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- 3-Bromopyruvate boosts the effect of chemotherapy in acute myeloid leukemia by a pro-oxidant mechanismPublication . Vieira, Joana Pereira; Preto, Ana; Granja, Sara; Queirós, Odília; Celeiro, Sónia Pires; Ko, Young Hee; Casal, Margarida; Matos, Catarina Barbosa; Baltazar, Fátima; Granja, SaraAcute myeloid leukemia (AML) comprises a diverse group of blood cancers with varying genetic, phenotypic, and clinical traits, making development of targeted therapy challenging. Metabolic reprogramming in AML has been described as relevant for chemotherapy effectiveness. 3-Bromopyruvate (3-BP) is an anticancer agent that undermines energy metabolism of cancer cells. However, the effect of 3-BP in hematologic malignancies, such as AML, needs further investigation. Thus, we aimed to explore 3-BP as a chemo-sensitizing agent in AML. Different approaches of combining 3-BP with classical chemotherapy (daunorubicin and cytarabin) were tested in diverse AML cell lines. Cell sensitivity to the different drug combinations was analyzed by Trypan blue staining. The effect of pre-treatment with a non-toxic concentration of 3-BP was assessed on the AML cell metabolic profile (Western blot and immunofluorescence), mitochondrial activity (cytometry flow), and antioxidant capacity (colorimetric detection kit). KG-1 and MOLM13 cells showed increased sensitivity to chemotherapy (decreased EC 50 values) after exposure to a non-toxic concentration (5 μ M) of 3-BP. In both cell lines, 5 glucose consumption without changing extracellular lactate levels. 5 μ μ M 3-BP decreased M 3-BP treatment increased reactive oxygen species levels and decreased cell antioxidant capacity by depleting reduced glutathione levels in both KG-1 and MOLM13 cells. Our results demonstrate that non-toxic concentrations of 3-BP enhance the effect of classical chemotherapy in AML cells through a pro-oxidant mechanism. These data unveiled a new approach for AML treatment, using 3-BP or other pro-oxidant agents as co-adjuvants of chemotherapy, subsiding chemotherapy- induced side effects.
- Adaptação cultural, tradução e avaliação psicométrica do questionário de estigma sobre a perturbação de hiperatividade e défice de atenção para países de língua portuguesaPublication . Couto, Beatriz; Trigueiro, Maria João; Simões-Silva, Vítor; Almeida, Raquel Simões de; Trigueiro, Maria João; Simões-Silva, Vitor; Simões de Almeida, RaquelApesar do crescente conhecimento sobre a Perturbação de Hiperatividade e Défice de Atenção (PHDA), estas pessoas ainda enfrentam estigmas da sociedade. A pesquisa sobre o estigma associado à PHDA é limitada pela falta de instrumentos válidos e fiáveis. Este estudo teve como objetivo validar o Questionário de Estigma sobre a PHDA (ASQ) para a população portuguesa e perceber os níveis de estigma numa amostra comunitária. A amostra consistiu em 762 indivíduos, com idades entre 11 e 64 anos (média = 32,41 ±14,59 anos). A validação incluiu a tradução e adaptação cultural da versão original e a análise das propriedades psicométricas: fiabilidade (teste-reteste e consistência interna), validade de conteúdo e de construto. A consistência interna do ASQ foi excelente (α = 0,93) e os valores de teste-reteste (r = 0,86) suportam a fiabilidade do instrumento. Na validade de construto, a análise fatorial explicou 50,25% da variância e indicou uma nova distribuição dos itens 2, 3, 9 e 15 no instrumento. As mulheres (p<0,001) e os residentes em áreas costeiras (p=0,015) apresentaram níveis mais elevados de estigma. A utilização do ASQ para a pesquisa e prática clínica em Portugal é adequadamente suportada pelas suas propriedades psicométricas. Campanhas direcionadas de literacia e estigma da PHDA podem ser uma via importante para melhorar as atitudes da comunidade em geral em relação à PHDA
- Adaptação de Laboratórios Remotos a Cenários de Ensino: Casos de Estudo com VISIR e RemotElectLabPublication . Fidalgo, André V.; Alves, Gustavo R.; Marques, Maria A.; Viegas, Maria C.; Costa-Lobo, Maria C.; Hernández-Jayo, Unai; García-Zubía, Javier; Gustavsson, Ingvar; Alves, Gustavo; Fidalgo, André; Marques, Maria Arcelina; Viegas, Clara; Costa Lobo, Cristina; Garcia-Zubia, JavierOs laboratórios remotos são uma ferramenta tecnológica e pedagógica com uso crescente em todos os níveis de educação, e sua utilização generalizada é uma parte importante do seu próprio aperfeiçoamento e evolução. Este artigo descreve vários problemas encontrados em aulas laboratoriais, em cursos de ensino superior, na utilização de laboratórios remotos baseados em sistemas PXI, utilizando o sistema VISIR ou uma solução alternativa. São identificados e explicados três problemas que foram relatados por professores que deram apoio aos estudantes na utilização dos laboratórios remotos. O primeiro problema prende-se com a necessidade de permitir aos alunos selecionar a localização específica onde um amperímetro deve ser inserido nos circuitos elétricos, mesmo que incorreta, replicando as dificuldades do mundo real. O segundo é causado por falhas de sincronismo quando são necessárias várias medições em intervalos curtos, como no ciclo de descarga de um condensador. E o último problema é provocado pelo uso de um multímetro em modo DC na leitura de grandezas em CA, um procedimento que colide com as definições do equipamento. Todos os cenários são apresentados e discutidos, incluindo a solução encontrada para cada caso. A conclusão que se retira do trabalho descrito é que a área de laboratórios remotos é um campo em expansão, onde a sua utilização prática permite o aperfeiçoamento e a evolução das soluções disponíveis, exigindo uma cooperação e partilha de informação entre todos os intervenientes, i.e. investigadores, professores e alunos.
- Adherence to treatment in allergic rhinitis during the pollen season in Europe: A MASK‐air StudyPublication . Bousquet, Jean; Amaral, RitaAdherence to rhinitis treatment has been insufficiently assessed. We aimed to use data from the MASK-airmHealth app to assess adherence to oral antihistamines (OAH), intra-nasal corticosteroids (INCS) or azelastine-fluticasone inpatients with allergic rhinitis. We included regular European MASK-air users with self-reported allergic rhinitis and reporting at least 1 day of OAH,INCS or azelastine-fluticasone. We assessed weeks during which patients answered the MASK-air questionnaire on all days. Werestricted our analyses to data provided between January and June, to encompass the pollen seasons across the different assessedcountries. We analysed symptoms using visual analogue scales (VASs) and the combined symptom-medication score (CSMS),performing stratified analyses by weekly adherence levels. Medication adherence was computed as the proportion of days inwhich patients reported rhinitis medication use. Sensitivity analyses were performed considering all weeks with at most 1 day ofmissing data and all months with at most 4 days of missing data. We assessed 8212 complete weeks (1361 users). Adherence (use of medication > 80% days) to specific drug classesranged from 31.7% weeks for azelastine-fluticasone to 38.5% weeks for OAH. Similar adherence to rhinitis medication was foundin users with or without self-reported asthma, except for INCS (better adherence in asthma patients). VAS and CSMS levelsincreased from no adherence to full adherence, except for INCS. A higher proportion of days with uncontrolled symptoms was observed in weeks with higher adherence. In full adherence weeks, 41.2% days reported rhinitis co-medication. The sensitivityanalyses displayed similar results. A high adherence was found in patients reporting regular use of MASK-air. Different adherence patterns werefound for INCS compared to OAH or azelastine-fluticasone that are likely to impact guidelines.
- Adverse reactions by radiopharmaceuticals: Retrospective analysis of the Portuguese National Pharmacovigilance SystemPublication . Martins, Sara; Jesus, Ângelo; Andrade, Ricardo; Rocha, Mariana; Martín-Suarez, Ana; Jesus, ÂngeloRadiopharmaceuticals are essential in the field of nuclear medicine, but like any other medicinal product, radiopharmaceuticals can potentially cause adverse reactions in patients. To describe the adverse reactions to radiopharmaceuticals reported to the Portuguese National Pharmacovigilance System (SNF). Methods: We performed a retrospective, observational study by examining individual case safety reports (ICSRs) provided by the SNF related to all radiopharmaceuticals commercially available in Portugal from 2010 to 2023. The SNF received a total of 84 ICSRs. These reports resulted in a total of 224 adverse drug reactions (ADR), which involved a total of 15 different radiopharmaceuticals. The mean age of patients was 61.9 years old. Twenty-one different system organ classes (SOCs) were identified, with the most prevalent situations being “Gastrointestinal Disorders” (18.3%; n = 41) followed by “General disorders and administration site conditions” (16.5%; n = 37), “Skin and subcutaneous tissue disorders” (11.2%; n = 25) and “Blood and lymphatic system disorders” (10.3%; n = 23). Fifty-seven reports (67.85%) showed at least 1 serious ADR. Most notified radiopharmaceuticals were, respectively, radium—223 (n = 36, 41.4%), lutetium-177 oxotreotide (n = 12, 13.8%) and iodide—131 (n = 9, 10.3%). Although the number of notifications is limited, these findings provide valuable insights into the types and frequencies of adverse reactions associated with radiopharmaceuticals used in Portugal between 2010 and 2023. The data highlight the importance of continued pharmacovigilance efforts to monitor the safety of these specialized medical products and inform clinical decision-making.
- Adverse reactions mediated by 99mTc-tetrofosmin: Literature review and analysis of post-marketing reportsPublication . Martins, Sara; Costa, Sara Poças; Sousa, Mariana; Moreira, Fernando; Martín-Suaréz, A.; Jesus, Ângelo; Jesus, Ângelo; Moreira, Fernando99mTc-tetrofosmin is a diagnostic radiopharmaceutical used to evaluate cardiac pathologies. Despite the lower incidence of reactions compared to other drugs, radiopharmaceuticals can still cause adverse reactions. For this reason, pharmacovigilance plays a crucial role in detecting, understanding, evaluating and preventing them. This study aims to review the available literature,on the safety of99mTc-tetrofosmin, and to analyze spontaneous adverse drug reaction reports from the European EudraVigilance database. A literature review was conducted according to PRISMA methodology. An analysis of spontaneous notifications was carried out in EudraVigilance, until 2022. The review identified a selection of 7 articles. The most reported adverse reactions were skin irritation, strange taste in the mouth and nausea. Regarding the EudraVigilance analysis, 220 notifications were identified, accounting for 477 adverse reactions. The majority belong to males (51%), between 18-64 years (45%). Health professionals were the main reporters (84%). The most prevalent System Organ Class was “general disorders and administration site conditions” (21%) and the most reported adverse reaction was pruritus (10%). Approximately 67% of reactions were considered serious, with 6 fatal cases recorded. The results demonstrated that adverse reactions associated with99mTc-tetrofosmin do occur and should not be minimized. Over a period of 17 years, only 220 notifications were recorded, which may highlight potential challenges in pharmacovigilance for radiopharmaceuticals. Therefore, raising awareness about the importance of reporting adverse reactions is crucial.
- Age-related influence on reliability and learning effect in the assessment of lower limb strength using sit-to-stand tests: A cross-sectional studyPublication . Vilarinho, Rui; Montes, António Mesquita; Melo, Cristina; Mesquita Montes, AntónioDecreased muscle strength, especially in the muscles of lower limbs, is an important risk factor for early age‐related decline in physical function, morbidity, hospitalization, and mortality.1 This evidence should be a stimulus for healthcare professionals to include the assessment of muscular strength as a priority in the community due to its substantial value in predicting future health status.2 For this purpose, sit‐to‐stand tests represent one of the simple and valid options to quantify lower limb strength,3 and two of the most used are the 1‐min sit‐to‐stand (1MSTS)4 and the 5 times sit‐to‐stand (5TSTS).5 To standardize the use of 1MSTS and 5TSTS, it is important to explore whether a similar reliability and learning effect exist between adults and older adults in community settings. Since aging may cause a significant reduction in motor skill acquisition,6 it is important to carefully consider whether performances on these tests are the same for repeated measurement over time (test‐retest) and if a practice test is needed according to age. Another reason to establish the reliability and learning effect, before recommending the use of the sit‐to‐stand tests for adults and older adults, is because significantly different performances have been found between these populations.7,8 With this research, we aimed to determine the within‐day test‐ retest reliability and the learning effect of the 1MSTS and 5TSTS in adults (
- The agreement between a transducer and a microphone in the analysis of a synthesized vowel—Using a laboratory model as a preliminary experimentPublication . Pestana, Pedro; Byrne, Allison; Alegria, Rita; Araújo, André; Melo, Celso; Brasil, Christina César Praça; Manso, Maria Conceição; Guerreiro Martins Araújo, Pedro AndréThe objective of this study was to assess the agreement between the acoustic parameters of synthesized vowels, as measured by a piezoelectric transducer and a microphone. The central hypothesis posited that there would be a substantial degree of concordance between the acoustic parameters obtained by these two methods. A laboratory experiment was conducted using synthesized vowels. Acoustic parameters were recorded simultaneously using a microphone and a piezoelectric transducer. Vowels were synthesized using Madde software, with variations in fundamental frequency (fo) and amplitude level. Acoustic signals were captured by a Shure MX153 T microphone and a Shadow SH712 piezoelectric transducer. Signals were recorded using a Behringer FCA1616 audio interface and analyzed using Sopran and VOXplot software. Bland–Altman plots were used for statistical comparison of acoustic parameters. The degree of agreement between the microphone and the transducer varied according to acoustic parameters. Excellent agreement was observed for jitter, mean fo, fo standard deviation, and fo range. Good agreement was found for tilt, equivalent continuous sound level, harmonics-to-noise ratio from Dejonckere, high frequency noise, minimum fo, and maximum fo. Moderate agreement was observed for slope, amplitude difference H1–H2, shimmer, harmonics-to-noise ratio, smoothed cepstral peak prominence, and period standard deviation. While there was moderate to high agreement between the two methods for several acoustic parameters, discrepancies were noted. The microphone exhibited a tendency to record slightly higher values for the majority of the parameters; however, the transducer did demonstrate heightened sensitivity for certain parameters. The findings indicate that neither method can be universally interchanged with the other, and the selection of a method should be contingent on the particular requirements of the analysis.
- Altered NRF2 signalling in systemic redox imbalance: Insights from non-communicable diseasesPublication . Santos, Marlene; Morgenstern, Christina; Santos, MarleneThe balanced activity of the cytoprotective transcription factor NRF2 is central for maintaining redox, metabolic-energetics, and proteome homeostasis, as well as for regulating inflammatory responses, among other functions. Activated NRF2 regulates the expression of hundreds of genes containing antioxidant response elements (AREs) or electrophile response elements (EpRE) in their regulatory regions, often promoting cytoprotection under stress conditions and contributing to defence against various pathologies and non-communicable diseases (NCDs). The products of increased NRF2 activity, detected systemically, may originate from either the white blood cells, the cells of the vasculature or tissue-derived products that could be secreted into biological fluids. Therefore, assessing basal and inducible NRF2 activity in blood or other biofluids is crucial for inferring NRF2 responses in local and often inaccessible tissues. In previous work, we identified a panel of six biomarkers - Glutamate-cysteine ligase catalytic subunit (GCLC), Glutamate-cysteine ligase modifier subunit (GCLM), Haem oxygenase 1 (HMOX1), NAD(P)H quinone dehydrogenase 1 (NQO1), Sulfiredoxin 1 (SRXN1), and Thioredoxin reductase 1 (TXNRD1) - as indicators of NRF2 activity. In the current study, we assess their utility in a clinical setting to measure NRF2 activation in a disease context. Here we discuss findings on how NRF2 activity in accessible human samples can reveal its involvement in various NCDs and its connection to clinical aspects such as diagnosis, disease progression and response to therapy.
- An evolutionary perspective on the relationship between kinetochore size and CENP-E dependence for chromosome alignmentPublication . Almeida, Ana C.; Almeida, Ana C.; Rocha, Hélder; Rocha, Hélder; Raas, Maximilian W. D.; Raas, Maximilian W. D.; Witte, Hanh; Witte, Hanh; Sommer, Ralf J.; Sommer, Ralf J.; Snel, Berend; Snel, Berend; Kops, Geert J. P. L.; Kops, Geert J. P. L.; Gassmann, Reto; Gassmann, Reto; Maiato, Helder; Maiato, HelderChromosome alignment during mitosis can occur as a consequence of bi-orientation or is assisted by the CENP-E (kinesin-7) motor at kinetochores. We previously found that Indian muntjac chromosomes with larger kinetochores bi-orient more efficiently and are biased to align in a CENP-E-independent manner, suggesting that CENP-E dependence for chromosome alignment negatively correlates with kinetochore size. Here, we used targeted phylogenetic profiling of CENP-E in monocentric (localized centromeres) and holocentric (centromeres spanning the entire chromosome length) clades to test this hypothesis at an evolutionary scale. We found that, despite being present in common ancestors, CENP-E was lost more frequently in taxa with holocentric chromosomes, such as Hemiptera and Nematoda. Functional experiments in two nematodes with holocentric chromosomes in which a CENP-E ortholog is absent (Caenorhabditis elegans) or present (Pristionchus pacificus) revealed that targeted expression of human CENP-E to C. elegans kinetochores partially rescued chromosome alignment defects associated with attenuated polar-ejection forces, whereas CENP-E inactivation in P. pacificus had no detrimental effects on mitosis and viability. These data showcase the dispensability of CENP-E for mitotic chromosome alignment in species with larger kinetochores.