Faculdade de Medicina e Ciências Biomédicas
URI permanente desta comunidade:
Navegar
Percorrer Faculdade de Medicina e Ciências Biomédicas por Objetivos de Desenvolvimento Sustentável (ODS) "10:Reduzir as Desigualdades"
A mostrar 1 - 10 de 34
Resultados por página
Opções de ordenação
- Analysis of mutational allelic imbalances’ Influence on drug treatment responsePublication . Fontes, Melissa Ferreira; Maia, Ana-Teresa; Ferreira, Bibiana I.Breast cancer exhibits significant heterogeneity across various dimensions concerning histological and molecular classification, as well as mutational profile and clinical outcome. Defining treatment courses is likewise a complex task, as patients share similar features but different clinical prognoses. Nowadays, prognostic assessment tries to capture the morphologic and genetic variation within breast tumours, employing a variety of multigene molecular tests focusing on measuring gene expression of a specific gene panel, to predict patient outcome. In current clinical practice, the assessment of the PIK3CA mutational status is a routine procedure for hormone-receptor positive, HER2 negative metastatic breast cancers. Evaluation of gain-of-function mutations in the PIK3CA gene within this patient cohort helps to identify individuals who may benefit from systemic treatment with alpelisib, a PI3Kα-specific inhibitor. Previous studies have demonstrated that widespread allelic imbalances in the expression of somatic mutations in PIK3CA are associated with prognosis in breast cancer. Particularly, preferential expression of PIK3CA’s mutated allele is associated with poorer prognosis. Here, we hypothesise that differential allelic expression of PIK3CA mutations influences protein levels in breast cancer cells, thereby potentially affecting drug treatment response. We aimed to create an inducible PIK3CA breast cell-based tool capable of inducing different levels of PIK3CA mutational expressions as a platform to evaluate the impact of mutational expression levels on the response to PI3K-targeted therapies. Our goal was to create a cell-based system to precisely identify patients eligible for PI3K-α inhibitor therapies by modelling PIK3CA mutant expression dosages and assessing cell drug response. Our results show that we successfully generated a plasmid capable of constitutively expressing the wild-type isoform of the PIK3CA gene and also three inducible plasmids that can express three different levels of each PIK3CA mutant in a controlled manner. These plasmids constitute the tools required to transfect breast cell lines and generate the PIK3CA inducible system. Once the system is not yet created, our hypothesis is still subject to proof.
- Associação entre o infiltrado linfoide e expressão de KI-67 com diversos fatores clínico-patológicos em cancro da mama luminalPublication . Almeida, Érica Filipa Pinto de; Borralho, Paula; Tavares, ÁlvaroAtualmente o cancro da mama continua a ter uma grande importância a nível mundial, particularmente no que respeita à sua incidência e mortalidade. Neste contexto, o diagnóstico correto e precoce apresentam um valor imensurável, contribuindo assim para a cura deste tumor. Muitos são os estudos realizados que procuram encontrar fatores preditivos e de prognóstico, de modo a auxiliar a tarefa árdua de diagnosticar, orientar a terapêutica e avaliar o prognóstico do cancro da mama. No entanto, atualmente este tema ainda carece de respostas para muitas questões. Com o intuito de encontrar algumas respostas, no presente estudo foram analisadas correlações entre várias variáveis clínicas, histológicas e biológicas, a fim de validar determinados biomarcadores, como fatores preditivos e de prognóstico. Neste projeto, foi nosso objetivo comparar duas coortes de carcinoma da mama de tipos histológicos diferentes (carcinoma lobular invasivo e carcinoma sem tipo especial), mas com grau de diferenciação e estádios clínicos e patológicos sobreponíveis. Foram selecionados 60 casos de carcinoma da mama, dos quais 30 carcinomas lobulares e 30 carcinomas de tipo NST e foram recolhidas as características específicas de cada tipo de tumor, bem como os dados clínicos relevantes. Foram comparadas variáveis clínicas (idade, a presença ou ausência de metástases, recidiva e por fim, seguimento) e variáveis histológicas e biológicas (expressão de recetores hormonais, amplificação de HER2, expressão de Ki-67 e densidade da infiltração linfocitária) entre as duas coortes e correlacionadas estas variáveis entre si e com os dados de seguimento. Um total de 8 correlações foram identificadas, em ambos os carcinomas, entre os vários parâmetros de interesse. Evidencia-se a correlação da expressão de Ki-67 com a infiltração linfocitária peritumoral e intratumoral, que revelaram relações ligeiramente superiores às restantes correlações efetuadas.
- Autistic vs. control differences in MRI scan quality across ABIDE-II sitesPublication . Pinheiro, João; Afonso, Beatriz; Seiça, Emanuel Cortesão de; Gonçalves, Rita; Ribeiro, Luís; Reis, JoanaBackground: Head motion and variability in scan quality remain major methodological challenges in autism neuroimaging. Large multi-site datasets such as ABIDE-II provide a unique opportunity to systematically quantify diagnostic differences in MRI data quality and assess the influence of site-level heterogeneity. Methods: Functional MRI Quality Assessment Protocol (QAP) metrics were combined with phenotypic data from ABIDE-II. Participants were classified as autistic (ASD) or typically developing (TD). Key quality metrics—including mean framewise displacement (mFD), proportion of volumes exceeding 0.20 mm (FD > 0.20), signal-to-noise ratio (SNR), and entropy focus criterion (EFC)—were analyzed alongside age, sex, IQ, and site. Group differences were evaluated using non parametric tests and linear mixed-effects models with site as a random factor. Additional analyses examined site-level heterogeneity and the impact of quality-control (QC) thresh olds on sample composition. Results: The final sample included 1277 participants (579 ASD; 698 TD) across 14 sites. ASD participants exhibited significantly greater head motion (median mFD = 0.101 vs. 0.081 mm; p < 1 × 10−10) and modest reductions in signal quality (lower SNR, higher EFC). Elevated motion in ASD was observed in 12 of 14 sites, although effect sizes varied substantially. Mixed-effects models confirmed that diagnosis remained a significant predictor of motion after adjusting for covariates. In contrast, signal-quality differences were small and largely explained by site effects. Simulated QC procedures disproportionately excluded ASD participants, with exclusion rates up to 31% compared to 18% in TD. Conclusions: ASD participants show consistently higher head motion, while signal-quality differences are minimal and largely site-driven. Standard QC procedures disproportionately exclude ASD individuals, highlighting the need for improved motion handling and more balanced quality-control strategies in multi-site studies.
- Autoantibodies against myelin oligodendrocyte glycoprotein in a subgroup of patients with psychotic symptomsPublication . Burgt, Nikita A. van de; Kulsvehagen, Laila; Mané-Damas, Marina; Lutz, Luc; Lecourt, Anne-Catherine; Monserrat, Clara; Vinke, Anita M.; Küçükali, Cem İ.; Zong, Shenghua; Hoffmann, Carolin; González-Vioque, Emiliano; Arango, Celso; Leibold, Nicole K.; Losen, Mario; Molenaar, Peter C.; Tüzün, Erdem; Beveren, Nico J. M. van; Mané, Anna; Rouhl, Rob P. W.; Amelsvoort, Therese A. M. J. van; Pröbstel, Anne-Katrin; Martinez-Martinez, PilarThe presence of autoantibodies against myelin oligodendrocyte glycoprotein (MOG) is a hallmark of MOG antibody-associated disease (MOGAD), a recently defined demyelinating disease entity presenting with core clinical features of optic neuritis, myelitis, and acute disseminated encephalomyelitis. Although MOG antibodies have also been described in a small number of patients with other conditions, including mental disorders, their prevalence and clinical specificity in patients with isolated psychotic symptoms remain unclear. Here, we screened sera from 262 patients with at least one psychotic episode and 166 control subjects for the presence of MOG antibodies of the immunoglobulin G (IgG) isotype with a live cell-based assay. Serum reactivity to additional antigens was assessed by immunohistochemistry. Four patients, representing 1.5% of the patient cohort, and one control individual, representing. 0.6% of the healthy control cohort, were seropositive for MOG-IgG antibodies. Of the four MOG-IgG seropositive patients, three experienced visual hallucinations. Overall, MOG antibodies were detected at a low frequency in patients with psychotic episodes. While we cannot exclude the possibility of false-positive results or seroconversion due to secondary myelin damage, the association with visual hallucinations in three out of four MOG-IgG seropositive patients may point toward an underlying autoimmune etiology.
- The burden of COVID-19 care in community and academic intensive care units in Ontario, Canada: a retrospective cohort studyPublication . Pestana, Daniel; Joshi, Divya; Duan, Erick; Fowler, Robert; Tsang, Jennifer; Binnie, AlexandraDuring the COVID-19 pandemic, neighbourhoods with high material deprivation and high proportions of racialized Canadians were disproportionately affected by COVID-19. Many of these neighbourhoods were served by community hospitals. We sought to compare the burden of COVID-19 care in community and academic intensive care units (ICUs) in Ontario, Canada. We included all adult patients admitted to Ontario ICUs with COVID-19 between 1 March 2020 and 31 July 2021 in a retrospective cohort study. We compared patient volumes, demographics, interventions, and outcomes between community hospital corporations (CHCs) and academic hospital corporations (AHCs). During the first three waves of the pandemic, 9,651 adult ICU admissions for COVID-19 were reported across 72 hospital corporations in Ontario: 6,902 (71.5%) in CHCs and 2,749 (28.5%) in AHCs. Days of ICU care per baseline ICU bed were highest in large CHCs ([ 10 baseline ICU beds) relative to AHCs and small CHCs (median [interquartile range], 73.7 [53.8–110.6] vs 42.2 [32.7–71.8] vs 21.4 [7.2–40.3]; Kruskal–Wallis test, P \ 0.001). Among direct ICU admissions, CHC patients had greater severity of illness whereas among transfer ICU admissions, AHC patients were more severely ill. In a multivariable logistic regression model, mortality was similar among patients with index admission to a CHC or AHC; however, patients with index admission to an AHC were more likely to receive extracorporeal membrane oxygenation (adjusted odds ratio, 6.16; 95% confidence interval, 4.72 to 8.11). During the pandemic, Ontario’s large CHCs provided significantly more days of ICU COVID-19 care per baseline ICU bed compared with AHCs and small CHCs. Equipping large CHCs to handle ICU surges during future emerging disease outbreaks should be a priority for pandemic preparedness.
- Caracterização da expressão do gene ZFP36L1 associado a mecanismos de patogénese da osteoartrose e osteoporosePublication . Lázaro, Mafalda Guela; Simão, MárcioO organelo sem membrana, designado como grânulo TIS, é caracterizado pela interação da proteína ZFP36 ring finger protein like 1 (ZFP36L1), também conhecida como TIS11B, com mRNAs que codificam proteínas membranares. ZFP36L1 promove o enriquecimento ou exclusão de transcritos, dependendo do tamanho dos seus 3'UTR e número de elementos ricos em adeninas (A) e uracilos (U) (AREs). A associação de grânulos TIS à superfície do retículo endoplasmático cria um microambiente que favorece a tradução e localização de proteínas específicas na superfície da membrana das células. ZFP36L1 também é conhecido por regular a estabilidade e degradação de transcritos de vários genes alvo, como é o caso de vários intermediários inflamatórios, o que sugere um papel duplo para o ZFP36L1, favorecendo a transcrição de proteínas membranares e destabilizando outros alvos. Para além dos marcadores de inflamação, também regula os intermediários da via de sinalização das BMPs e está envolvido em mecanismos de senescência o impacto do ZFP36L1 nas células precursoras de osteoblastos e de condrócitos e na sua diferenciação terminal é praticamente desconhecido. Recentemente, o ZFP36L1 tem sido implicado na promoção da diferenciação de osteoblastos e a sua expressão foi identificada como sendo diminuída em ratinhos mais idosos, resultando numa diferenciação preferencial das células mesenquimais para a linhagem adipocitária. Também foi publicado que o aumento da expressão de ZFP36L1 está associado aos mecanismos de progressão da osteoartrose. Este projeto tem como objetivo a identificação, compilação e discussão de estudos publicados que descrevem a expressão de ZFP36L1 em contextos patológicos associados ao desenvolvimento de osteoporose e osteoartrose, focando a discussão dos resultados obtidos no impacto que ZFP36L1 pode ter no metabolismo do osso e da cartilagem. Através da pesquisa da base de dados Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geoprofiles) e bibliografia associada vai-se procurar compilar e comparar dados relativos à expressão de ZFP36L1 em experiências usando tecidos de humano e de ratinho. Com base nesses resultados vai-se procurar contextualizar a expressão desta proteína nos mecanismos associados ao desenvolvimento de osteoartrose e osteoporose. Serão igualmente estudadas (i) as relações filogenéticas destes genes nas principais espécies utilizadas como modelos biológicos em ciências biomédicas, e (ii) a presença de polimorfismos no gene que codifica para a ZFP36L1 e possam ser associados a patologias no sistema musculoesquelético e contextualizar os resultados relativamente às funções das proteínas codificadas.
- Challenges and insights in the measurement of clinical reasoning skills: Implications for instructional design and assessmentPublication . Collares, CarlosDear Editor Among the original contributions in the recent paper from Hornos et al. (2024), the introduction of cognitive diagnostic modelling (CDM) as an alternative to unidimensional item response theory (IRT) for evaluating clinical reasoning skills was a truly innovative step. Unidimensional IRT analysis of the data collected by Hornos et al. (2024) revealed a low percentage of explained variance, echoing a previous concern about its inherent reductionism (Collares, 2023). While IRT is suitable for ranking students and adjusting scores to different difficulty levels, it falls short in providing nuanced insights compared to CDM. CDM’s ability to offer skill-specific feedback and accommodate the multidimensional complexity of clinical reasoning makes it a compelling choice.
- Characterization of knowledge, attitudes, comfort, and perception of discrimination regarding sexual and/or gender minoritized people: comparison between two cohorts of medical students - 2018–2023Publication . Macedo, Ana; Ferreira, João; Gutierrez, Ana Rita; Gato, JorgeObjectives: Despite progress made in the medical field to address the health concerns ofsexual and gender minoritized identities, LGBTQIAþ individuals continue to experience dis-crimination in healthcare. This study aims to evaluate the effects of incorporating a seminaron gender identity and sexual orientation into the medical curriculum of a PortugueseMedical School, after 5 years. The study’s main objective was to compare the changes in stu-dents’ knowledge, attitudes, comfort, and perception of discrimination against LGBTQIAþ,pre and post-intervention.Methods: A total of 313 students in their third, fourth, fifth, and sixth year at a PortugueseMedical School were assessed in 2018 (pre-intervention) and 2023 (post-intervention). Thedata collected were analyzed regarding age, gender identity, sexual orientation, number offriends or family members who identify themselves as LGBTQIAþ, and level of religiosity.Results: The overall knowledge regarding LGBTQIAþ people specific health aspects improvedfrom the 2018 cohort to the 2023 cohort, with significant differences in questions regardinggender identity (OR ¼ 2.0, p ¼ .007), sexual orientation (OR ¼ 2.9, p <.001), and mentalhealth (OR ¼ 3.2, p <.001). The perceived discrimination against homosexual patients wassimilar in both cohorts, with approximately 60% of respondents from both groups agreeingthat homosexual patients were discriminated against in healthcare.Conclusion: Although the perception of discrimination against LGBTQIAþ people in health-care remained high across the two cohorts, positive changes were observed regarding stu-dents’ overall knowledge of LGBTQIAþ individuals’ health, clinical preparation and comfortin treating LGBTQIAþ people, and attitudes toward lesbian women and gay men. Theseresults reinforce the need to develop training and information strategies targeting medicalstudents, promoting greater knowledge and, above all, increasing contact and clinical prac-tice with LGBTQIAþ people, since relationships and personal contact are the most differenti-ating aspects for nondiscrimination.
- Characterization of the role of H2S in neuronal differentiation in Trisomy 21Publication . Marques, Vera; Araújo, Inês; Simão, SóniaDown syndrome (DS) is caused by trisomy of chromosome 21 and is one of the most prevalent aneuploidies compatible with life. The characteristics of DS include congenital heart defects, craniofacial abnormalities, gastrointestinal anomalies, leukemia, seizures, early onset of Alzheimer´s disease, and cognitive impairment among others. Disturbances in the neurological signal processing during critical stages of neurogenesis can affect proliferation, migration, and differentiation of stem cells which may be responsible for the mental impairment of these individuals. These features are important to understanding how DS's brain development is affected. The gene coding for cystathionine-beta-synthase (CBS) is present in chromosome 21 with an extra copy in individuals with DS. CBS is one of the enzymes responsible for the cellular production of hydrogen sulfide (H2S). This is a ubiquitous small gaseous signaling molecule that plays an important role in many physiological processes. However, the contribution of H2S to the abnormal neurodevelopment of DS individuals has not been addressed and is currently under investigation under the Araújo lab. In this study, we aimed to evaluate the contribution of H2S in DS fibroblasts prior to reprogramming these cells into induced pluripotent stem cells (iPSC) to be used in the future as a human cellular model to address the role of H2S in neuronal differentiation in DS. To accomplish this objective, fibroblasts collected from Down Syndrome patients and healthy donors were obtained and H2S production was assessed by time-lapse imaging using a fluorescent probe selective for H2S. The fibroblasts were afterward reprogrammed into iPS cells. The levels of intracellular H2S were higher in the DS cell line when compared to the healthy donor cell line. iPS cells from the DS individuals and the healthy donor fibroblasts were reprogrammed with success and both cell lines expressed the main pluripotency markers Sox2, Nanog, and Oct4 observed by immunocytochemistry and flow cytometry analysis. The data obtained in this work and the iPS lines developed will allow in the future the establishment of an important cellular model to study how H2S affects neurodevelopment in DS.
- Characterization of TYK2 role in IL-7/IL-7R signaling in T-cell Acute Lymphoblastic LeukemiaPublication . Cavaco, Joana Margarida Bartolomeu; Fragoso, Ana Rita; Tavares, ÁlvaroA leucemia linfoblástica aguda (LLA) é uma neoplasia hematológica que pode ser subdividida de acordo com o tipo de linfócitos afetados. Assim sendo, denomina-se leucemia linfoblástica aguda de células T (LLA-T), quando existe a expansão e proliferação de linfócitos T imaturos, e leucemia linfoblástica aguda de células B (LLA-B), quando associada à proliferação de linfócitos B imaturos. A LLA é o cancro pediátrico mais comum, sendo que dentro destes casos, aproximadamente 15% são de LLA-T. Após tratamento, 85% das crianças com LLA-T atingem remissão. No entanto, nos adultos esta percentagem é mais reduzida, ficando entre os 20-40%. O tratamento da LLA-T consiste num programa intenso de quimioterapia, que está associado a vários efeitos secundários. Para além disso, apesar destes doentes terem um prognóstico favorável à data do diagnóstico, a taxa de recidiva é elevada e está associada a um pior prognóstico, uma vez que a doença persistente é geralmente resistente à quimioterapia. Como tal, os efeitos secundários associados à quimioterapia e a falta de tratamento alternativos após recidiva realça a necessidade urgente da descoberta de novas abordagens terapêuticas. Este tipo de leucemia (LLA-T) está associada a diversas alterações genéticas, que resultam na desregulação do processo de desenvolvimento de células T, e por sua vez, levam à proliferação não controlada de células imaturas. A via de sinalização da interleucina-7 (IL-7) desempenha um papel muito importante no processo de diferenciação das células T. Estudos realizados demonstram que a eliminação desta via resulta no bloqueio do desenvolvimento de linfócitos T e B, e consequentemente na produção de linfócitos T não funcionais e numa população de linfócitos B reduzida. A ativação desta via requer a participação da IL-7 e do seu recetor, o IL-7R. O recetor da IL-7 é composto por duas subunidades, nomeadamente a cadeia a (IL-7Ra) e a cadeia g comum. Estas subunidades não possuem atividade catalítica intrínseca e como tal, para poderem fosforilar substratos e darem início à transdução de sinal necessitam da ação de outras proteínas, como as cinases Janus (JAK) JAK1 e JAK3, que se ligam à cadeia IL-7Ra e à cadeia g comum, respetivamente. Quando a interleucina se liga ao recetor, JAK1 e JAK3 fosforilam-se mutuamente, causando a sua ativação, o que resulta na fosforilação de tirosinas presentes nas cadeias do recetor, criando locais de ancoragem para a proteína STAT5. Esta proteína, ao ser ativada por JAK1 e JAK3, sofre dimerização e é transportada para o núcleo onde, atuando como um fator de transcrição, dá início à transcrição de genes envolvidos na proliferação, diferenciação e apoptose. (...)