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- Acute venous thromboembolism plasma and red blood cell metabolomic profiling reveals potential new early diagnostic biomarkers: observational clinical studyPublication . Febra, Claúdia; Saraiva, Joana; Vaz, Fátima; Soares, Nelson; Penque, PenqueBackground: Venous thromboembolism (VTE) is a leading cause of cardiovascular mortality. The diagnosis of acute VTE is based on complex imaging exams due to the lack of biomarkers. Recent multi-omics based research has contributed to the development of novel biomarkers in cardiovascular diseases. Our aim was to determine whether patients with acute VTE have differences in the metabolomic profile compared to non-acute VTE. Methods: This observational trial included 62 patients with clinical suspicion of acute deep vein thrombosis or pulmonary embolism, admitted to the emergency room. There were 50 patients diagnosed with acute VTE and 12 with non-acute VTE conditions and no significant differences were found between the two groups for clinical and demographic characteristics. Metabolomics assays identified and quantified a final number of 91 metabolites in plasma and 55 metabolites in red blood cells (RBCs). Plasma from acute VTE patients expressed tendency to a specific metabolomic signature, with univariate analyses revealing 23 significantly different molecules between acute VTE patients and controls (p < 0.05). The most relevant metabolic pathway with the strongest impact on the acute VTE phenotype was D-glutamine and D-glutamate (p = 0.001, false discovery rate = 0.06). RBCs revealed a specific metabolomic signature in patients with a confirmed diagnosis of DVT or PE that distinguished them from other acutely diseased patients, represented by 20 significantly higher metabolites and four lower metabolites. Three of those metabolites revealed high performant ROC curves, including adenosine 3',5'-diphosphate (AUC 0.983), glutathione (AUC 0.923), and adenine (AUC 0.91). Overall, the metabolic pathway most impacting to the differences observed in the RBCs was the purine metabolism (p = 0.000354, false discovery rate = 0.68). Conclusions: Our findings show that metabolite differences exist between acute VTE and nonacute VTE patients admitted to the ER in the early phases. Three potential biomarkers obtained from RBCs showed high performance for acute VTE diagnosis. Further studies should investigate accessible laboratory methods for the future daily practice usefulness of these metabolites for the early diagnosis of acute VTE in the ER.
- Alternative Splicing at the Crossroad of Inflammatory Bowel Diseases and Colitis-Associated Colon CancerPublication . Matos, Paulo; Jordan, PeterSimple Summary: Patients with ulcerative colitis (UC) face a higher risk of developing colorectal cancer (CRC) due to chronic inflammation, a known promoter of tumour growth. Here, we review the molecular differences between colitis-associated cancer (CAC) and sporadic CRC, with a focus on “alternative splicing”, a mechanism by which the same gene can produce various protein forms. We explore how inflammation triggers changes in this process, increasing cancer risk for UC patients. The revised data emphasize that additional research into these molecular changes could help identify new biomarkers (molecules that indicate disease progression) and pave the way for innovative treatments targeting these alterations. Such advances would improve outcomes and quality of life for patients while contributing to cancer prevention and care.
- CCL2 expression predicts clinical outcomes and regulates E-cadherin and angiogenesis in pituitary tumoursPublication . Silva, Ana Luísa; Barry, Sayka; Lopes-Pinto, Mariana; Joaquim, Rita; Miranda, Catarina; Reis, Fábio; Miranda, Micaella; Matos, Paulo; Suleyman, Oniz; Oliveira, Tiago; López-Presa, Dolores; Borrecho, Gonçalo; Tortosa, Francisco; Faria, Claúdia C.; Korbonits, Márta; Marques, PedroThe crosstalk between tumour cells and microenvironment components in pituitary neuroendocrine tumours (PitNETs), including chemokines, may impact tumour behaviour and clinical outcomes. CCL2 was previously identified as a key chemokine in PitNETs, but its role remains unknown. We aimed to study the role of CCL2 in defining the phenotype and clinical outcomes of PitNETs and in regulating macrophage chemotaxis, epithelial-to-mesenchymal transition (EMT) and angiogenesis. We studied CCL2 and E-cadherin expression, macrophages (CD68 and CD163) and vessels (CD31) in samples from 86 PitNET patients. Higher CCL2 mRNA expression was found in patients who required multimodal and multiple treatments and had active disease at the last follow-up. Higher CCL2 immunoreactivity was observed in patients with larger PitNETs. Among somatotroph tumours, CCL2 mRNA expression correlated with serum IGF-1 at the last follow-up. CCL2 mRNA expression levels correlated negatively with CDH1 expression and with E-cadherin complete membranous staining. In vitro, CCL2 downregulated E-cadherin expression in GH3 cells but did not affect cell morphology or migration. CCL2 expression correlated with the number of vessels, vessel perimeter and vessel area in PitNETs but not with PitNET-infiltrating macrophages. Our data suggest that CCL2 may lead to (or is at least a predictive marker of) poorer clinical outcomes and more difficult-to-treat PitNETs, potentially through its regulatory effects on different tumour-related mechanisms beyond immune cell chemotaxis, including in the activation of the EMT pathway and modulation of angiogenesis in PitNETs. Further studies are needed to corroborate our findings and to validate CCL2 as a potential predictive marker and therapeutic target in PitNETs.
- Evaluating the Impact of Newborn Screening for Cystic Fibrosis in Portugal: A Decade of Insights and OutcomesPublication . Camacho, Bernardo; Pereira, Luísa; Bragança, Raquel; Castanhinha, Susana; Penteado, Raquel; Silva, Teresa Reis; Miragaia, Pedro; Silva, Sónia; Cardoso, Ana L.; Barbosa, Telma; Freitas, Cristina; Gonçalves, Juan; Marcão, Ana; Vilarinho, Laura; Barreto, Celeste; Constant, CarolinaThe implementation of newborn screening (NBS) has revolutionized the diagnostic landscape of cystic fibrosis (CF). In Portugal, NBS was initiated in October 2013 through a pilot study and was subsequently fully integrated into a nationwide program by December 2018. Infants with positive screening results are referred to a specialized CF reference center for diagnostic confirmation, employing Sweat Chloride Testing (SCT) and genetic testing for CFTR variants. We aimed to analyze infants with a positive CF screening and determine the false positive and false negative rates, as well as to calculate the positive predictive value and sensitivity of our NBS program. A retrospective nationwide analysis was conducted on infants with a positive NBS for CF between October 2013 and February 2023. Two hundred and forty infants were referred from the NBS program; 74 (30.8%) were confirmed to have CF through SCT and genetic testing. Sensitivity was 93.2%, and the positive predictive value (PPV) was 30.8%. In addition, 48.5% were homozygous for F508del variants, and 87.8% had at least one F508del variant. Guidelines set forth by the European Cystic Fibrosis Society advise NBS programs to achieve a minimum PPV of 30% and a minimum sensitivity of 95%. Our report demonstrated good compliance with these recommendations.
- From Food to Humans: The Toxicological Effects of Alternaria Mycotoxins in the Liver and ColonPublication . Vilela, Rita Sofia; Pina-Martins, Francisco; Ventura, CéliaAlternaria mycotoxins represent a significant and emerging concern in the field of food safety due to their widespread occurrence in diverse food and feed commodities, including cereals, tomatoes, oilseeds, and dried fruits. Among these, alternariol (AOH), alternariol monomethyl ether (AME), tenuazonic acid (TeA), and altertoxin-I (ATX-I) are the most frequently detected, often co-occurring at varying concentrations, thereby increasing the complexity of exposure and risk assessment. The gastrointestinal tract (GIT) is a crucial target of these toxins, as well as the liver, particularly considering its detoxifying role. Nevertheless, despite being a source of possible gastrointestinal and hepatic toxicity, there is still scarce data on the toxicokinetics of Alternaria toxins, on their mode of action, and respective toxic effects. To date, in vitro studies have shown that different Alternaria mycotoxins exhibit diverse toxicological effects, which may be dependent on their chemical structure. AOH and ATX-I have shown genotoxicity and cytotoxicity, mainly through interaction with the DNA and apoptosis, respectively. Tentoxin (TEN) has displayed hepatotoxic potential via impairment of detoxification pathways, and altenuene (ALT) has revealed lower toxicity. In vivo, AME and ATX-II revealed genotoxicity, while AOH and ATX-I showed context-dependent variability in their effects. Altogether, this review emphasizes that there is still a great lack of knowledge on these mycotoxins and an urgent need for more comprehensive toxicological and occurrence data to support proper risk assessment and, ultimately, regulatory decision-making.
- Lactate-coated polyurea-siRNA dendriplex: a gene therapy-directed and metabolism-based strategy to impair glioblastoma (GBM)Publication . Martins, Filipa; Arada, Renata; Barros, Hélio; Matos, Paulo; Ramalho, José; Ceña, Valentín; Bonifácio, Vasco D.B.; Gonçalves, Luís G.; Serpa, JacintaGlioblastoma (GBM) is a highly lethal disease with limited treatment options due to its infiltrative nature and the lack of efficient therapy able to cross the protective blood-brain barrier (BBB). GBMs are metabolically characterized by increased glycolysis and glutamine dependence. This study explores a novel metabolism-based therapeutic approach using a polyurea generation 4 dendrimer (PURE) surface functionalized with lactate (LA) (PURE-LA), to take advantage of glucose-dependent monocarboxylate transporters (MCTs) overexpression, loaded with selenium-chrysin (SeChry) and temozolomide (TMZ) or complexed with anti-glutaminase (GLS1) siRNAs to abrogate glutamine dependence. The nanoparticles (PURE-LA) were efficient vehicles for cytotoxic compounds delivery, since SeChry@PURE-LA and TMZ@PURE-LA induced significant cell death in GBM cell lines, particularly in U251, which exhibits higher MCT1 expression. The anti-GLS1 siRNA-dendriplex with PURE-LA (PURE-LA-anti-GLS1-siRNA) knocked down GLS1 in the GBM cell lines. In two in vitro BBB models, these dendriplexes successfully crossed the BBB, decreased GLS1 expression and altered the exometabolome of GBM cell lines, concomitantly with autophagy activation. Our findings highlight the potential of targeting glucose and glutamine pathways in GBM using dendrimer-based nanocarriers, overcoming the BBB and disrupting key metabolic processes in GBM cells. PURE-LA-anti-GLS1-siRNA dendriplexes cross the blood-brain barrier (BBB) and impair glioblastoma (GBM) metabolism. The BBB is formed by a thin monolayer of specialized brain microvascular endothelial cells joined together by tight junctions that selectively control the passage of substances from the blood to the brain. It is a major obstacle in the treatment of GBM, since many chemotherapeutic drugs are unable to penetrate the brain. Therefore, we developed a strategy to overcome this obstacle: a lactate-coated polyurea dendrimer generation 4 (PURE) able to cross the BBB in vitro, that act as a nanocarrier of drugs and siRNA to the GBM cells. PURE-LA are nanoparticles functionalized with lactate (LA) to target MCT1, a lactate transporter highly expressed by GBM cells. Moreover, a complex of this nanoparticle with anti-GLS1 (glutaminase) siRNA (PURE-LA-anti-GLS1-siRNA) was made, to target glutamine metabolism. It efficiently knocked down GLS1. Moreover, PURE-LA loaded with SeChry led to BBB disruption.
- Occupational second-hand smoke exposure: A comparative shotgun proteomics study on nasal epithelia from healthy restaurant workersPublication . Neves, Sofia; Pacheco, Solange; Vaz, Fátima; James, Peter; Simões, Tânia; Penque, Deborah; NevesNon-smokers exposed to second-hand smoke (SHS) present risk of developing tobacco smoke-associated pathologies. To investigate the airway molecular response to SHS exposure that could be used in health risk assessment, comparative shotgun proteomics was performed on nasal epithelium from a group of healthy restaurant workers, non-smokers (never and former) exposed and not exposed to SHS in the workplace. HIF1α-glycolytic targets (GAPDH, TPI) and proteins related to xenobiotic metabolism, cell proliferation and differentiation leading to cancer (ADH1C, TUBB4B, EEF2) showed significant modulation in non-smokers exposed. In never smokers exposed, enrichment of glutathione metabolism pathway and EEF2-regulating protein synthesis in genotoxic response were increased, while in former smokers exposed, proteins (LYZ, ATP1A1, SERPINB3) associated with tissue damage/regeneration, apoptosis inhibition and inflammation that may lead to asthma, COPD or cancer, were upregulated. The identified proteins are potential response and susceptibility/risk biomarkers for SHS exposure.
- Re‐assessment of the risks to public health related to the genotoxicity of styrene present in plastic food contact materialsPublication . EFSA Panel on Food Contact Materials (FCM); Claude, Lambré; Crebelli, Riccardo; Silva, Maria Da; Grob, Konrad; Lampi, Evgenia; Milana, Maria Rosaria; Pronk, Marja; Ščetar, Mario; Theodoridis, Georgios; Van Hoeck, Els; Waegeneers, Nadia; Bolognesi, Claudia; Consiglio, Emma Di; Mengelers, Marcel; Al Harraq, Zainab; Pilar, Irene Muñoz; Rainieri, Sandra; Rivière, GillesThe EFSA Panel on Food Contact Materials (FCM) was requested by the European Commission to re‐evaluate the potential genotoxicity of styrene after oral exposure and its safety for use in plastic FCM with a specific migration limit (SML) of 40 μg/kg food. A rigorous assessment of the in vivo genotoxicity studies (i) provided by third parties, (ii) identified by a targeted literature search and (iii) reported in the 2019 IARC Monograph was performed. All studies were assessed for reliability and relevance and the results integrated in the weight of evidence. The results provided by reliable in vivo oral genotoxicity studies, covering different genetic endpoints and target tissues, including liver, the primary site of metabolism, demonstrated that the oral administration of styrene in mice and rats up to the maximum tolerated dose (300 and 500 mg/kg body weight (bw), respectively) did not induce genotoxic effects. The Panel concluded that there was no evidence that styrene is genotoxic following oral exposure. For substances demonstrated to be non‐genotoxic, according to the EFSA Note for Guidance for FCM, an SML up to 50 μg/kg food would not be of safety concern. Consequently, the use of styrene in the manufacture of FCM respecting the SML of 40 μg/kg food proposed by the European Commission is not of safety concern.
- Safety assessment of the process brtCOMBIPET used to recycle post‐consumer PET into food contact materialsPublication . EFSA FCM Panel (EFSA Panel on Food Contact Materials); Lambré, Claude; Crebelli, Riccardo; da Silva, Maria; Grob, Koni; Milana, Maria Rosaria; Pronk, Marja; Rivière, Gilles; Ščetar, Mario; Theodoridis, Georgios; Van Hoeck, Els; Waegeneers, Nadia; Dudler, Vincent; Papaspyrides, Constantine; Tavares Poças, Maria de Fátima; Lioupis, Alexandros; Tsochatzis, Emmanouil; Lampi, EvgeniaThe EFSA Panel on Food Contact Materials (FCM) assessed the safety of the recycling process brtCOMBIPET (EU register number RECYC338). The input is washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are dried (step 6), melted in an extruder (step 7) and pelletised, dried and crystallised (step 8). The pellets are then preheated, further crystallised, then decontaminated in a solid‐state polymerisation (SSP) reactor (step 9) and cooled down. Having examined the challenge tests provided, the Panel concluded that the extrusion, the preheating and the SSP are critical in determining the decontamination efficiency of the process. The operating parameters to control the performance are the temperature and the pressure for step 7 (extrusion) as well as the temperature, residence time and gas flow rate for step 9 (preheating and SSP). It was demonstrated that this recycling process ensures that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.0481 or 0.0962 μg/kg food, depending on the molar mass of the contaminant substance. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern, when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature or below, with or without hot‐fill. Articles made of this recycled PET are not intended to be used in microwave and conventional ovens and such uses are not covered by this evaluation.
- Safety assessment of the process Diamat SC used to recycle post‐consumer PET into food contact materialsPublication . EFSA FCM Panel (EFSA Panel on Food Contact Materials); Lambré, Claude; Crebelli, Riccardo; Silva, Maria da; Grob, Koni; Milana, Maria Rosaria; Pronk, Marja; Rivière, Gilles; Ščetar, Mario; Theodoridis, Georgios; Van Hoeck, Els; Waegeneers, Nadia; Dudler, Vincent; Papaspyrides, Constantine; Poças, Maria de Fátima Tavares; Lioupis, Alexandros; Lampi, EvgeniaThe EFSA Panel on Food Contact Materials (FCM) assessed the safety of the recycling process Diamat SC (EU register number RECYC334). The input is hot caustic washed and dried poly(ethylene terephthalate) (PET) flakes mainly originating from collected post‐consumer PET containers, with no more than 5% PET from non‐food consumer applications. The flakes are crystallised (step 2), dried (step 3) and extruded into sheets (step 4). Having examined the challenge test provided, the Panel concluded that the crystallisation, drying and extrusion steps (steps 2–4) are critical in determining the decontamination efficiency of the process. The operating parameters to control the efficiency of the process are the temperature and the residence time for all steps (steps 2–4), the air flow rate for step 3, the pressure and the characteristics of the extruder (step 4). It was demonstrated that this recycling process ensures that the level of migration of potential unknown contaminants into food is below the conservatively modelled migration of 0.0481 or 0.0962 μg/kg food, depending on the molar mass of a contaminant substance. Therefore, the Panel concluded that the recycled PET obtained from this process is not of safety concern when used at up to 100% for the manufacture of materials and articles for contact with all types of foodstuffs, including drinking water, for long‐term storage at room temperature or below, with or without hot‐fill. Articles made of this recycled PET are not intended to be used in microwave and conventional ovens, and such uses are not covered by this evaluation.
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