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Percorrer Faculdade de Medicina e Ciências Biomédicas por Objetivos de Desenvolvimento Sustentável (ODS) "03:Saúde de Qualidade"
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- Activity induced genes expression is impaired in polyglutamine spinocerebellar ataxiasPublication . Torquato Afonso, Inês; Vilhena Catarino Brito, David; Bading, Hilmar; Nóbrega, ClévioPolyglutamine Spinocerebellar ataxias (SCAs) are a group of 6 incurable genetic disorders, caused by an expansion of the trinucleotide cytosine-adenine-guanine in their causative genes, which produces a protein with an expanded glutamine region. This project focuses on the study of Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) (1), which are rare dominantly inherited disorders that primarily impair the cerebellum therefore leading to motor ataxia. Activity-induced inhibitor of death (AID), are a group of pro-survival 9 genes which were found to be neuroprotector in several neurological disorders, including stroke, glaucoma, AD, HD, and ALS (2). In this project, we aim to investigate about the relevance of the expression of AID genes for cerebellum function and whether their expression levels are impaired in SCA2 and SCA3
- AI-enhanced adaptive testing with cognitive diagnostic feedback and its association with performance in undergraduate surgical education: a pilot studyPublication . Gonçalves, Nuno Silva; Collares, Carlos; Pêgo, José MiguelBackground: Effective feedback in the cognitive domain is essential for surgical education but often limited by resource constraints and traditional assessment formats. Artificial Intelligence (AI) has emerged as a catalyst for innovation, enabling automated feedback, real-time cognitive diagnostics, and scalable item generation, thereby transforming how future surgeons learn and are assessed. Methods: An item bank of 150 multiple-choice questions was developed using AI-assisted item generation and difficulty estimation. A formative Computerized Adaptive Testing (CAT), balanced across three cognitive domains (memory, analysis, and decision) and surgical topics, was delivered via QuizOne® 3–5 days before the summative Progress Test. A total of 147 students participated, of whom 116 completed the formative CAT. Performance correlations, group comparisons, analysis of covariance (ANCOVA), and regression analyses were conducted. Results: Students who voluntarily completed CAT showed higher Progress Test scores, though causality cannot be established due to self-selection bias (p = 0.021), with the effect persisting after adjusting for prior academic performance (ANCOVA p = 0.041). Memory skills were the strongest predictors of summative outcomes (R2 = 0.180, β = 0.425), followed by analysis (R2 = 0.080, β = 0.283); decision was not significant (R2 = 0.029, β = 0.170). Conclusion: AI-enhanced CAT–Cognitive Diagnostic Modeling (CDM) represents a promising formative approach in undergraduate surgical education, being associated with higher summative performance and providing individualized diagnostic feedback. Refining feedback presentation and enhancing decisionmaking assessment could further optimize its educational impact.
- Análise Bioinformática da Via Hedgehog em Cancros Humanos: Expressão, Metilação e Impacto Prognóstico no KIRC e LGGPublication . Aguiar, Diogo Gonçalo Ribeiro Paulo e Soares; Tavares, ÁlvaroO cancro é um dos maiores desafios da saúde global, resultando de alterações genéticas, epigenéticas e da desregulação de vias de sinalização. Esta tese centrou-se na via Hedgehog (HH), conservada evolutivamente e crucial no desenvolvimento embrionário, frequentemente desregulada em vários tipos de neoplasias. O objetivo principal foi analisar a expressão diferencial dos genes da via HH e associados em diversos cancros, com foco no carcinoma renal de células claras (KIRC) e no glioma de baixo grau (LGG), avaliando também o seu impacto prognóstico e potenciais mecanismos regulatórios. Utilizando abordagens bioinformáticas e bases de dados públicas (TCGA, GTEx, GEPIA2, cBioPortal, MethSurv, STRING, TIMER2.0, UCSC Xena Browser e UALCAN), foram analisados dados de expressão génica, metilação de DNA, mutações, infiltração imune e interações moleculares. Verificaram-se diferenças relevantes na expressão de CDON e LRP2 (KIRC) e de KIF7, BOC, CSNK1A1, CSNK1G3, PTCH1, GAS1, SMO e SUFU (LGG) entre tecidos tumorais e normais. A expressão elevada de LRP2 e CDON associou-se a melhor sobrevivência em KIRC, enquanto SUFU e PTCH1 mostraram efeito protetor em LGG. Por outro lado, SMO e GAS1 foram associados a pior prognóstico em LGG. Foi ainda observada hipermetilação dos promotores de CDON e LRP2 em KIRC, sugerindo regulação epigenética, enquanto em LGG a desregulação parece ocorrer por mecanismos não mutacionais. As redes de coexpressão revelaram interações com vias como Wnt e PI3K/AKT. Conclui-se que a via HH tem impacto distinto consoante o subtipo tumoral, e alguns genes, como LRP2 e CSNK1A1, podem constituir biomarcadores ou alvos terapêuticos promissores, reforçando a importância de análises multi-ómicas aplicadas à oncologia de precisão.
- 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.
- Assessing the importance of deltaC mRNA 3’utr for zebrafish somitogenesisPublication . Rodrigues, Leonardo Abraão da Silva; Andrade, Raquel P.; Carraco, GilSomitogenesis is a critical process in early vertebrate development, leading to the periodic formation of somites from the presomitic mesoderm (PSM) along the rostral-caudal axis during body elongation. These somites, which serve as embryonic precursors to the axial skeleton, are crucial for the proper development of vertebrae and other segmented structures. While the periodicity of somite formation can vary significantly between species, it remains highly constant within each species. This periodicity is driven by the embryo clock (EC), an intrinsic mechanism in PSM cells that relies on oscillations of gene expression, regulated through negative feedback loops, requiring short-lived mRNA transcripts. The stability of these transcripts is influenced by regulatory regions (RR) within the mRNA 3’ Untranslated Region (3’UTR). Proper somite formation requires synchronization between PSM cells, facilitated by Notch-Delta signaling, which coordinates cellular division and differentiation. This work investigated the role of the 3’UTR of the zebrafish deltaC clock gene in somite formation periodicity. Various zebrafish mutant lines were generated using CRISPR/Cas9. A previously generated mutant line (RR2) was characterized, assessing somite number, size, periodicity of formation, as well as the expression of EC genes. The comparison between the RR2 mutant and wildtype embryos showed no differences in somite size or number. Also, deltaC and her7 clock gene expression were unaltered. However, the RR2 mutant showed a slight decrease in the periodicity of somite formation. In conclusion, this work describes new animal model systems to study the embryo clock and provided new data on the importance of deltaC mRNA 3’UTR for somite formation.
- Assessing the role of CT imaging in identifying candidates for neoadjuvant chemotherapy in right colon cancer: a critical analysisPublication . Lopes, João Leão; Soares, Ana Sofia S.; Mendes, Beatriz; Tomada, Elisa Paoluzzi; Cunha, Miguel F.; Melina Fernandez, Laura; Amorim, Edgar; Azevedo, José; Parvaiz, AmjadBackground and purpose Standard treatment for localized right colon cancer is radical surgery, followed by adjuvant chemotherapy for stage III or intermediate MSS and high-risk stage II tumours. Recent studies suggest a benefit from neoadjuvant chemotherapy (NAC), particularly for T4b and/or N+tumours. Patient selection for NAC relies on CT-based clinical staging, but the accuracy of CT in detecting high-risk features is variable, raising concerns about potential overtreatment. The study aims to demonstrate the accuracy of CT staging of the right colon with the purpose of indicating neoadjuvant CT. Methods Patients undergoing curative right hemicolectomy between 2013 and 2023 at two Portuguese institutions were included. All had preoperative CT; those receiving NAC were excluded. Sensitivity, specificity, positive predictive value, and negative predictive value of CT in identifying T4b and N+tumours were calculated by comparing clinical (cTNM) and pathological (pTNM) staging. Results Among 165 patients (48% male, mean age 70.5 years), CT showed low sensitivity (26%) but high specificity (91%) for pT4b tumours, with a tendency toward understaging. For nodal disease, sensitivity was 87% and specificity 41%. Only 57% of cT4b and/or cN+cases confirmed at least one unfavorable pathological factor, implying potential overtreatment in 43% of patients if NAC were applied solely based on CT findings. Conclusion CT remains the standard for clinical staging but demonstrates limited accuracy in identifying high-risk right colon cancers. NAC decisions should integrate additional criteria beyond CT findings to avoid overtreatment.
- 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.
- Biomarkers for predicting malignant transformation of premalignant lesions of the larynx: a systematic reviewPublication . Rodrigo, Juan P.; Lima-Souza, Reydson Alcides de; López, Fernando; Stenman, Göran; Agaymy, Abbas; Quer, Miquel; Paleri, Vinidh; Leivo, Ilmo; Nadal, Alfons; Zidar, Nina; Mariano, Fernanda V.; Hellquist, Henrik; Gale, Nina; Ferlito, AlfioBackground/Objectives: Premalignant laryngeal lesions carry a variable risk of malignant transformation to squamous cell carcinoma. Identifying reliable biomarkers that predict malignant transformation could improve patient management and surveillance strategies. The objective of this work is to perform a systematic review of the literature on biomarkers that predict malignant transformation of premalignant laryngeal lesions. Methods: We conducted a systematic review following PRISMA 2020 guidelines. The PubMed, Scopus and Embase databases, and Google Scholar were searched for studies published between January 2011 and November 2025. Studies investigating biomarkers that predict malignant transformation of histopathologically confirmed premalignant laryngeal lesions were included. Risk of bias was assessed using the ROBINS-I tool. Results: From 166 initially identified records, 11 studies met the inclusion criteria, including 730 patients. These studies investigated diverse biomarker categories such as protein markers (cortactin, FAK, NANOG, SOX2, CSPG4), immune markers (tumor-infiltrating lymphocytes, immune gene signatures), microRNAs (miR-183-5p, miR-155-5p, miR-106b-3p), and genetic markers (chromosomal instability, PIK3CA amplification and mutations, FGFR3 mutations). Five studies provided adequate follow-up data on transformation outcomes. Most studies showed a moderate to serious risk of bias primarily due to limited confounder control and incomplete reporting. Conclusions: While several promising biomarker candidates have been identified, the evidence base remains limited due to small sample sizes, heterogeneous methodologies, and inadequate follow-up data. Cortactin/FAK protein expression and immune signatures are the most promising but require validation in larger, well-designed prospective cohorts.