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- 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.
- Editorial: advancing cancer therapy: innovative strategies targeting immune evasion and metabolic modulationPublication . Teotónio Fernandes, Mónica Alexandra; De Sousa-Coelho, Ana Luísa; Méndez-Lucas, AndrésCancer remains one of the leading causes of death worldwide, with both incidence and mortality continuing to rise despite advances in diagnosis and treatment (1). While early-stage cancers often respond to conventional therapies, advanced and recurrent tumors frequently develop resistance, limiting long-term therapeutic efficacy (2).Two fundamental hallmarks of cancer, immune evasion and metabolic reprogramming, enable tumors to thrive in hostile microenvironments (3, 4). Although immunotherapies have revolutionized cancer care, a significant proportion of patients either fail to respond or acquire resistance over time (5). In parallel, altered tumor metabolism is increasingly recognized as a promising therapeutic target, particularly for enhancing responses to immunotherapy (7).This Research Topic highlights recent advances that move beyond traditional treatment. Collectively, the nine featured articles provide valuable insights into the interplay between immunity and metabolism in cancer, exploring strategies to overcome therapeutic resistance and improve clinical outcomes across diverse cancer types.
- Long-term predictive accuracy of the ‘mild cognitive impairment due to Alzheimer's disease’ criteriaPublication . Cardoso, Sandra; Montalvo, Alexandre; Maroco, João; Silva, Dina; Alves, Luísa; Guerreiro, Manuela; Mendonça, Alexandre deBackground: The development and clinical use of biomarkers has dramatically changed the framework of Alzheimer’s disease (AD) management, allowing the diagnosis at the mild cognitive impairment (MCI) stage. In 2015 we compared the prevalence and prognosis of AD at the MCI stage according to different criteria available at that time, and we found that the National Institute of Aging-Alzheimer Association (NIA-AA) criteria provided higher predictive accuracy for AD dementia after 3 years. Since then, we adopted these criteria in clinical practice. Objective: To evaluate the long-term predictive accuracy of the ‘MCI due to AD - high likelihood’ criteria by taking advantage from an extended follow-up in a memory clinic setting. Methods: Patients were diagnosed according to the ‘MCI due to AD - high likelihood’ criteria and followed up until conversion to dementia. Results: One hundred and fourteen patients with ‘MCI due to AD - high likelihood’ were enrolled in the study and followed-up for 3.0±1.8 [0.4–8.3] years. During the follow-up 106 (93.0%) patients progressed to dementia, 2 (1.8%) had stroke, 6 (5.3%) died, and none remained in MCI or reverted to normal cognitive status. The average survival time remaining in MCI, analyzed with Kaplan-Meier curve, was 3.2 (95% CI 2.9–3.6) years. Using a multivariate Cox proportional hazards regression model, patients with higher Mini-Mental State Examination kept the MCI status longer. Conclusions: The diagnostic criteria of NIA-AA ‘MCI due to AD - high likelihood’ have an excellent long-term predictive accuracy in a memory clinic setting.
- Molecular detection of multiple antimicrobial resistance genes in helicobacter pylori-positive gastric samples from patients undergoing upper gastrointestinal endoscopy with gastric biopsy in Algarve, PortugalPublication . Nunes, Francisco José Viegas Cortez; Aguieiras, Catarina; Calhindro, Mauro; Louro, Ricardo; Peixe, Bruno; Queirós, Patrícia; Castelo-Branco, Pedro; Mateus, Teresa LetraBackground/Objectives: Helicobacter pylori (H. pylori) is a common gastric pathogen linked to gastritis, gastroduodenal ulcers, and gastric cancer. Rising antimicrobial resistance (AMR) poses challenges for effective treatment and has prompted the WHO to classify H. pylori as a high-priority pathogen. This study aimed to detect the prevalence of AMR genes in H. pylori-positive gastric samples from patients in Algarve, Portugal, where regional data is scarce. Methods: Eighteen H. pylori-positive gastric biopsy samples from patients undergoing upper gastrointestinal endoscopy were analyzed. PCR and sequencing were used to identify genes associated with resistance to amoxicillin (Pbp1A), metronidazole (rdxA, frxA), tetracycline (16S rRNA mutation) and clarithromycin (23S rRNA). Sequence identity and homologies were verified using tBLASTx and the Comprehensive Antibiotic Resistance Database (CARD). Results: Out of the 18 H. pylori-positive samples, 16 (88.9%) contained at least one AMR gene. The most frequent genes were rdxA (83.3%) and frxA (66.7%) for metronidazole resistance, and the 16S rRNA mutation (66.7%) for tetracycline. Resistance to amoxicillin and clarithromycin was detected in 27.8% and 16.7% of cases, respectively. Most samples (72.2%) had multiple resistance genes. A significantly strong association was found between female sex and the presence of the rdxA gene (p = 0.043). Conclusions: The study reveals a high prevalence of H. pylori resistance genes in Algarve, particularly against metronidazole and tetracycline. These findings highlight the need for local surveillance and tailored treatment strategies. Further research with larger populations is warranted to assess regional resistance patterns and improve eradication efforts.
- Targeting trypanothione synthetase and Trypanothione reductase: development of common inhibitors to tackle Trypanosomatid diseasePublication . Augusto, André; Costa, Inês; Conceição, Jaime; Cristiano, Maria de LurdesNeglected Tropical Diseases (NTDs) encompass a range of disorders, including infectious diseases caused by viruses, bacteria, parasites, fungi, and toxins, mainly affecting underprivileged individuals in developing countries. Among the NTDs, those caused by parasites belonging to the Trypanosomatidae family are particularly impacting and require attention, since the lack of financial incentives has led to constraints on the development of novel drugs to tackle them effectively. To circumvent the minor advances in drug discovery in this area, academic research emerges as a crucial player, namely through the identification and validation of new drug targets, thereby contributing to the development of more efficient, safe, and less expensive therapies against Trypanosomatidae infections. Noteworthy, this is a matter of utmost urgency since these diseases are endemic in countries with low socioeconomic standards. This review provides a comprehensive understanding of the current paradigm of NTDs caused by parasites belonging to the Trypanosomatidae family, addressing the ongoing limitations and challenges associated to the current chemotherapy solutions for these diseases and discussing the opportunities unravelled by recent research that led to the identification of new biomolecular targets that are common to Trypanosomatidae parasites. Among these, the unique properties of Trypanothione Synthetase (TryS) and Trypanothione Reductase (TryR), two key protozoan enzymes that are essential for the survival of Trypanosoma and Leishmania parasites, will be emphasised. In addition to a critical analysis of the latest advances in the discovery of novel molecules capable of inhibiting TryS and TryR, the possibility of dual targeting through a combination of TryS and TryR inhibitors will be addressed.