Combination of Histone Deacetylase Inhibitor Panobinostat (LBH589) with β-Catenin Inhibitor Tegavivint (BC2059) Exerts Significant Anti-Myeloma Activity Both In Vitro and In Vivo

Over the last three decades changes in the treatment paradigm for newly diagnosed multiple myeloma (MM) have led to a significant increase in overall survival. Despite this, the majority of patients relapse after one or more lines of treatment while acquiring resistance to available therapies. Panobinostat, a pan-histone deacetylase inhibitor, was approved by the FDA in 2015 for patients with relapsed MM but how to incorporate panobinostat most effectively into everyday practice remains unclear. Dysregulation of the Wnt canonical pathway, and its key mediator β-catenin, has been shown to be important for the evolution of MM and the acquisition of drug resistance, making it a potentially attractive therapeutic target. Despite concerns regarding the safety of Wnt pathway inhibitors, we have recently shown that the β-catenin inhibitor Tegavivint is deliverable and effective in in vivo models of MM. In this study we show that the combination of low concentrations of panobinostat and Tegavivint have significant in vitro and in vivo anti-MM effects including in the context of proteasome inhibitor resistance, by targeting both aerobic glycolysis and mitochondrial respiration and the down-regulation of down-stream β-catenin targets including myc, cyclinD1, and cyclinD2. The significant anti-MM effect of this novel combination warrants further evaluation for the treatment of MM patients with relapsed and/or refractory MM

Role of Wnt pathway dysregulation in Multiple Myeloma (MM)

MM is a highly heterogeneous and incurable disease. Available evidence suggests that the Wnt/canonical pathway contributes to both disease progression and drug resistance confirming the pathway as an attractive potential therapeutic target. Wnt/β-catenin up-regulation can be the result of multiple factors, which in solid tumour can co-exist, all further enhancing pathway activity. Moreover, we identified a possible additional mechanism relating to the receptor complex expression. Among a variety of Wnt/canonical pathway inhibitors that we tested, BC2059 was shown to have the best anti-MM results in clinically feasible doses, with a favourable in vivo toxicity profile. In the era of combinational chemotherapy BC2059 also proved to exert significant synergistic anti-MM effect both in combination with well-established and novel anti-MM drugs, warranting further investigation. Finally, exploring in more detail the cytotoxic and pro-survival effect of BC2059 we were able to identify that inhibition of autophagy was able to amplify its anti-MM effect. This approach may represent a new paradigm for enhancing the activity of established or novel anti-MM regimens. <br> <br

Social reconstruction and critical literacy: a teaching proposal

The focus of this dissertation is on the role of education in the development of student’s critical thinking and critical consciousness, in order for them to become capable of dealing with the problems of modern society and participate consciously and critically in social institutions. A Critical Action Research is presented in this dissertation based on the practice and the reflective observation of a pedagogical proposal which is founded on the principles of Social Reconstruction for the primary Curriculum and Critical Literacies Practices aimed at developing critical consciousness on Primary School students. The research was carried out in a public Primary School in the area of Chryssoupoli-Kavala (Greece), 20 students participated in an integrated Social Studies subject (organized in three units of understanding). The students’ Discourse and tasks are presented through the simultaneous use of Interpretative Phenomenological Analysis and Critical Analysis of Classroom Literacy. The results of the research are positively related with the student’s development of critical thinking as well as their personal transformation and will to take over social action (critical consciousness).Ο προβληματισμός σε σχέση με τον τρόπο που η εκπαίδευση μπορεί να ανταπεξέλθει στον πολυδιάστατο κοινωνικό της ρόλο, αναπτύσσοντας κριτικά σκεπτόμενους ανθρώπους, έτοιμους να αντιλαμβάνονται και να διαχειρίζονται τα προβλήματα της σύγχρονης κοινωνίας και να συμμετέχουν συνειδητά και κριτικά στους κοινωνικούς θεσμούς, οδήγησε στην εκπόνηση της συγκεκριμένης διδακτορικής διατριβής με τίτλο: «Η Οπτική της Κοινωνικής Ανασυγκρότησης για το Αναλυτικό Πρόγραμμα και ο Κριτικός Γραμματισμός-Μια Διδακτική Πρόταση». Στην εργασία παρουσιάζεται μια Κριτική Έρευνα Δράσης που βασίζεται στην εφαρμογή και παρατήρηση διδακτικής πρότασης που βασίζεται στις αρχές της Κοινωνικής Ανασυγκρότησης για το αναλυτικό πρόγραμμα και εμπλουτίστηκε με πρακτικές κριτικού γραμματισμού με σκοπό την ανάπτυξη του κριτικού προβληματισμού των μαθητών/τριών του Δημοτικού Σχολείου που οδηγεί στην κριτική συνειδητοποίηση. Η έρευνα διεξήχθη σε μια τάξη Στ’ Δημοτικού σε ένα από τα δημόσια σχολεία της περιοχής Χρυσούπολης-Καβάλας. Στην έρευνα συμμετείχαν 20 μαθητές/τριες, οι οποίοι/ες ενεπλάκησαν σε μια σειρά από δραστηριότητες κριτικού γραμματισμού στο πλαίσιο ενός ενοποιημένου μαθήματος κοινωνικών επιστημών διάρκειας 110 διδακτικών ωρών. Οι αναφορές που συγκεντρώθηκαν χωρίστηκαν σε ενότητες νοημάτων με τη συνδρομή της Ερμηνευτικής Φαινομενολογικής Ανάλυσης. Κατόπιν, ο Λόγος των μαθητών/τριών παρουσιάστηκε και αναλύθηκε κριτικά με τη συνδρομή εργαλείων που προσφέρει η Κριτική Ανάλυση του Γραμματισμού της Σχολικής Τάξης. Αναδείχθηκαν με αυτόν τον τρόπο μια σειρά από παιδαγωγικές πρακτικές που μπορούν να λειτουργήσουν απελευθερωτικά τόσο για τους/τις μαθητές/τριες όσο και για τους/τις εκπαιδευτικούς. Τα αποτελέσματα της έρευνας, όπως παρουσιάστηκαν και αναλύθηκαν μετά την εφαρμογή της διδακτικής παρέμβασης, κρίνονται καταρχήν ως θετικά τόσο σε σχέση με την ανάπτυξη της κριτικής σκέψης των μαθητών/τριών όσο και αναφορικά με τον προσωπικό μετασχηματισμό των μαθητών/τριών, αλλά και την επιθυμία τους να αναλάβουν σχετικές δράσεις για τη βελτίωση της τοπικής κοινωνίας (κριτική συνειδητοποίηση)

The Role of Emotions, Mood, Personality and Contagion in Multi-agent System Decision Making

Part 8: Agents-Robotics-Control (AROC)International audienceEmotions have attracted much interest in the Multi Agent Systems community, mainly due to their significance in creating simulations that more accurately predict crowd behaviours. Undoubtedly, infusion of agents with artificial emotions has to be supported by current psychology theories. The present work describes a formal model of artificial emotions based on the dimensionality theory, together with simulation results of an initial experimental evaluation. The model includes interesting aspects of emotions, such as emotion changes due to perception, long term affects due to mood, and emotion contagion due to social interactions

Additional file 2: Table S2. of Birth weight in relation to health and disease in later life: an umbrella review of systematic reviews and meta-analyses

Comparison of random-effects summary effect size and largest study effect size, expected and observed number of significant associations and excess significance test in each meta-analysis. †Random-effects summary effect size estimated from standardized mean difference transformed to odds ratio. AGA: adequate-for-gestational age, BMC: bone mineral concentration, BMD: bone mineral density, CI: confidence interval, FEV: forced expiratory volume in the first second, HR: hazard ratio, OR: odds ratio, RR: risk ratio, MD: mean difference, RSV: respiratory syncytial virus, SD: standard error, SE: standard error, SGA: small-for-gestational age. (DOC 447 kb

Additional file 1: Table S1. of Birth weight in relation to health and disease in later life: an umbrella review of systematic reviews and meta-analyses

Overlapping associations examined in older papers and/or under different levels of comparison. BMC: bone mineral concentration, BMD: bone mineral density, BMI: body mass index, MD: mean difference, NBW: normal birth weight, OR: odds ratio, RR: risk ratio [82–90]. (DOC 229 kb