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- Exploring molecular signatures of senescence with marker, an R Toolkit for evaluating gene sets as phenotypic markersPublication . Martins-Silva, Rita; Kaizeler, Alexandre; Barbosa-Morais, Nuno L.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; Oxford University PressMany biological processes, including cellular senescence, manifest as diverse phenotypes across cell types and conditions. Lacking definitive markers, researchers often rely on the expression of sets of genes to identify these complex states. However, multiple approaches exist to summarize gene set expression into quantitative metrics (i.e. signatures), each with distinct strengths and limitations, and we know of no consensual framework to systematically evaluate their performance across datasets. We therefore developed markeR, an open-source, modular R package that evaluates gene sets as phenotypic markers using scoring and enrichment-based approaches. markeR generates interpretable metrics and intuitive visualizations for benchmarking gene signatures and exploring their associations with study variables. As a case study, we applied markeR to 9 published senescence-related gene sets across 25 RNA-seq datasets, 6 human cell types and 12 senescence-inducing conditions. Gene set performance varied widely: some signatures (e.g. SenMayo) were robust senescence markers across contexts, while others (e.g. MSigDB sets) performed poorly. We further applied markeR to 49 GTEx tissues, revealing tissue- and age-related differences in senescence-associated signals. Together, these findings emphasize the difficulty of characterizing molecular phenotypes and demonstrate markeR’s potential for the systematic evaluation of gene sets in various biological contexts.
- Building Research Competence Across a Nursing ProgramPublication . Nunes, Lucília; Cerqueira, Andreia Ferreri; Poeira, Ana; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; MDPI - Multidisciplinary Digital Publishing InstituteThe organized integration of research competencies into nursing curricula is still a global challenge and is key for preparing professionals to respond to complex clinical contexts, technological advancements, and contemporary societal demands. At the School of Health of the Polytechnic Institute of Setúbal, a longitudinal research axis was implemented across the four years of the undergraduate nursing program, involving epistemological foundations, the research process, evidence-based practice, and applied practice. Objective: The objective of this study was to describe the design and implementation of the longitudinal axis of research, analyzing institutional indicators of academic success and the progressive development of students’ scientific competencies. Methods: A descriptive documentary study based on institutional data analysis (the number of enrolled students, pass rates, and mean grades in the four research-related curricular units) was conducted, complemented by a review of pedagogical materials produced (two published course booklets: “Research I—From the origin to the dissemination of knowledge” and “Research II—(De)Constructing the Research Process: A Critical and Practical Analysis”) and evidence of scientific dissemination (conference presentations and published articles). Results: A continuous progression in academic performance was observed across the research curricular units, accompanied by increased complexity of student work and enhanced scientific literacy. The sequential structure proved essential: the articulation of epistemology, methodology, critical appraisal, and scientific production demonstrated strong coherence and pedagogical efficiency. Conclusions: The longitudinal research axis constitutes a curricular innovation that strengthens essential scientific competencies in undergraduate nursing education. Longitudinal models that reflect both conceptual and practical progression can significantly contribute to the development of nurses who are critical thinkers, reflective practitioners, and capable of integrating evidence into clinical decision-making.
- Autoencoder/RandomForest–TabPFN for cross-cancer metabolomicsPublication . Hauns, Sven; Pinto, Frederico G.; Khyriem, Costerwell; Singh, Ankita; Al-Sadi, Azzat; Yazeedi, Talal Al; Mohammad, Rasheed; Cisse, Babacar; Garrett, Timothy J.; Uddin, Mohammed; Soares, Nelson C.; Backofen, Rolf; Alkhnbashi, Omer S.; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; Oxford University PressAccurate and rapid disease diagnosis, particularly in prostate cancer (PC) and breast cancer (BC), is critical for early intervention and improved patient outcomes. Metabolomic signatures represent a robust molecular framework for elucidating cancer-associated biochemical reprogramming. The use of artificial intelligence (AI) in biology in recent years has become widespread and promising. This study introduces a novel predictive method that integrates an Autoencoder, random forest-based feature selection and Tabular Prior-data Fitted Network (TabPFN) to achieve high diagnostic accuracy from metabolomics data of prostate and BC patients. The datasets were acquired using paper spray ionization mass spectrometry and flow injection-traveling-wave ion mobility-mass spectrometry of individuals diagnosed with PC and BC. When leveraging metabolomic profiling data from two distinct sources, PC urine and serum samples, the proposed model achieved an accuracy up to 98.75% in distinguishing diseased from healthy conditions. Additionally, we employed a BC dataset containing metabolic and lipidomic signatures acquired from core needle biopsies using a miniature MS platform coupled with PSI to assess the fidelity of our implementation across distinct cancer types. Our results on a well-characterized targeted dataset show that we can effectively reduce high-dimensional data into latent feature representations. At the same time, TabPFN captures tumor progression-related changes and feature interaction, thereby enhancing the possibility that the model will be a highly potent and effective tool for stage-specific diagnostic precision. Most existing machine learning approaches for disease diagnosis primarily rely on imaging, genomics, or clinical parameters, often overlooking the critical role of metabolites in identifying disease-specific biochemical signatures. By integrating metabolite-specific data with a robust deep-learning approach, this study demonstrates the transformative potential of AI in metabolomics-based diagnostics. The proposed model offers scalability and versatility, with applications extending beyond oncology to a much broader disease profiling aspect. These findings emphasize the value of combining multi-source metabolomic data with deep learning to advance personalized medicine and enhance diagnostic efficiency in clinical practice.
- Rescue transcatheter tricuspid valve replacement with a 56-mm expandable prosthesis following edge-to-edge repairPublication . Teles, Rui Campante; Presume, Márcia José Oliveira; Ribeiras, Regina; Gonçalves, Pedro Araújo; de Sousa Almeida, Manuel; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; Laboratório Associado de Translacção e Inovação para a Saúde Global - LA Real (Pólo NMS); Oxford University PressBackground: Tricuspid regurgitation (TR) is a challenging condition, particularly in advanced stages. Transcatheter therapies are emerging as viable alternatives for selected patients. Case summary: We present an 85-year-old woman with longstanding right heart failure symptoms and torrential TR who underwent edge-to-edge repair (T-TEER), complicated by single leaflet partial device attachment (SLDA). Her condition deteriorated, with readmission for decompensated heart failure. Given persistent torrential TR, clinical deterioration, and unsuitable anatomy for further leaflet-based repair due to septal leaflet plastering, she underwent successful transcatheter tricuspid valve replacement (TTVR) with a newly available 56-mm prosthesis. The patient experienced symptomatic and haemodynamic improvement. Discussion: This case highlights the limitations of leaflet-based repair in anatomically complex TR and supports TTVR as an effective alternative even in SLDA cases. The availability of newer, larger valve sizes expands its feasibility, reinforcing its role in patients previously considered unsuitable for intervention.
- Atlas of interventional cardiology 2023Publication . Van Belle, Eric; Parma, Radoslaw; Teles, Rui Campante; Saia, Francesco; Hawranek, Michal; Paradies, Valeria; Rafflenbeul, Erik; Mamas, Mamas A; Cruz-Gonzalez, Ignacio; Triantis, Georgios; Kilic, Teoman; Jeger, Raban; Magdy, Ahmed; Kefer, Joelle; Linder, Rickard; Sokolov, Maksym; Tormilainen, Hanna; Kazakiewicz, Denis; Huculeci, Radu; Townsend, Nick; Petersen, Steffen E; Timmis, Adam; Vardas, Panos; Gilard, Martine; Chieffo, Alaide; Barbato, Emanuele; Dudek, Dariusz; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; European Society of Cardiology | Oxford University PressAIMS: To provide the most comprehensive assessment to date of interventional cardiology practices across ESC national society member countries, with a focus on infrastructure, procedural volumes, temporal trends (2013-2022), regional disparities, and adherence to guideline-recommended care. METHODS: The third edition of the ESC-EAPCI Atlas presents data from 50 ESC national society member countries, collected through a dedicated 2023 survey of national cardiac societies and interventional working groups. Data were subjected to a rigorous multi-step quality control process to ensure consistency and accuracy.Key metrics include interventional resources, such as the number of hospitals with catheterization laboratories, trained personnel, and the proportion of women in the interventional workforce; procedural volumes and types, including percutaneous coronary intervention (PCI), primary PCI, transcatheter aortic valve implantation (TAVI), transcatheter mitral valve procedures (TMVP), transcatheter tricuspid valve procedures (TTVP), as well as procedural characteristics, including arterial access site, use of intracoronary imaging, physiological lesion assessment, and sex-specific data on patient care delivery. RESULTS: Despite the ongoing expansion of structural heart transcatheter interventions, PCI remains the dominant procedure, accounting for over 90% of all percutaneous cardiovascular interventions. PCI volumes showed limited variation across ESC member countries and demonstrated no significant association with gross national income per capita (GNI). In contrast, important regional disparities were observed in the use of TAVI, TMVP and TTVP with procedure rates strongly correlated with GNI (r=0.86, r=0.63 and r=0.64). Workforce data revealed that while women constitute 39% of all cardiologists, they represent only 10% of interventional cardiologists across ESC member countries. Although interventional cardiology has helped reduce female disparity in access compared with cardiac surgery, inequalities persist, e.g. less than 30% of PCI recipients are women, despite women representing more than 40% of patients with ischemic heart disease. Temporal trend analysis showed a narrowing gap in PCI and primary PCI volumes between regions, reflecting improved access across all economic strata. However, growth in structural valve interventions remained disproportionately concentrated in wealthier countries. CONCLUSIONS: The third edition of the ESC-EAPCI Atlas highlights significant progress in percutaneous cardiovascular interventions across Europe but also underscores persistent disparities. These findings reinforce the need for balanced investment strategies, harmonized training, greater sex equity, and enhanced data infrastructures to support more equitable and evidence-based cardiovascular care.
- Structural context of NADPH-cytochrome P450 reductase mutations that alter cytochrome P450 1A2 substrate regioselectivityPublication . Burris-Hiday, Sarah D.; Esteves, Francisco; Kranendonk, Michel; Scott, Emily E.; Comprehensive Health Research Centre (CHRC) - pólo NMS; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); ASPET - American Society for Pharmacology and Experimental TherapeuticsNADPH-cytochrome P450 (P450) reductase serves as the obligate redox partner for the majority of human P450 enzymes, those responsible for both drug metabolism and homeostasis. NADPH-derived electrons are accepted by the reductase FAD-containing domain and then transferred to its flavin mononucleotide–containing domain (FMND). This domain directly binds P450 enzymes, providing electrons essential for P450 catalysis. Reductase mutations, and specifically those of its FMND, have been widely studied and variously affect P450 function. Most intriguing, previous studies identified 5 specific FMND single amino acid mutations that alter the regioselectivity of CYP1A2 caffeine metabolism. The studies herein further show that these same mutations also alter CYP1A2 methoxyresorufin O-demethylation, mostly in the same direction and scale. To provide experimental information about these FMND mutants, their X-ray crystal structures were determined (1.1–1.5 Å resolution). Although only subtle changes in FMND structure were observed, they were not confined to the local vicinity of the mutation. Changes were instead primarily in the loops binding the flavin cofactor, shifting the backbone of these loops farther from or closer to the flavin cofactor. The extent of loop shifting varies depending on the mutation but indicates that only subtle changes in these loops are required to affect the P450 interaction enough to transmit structural changes to the P450 active site. Significance Statement: Experimental structural information is lacking for the interaction between human cytochrome P450 (P450) enzymes and their reductase, but some reductase mutations alter P450 catalytic regioselectivity, suggesting that the protein/protein interaction alters substrate orientation in the distant P450 active site. The current work establishes that such mutations yield only small changes in the structure of the reductase flavin mononucleotide–containing domain, suggesting that small changes in the interaction nonetheless significantly influence P450 active site catalysis.
- Proteomic and metabolomic profiling of methicillin-resistant Staphylococcus aureus associated with invasive vs. non-invasive infectionsPublication . Boucherabine, Syrine; Giddey, Alexander D.; Nassar, Rania; Mohamed, Lobna; Verma, Subham; Soares, Nelson C.; Senok, Abiola; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; Frontiers Research FoundationIntroduction – Understanding the behavioral differences between invasive and non-invasive methicillin-resistant Staphylococcus aureus (MRSA) is essential for unraveling infection mechanisms and identifying biomarkers with translational potential. This study compared the proteomic and metabolomic profiles of MRSA isolates from diverse clinical presentations to uncover distinct molecular signatures. Methods – Invasive isolates were obtained from blood cultures (n = 23), while non-invasive isolates were derived from superficial skin infections (n = 49) and nasal colonizers (n = 24) from screening swabs. Proteins and metabolites were simultaneously extracted using a dual-phase methanol-based protocol. Proteomic analysis was performed on the Orbitrap Exploris 480, while metabolites were characterized using a TimsTOF mass spectrometer with an Apollo II electrospray ionization source. Data-independent acquisition (DIA) was applied, with peptide assignment carried out in DIA-NN and metabolite analysis using MetaboScape® 4.0. Results – Across all isolates, 2, 000 proteins and 150 metabolites were identified. Comparative analysis revealed that invasive isolates exhibited consistently higher levels of two metabolites (sphinganine and phosphoserine) and one protein (staphylococcal secretory antigen SsaA2) compared to non-invasive. In contrast, three metabolites (cytidine, benzoic acid, and guanosine) and two proteins (small ribosomal subunit protein bS20 and bifunctional autolysin) were significantly reduced in invasive isolates. These findings highlight key molecular differences underpinning invasive potential in MRSA, providing insights into candidate diagnostic and therapeutic biomarkers. These findings highlight critical biological differences between invasive and non-invasive MRSA, offering valuable insights into potential diagnostic and therapeutic biomarkers.
- Laryngeal Tuberculosis in the Modern EraPublication . Teles de Figueiredo, Inês; Pereira Lemos, Ana; Stella, Lorena; Cardoso de Oliveira, Mariana; Madureira, Inês; Gouveia, Catarina; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; Williams & Wilkins
- Materials-Guided Gene-Ionizable Lipid Nanoparticles to Reverse Iron-Associated Immune Resistance in Renal CancerPublication . Jin, Xin; Hong, Yulong; Yin, Chengliang; Guo, Wanyang; Wang, Yaxuan; Zeng, Ruijiang; Liu, Ruilin; Ding, Zexian; Liu, Xinlin; Ren, Shangqing; Liang, Qiyang; Wang, Yaohui; Zhang, Xu; Conde, João; Li, Yuan; Ma, Xin; Gu, Liangyou; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; Wiley-VCH VerlagIron overload is a common metabolic disturbance in cancer and contributes to poor outcomes in renal cell carcinoma (RCC), yet its effects on the tumour immune microenvironment remain unclear. Here we identify a previously unrecognized immunosuppressive axis in which iron overload downregulates the palmitoyltransferase ZDHHC12 in CD8+ T cells, leading to impaired palmitoylation of the mitochondrial protein FDX1. This stabilizes FDX1 and drives cuproptosis, a recently described copper-dependent cell death pathway, thereby compromising T cell effector function and diminishing responses to immune checkpoint blockade. To restore T cell activity, we engineered lipid nanoparticles (ZDHHC12-LNPs) for the delivery of Zdhhc12. These nanoparticles exhibited optimal physicochemical properties, efficiently restored FDX1 palmitoylation, rescued CD8+ T cell function, and synergized with PD-1 blockade in preclinical RCC models without inducing systemic toxicity. Our findings uncover the iron-ZDHHC12-FDX1 axis as a metabolic checkpoint of T cell immunity and demonstrate a nanotechnology-based strategy to overcome iron-driven immunosuppression, offering translational potential for patients with iron-overloaded RCC.
- MCT8 deficiencyPublication . Costa, Cristiana; Painho, Teresa; Alcafache, Margarida; Marques-Matos, Cláudia; Fitas, Ana Laura; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Comprehensive Health Research Centre (CHRC) - pólo NMS; ElsevierBackground: MCT8 deficiency is an X-linked disorder caused by pathogenic variants in the SLC16A2 gene. It results in a state of T3 deprivation in the brain from early development, leading to severe psychomotor impairment and peripheral hyperthyroidism. Endocrinological symptoms develop over time due to thyrotoxicosis in tissues outside the brain. Methods: We present a case series of three male patients with genetically confirmed MCT8 deficiency. Results: All three patients exhibit profound psychomotor delay, with axial hypotonia, limb dystonia, and bradykinesia as consistent features. Genetic analysis identified three distinct SLC16A2 variants: two missense mutations (Thr353Pro and Ser232Phe) and one nonsense mutation (Glu144∗). The characteristic thyroid hormone profile of MCT8 deficiency – high T3, low T4 and reverse T3, and normal TSH – was observed in all cases. Conclusion: These cases illustrate the clinical and genetic heterogeneity of MCT8 deficiency, highlighting the key challenges faced by patients and their caregivers, and the need for earlier diagnosis.