ABC2-Artigos (em revistas ou actas indexadas)
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- Induced pluripotent stem cell-derived mesenchymal stem cells for modeling and treating metabolic associated fatty liver disease and metabolic associated steatohepatitis: challenges and opportunitiesPublication . Marques da Silva, Barbara Sofia; Bragança, JoséThe potential of induced pluripotent stem cells (iPSCs) for modeling and treating metabolic associated fatty liver disease (MAFLD) and metabolic associated steatohepatitis (MASH) is emerging. MAFLD is a growing global health concern, currently with limited treatment options. While primary mesenchymal stem cells hold promise, iPSCs offer a versatile alternative due to their ability to differentiate into various cell types, including iPSC-derived mesenchymal stem cells. However, challenges remain, including optimizing differentiation protocols, ensuring cell safety, and addressing potential tumorigenicity risks. In addition, iPSCs offer the possibility to generate complex cellular models, including three-dimensional organoid models, which are closer representations of the human disease than animal models. Those models would also be valuable for drug discovery and personalized medicine approaches. Overall, iPSCs and their derivatives offer new perspectives for advancing MAFLD/MASH research and developing novel therapeutic strategies. Further research is needed to overcome current limitations and translate this potential into effective clinical applications.
- Advancing glioblastoma research with innovative brain organoid-based modelsPublication . Dias Correia, Cátia; Calado, Sofia; Matos, Alexandra; Oleiro Esteves, Filipa Alexandra; De Sousa-Coelho, Ana Luísa; Campinho, Marco António; Teotónio Fernandes, Mónica AlexandraGlioblastoma (GBM) is a relatively rare but highly aggressive form of brain cancer characterized by rapid growth, invasiveness, and resistance to standard therapies. Despite significant progress in understanding its molecular and cellular mechanisms, GBM remains one of the most challenging cancers to treat due to its high heterogeneity and complex tumor microenvironment. To address these obstacles, researchers have employed a range of models, including in vitro cell cultures and in vivo animal models, but these often fail to replicate the complexity of GBM. As a result, there has been a growing focus on refining these models by incorporating human-origin cells, along with advanced genetic techniques and stem cell-based bioengineering approaches. In this context, a variety of GBM models based on brain organoids were developed and confirmed to be clinically relevant and are contributing to the advancement of GBM research at the preclinical level. This review explores the preparation and use of brain organoid-based models to deepen our understanding of GBM biology and to explore novel therapeutic approaches. These innovative models hold significant promise for improving our ability to study this deadly cancer and for advancing the development of more effective treatments.
- High prevalence of cardiovascular disease and risk factors among type 2 diabetes patients followed in a hospital setting in Portugal: the PICT2RE observational studyPublication . Cardoso, Helena; Bello, Carlos Tavares; Andrade, Luís; Rosário, Francisco Sobral do; Louro, Joana; Nogueira, Cláudia; Rodrigues, Elisabete; Bernardino Vieira, Nuno; Carqueja, TeresaPortugal is a country with a high prevalence of type 2 diabetes (T2D) and cardiovascular disease (CVD). The prevalence of CVD and cardiovascular (CV) risk factors among T2D patients followed in hospitals in Portugal is not known. The primary objective of this study was to assess the prevalence of CVD and CV risk factors among T2D patients in a hospital setting in Portugal. The clinical management of CVD in the hospital setting was also assessed.
- Role of ancillary techniques in the differential diagnosis of salivary gland carcinomasPublication . Paiva Correia, Antonio; Hellquist, Henrik; Apolónio, Joana; Castelo-Branco, PedroPaiva-Correia A, Hellquist H, Apolónio J, Castelo-Branco P. Role of ancillary techniques in the differential diagnosis of salivary gland carcinomas. The diagnosis of salivary gland carcinomas (SGC) rests mainly on histology, but immunohistochemical and molecular investigations are often necessary for differential diagnosis. This review is primarily aimed as a tool for pathologists in non-specialised head and neck hospitals who encounter a limited number of SGC annually. The use of testing an initial antibody panel, which may comprise both positive and negative expression for a suspected entity, and examples of different panels are outlined. We also focused on acinic cell carcinoma (AcCC), which is positive for DOG1 and negative for mammaglobin, whilst secretory carcinoma (SC) is positive for mammaglobin and negative for DOG1. In addition, the exclusive expression of androgen and HER2 in salivary duct carcinoma (SDC) and its use for differential diagnosis are also addressed. This review also highlights the particularities of mucoepidermoid carcinoma (MEC) and its negativity for S100 and SOX10, which distinguishes it from some of its mimics. In laboratories with limited access to antibodies for SGC, we recommend inclusion of mammaglobin. The use of molecular techniques for the diagnosis of MEC (MAML2), SC (ETV6), adenoid cystic carcinoma (MYB), and AcCC (NR4A3) is discussed. We highlight the role of commonly available antibodies for the histological classification of SGC.
- Comparing international guidelines for the remission of hypertension after bariatric surgeryPublication . Dias, Carina Vieira; Silva, Ana Lúcia; Dias, Joana; Cardoso, Paulo; Castanheira, Rute; Fernandes, Andreia; Nunes, Filipa; Sanai, Tina; Sanchez, Mercedes; Maia-Teixeira, João; De Sousa-Coelho, Ana LuísaBackground/Objectives: Obesity remains a global health concern and is associated with increased risk of type 2 diabetes, hypertension, and cardiovascular disease overall. Dissimilar hypertension guidelines are available for clinicians, namely those prepared by the American Heart Association (AHA) and the European Society of Cardiology (ESC), which may lead to distinctive appreciation of health outcomes of patients with obesity after bariatric and metabolic surgery, such as hypertension remission. The main goal of this study was to compare the effects of applying stricter (AHA) versus looser (ESC) blood pressure criteria on hypertension diagnosis pre-bariatric surgery and remission assessment one year post-op. Methods: A retrospective analysis of clinical data from patients who underwent surgical treatment for obesity at a single university hospital was performed. To evaluate the hypertension improvement or remission, two different types of blood pressure (BP) categorization were considered (based on AHA and ESC guidelines), in which each patient would fit according to their BP values pre- (m0) and 12 months postoperative (m12). Results: From a sample of 153 patients submitted for surgical treatment of obesity, more patients were considered with hypertension based on the AHA guideline (130 vs. 102; p < 0.001), while a higher rate of hypertension remission at 12 months after bariatric surgery was observed when following the ESC guideline (58.82 vs. 53.08%). Baseline patients' clinical characteristics based on each hypertension outcome were mostly independent of the guideline used (p > 0.05), where only age and systolic blood pressure were relatively higher in "ESC groups". Conclusions: We conclude that only minor differences exist between the two guidelines used. If evaluated based on ESC guidelines, it is expected that less patients are considered with hypertension, and the remission rate may be, at least numerically, higher.
- Brain-targeted drug delivery - nanovesicles directed to specific brain cells by brain-targeting ligandsPublication . Moreira, Ricardo; Nóbrega, Clévio; Almeida, Luís Pereira de; Mendonça, LilianaNeurodegenerative diseases are characterized by extensive loss of function or death of brain cells, hampering the life quality of patients. Brain-targeted drug delivery is challenging, with a low success rate this far. Therefore, the application of targeting ligands in drug vehicles, such as lipid-based and polymeric nanoparticles, holds the promise to overcome the blood-brain barrier (BBB) and direct therapies to the brain, in addition to protect their cargo from degradation and metabolization. In this review, we discuss the barriers to brain delivery and the different types of brain-targeting ligands currently in use in brain-targeted nanoparticles, such as peptides, proteins, aptamers, small molecules, and antibodies. Moreover, we present a detailed review of the different targeting ligands used to direct nanoparticles to specific brain cells, like neurons (C4-3 aptamer, neurotensin, Tet-1, RVG, and IKRG peptides), astrocytes (Aquaporin-4, D4, and Bradykinin B2 antibodies), oligodendrocytes (NG-2 antibody and the biotinylated DNA aptamer conjugated to a streptavidin core Myaptavin-3064), microglia (CD11b antibody), neural stem cells (QTRFLLH, VPTQSSG, and NFL-TBS.40–63 peptides), and to endothelial cells of the BBB (transferrin and insulin proteins, and choline). Reports demonstrated enhanced brain-targeted delivery with improved transport to the specific cell type targeted with the conjugation of these ligands to nanoparticles. Hence, this strategy allows the implementation of high-precision medicine, with reduced side effects or unwanted therapy clearance from the body. Nevertheless, the accumulation of some of these nanoparticles in peripheral organs has been reported indicating that there are still factors to be improved to achieve higher levels of brain targeting. This review is a collection of studies exploring targeting ligands for the delivery of nanoparticles to the brain and we highlight the advantages and limitations of this type of approach in precision therapies.
- Transgenic αβ TCR tonic signaling is leukemogenic while strong stimulation is leukemia suppressivePublication . Catarino, Telmo A.; Pacheco-Leyva, Ivette; Baessa, Marina; Pereira, João L.; Rodrigues dos Santos, NunoThe pre–T cell receptor (TCR) and TCR complexes are frequently expressed in T cell acute lymphoblastic leukemia (T-ALL), an aggressive T cell precursor malignancy. Although mutations in TCR components are infrequent in T-ALL, earlier research indicated that transgenic αβ TCR expression in mouse T cell precursors promoted T-ALL development. However, we recently found that stimulation of TCR signaling in T-ALL induced leukemic cell apoptosis and suppressed leukemia. Our aim was to elucidate if a given αβ TCR complex has a dual role in leukemogenesis depending on the nature of the stimulus. We demonstrate that transgenic expression of the Marilyn αβ TCR, specific for the H-Y male antigen presented by major histocompatibility complex class II, triggers T-ALL development exclusively in female mice. This T-ALL exhibited Notch1 mutations, Cdkn2a copy number loss, and immature immunophenotype, and infiltrated both lymphoid and nonlymphoid organs. Furthermore, leukemic cells expressed surface CD5, a marker of tonic TCR signaling. T-ALL efficiently developed in Rag2-deficient Marilyn transgenic females, indicating that Rag2-mediated recombination is not implicated in this T-ALL model. T-ALL development was also observed in the OT-I TCR transgenic mouse model, but it did not occur when major histocompatibility complex class I was abrogated through genetic inactivation of β2-microglobulin. Remarkably, exposure of Marilyn female T-ALL cells to endogenous agonist antigens in male recipient mice or exogenous peptides in female recipient mice resulted in T-ALL apoptosis and prolonged mouse survival. These findings underscore the dual role of the same αβ TCR complex in T-ALL, in which tonic stimulation is leukemogenic, while strong stimulation suppresses leukemia.
- Transcriptional regulation of the Human MGP promoter: Identification of downstream repressorsPublication . Caiado, Helena; Cancela, M. Leonor; Conceição, NatérciaMatrix Gla protein (MGP) is a vitamin K-dependent γ-carboxylated protein that was initially identified as a physiological inhibitor of ectopic calcification, primarily affecting cartilage and the vascular system. Mutations in the MGP gene were found to be responsible for the Keutel syndrome, a condition characterized by abnormal calcifications in the cartilage, lungs, brain, and vascular system. MGP has been shown to be dysregulated in several tumors, including cervical, ovarian, urogenital, and breast cancers. Using bioinformatic approaches, transcription factor binding sites (TFBSs) containing CpG dinucleotides were identified in the MGP promoter, including those for YY1, GATA1, and C/EBPα. We carried out functional tests using transient transfections with a luciferase reporter assay, primarily for the transcription factors YY1, GATA1, C/EBPα, and RUNX2. By co-transfection analysis, we found that YY1, GATA1, and C/EBPα repressed the MGP promoter. Furthermore, the co-transfection with RUNX2 activated the MGP promoter. In addition, MGP expression is negatively or positively correlated with the studied TFs’ expression levels in several cancer types. This study provides novel insights into MGP regulation by demonstrating that YY1, GATA1, and C/EBPα are negative regulators of the MGP promoter, and DNA methylation may influence their activity. The dysregulation of these mechanisms in cancer should be further elucidated.
- Serum neutrophil biomarkers to predict crohn's disease progression and infliximab treatment outcomesPublication . Magalhaes, D.; Santiago, M.; Patita, M.; Arroja, B.; Lago, P.; Rosa, I.; Sousa, Helena Tavares; Ministro, P.; Mocanu, I.; Vieira, A.; Castela, J.; Moleiro, J.; Roseira, J.; Eugenia, C.; Sousa, P.; Portela, F.; Correia, L.; Dias, S.; Afonso, J.; Danese, S.; Peyrin‐Biroulet, L.; Dias, C. C.; Magro, F.Background and aims: Predicting the treatment outcomes of biological therapies is an unmet need in Crohn's Disease. In this study, we explored the potential of serum neutrophil-related biomarkers to predict infliximab therapeutic results and disease progression in Crohn's Disease patients, over a 2-year period, in a real-world setting. Methods: The study included 100 asymptomatic Crohn's Disease patients in the IFX maintenance phase from the prospective, observational, multicenter DIRECT study. Patients were categorized according to a composite outcome reflecting progression that included surgery, hospitalizations, new fistulae, abscess or stricture, and drug treatment escalation. Serum neutrophil elastase, lipocalin-2, lactoferrin, and resistin (non-neutrophil control) were analyzed via multiplex magnetic bead assays at multiple touchpoints. Fecal calprotectin was assessed by ELISA. Results: Over up to 2 years of follow-up, serum biomarkers did not differentiate between the composite outcome groups, whereas fecal calprotectin was significantly higher in patients with worse outcomes. During the infliximab maintenance phase, there was a significant, sustained reduction of neutrophil elastase (p < 0.001), lipocalin-2 (p < 0.001), and lactoferrin (p < 0.001), but not of resistin, despite stable neutrophil levels. Correlations between NE and NGAL levels were strong (Pearson correlations 0.75-0.85); all other correlations were of small magnitude. Conclusion: Our real-world data do not support using serum neutrophil elastase, lipocalin-2, or lactoferrin concentrations as predictors of treatment outcomes or disease evolution in infliximab -treated Crohn's Disease patients. On the other hand, the sustained decrease in biomarkers over time suggests that neutrophil stabilization might be an additional infliximab mechanism of action.
- Massive parallel sequencing of head and neck conventional squamous cell carcinomas: A comprehensive reviewPublication . Nadal, Alfons; Cardesa, Antonio; Agaimy, Abbas; Almangush, Alhadi; Franchi, Alessandro; Hellquist, Henrik; Leivo, Ilmo; Zidar, Nina; Ferlito, AlfioHead and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is a cause of signifcant mortality and morbidity. The epidemiology of this cancer varies worldwide due to either genetic diferences in populations or diferences in carcinogen exposure. The application of massive parallel sequencing-based techniques in HNSCC should provide a helpful understanding of the genetic alterations that eventually lead to HNSCC development and progression, and ideally, could be used for personalized therapy. In this review, the reader will fnd an overview of the mutational profle of conventional HNSCC according to published results on massive parallel sequencing data that confrm the pivotal role of TP53 and the frequent involvement of CDKN2A and PIK3CA. The reader will also fnd a more detailed description of the genes, such as NOTCH1 and FBXW7, that were not identifed in HNSCCs before the development of these techniques, the diferences that can be site-specifc, such as the diferent mutational signatures that indicate specifc carcinogens for various subsites of the head and neck, and fnally, the actionability of these fndings that should allow more personalized therapy for patients.