WIPI1, BAG1 and PEX3 autophagy-related genes are relevant melanoma markers

ROS and oxidative stress may promote autophagy; on the other hand, autophagy may help reduce oxidative damages. According to the known interplay of ROS, autophagy, and melanoma onset, we hypothesized that autophagy-related genes (ARGs) may represent useful melanoma biomarkers. We therefore analyzed the gene and protein expression of 222 ARGs in human melanoma samples, from 5 independent expression databases (overall 572 patients). Gene expression was first evaluated in the GEO database. Forty-two genes showed extremely high ability to discriminate melanoma from nevi (63 samples) according to ROC (AUC ≥ 0.85) and Mann-Whitney (p < 0.0001) analyses. The 9 genes never related to melanoma before were then in silico validated in the IST online database. BAG1, CHMP2B, PEX3, and WIPI1 confirmed a strong differential gene expression, in 355 samples. A second-round validation performed on the Human Protein Atlas database showed strong differential protein expression for BAG1, PEX3, and WIPI1 in melanoma vs control samples, according to the image analysis of 80 human histological sections. WIPI1 gene expression also showed a significant prognostic value (p < 0.0001) according to 102 melanoma patients' survival data. We finally addressed in Oncomine database whether WIPI1 overexpression is melanoma-specific. Within more than 20 cancer types, the most relevant WIPI1 expression change (p = 0.00002; fold change = 3.1) was observed in melanoma. Molecular/functional relationships of the investigated molecules with melanoma and their molecular/functional network were analyzed via Chilibot software, STRING analysis, and gene ontology enrichment analysis. We conclude that WIPI1 (AUC = 0.99), BAG1 (AUC = 1), and PEX3 (AUC = 0.93) are relevant novel melanoma markers at both gene and protein levels

Ion channel expression in human melanoma samples. in silico identification and experimental validation of molecular targets

Expression of 328 ion channel genes was investigated, by in silico analysis, in 170 human melanoma samples and controls. Ninety-one members of this gene-family (i.e., about 28%) show a significant (p 0.90 and p 90% in most cases). Such five genes (namely, SCNN1A, GJB3, KCNK7, GJB1, KCNN2) are novel potential melanoma markers or molecular targets, never previously related to melanoma. The “druggable genome” analysis was then carried out. Miconazole, an antifungal drug commonly used in clinics, is known to target KCNN2, the best candidate among the five identified genes. Miconazole was then tested in vitro in proliferation assays; it dose-dependently inhibited proliferation up to 90% and potently induced cell-death in A-375 and SKMEL-28 melanoma cells, while it showed no effect in control cells. Moreover, specific silencing of KCNN2 ion channel was achieved by siRNA transfection; under such condition miconazole strongly increases its anti-proliferative effect. In conclusion, the present study identified five ion channels that can potentially serve as sensitive and specific markers in human melanoma specimens and demonstrates that the antifungal drug miconazole, known to target one of the five identified ion channels, exerts strong and specific anti-melanoma effects in vitro

Meeting Immigrant Community College Students' Needs on One Greater Toronto Area College Campus

One hundred and forty-six students who entered Canada after their twelfth birthday and are now in one of six technical programs on a Greater Toronto Area (GTA) community college campus were surveyed. Technical programs enrol over half the students on this campus, and the six programs enrol over half the technical students. Over half had entered Canada past the usual age for high school (and over two-thirds in the past six years), making the college their point of entry into the Canadian educational system. Degrees and types of needs were analyzed, as well as degrees and sources of support. Differences occurred across numerous background traits but the most striking finding is the students' perception of a low degree of support from the college itself. This has clear policy implications for funders of GTA colleges, which attract such high numbers of new immigrants to Canada.Notre échantillon se compose de cent quarante-six étudiants qui sont arrivés au Canada après l'âge de douze ans et qui font maintenant parti de l'un des six programmes du réseau collégial du Toronto métropolitain (GTA). Plus de la moitié de ces étudiants immigrants sont arrivés au Canada après l'âge habituel pour l'école secondaire (et plus des deux tiers sont arrivés au cours des six dernières années). Ainsi le collège est leur point d'entrée dans le système d'éducation canadien. Leurs besoins ont été analysés ainsi que les ressources qui leur étaient disponibles. Des différences ont été trouvées à travers plusieurs catégories, mais la différence fondamentale se retrouve surtout dans la perception de ces nouveaux arrivants d'une quasi absence d'aide financière offerte par le collège lui-même. Ceci est de grande importance pour les gestionnaires des collèges qui accueillent un grand nombre d'immigrants au Canada

MULTILATERAL TRAINING METHOD AS A PROACTIVE EDUCATIONAL STRATEGY TO PREVENT BULLYING IN ADOLESCENTS

To date, there is no standard definition of bullying, however, it can be characterized as a type of aggression, systematic and repeated, and based upon an imbalance of power in relationships through repeated verbal, physical and/or social behaviour that intends to cause physical, social and/or psychological harm. Youth with higher levels of resilience and self-efficacy are less likely to engage in aggressive behaviours or be victims of bullying. Previous anti-bullying approaches have often achieved no reduction in bullying behaviour. Therefore, the purpose of this study was to examine the effect of 12 weeks of extracurricular multilateral training on the risk for students (14-16 years) to be involved in bullying. Sixty male students were allocated to an experimental group (n = 30) that performed psychoeducational activities combined with physical exercise training and team games (90 min, 2d·week-1) or control group (n=30). Before and after the intervention, we used CYRM-28 that assessed individual capacities and resources, relationship with primary caregiver, contextual factors and total resilience, and SEQ-C that measured academic, social, emotional, and total self-efficacy. Four participants from the experimental group withdrew. Significant improvements of crucial relevance were found for the resilience and self-efficacy scales (p < 0.05) in the experimental group. We found that extracurricular multilateral training may improve the resilience and self-efficacy in adolescents and make them less likely to engage in aggressive behaviour or be bullied. Multilateral training method should be considered as an effective alternative to the anti-bullying approach, highlighting the crucial role of the Physical Education professionals in the promotion of proactive educational strategies to prevent bullying. Article visualizations

The Point of Origin of the Radio Radiation from the Unresolved Cores of Radio-Loud Quasars

Locating the exact point of origin of the core radiation in active galactic nuclei (AGN) would represent important progress in our understanding of physical processes in the central engine of these objects. However, due to our inability to resolve the region containing both the central compact object and the jet base, this has so far been difficult. Here, using an analysis in which the lack of resolution does not play a significant role, we demonstrate that it may be impossible even in most radio loud sources for more than a small percentage of the core radiation at radio wavelengths to come from the jet base. We find for 3C279 that $\sim85$ percent of the core flux at 15 GHz must come from a separate, reasonably stable, region that is not part of the jet base, and that then likely radiates at least quasi-isotropically and is centered on the black hole. The long-term stability of this component also suggests that it may originate in a region that extends over many Schwarzschild radii.Comment: 7 pages with 3 figures, accepted for publication in Astrophysics and Space Scienc

Physical exercise and health: a focus on its protective role in neurodegenerative diseases

Scientific evidence has demonstrated the power of physical exercise in the prevention and treatment of numerous chronic and/or age-related diseases, such as musculoskeletal, metabolic, and cardiovascular disorders. In addition, regular exercise is known to play a key role in the context of neurodegenerative diseases, as it helps to reduce the risk of their onset and counteracts their progression. However, the underlying molecular mechanisms have not yet been fully elucidated. In this regard, neurotrophins, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glia cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and neurotrophin4 (NT-4), have been suggested as key mediators of brain health benefits, as they are involved in neurogenesis, neuronal survival, and synaptic plasticity. The production of these neurotrophic factors, known to be increased by physical exercise, is downregulated in neurodegenerative disorders, suggesting their fundamental importance in maintaining brain health. However, the mechanism by which physical exercise promotes the production of neurotrophins remains to be understood, posing limits on their use for the development of potential therapeutic strategies for the treatment of neurodegenerative diseases. In this literature review, we analyzed the most recent evidence regarding the relationship between physical exercise, neurotrophins, and brain health, providing an overview of their involvement in the onset and progression of neurodegeneration

Impaired Activation of CA3 Pyramidal Neurons in the Epileptic Hippocampus.

We employed in vitro and ex vivo imaging tools to characterize the function of limbic neuron networks in pilocarpine-treated and age-matched, nonepileptic control (NEC) rats. Pilocarpine-treated animals represent an established model of mesial temporal lobe epilepsy. Intrinsic optical signal (IOS) analysis of hippocampal-entorhinal cortex (EC) slices obtained from epileptic rats 3 wk after pilocarpine-induced status epilepticus (SE) revealed hyperexcitability in many limbic areas, but not in CA3 and medial EC layer III. By visualizing immunopositivity for FosB/DeltaFosB-related proteins which accumulate in the nuclei of neurons activated by seizures we found that: (1) 24 h after SE, FosB/DeltaFosB immunoreactivity was absent in medial EC layer III, but abundant in dentate gyrus, hippocampus proper (including CA3) and subiculum; (2) FosB/DeltaFosB levels progressively diminished 3 and 7 d after SE, whereas remaining elevated (p < 0.01) in subiculum; (3) FosB/DeltaFosB levels sharply increased 2 wk after SE (and remained elevated up to 3 wk) in dentate gyrus and in most of the other areas but not in CA3. A conspicuous neuronal damage was noticed in medial EC layer III, whereas hippocampus was more preserved. IOS analysis of the stimulus-induced responses in slices 3 wk after SE demonstrated that IOSs in CA3 were lower (p < 0.05) than in NEC slices following dentate gyrus stimulation, but not when stimuli were delivered in CA3. These findings indicate that CA3 networks are hypoactive in comparison with other epileptic limbic areas. We propose that this feature may affect the ability of hippocampal outputs to control epileptiform synchronization in EC

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus.

Several neurodegenerative disorders are associated with impaired cholesterol homeostasis in the nervous system where cholesterol is known to play a role in modulating synaptic activity and stabilizing membrane microdomains. In the present report, we investigated the effects of methyl-beta-cyclodextrin-induced cholesterol depletion on synaptic transmission and on the expression of 1) paired-pulse facilitation (PPF); 2) paired-pulse inhibition (PPI) and 3) long-term potentiation (LTP) in the CA1 hippocampal region. Results demonstrated that cyclodextrin strongly reduced synaptic transmission and blocked the expression of LTP, but did not affect PPF and PPI. The role of glutamatergic and GABAergic receptors in these cholesterol depletion-mediated effects was evaluated pharmacologically. Data indicate that, in cholesterol depleted neurons, modulation of synaptic transmission and synaptic plasticity phenomena are sustained by AMPA-, kainate-and NMDA-receptors but not by GABA-receptors. The involvement of AMPA-and kainate-receptors was confirmed by fluorimetric analysis of intracellular calcium concentrations in hippocampal cell cultures. These data suggest that modulation of receptor activity by manipulation of membrane lipids is a possible therapeutic strategy in neurodegenerative disease