ABC2-Artigos (em revistas ou actas indexadas)
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- Maternal thyroid hormone is required to develop the hindbrain vasculature in zebrafishPublication . Trindade, Marlene; Silva, Nádia; Rodrigues, Joana; Kawakami, Koichi; Campinho, Marco AntónioThyroid hormone (TH) signaling is important and necessary for proper neurodevelopment. Inadequate levels of maternally derived THs (MTH) supply affect target gene expression profiles, which are fundamental for the brain’s normal growth, maturation, and function. The monocarboxylate transporter 8 (SLC16A2, MCT8) is the main TH transporter present in the brain during embryonic development, and mutations in this transporter lead to a rare and debilitating human condition known as the Allan-Herndon-Dudley Syndrome (AHDS). This mutation affects the capacity for intracellular transport of the hormone, leading to impaired brain development that constitutes the main pathophysiological basis of AHDS. Like humans, zebrafish embryos express slc16a2 that transports exclusively T3 at zebrafish physiological temperature. Studies in zebrafish Mct8 knockdown (KD) models found impaired hindbrain vasculature development. Here, using zebrafish Mct8 KD and knockout (KO) models, we shed light on the maternal T3 (MT3)-dependent developmental mechanism behind hindbrain vasculature development. We first demonstrate that MT3-regulates hindbrain vegfaa expression. We provide evidence that hindbrain neurons are not the source of vegfaa, instead, restricted pax6a+ neuroprogenitor cells (NPCs) instruct central arteries (CtAs) ingression into the hindbrain. Therefore, MT3 acts as an integrator, providing the regulatory cues necessary for the timely ingression of the CtAs into the hindbrain.
- Using ECG-derived respiration for explaining BOLD-fMRI fluctuations during rest and respiratory modulationsPublication . Esteves, Inês; Rodrigues Fouto, Ana Lúcia; Ruiz-Tagle, Amparo; Caetano, Gina; Figueiredo, PatríciaRecording physiological signals during fMRI is valuable for multiple purposes but often requires additional setup, increasing complexity and participant discomfort. This is particularly challenging in simultaneous EEG-fMRI studies, which typically already include electrocardiogram (ECG) recordings. Here, we aim to leverage the known modulation of ECG by respiration to obtain an ECG-derived respiration (EDR) signal without extra equipment. We acquired EEG-fMRI data from 15 healthy subjects during resting state and two respiratory challenges (slow-paced breathing and breath-holding), with simultaneous ECG and respiratory recordings. Multiple methods were used to extract EDR signals, and the results were evaluated by comparing them with recorded respiration and assessing the quality of physiological regressors for denoising and cerebrovascular reactivity estimation. Amplitude-based EDR methods showed lower correlations with respiration, likely due to ECG distortion in the MRI. Nevertheless, coherence analysis showed that EDR preserved the relevant spectral content. EDR-based regressors were similar to those obtained from measured respiration. Notably, a method based on heart rate variability performed best overall, yielding physiological noise correction and reactivity estimates comparable to those using recorded respiration. Our results demonstrate that meaningful respiratory information can be extracted from ECG within the MRI environment, benefiting EEG-fMRI studies when respiration cannot be reliably recorded.
- Syngap1 and the development of murine neocortical progenitor cellsPublication . Barao, Soraia; Xu, Yijun; Hong, Ingie; Müller, Ulrich; Huganir, Richard L.SYNGAP1 regulates synaptic plasticity through interactions with scaffold proteins and modulation of Ras and Rap GTPase signaling. Human SYNGAP1 mutations are linked to intellectual disability, epilepsy, and autism. In mice, Syngap1 haploinsufficiency causes impaired LTP, premature maturation of dendritic spines, learning disabilities, and seizures, reflecting the human phenotypes of SYNGAP1 syndrome. Recently, SYNGAP1 was shown to influence cortical neurogenesis and progenitor proliferation in human organoids. Here, we show that Syngap1 absence or haploinsufficiency does not alter neocortical progenitors and their cellular output in mice. Despite careful analysis of cortical progenitor properties, we fail to replicate the main findings from human organoids. This discrepancy suggests species-specific or methodological differences and raises questions about the broader relevance of SYNGAP1’s role in neurogenesis. The absence of cortical progenitor deficits in haploinsufficient mice, which exhibit cognitive deficits and seizures, indicates these arise from SYNGAP1’s regulation of synapse function rather than its role on neurogenesis.
- P0463 Distinct hepcidin dynamics in crohn’s disease and ulcerative colitis: links to iron homeostasis and inflammatory activityPublication . Magro, F.; Santos, M. P. Ministro dos; Sousa, Helena Tavares; Roseira, Joana; Fernandes, S. R.; Crespo, R.; Dias, S.; Beatriz, D.; Dias, C. C.; Miranda, R.; Santiago, M.; Portela, F.Background: Hepcidin, the master regulator of systemic iron metabolism, is influenced by iron availability and inflammation.1 In inflammatory bowel disease (IBD), iron deficiency and anaemia are common, yet how hepcidin is regulated in relation to disease phenotype, iron status and inflammatory burden remains incompletely understood.2 We aimed to characterise hepcidin regulation in ulcerative colitis (UC) and Crohn’s disease (CD) according to iron status and inflammatory markers. Methods: In this cross-sectional multicentre study, 589 individuals were enrolled (178 healthy controls, 130 UC, 281CD). Patients were stratified by iron status and activity. Serum hepcidin, iron parameters, and inflammatory and clinical data were collected. Iron deficiency was defined using the ECCO criteria2 , which focuses on ferritin, and a combined ferritin and transferrin saturation definition. Group comparisons, correlations, and multivariable linear regressions were performed. Results: Hepcidin correlated positively with C-reactive protein (CRP) in CD (r=0.125; p=0.038) and negatively with faecal calprotectin (FCAL) in UC (r=-0.311; p.
- zAvatar-test—a functional precision model to personalize ovarian cancer treatments: Results from a co-clinical studyPublication . Estrada, Marta F.; Amorim, Filipa; Silva, Filipa Ferreira da; Almeida, Cátia Rebelo de; Fontes, Márcia; Coelho, Ricardo; Ferreira, Sónia; Canas-Marques, Rita; Castillo-Martin, Mireia; Casanova, João; Batarda, Maria de Lurdes; Yaniz-Galende, Elisa; LeFormal, Audrey; Marreiros, Ana; Jacob, Francis; Heinzelmann-Schwarz, Viola; Leary, Alexandra; Nabais, Henrique; Fior, RitaIn ovarian cancer, 80% of patients relapse after first-line therapy. In recurrent cases, oncologists lack reliable tests to guide chemotherapy choices, creating an unmet clinical need. Here, we develop the ovarian cancer zebrafish Avatar-test, a functional in vivo model using patient tumor cells implanted in zebrafish embryos to predict treatment responses. We present the largest observational study (32 patients), where the zAvatar-test achieves 91% accuracy in predicting patient outcomes. Patients with a zAvatar-sensitive-test correlate with longer progression-free survival (17 vs. 6 months). Tumors in zAvatars are dynamic, with human-host cell interactions, and higher metastatic potential in poor-prognosis cases. Finally, as a proof of concept, we demonstrate that venetoclax has the potential to sensitize multidrug-resistant tumors. Altogether, this clinical study demonstrates that the zAvatar-test may help clinicians personalize treatments for ovarian cancer patients. We are now conducting a multicentric randomized clinical trial to evaluate the zAvatar-test as a companion tool in clinical oncology.
- Optimizing the input: can large language models standardize radiology requisitions?Publication . Santinha, João; Guerreiro, Helena Isabel de SousaRadiology stands as a central pillar of modern healthcare, non-invasively visualizing anatomy and physiology to guide critical diagnostic and treatment decisions. Over the last decade, the radiology community has made significant strides in standardizing its “outputs,” the radiology report [1]. Through initiatives like the various Reporting and Data Systems (RADS) for breast, liver, prostate, and thyroid imaging, we have improved communication, reduced ambiguity, and enhanced the clinical utility of our findings. However, a high-quality output depends fundamentally on a high-quality input.
- Metabolism and the impact of protein intake in chronic critically ill adult patients: protocol for a unicentric prospective cohort study (MetaChronic Study)Publication . Castro, Sílvia; Granja, Cristina; Dionne, Joanna C.; Pires, Teresa; Oliveira, Carolina; Binnie, AlexandraBackground: Survival of acutely critically ill patients has improved, resulting in a growing population of chronic critically ill (CCI) patients with prolonged organ dysfunction, mechanical ventilation, and high morbidity. While nutritional guidelines during the acute phase of critical illness are well defined, our understanding of metabolism and nutritional needs in CCI patients is limited. Persistent inflammation may influence the metabolic response and nutritional uptake, highlighting the need for prospective studies in this area. Methods: The MetaChronic Study is a single-center, prospective cohort study of metabolism in patients with CCI. Adult ICU patients with invasive mechanical ventilation ≥48 h and ICU stay >7 days are eligible. Patients are followed for up to 42 days after ICU admission, with final outcomes assessed at 90 days. Resting energy expenditure is measured weekly by serial indirect calorimetry. Weekly protein and calorie intake are recorded and inflammation is assessed using serum C-reactive protein and procalcitonin measurements. Patients are categorized according to high or low protein intake (>1.3 g/kg/ day vs. ≤1.3 g/kg/day after the first week). The primary objective is to characterize longitudinal metabolic trajectories. Secondary objectives include subgroup analyses (septic, trauma, neurocritical patients), assessment of the interaction between inflammation and metabolic rate, and exploratory analyses of the association between protein intake and clinical outcomes. Ethics and dissemination: The study has been approved by the institutional ethics committee. Findings will be disseminated through peer-reviewed journals and scientific conferences.
- P0397 Soluble transferrin receptor as a reliable inflammation-independent marker of iron deficiency in crohn’s disease and ulcerative colitisPublication . Portela, F.; Santos, M. P. Ministro dos; Sousa, Helena Tavares; Roseira, Joana; Fernandes, S. R.; Crespo, R.; Domingues, B.; Santiago, M.; Miranda, R.; Dias, S.; Dias, C. C.; Magro, F.Background: Iron deficiency is a common complication in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD).1 However, standard iron markers are influenced by inflammation, complicating the diagnosis of true iron deficiency.1,2 Soluble transferrin receptor (sTfR) has been proposed as a more reliable, inflammation-independent marker of iron demand.3 This study aimed to assess the utility of sTfR in identifying iron deficiency without anaemia (IDWA). Methods: The ID_IBD study was a multicentre, cross-sectional study. Iron status was classified using two approaches: the ECCO consensus definition, focusing on ferritin thresholds adjusted for inflammatory markers (C-reactive protein [CRP] and faecal calprotectin [FCAL]), and a stricter definition that adds transferrin saturation to the ECCO criteria. sTfR levels were compared across groups, and ROC curve analysis was used to identify optimal diagnostic cut-offs. Results: This analysis included 411 IBD patients (130 UC, 281CD) and 178 controls. sTfR showed no correlation with CRP or FCAL. In UC, patients with IDWA had significantly higher sTfR levels (median 1.20mg/L, IQR 1.02-1.42) compared to non-IDWA patients (median 1.05mg/L, IQR 0.92-1.22; p=0.013). Anaemic UC patients also showed elevated sTfR levels (median 1.27mg/L, IQR 1.14-1.59) compared to non-IDWA individuals (patients but was significantly higher in anaemic patients (p=0.003). Conclusion: sTfR appears to be an inflammation-independent marker of iron status in IBD. It showed potential for identifying IDWA in UC, while in CD it mainly reflected increased iron demand in anaemia. Further longitudinal studies are warranted to validate its role and assess its clinical utility in IBD.
- Annexin A2 regulates AKT upon H2O2-dependent signaling activation in cancer cellsPublication . Castaldo, Stéphanie Anais; Ajime, Tom; Serrão Fernandes, Lina Gisela; Anastácio, Fábio; Rosa, Joana Teixeira; Giacomantonio, Carman Anthony; Howarth, Alison; Hill, Richard; Madureira, PatriciaHydrogen peroxide (H2O2) is a main second messenger in oncogenic signaling networks including the Ras and the growth factor receptor pathways. This is achieved predominantly through the oxidation of redox-sensitive cysteine (Cys) residues in proteins resulting in changes to their structure and function. We previously identified annexin A2 (ANXA2) as a redox regulatory protein that plays an important cellular role during oxidative stress and also promoting tumorigenesis. Here we investigated the role of ANXA2 in the regulation of H2O2-dependent signaling that drives tumor progression. We show that depletion of ANXA2 leads to the enhanced activation of AKT following either EGF/EGFR stimulation or oncogenic Ras transformation. The phosphatase and tensin homologue (PTEN) protein negatively regulates the PI3K/AKT pathway. We demonstrate that ANXA2 via its reactive Cys-8 residue, binds to PTEN and that the co-expression of PTEN and ANXA2, but not ANXA2 Cys-8-Ala mutant, inhibits AKT phosphorylation on Ser 473. These results indicate that ANXA2 is important for PTEN regulation within the PI3K/AKT signaling cascade. Furthermore, we also reveal that ANXA2 inversely regulates the expression of the peroxidase, peroxiredoxin 2, in a reactive oxygen species dependent manner.
- Investigating glioblastoma response to hypoxiaPublication . Chédeville, Agathe L.; Lourdusamy, Anbarasu; Monteiro, Ana Rita; Hill, Richard; Madureira, PatriciaGlioblastoma (GB) is the most common and deadly type of primary malignant brain tumor with an average patient survival of only 15–17 months. GBs typically have hypoxic regions associated with aggressiveness and chemoresistance. Using patient derived GB cells, we characterized how GB responds to hypoxia. We noted a hypoxia-dependent glycolytic switch characterized by the up-regulation of HK2, PFKFB3, PFKFB4, LDHA, PDK1, SLC2A1/GLUT-1, CA9/CAIX, and SLC16A3/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD, PGF/PlGF, ADM, ANGPTL4, and SERPINE1/PAI-1 were up-regulated during hypoxia. We detected the hypoxic induction of invasion proteins, including the plasminogen receptor, S100A10, and the urokinase plasminogen activator receptor, uPAR. Furthermore, we observed a hypoxia-dependent up-regulation of the autophagy genes, BNIP-3 and DDIT4 and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation of EGR1 and TFRC (Graphical abstract). Analysis of GB patient cohorts’ revealed differential expression of these genes in patient samples (except SLC16A3) compared to non-neoplastic brain tissue. High expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, TFRC, and ADM was associated with significantly lower overall survival. Together these data provide important information regarding GB response to hypoxia which could support the development of more effective treatments for GB patients.