Activiteit

Adult cognitive neuroscience has guided the study of human brain development by identifying regions associated with cognitive functions at maturity. The activity, connectivity, and structure of a region can be compared across ages to characterize the developmental trajectory of the corresponding function. However, developmental differences may reflect both the maturation of the function and also its organization across the brain. That is, a function may be present in children but supported by different brain regions, leading its maturity to be underestimated. Here we test the presence, maturity, and localization of adult functions in children using shared response modeling, a machine learning approach for functional alignment. After learning a lower-dimensional feature space from fMRI activity as adults watched a movie, we translated these shared features into the anatomical brain space of children 3-12 years old. To evaluate functional maturity, we correlated this reconstructed activity with children’s actual fMRI activity as they watched the same movie. We found reliable correlations throughout cortex, even in the youngest children. The strength of the correlation in the precuneus, inferior frontal gyrus, and lateral occipital cortex predicted chronological age. These age-related changes were driven by three types of developmental trajectories emergence from absence to presence, consistency in anatomical expression, and reorganization from one anatomical region to another. We also found evidence that the processing of pain-related events in the movie underwent reorganization across childhood. This data-driven, naturalistic approach provides a new perspective on the development of functional neuroanatomy throughout childhood.Neuroblastoma (NBL), the most frequent and lethal pediatric cancer of children in pre-school age, is considered enigmatic in view of its extreme heterogeneity, from spontaneous regression in the IV-S form to incurable disease in approx. 40% of cases (High Risk, HR-NBL). It has an embryonal origin and a very heterogeneous genomic landscape, hampering the success of targeted strategies. Fimepinostat cost The glycosphingolipid GD2 was shown to be expressed on NBL cells and utilized as target for passive immunotherapy with anti-GD2 antibodies (GD2-IMT). An international protocol was established with GD2-IMT, which increases remission length and survival in HR-NBL. By reviewing the different biological and molecular aspects of NBL and GD2-IMT, this mini-review questions the present lack of association between GD2-IMT and the underlying molecular landscape. The alternative model of Micro-Foci inducing virus (MFV) is presented, since MFV infection can induce extensive genomic aberrations (100X NMYC DNA-amplification). Since this family of viruses uses molecules for cell penetration similar to GD2 (i.e., GM2), it is hypothesized that GD2 is the port-of-entry for MFV and that success of anti-GD2 therapies is also associated to inhibition of this clastogenic virus in HR-NBL.Pancreatic ductal adenocarcinoma(PDAC) is resistant to the PD-1/PD-L1 blockade therapy. Previously, the combination of PD-1 blockade and vaccine therapy was shown to have a modest antitumor activity in murine models of PDAC. We used a murine syngeneic model of metastatic PDAC to identify, among multiple T cell modulators tested, which therapeutic agents in combination with the GVAX cancer vaccine and an anti-PD-1 antagonist antibody(αPD-1) are able to improve the survival. We found that an anti-CD137 agonist antibody(αCD137) most significantly improved survival in the mouse PDAC model. Moreover, αPD-1 and αCD137 together in combination with vaccine therapy more significantly increased the expression of costimulatory molecules CD137 and OX40 on CD4+PD-1+ and CD8+PD-1+ T cells comparing to αPD-1 or αCD137, respectively, suggesting that T cell activation within PDACs were enhanced by a synergy of αCD137 and αPD-1. On another hand, αCD137 treatment led to an increase in effector memory T cells independent of αPD-1. Although αCD137 does not increase the cytotoxic effector T cell function, the addition of αCD137 to GVAX+αPD-1 increased expression of IFNγ in EOMES + exhausted tumor-infiltrating T cells. Taken together, this preclinical study established the mechanism of targeting CD137 to enhance effector memory and activated T cells in PDAC. Immunohistochemistry analysis of resected human PDACs following the neo-adjuvant GVAX treatment showed increased levels of CD8+ T cells in those with high levels of CD137 expression, supporting an ongoing clinical trial of testing CD137 as a potential target in treating PDACs that are inflamed with T cells by vaccine therapy.Protocadherin 10 (PCDH10) is identified as a tumor suppressor in multiple cancers. The molecular mechanisms that mediate the functions of PCDH10 have yet to be fully elucidated. Here, we demonstrated that ectopic expression of PCDH10 in colorectal cancer (CRC) cells induced cell cycle retardation and increased apoptosis through regulation of the p53/p21/Rb axis and Bcl-2 expression. Overexpression of PCDH10 reversed the epithelial-mesenchymal transition (EMT) process with morphological changes and EMT marker alterations. Mechanistic study revealed that PCDH10 inhibited AKT/GSK3β signaling pathway which in turn reduced β-catenin activity and thus attenuated Snail and Twist1 expression. Furthermore, PCDH10 inhibited the stemness of CRC cells, including spheroid formation and stem cell markers. A proteomics approach revealed that PCDH10 could interact with EGFR, which was further verified by co-immunoprecipitation. Moreover, restoration of PCDH10 expression reduced EGFR phosphorylation. Accordingly, our work proposes a novel pathway by which PCDH10 directly engages in the negative regulation of EGFR/AKT/β-catenin signaling pathway, resulting in tumor suppression.Spices are susceptible to mycotoxin contamination which can cause gastrointestinal and adverse central nervous symptoms in humans, which highlights the importance of assessing the risk of their consumption on a daily basis. The aim of this study was to assess the risk of mycotoxin intake from spices in routinely prepared Lebanese dishes. 150 households were interviewed about their usage of 27 type of spices and 6 routinely prepared Lebanese dishes. Results showed a high variability in consumption levels. Among the investigated dishes, the minimum number of spices that were consumed in a dish was 13 while the maximum was 18. The mean intake of one spice ranged from 0.26 g/portion observed for cloves to 5.37 g/portion for cinnamon, with its intake per portion more than 1 g in 2/3 of dishes. 20% of portion sizes of coriander, cinnamon and fennel, had an intake exceeding 5 g/portion. Ochratoxin A (OTA) Probable Daily Intake (PDI) had a mean of 0.11 ng/kg-bw/day. Mean PDI of fumonisin B1 (FB1) was 79.3 ng/kg-bw/day.