European Chapter of the International Society of Exposure Science (ISES Europe) HBM working group and the HBM Global Network. MIR-HBM describes the minimal set of information that must be provided to enable effective communication of the setup of an HBM study to others. It enables the generation of the metadata ('data about the data') that will cover all components of the study, including rationale and objectives, study population characteristics, biological specimen collection, laboratory analysis and method parameters, data analysis plan, data interpretation, and communication and reporting. Results Adherence to these reporting guidelines will result in publications of increased clarity,quality, comparability, and usefulness to the scientific community and other stakeholders. Integrating MIR-HBM as a FAIR metadata schema into the FAIREHR (Findable, Accessible, Interoperable, and Reusable Environmental and Health Registry) platform is the next key step planned to enable its implementation and adoption. Conclusions Overall, the MIR-HBM on HBM study metadata promotes transparency and completeness in reporting and enhances rapid capturing of the contents of the HBM study, thereby stimulating findability and accessibility to HBM data and supporting effective quality assessment.
- PARC Waste Management Survey: early health effects among workers from waste management industries in PortugalPublication . Tavares, Ana; Rosário, R.; Aimonen, K..; Louro, Henriqueta; Martins, Carla; Viegas, Susana; Santonen, T.; Silva, Maria João; PARC Waste Management Survey TeamIn a society increasingly generating waste, the Circular Economy Action Plan advocates for a more sustainable management of waste. Recycling of plastics and electronic devices (e-waste) is a rapidly growing sector, with more workers involved in tasks possibly favouring exposure to hazardous chemicals, (i.e. bisphenols, heavy metals, etc.). Under the framework of the European Partnership for the Assessment of Risks from Chemicals (PARC), a human biomonitoring study was developed on workers from plastic and e-waste recycling industries in European countries. In Portugal, workers involved in household plastic recycling and non-exposed individuals were included. Blood samples and demographic/lifestyle information were collected upon informed consent, and the cytokinesis-block micronucleus assay was performed in lymphocytes from 28 participants. The exposed group (n=18) presented significantly higher frequencies of micronucleated lymphocytes vs. controls (n=10) (p= 0.045). The same was observed for nuclear buds (p= 0.007) and nucleoplasmic bridges (p<0.001). However, no significant differences were observed between both groups regarding demographic/lifestyle variables. Our findings revealed genotoxic effects, possibly related with occupational exposure to e-waste and plastic waste. Such early effects indicate a possibility for future adverse health outcomes, such as cancer, if exposure continues. An assessment of levels of exposure to several substances among these workers is also currently underway. Such exposure data will allow us to analyse possible correlations between exposure levels and early biological effects, and infer on groups/tasks at higher risk, promoting risk management measures.
- Results and experiences on effect biomarkers in HBM4EU and PARC occupational studies – what recommendations can be given?Publication . Aimonen, Kukka; Silva, Maria João; Viegas, Susana; Scheepers, P.; Louro, Henriqueta; Martins, Carla; Duca, R.C.; Santonen, T.; HBM4EU; PARC occupational studies project groupsTable of content: -Selection criteria for biomarkers of effect in PARC (PARC – WP4: Roadmap Linking HBM and Health; Biomarkers of effect in HBM4EU and PARC Occupational studies); - Lessons learned (Considerations; Advantages; Challenges; Success stories from HBM4EU); - Validation and Regulatory integration.