ABC2-Artigos (em revistas ou actas indexadas)
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- A new variant in the NALCN channel is responsible for cerebellar ataxia and cognitive impairmentPublication . Cabrita Pinto, Rute Luísa; Fancellu, Roberto; Markushi, Tiziana Benzi; Viaggi, Silvia; Testa, Barbara; Conteduca, Giuseppina; Fitzsimmons, Lane; Coviello, Domenico; Covone, Angela ElviraCLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Whole Exome Sequencing (WES) identified a novel missense variant c.1514A>T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. The patient's milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity.
- Drug repurposing for targeting cancer stem-like cells in glioblastomaPublication . De Sousa-Coelho, Ana Luísa; Solaković, Brigita; Bento, Alexandra Diogo; Teotónio Fernandes, Mónica AlexandraGlioblastoma (GBM) is one of the deadliest types of cancer, characterized by a short life expectancy after diagnosis, mostly related to therapy resistance and recurrence. GBM stem-like cells (GSCs) reside within the tumor and contribute to these features; therefore, finding drugs that specifically target such cells holds promise to halt GBM progression. The primary objective of this work is to comprehensively review and discuss the potential of hard drug repurposing to target GSCs. Several studies evaluating drugs showing anti-GSC activity, originally approved for non-cancer indications, were identified. These mainly included antidiabetics (e.g., Metformin, Phenformin, and Sitagliptin), antihypertensives (e.g., Nicardipine, Doxazosin, and Prazosin), antimicrobials (e.g., Pyrvinium pamoate, Flubendazole, and Clofazimine), and central nervous system-acting drugs (e.g., Chlorpromazine, Fluvoxamine, and Disulfiram). Relevant candidates include those that disrupt GSC metabolism, namely impairing mitochondrial function, such as Metformin, Chlorpromazine, and Pyrvinium pamoate. Multiple signaling pathways may be involved, namely the Wnt, PI3K/AKT, and STAT3 pathways, among others. Also significant were those drugs tested in combination, resulting in increased sensitivity to Temozolomide (TMZ), the standard pharmacological treatment available for GBM. Some repurposed agents, such as Disulfiram and Metformin, have already reached clinical testing, although none have yet been incorporated into clinical practice. Importantly, major translational barriers remain, like limited blood–brain barrier penetration and the lack of robust clinical trials. In conclusion, drug repurposing is an affordable and suitable strategy to target GSCs, impairing cell viability, reducing stemness, and enhancing their sensitivity to TMZ, which has potential that should be further explored to improve patients’ clinical outcomes.
- CITED Proteins in cardiac development and lifelong heart functionPublication . Bragança, José; Cabrita Pinto, Rute Luísa; Vairinho Ventura, Igor; Ferreira, Silvana; Marreiros, AntónioThe CITED proteins function as transcriptional modulators that are essential for vertebrate development. These proteins interact with numerous partners, notably transcription factors and co-activators. The hallmark of the CITED family is their conserved carboxy-terminal domain, which interacts strongly with the CBP/p300 co-activators. The expression of CITED genes is detected early during embryogenesis within embryonic and foetal regions critical for cardiac morphogenesis, among other developmental processes. Notably, CITED2 loss of function is strongly associated with congenital heart malformations in mice and zebrafish embryos, as well as congenital heart disease (CHD) in humans, whereas other CITED family members are not critical for cardiogenesis. Emerging evidence implicates CITED2 and CITED4 in regulating heart physiological adaptations and protective responses to pathological stress. This review provides a detailed analysis of CITED proteins and their interactors, focusing on CITED-target genes relevant for cardiogenesis and heart disease. We also highlight recent findings indicating that CITED2 and CITED4 may be instrumental for the development of novel therapeutic strategies to mitigate CHD and preserve adult cardiac function.
- Polypharmacy and the use of potentially inappropriate medications in elderly people in nursing homes: a cross-sectional studyPublication . Fest, Giulia; Costa, Lara; Pinto, Ezequiel; Leitao, Helena; Nascimento, TâniaPolypharmacy and the use of potentially inappropriate medications (PIM) are prevalent issues among institutionalized older adults, contributing to adverse drug events and decreased quality of life. This study aimed to describe the sociodemographic and clinical characteristics associated with polypharmacy and the use of PIM in elderly people in nursing homes. A cross-sectional descriptive study was conducted among 151 residents aged ≥ 65 years. Data was extracted from institutional records. The mean age of participants was 86.48 ± 8.00 years; 71.5% were female. Excessive polypharmacy was observed in 49.7% of residents. The mean number of medications was 9.66 ± 4.18, with nervous system drugs being the most prescribed (3.73 ± 2.31). PDDIs were detected in 94% of the sample and PIMs were present in 82.8% of residents. The most common PIMs were proton pump inhibitors (ATC A) and anxiolytics (ATC N). Binary logistic regression identified two independent predictors for PIMs: the total number of medications (AOR = 1.259) and the use of ATC A (Alimentary tract and metabolism) medications (AOR = 2.315). Conversely, age and sex were not significant predictors. The study reveals a critical prevalence of excessive polypharmacy, PIM use, and PDDIs among institutionalized elderly in the Algarve. These findings underscore the urgent need for systematic, multidisciplinary medication reviews in Portuguese nursing homes to promote safer and more rational prescribing practices.
- Tert expression in meningiomas predicts progression-free survival independent of tert promoter mutationPublication . Gui, Chloe; Wang, Justin; Patil, Vikas; Landry, Alexander; Castelo-Branco, Pedro; Singh, Olivia; Tabori, Uri; Aldape, Kenneth; Behling, Felix; Barnholtz-Sloan, Jill; Horbinski, Craig; Tabatabai, Ghazaleh; Ajisebutu, Andrew; Liu, Jeff; Patel, Zeel; Yakubov, Rebeca; Kaloti, Ramneet; Ellenbogen, Yosef; Wilson, Christopher; Cohen-Gadol, Aaron; Tatagiba, Marcos; Sloan, Andrew; Holland, Eric; Chambless, Lola; Gao, Andrew; Chotai, Silky; Makarenko, Serge; Yip, Stephen; Nassiri, Farshad; Zadeh, GelarehWhile TERT promoter mutation (TPM) has been es¬tablished as a marker of clinically aggressive meningiomas, this alteration is rare and found in less than 5% of all cases. However, a larger subset of meningiomas may exhibit aberrant TERT expression in the absence of TPMs. This study investigated the effect of TERT gene expression on clinical outcome in meningioma patients. METHODS: Clinical and mo¬lecular data were retrospectively collected on 1241 meningiomas, split into a Toronto discovery cohort and a multi-institutional validation co¬hort. Sanger sequencing and bulk RNA sequencing were used to determine TPM status and TERT gene expression. The effect of TERT expression on progression-free survival (PFS) was assessed using Kaplan-Meier and Cox regression analysis. RESULTS: While meningiomas with TPM showed expectedly higher TERT gene expression compared to wildtype (TP-WT) cases (p<0.0001), TERT expression was still detected in 28.7% (157/547) of TP-WT meningiomas. Meningiomas with TERT expression showed sig¬nificantly worse PFS compared to meningiomas without any TERT expres¬sion. In fact, WHO grade 1 meningiomas with TERT expression had PFS outcomes resembling WHO grade 2 meningiomas lacking TERT expression (p=0.59). In turn, WHO grade 2 meningiomas with TERT expression had clinical outcomes similar to WHO grade 3 meningiomas without TERT ex¬pression (p=0.42). Furthermore, the proportion of meningiomas expressing TERT as well as overall TERT expression levels increased with increasing WHO grade. Multivariable analysis showed that TERT expression was sig-nificantly associated with worse PFS even when controlling for other known predictors of clinical outcome including TPM, CDKN2A/B loss, 1p/22q status and WHO grade (HR 1.85 [95% CI 1.33-2.57], p=0.00024). CON¬CLUSION: TERT expression is a novel independent biomarker of outcome for meningiomas identifiable in up to one-third of cases that may be utilized to reclassify tumors to a higher WHO grade.
- Reinfection incidence following surgical intervention for infected aortic bypass: a meta-analysisPublication . Brazuna, Márcio; Costa, Marta Gonçalves; Marreiros, Ana; Andrade, Leonardo Araújo; Andrade, José Paulo; Neves, João RochaBackground Infection of vascular grafts after aortic revascularization surgery is a serious complication with high morbid ity and mortality. This systematic review and meta-analysis aims to determine reinfection incidence in patients undergoing surgical intervention for infected aortic bypass grafts and identify key risk factors in the literature. Materials and Methods This systematic review and meta-analysis followed PRISMA guidelines. Three electronic databases, PubMed/MEDLINE, Scopus, and Web of Science were used to search studies published after January 1, 2000, that assessed reinfection rates following surgical intervention for infected aortic bypass grafts. Random-effects meta-analysis was per formed to calculate pooled incidence of major outcomes.Results: Our systematic review included 30 studies with a total of 2,341 patients. Overall reinfection rate was 12.7% (95% CI: 8.6%–16.9%). In terms of morbidity 34.1% had acute kidney injury, 23.8% needed amputation, and 29.4% developed acute limb ischemia. The 30-day mortality rate was 27.8% (95% CI: 13.2%–42.4%).The medical approach to treatment varied significantly, however, the majority involved total removal of the infected prosthesis. The main microorganisms isolated in primary infections were mostly Staphylococcus and Enterococ cus species, with a notable representation of gram-negative bacteria.Conclusion: Reinfection rates after surgical treatment of infected aortic bypass grafts were relatively high and constitute a challenge of high clinical impact. This is further demon strated by the high 30-day mortality rate. The significant variation in treatment approaches observed above also highlights the lack of formalized management protocols. Further studies are needed to determine the best surgical approach and patientrelated risk factors to optimize outcomes in this difficult population.
- Polypharmacy and the Use of Potentially Inappropriate Medications in Elderly People in Nursing Homes: A Cross-Sectional StudyPublication . Fest, Giulia; Costa, Lara; Pinto, Ezequiel; Leitao, Helena; Nascimento, TâniaPolypharmacy and the use of potentially inappropriate medications (PIM) are prevalent issues among institutionalized older adults, contributing to adverse drug events and decreased quality of life. This study aimed to describe the sociodemographic and clinical characteristics associated with polypharmacy and the use of PIM in elderly people in nursing homes. A cross-sectional descriptive study was conducted among 151 residents aged ≥ 65 years. Data was extracted from institutional records. The mean age of participants was 86.48 ± 8.00 years; 71.5% were female. Excessive polypharmacy was observed in 49.7% of residents. The mean number of medications was 9.66 ± 4.18, with nervous system drugs being the most prescribed (3.73 ± 2.31). PDDIs were detected in 94% of the sample and PIMs were present in 82.8% of residents. The most common PIMs were proton pump inhibitors (ATC A) and anxiolytics (ATC N). Binary logistic regression identified two independent predictors for PIMs: the total number of medications (AOR = 1.259) and the use of ATC A (Alimentary tract and metabolism) medications (AOR = 2.315). Conversely, age and sex were not significant predictors. The study reveals a critical prevalence of excessive polypharmacy, PIM use, and PDDIs among institutionalized elderly in the Algarve. These findings underscore the urgent need for systematic, multidisciplinary medication reviews in Portuguese nursing homes to promote safer and more rational prescribing practices.
- Molecular hallmarks of neurodegeneration in polyglutamine spinocerebellar ataxiasPublication . Nóbrega, Clévio; Marcelo, Adriana; Vieira da Conceição, André Filipe; Encarnação Estevam, Bernardo Alexandre; Rajado, Ana Teresa; Albuquerque Andrade de Matos, Carlos Adriano; Vilhena Catarino Brito, David; Torquato Afonso, Inês; Antunes Codêsso, José Miguel; Koppenol, Rebekah; Costa, Rafael Gomes da; Afonso Reis, Ricardo António; Paulino, Rodrigo; Gomes, TiagoPolyglutamine spinocerebellar ataxias (PolyQ SCAs) comprise a group of six inherited rare neurodegenerative diseases. They are caused by abnormal mutation of a CAG tract in six otherwise unrelated genes, leading to a complex cascade of molecular events that culminate in neuronal death. Based on decades of research in these diseases, this review identifies and categorizes the distinctive hallmarks involved in the molecular pathogenesis of PolyQ SCAs. We organized these molecular signatures into three groups: (i) primary hallmarks, which directly refer to the transcription and translation of the abnormally expanded gene and protein, respectively; (ii) secondary hallmarks, which include alterations in pathways and organelles that are implicated in the disease pathogenesis; and iii) end-stage hallmarks, which highlight the final events of the pathogenesis cascade in PolyQ SCAs. This framework is expected to provide a platform for understanding the complex network of molecular mechanisms involved in these diseases and to guide current and future efforts in developing therapies.
- Immunomodulatory inhibition of osteoclastogenesis by a marine microalgal ethanol fraction targeting T-cells, antigen presentation, and macrophage fatePublication . Carletti, Alessio; Pes, Katia; Tarasco, Marco; Rosa, Joana; Poudel, Sunil; Pereira, Hugo; Louro, Bruno; Cancela, M. Leonor; Laizé, Vincent; Gavaia, PauloBackground: Targeting immune pathways to prevent bone loss represents a promising, yet underexplored therapeutic strategy. Methods: An ethanol-soluble fraction derived from the freeze-dried biomass of the marine microalga Skeletonema costatum (SKLT) was tested for its ability to modulate immune responses and inhibit osteoclastogenesis. Its effects were evaluated in a zebrafish model of bone regeneration, a medaka model of RANKLinduced osteoporosis, and in vitro using murine RAW 264.7 macrophages. Transcriptomic profiling of regenerating fin blastemas at 24 hours postamputation was performed to identify the affected molecular pathways. Results: In zebrafish, SKLT treatment suppressed the recruitment of osteoclast precursors and altered mineralization dynamics. Transcriptomic profiling revealed downregulation of genes involved in inflammation, antigen presentation, T-cell activation, and macrophage commitment towards osteoclastogenesis, accompanied by reduced expression of chemokines and cytokines that promote osteoclast precursor recruitment and fusion. In medaka, SKLT significantly reduced vertebral bone loss and enhanced neural arch mineralization in larvae with high RANKL expression. In vitro, SKLT inhibited proliferation and osteoclastic differentiation of murine RAW 264.7 macrophages exposed to RANKL without inducing cytotoxicity. Conclusion: These findings identify S. costatum as a source of bioactive immunomodulatory compounds capable of interfering with key osteoimmune mechanisms. Beyond providing proof of concept for their therapeutic potential in bone erosive disorders, this work opens avenues for isolating and characterizing the active molecules, optimizing their delivery, and evaluating their efficacy in preclinical mammalian models. Such strategies could expand the repertoire of safe, nutraceutical-based or adjuvant therapies for osteoporosis and other inflammation-driven skeletal diseases, complementing and potentially enhancing current antiresorptive and anabolic treatments.
- Comparing the diagnostic performance of ultrasound elastography and magnetic resonance imaging to differentiate benign and malignant breast lesions: a systematic review and meta-analysisPublication . Gomes, Ana Filipa; Justino, David; Tomás, Carina; Jesus, Diogo; Macedo, Ana; Pinto, Ezequiel; Leitao, HelenaObjective: The purpose of this systematic review and meta-analysis was comparing diagnostic performance of ultrasound elastography (UE), strain UE and shear wave elastography (SWE), with magnetic resonance imaging (MRI) in differentiating benign and malignant breast lesions. Methods: Literature search of MEDLINE, Web of Science, SCOPUS and Google Scholar was performed in June 2023. Included studies used Breast Imaging Reporting and Data System (BI-RADS) and histopathology as reference standard. A bivariate random-effects model was used to calculate sensitivity, specificity, diagnostic odds ratio (DOR), positive and negative likelihood ratios and area under the curve (AUC). Meta-regression subgroup analysis was performed. Results: Nine studies and 536 lesions were included. Pooled sensitivity was not different between MRI vs UE [MRI: 94% (95% CI: 88.2%-96.9%) vs UE: 90% (95% CI: 84.7%-93.1%); P=0.153] but a difference was found for specificity [UE: 78% (95% CI: 66.3%-86.4%) vs MRI: 71.3% (95% CI: 52.1%-85%); P=0.0065]. Strain UE showed higher specificity and similar sensitivity to SWE [strain UE: 0.85 (95% CI: 0.71-0.93) vs SWE: 0.72 (95% 0.58-0.83); P=0.017 and strain UE: 0.87 (95% CI 0.79-0.93) vs SWE: 0.91 (95% CI 0.85-0.95); P=0.311, respectively]. AUC was similar between MRI vs UE [0.91 (95% CI 0.87-0.95) vs 0.92 (95% CI 0.88-0.95); P=0.452, respectively] as was DOR [MRI: 38.083 (95% CI: 12.401-116.957) vs UE: 30.395 (95% CI: 16.572-55.75); P > 0.05]. Meta-regression analysis found no significant differences in the diagnostic accuracy between MRI, strain UE and SWE. Conclusion: Our results show that UE when compared to MRI has adequate performance in differentiating benign and malignant breast lesions.