FCB2-Artigos (em revistas ou actas indexadas)
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- Chromenone derivatives as CRM1 inhibitors for targeting glioblastomaPublication . Princiotto, Salvatore; Jiménez, Lucía; Domínguez, Lucía; Sequeira, João G. N.; Mourato Paulo, Cristiana Isabel; Orea-Soufi, Alba; da Silva Santos, Bruno Filipe; Dallavalle, Sabrina; Machuqueiro, Miguel; ferreira, Bibiana; Link, WolfgangGlioblastoma (GBM) is one of the most aggressive and deadly cancers. Due to the complexity and redundancy within signaling networks in GBM, targeted inhibitors of specific pathways have shown only limited success. The nuclear export receptor chromosome region maintenance 1 (CRM1) has recently emerged as a promising therapeutic target, as its inhibition can simultaneously disrupt multiple key oncogenic drivers. Herein, whether chromenone derivatives, known for detecting thiol-containing molecules, can function as CRM1 inhibitors is explored. Several chromenonebased derivatives are synthesized and it is demonstrated that they inhibit CRM1-driven nuclear export in a structure- and dose-dependent manner. A preliminary structure–activity relationship is established, providing a rationale for selective CRM1 binding based on molecular docking studies. Additionally, it is showed that the active chromenone derivatives effectively inhibit the nuclear export of endogenous nuclear export signal-containing substrates in GBM cells. Several of these compounds exhibit selective cytotoxicity againstGBM cell lines, highlighting their potential as targeted therapies for GBM.
- Pretreatment antithrombotic strategies in non-ST elevation acute coronary syndromes in contemporaneous clinical practicePublication . Costa, Hugo; Espírito-Santo, Miguel; Fernandes, Raquel; Bispo, João; Guedes, João; Azevedo, Pedro; Carvalho Silva, Daniela; Vinhas, Hugo; Gonçalves, Rui Baptista; Mimoso, JorgeBACKGROUND Pretreatment antithrombotic strategies in non-ST elevation acute coronary syndromes (NSTE-ACS) during hospitalization is still a matter of contention within the cardiology community. Our aim was to analyze in-hospital and one-year follow-up outcomes of patients with NSTE-ACS pretreated with dual antiplatelet therapy (DAPT) versus single antiplatelet therapy (SAPT). METHODS A retrospective study was carried out with NSTE-ACS patients who planned to undergo an invasive strategy and were included in the Portuguese Registry of ACS between 2018 and 2021. A composite primary outcome (in-hospital re-infarction, stroke, heart failure, hemorrhage, death) was compared regarding antiplatelet strategy (DAPT versus SAPT). Secondary outcomes were defined as one-year all-cause mortality and one-year cardiovascular rehospitalization. RESULTS A total of 1469 patients were included, with a mean age of 66 12 years, and 73.9 % were male. The DAPT regime was used in 38.2 % of patients and SAPT in 61.8 % of patients. NSTE myocardial infarction was the most frequent presentation (88.5 %). Revascularization was performed within 24 h in 55.2% of patients. Time until revascularization >24 h occurred in 44.8% of patients, with 16.5% of these between [24 h–48 h], 10.6% in [48 h–72 h] and 17.6% > 72 h. The primary outcome was more frequently observed in the SAPT group (10.4 %, p ¼ 0.033), mainly driven by more ischemic events. Time until revascularization >72 h and the SAPT regime were independent predictors of the primary outcome (OR 3.09, p ¼ 0.005, and OR 2.03, p ¼ 0.008, respectively).
- The research activities of Canadian community hospitals: a bibliometric analysisPublication . Rego, Kian; Patel, Prey; Binnie, Alexandra; Tsang, JenniferCommunity hospitals represent 90% of Canadian hospitals, yet many lack the necessary infrastructure to conduct health research. This shortfall limits patient access to research studies, reduces study efficiency, and decreases the generalizability of study results. Previous work from our group identified an increase in publications from Ontario’s large community hospitals between 2013 and 2022. However, data from other Canadian provinces is lacking. This bibliometric analysis identified indexed publications from authors affiliated with Canada’s 544 community hospitals between 2018 and 2023. Among 13,689 publications, 12,472 unique articles were identified. Most were primary research articles (67%), with only 5% being clinical trials. Ontario’s community hospitals had the highest number of publications (n = 7,925), followed by Alberta (n = 2,086) and Quebec (n = 1,480). Of Canada’s 544 community hospitals, only 42% were affiliated with one or more publications from 2018 to 2023, highlighting the need to strengthen Canadian community hospital research capacity at a systems level.
- Letter to the editor: robustness of osteoporosis risk prediction models with enhanced statistical analysesPublication . Pires de Carvalho, Filipe Ricardo; Gavaia, PauloIn response to Oka et al.’s letter, we conducted additional statistical analyses to validate the robustness of our osteoporosis risk prediction model using NHANES 2007–2014 data (n = 7924). We evaluated 10 key predictors through Spearman’s rho, Kendall’s tau, Mutual Information (MI), and Total Correlation. Weight (BMX_BMXWT) and arm circumference (BMX_BMXARMC) showed strong negative correlations with osteoporosis risk (rho: 0.49, 0.47, p < 1e-270; MI: 0.17, 0.15), while age (DEMO_RIDAGEYR) exhibited a positive correlation (rho: 0.33, p < 1e-128; MI: 0.08). Total Correlation (32.68) confirmed significant multivariate interactions among predictors. These findings reinforce the model’s predictive strength, addressing Oka et al.’s recommendations and affirming the importance of anthropometric and demographic factors in osteoporosis risk assessment.
- Fibrosis-related transcriptome unveils a distinctive remodelling matrix pattern in penetrating ileal Crohn’s diseasePublication . Sousa, Helena Tavares; Ferreira, Marta; Gullo, Irene; Rocha, Ana Mafalda; Pedro, Ana; Leitão, Dina; Oliveira, Carla; Carneiro, Fátima; Magro, FernandoBackground and Aims: Stricturing [B2] and penetrating [B3] ileal Crohn’s disease have been reported to present similar levels of histopathological transmural fibrosis. This study aimed to compare the fibrosis-related transcriptomic profiles of penetrating and stricturing ileal Crohn’s disease. Methods: Using Nanostring technology and comparative bioinformatics, we analysed the expression of 787 fibrosis-related genes in 36 ileal surgical specimens, 12 B2 and 24 B3, the latter including 12 cases with associated stricture[s] [B3s] and 12 without [B3o]. Quality control of extracted RNA was performed according to Nanostring parameters and principal component analysis for the distribution analysis. For the selection of the differentially expressed genes, a p-adjusted Results: We included 34 patients with B2 and B3 phenotypes, balanced for age at diagnosis, age at surgery, gender, Crohn’s disease localisa tion, perianal disease, and therapy. Inflammation and fibrosis histopathological scoring were similar in all cases. B2 and B3 groups showed a very good clustering regarding 30 significantly differentially expressed genes, all being remarkably upregulated in B3. More than half of these genes were involved in Crohn’s disease fibrogenesis, and eight differentially expressed genes were so in other organs. The most significantly active biological processes and pathways in penetrating disease were response to TGFβ and matrix organisation and degradation, as validated by immunohistochemistry. Conclusions: Despite the histopathological similarities in fibrosis between stricturing and penetrating ileal Crohn’s disease, their fibrosis-related transcriptomic profiles are distinct. Penetrating disease exhibits a distinctive transcriptomic landscape related to enhanced matrix remodelling.
- Mental illness risk prediction in high school students using artificial neural networkPublication . Encarnação, Samuel; Vaz, Paula Fortunato; Vaz, Filipe; Fortunato, Álvaro; Monteiro, António Miguel de BarrosIntroduction: The sustainable development goals of the United Nations 2030 agenda, goal number 3 – Good health and well-being- align with student mental health. Objective: To conduct an artificial neural network (ANN) to predict the students' self-reported mental health dimensions. Methods: A cross-sectional and observational study enrolling sociodemographic and health state data from 2050 university students aged (18–30 years). Results: The best algorithm's result was by predicting the students' depressive state with 97 % accuracy (weighted average = [precision = 0.79 %, recall = 0.79 %, F-1 score 0 0.79 %, cross-validation (73 %)]), while dimensions such overall mental health self-perception (validation accuracy = 60 %) and lack of interest in performing their activities of daily living [(ADLs), validation accuracy = 67 %], presented inferior predictions. Conclusions: The ANN best predicted the university students' depressive state (73 %).
- Exploring the clinical benefits of genomic profiling for advanced solid tumors in Portugal.Publication . Tavares, Nuno; Damaso, Sara; Brás, Raquel Lopes; Guedes, Helena; Simões, Pedro; Rodrigues, Tania; Costa, Diogo Alpuim; Bonito, Nuno Antunes; Pratas, Edgar; Macedo, Daniela; Filipe, Frederico Ferreira; Martins Cavaco, Ana Cláudia; Pavanello, Marina; Costa, LuisBackground: Comprehensive genomic profiling (CGP) plays a significant role in precision oncology by pairing genomic alterations from different tumor types with molecularly targeted therapies. However, the evaluation of its real-world impact, clinical utility, and effects on quality of life remain unexplored. The FRONTAL study (Foundation medicine Real wOrld evideNce in porTugAL) is an ongoing multicentric academic study that aims to establish a national registry of portuguese patients with solid tumors that underwent CGP through Foundation Medicine tests (FoundationOne CDx, Liquid CDx, and Heme). Methods: The study enrolled portuguese patients diagnosed with advanced solid tumors who were not eligible for curative treatment at the time of recruitment. Patients who had previously done CGP evaluation could be included if the test was conducted within one year before the start of the study. CGP data was retrieved from the Foundation Medicine reports and clinical data from the medical records. Actionable genomic findings were reported if associated to therapies for the patient’s tumor type or with proven clinical benefit in other tumor types based on the NCCN Categories of Evidence and Consensus. In addition, quality of life questionnaires (QLQ-C30) were collected for a subset of patients. The primary outcome was a binary endpoint of disease control at 16 weeks of treatment, defined by the absence of progression at that timepoint. Results: Genomic and real-world clinical data were collected and analyzed for 146 patients ( . 70% of the cohort), from 10 different sites in Portugal. Several cancer types were included, with colorectal tumors being the most common (19%), followed by sarcomas (18%) and pancreatic tumors (12%). According to the Foundation Medicine reports, actionable molecular alterations were described in 52% of the cohort. Twenty-three percent of the patients had their therapeutic decision changed due to the CGP result. The most frequent alterations among these patients included high tumor mutational burden (TMB) and/or microsatellite instability (MSI) (35%), as well as pathogenic mutations in PIK3CA (15%) and ATM (12%). Forty-three percent of patients with changed therapy were reported to have achieved disease control at 16 weeks of treatment. Half of the patients with disease control had either high TMB, MSI, or BRAF mutations, reinforcing that evaluating actionable alterations with tissue-agnostic FDA approvals benefit oncology patients. Conclusions: The FRONTAL study highlights the clinical utility of CGP in advanced solid tumors. We identified actionable alterations in 52% of patients, leading to changes in treatment for 23% of the cohort. These findings support the value of CGP in guiding personalized therapies and emphasize the need for further research into its impact on patient outcomes and quality of life. Research Sponsor: None.
- 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.
- Frailty and outcomes in elderly ICU patients: insights from a portuguese cohortPublication . Lourenço, Eva; Rodrigues, Isabel; Sampaio, Mário; da Costa, EmiliaBackground: Frailty is a key determinant of outcomes in critically ill elderly patients, but data from Portugal remain limited. To our knowledge, this is the first study to examine the prevalence and prognostic impact of frailty among elderly ICU patients in a Portuguese hospital setting. Objective: To determine the prevalence of frailty among elderly patients admitted to an intensive care unit (ICU) in southern Portugal and to examine its crude associations with illness severity, organ support, and mortality outcomes. Methods: We conducted a retrospective cohort study including 125 patients aged ≥ 65 years admitted to the polyvalent ICU of Hospital de Faro over the last six months of 2024. Data included demographics, comorbidities, Charlson Comorbidity Index (CCI), severity scores (SOFA, SAPS II, APACHE II), and frailty status assessed by the Clinical Frailty Scale (CFS). Outcomes were the need for organ support, ICU and hospital mortality, and length of stay. Results: Frailty (CFS ≥ 5) was identified in 30.4% of patients. Frail patients were older, had higher comorbidity burden (CCI), and presented with significantly higher severity scores at admission. They also required more invasive support, including vasopressors and invasive mechanical ventilation, while acute kidney injury (AKI) requiring renal replacement therapy (RRT) was similar between groups. ICU mortality was significantly higher among frail patients (50.0% vs. 31.0%), as was hospital mortality (76.3% vs. 33.3%). Length of ICU stay did not differ, although frail patients tended to have longer hospitalizations overall. Conclusions: Frailty was highly prevalent and strongly associated with increased severity, greater need for organ support, and higher mortality. Routine frailty assessment at ICU admission may enhance prognostic accuracy and support patient-centered decision-making.
- Description of the Hamburg Alexander Leukodystrophy Cohort—Insights into Practical Classification and the Care SituationPublication . Kokaly, Nadia; Guerreiro, Helena; Bredow, Janna; Dreha-Kulaczewski, Steffi; Ohlenbusch, Andreas; Köhler, Wolfgang; Reinhardt, Tabea; Schön, Gerhard; Volk, Alexander E.; Sigel, Helen; Bley, AnnetteBackground: Alexander disease (AxD) is a rare severe leukodystrophy that has no cure to date. A pathogenic gain-of-function variant in the GFAP gene affects the astrocytes and subsequently the function of the white matter in the CNS. Methods: We retrospectively analyzed the most frequent symptoms of nine AxD cases, classified them according to published classifications, and described the need of care and support. Results: The description of the courses of disease of nine cases with AxD reflects the broad spectrum of different phenotypes of AxD, with often occurring apnoea. Data about care and support for AxD patients indicate a high and heterogeneous need of support. Treatment with steroids reduced symptoms in two patients. Some patients showed lasting improvement during their course of disease. Conclusions: The course of AxD is very heterogeneous. Thus, we extracted relevant key features to describe the severity of the disease, namely feeding problems, epilepsy, age-appropriate motor function, failure to thrive, age-appropriate language and apnoea. We recommend early evaluation for clinical care and support. For some AxD patients, treatment with steroids may alleviate symptoms. Further development of efficient treatments is necessary