Favorable prognostic role of tropomodulins in neuroblastoma

Neuroblastoma is a pediatric tumor of the sympatoadrenal lineage of the neural crest characterized by high molecular and clinical heterogeneity, which are the main causes of the poor response to standard multimodal therapy. The identification of new and selective biomarkers is important to improve our knowledge on the mechanisms of neuroblastoma progression and to find the targets for innovative cancer therapies. This study identifies a positive correlation among tropomodulins (TMODs) proteins expression and neuroblastoma progression. TMODs bind the pointed end of actin filaments, regulate polymerization and depolymerization processes modifying actin cytoskeletal dynamic and influencing neuronal development processes. Expression levels of TMODs genes were analyzed in 17 datasets comprising different types of tumors, including neuroblastoma, and it was demonstrated that high levels of tropomodulin1 (TMOD1) and tropomodulin 2 (TMOD2) correlate positively with high survival probability and with favorable clinical and molecular characteristics. Functional studies on neuroblastoma cell lines, showed that TMOD1 knockin induced cell cycle arrest, cell proliferation arrest and a mature functional differentiation. TMOD1 overexpression was responsible for particular cell morphology and biochemical changes which directed cells towards a neuronal favorable differentiation profile. TMOD1 downregulation also induced cell proliferation arrest but caused the loss of mature cell differentiation and promoted the development of neuroendocrine cellular characteristics, delineating an aggressive and unfavorable tumor behavior. Overall, these data indicated that TMODs are favorable prognostic biomarkers in neuroblastoma and we believe that they could contribute to unravel a new pathophysiological mechanism of neuroblastoma resistance contributing to the design of personalized therapeutics opportunities

Comparison of multi-objective optimization methodologies for engineering applications

Computational models describing the behavior of complex physical systems are often used in the engineering design field to identify better or optimal solutions with respect to previously defined performance criteria. Multi-objective optimization problems arise and the set of optimal compromise solutions (Pareto front) has to be identified by an effective and complete search procedure in order to let the decision maker, the designer, to carry out the best choice. Four multi-objective optimization techniques are analyzed by describing their formulation, advantages and disadvantages. The effectiveness of the selected techniques for engineering design purposes is verified by comparing the results obtained by solving a few benchmarks and a real structural engineering problem concerning an engine bracket of a ca

Exosomal microRNAs from Longitudinal Liquid Biopsies for the Prediction of Response to Induction Chemotherapy in High-Risk Neuroblastoma Patients: A Proof of Concept SIOPEN Study

Despite intensive treatment, 50% of children with high-risk neuroblastoma (HR-NB) succumb to their disease. Progression through current trials evaluating the efficacy of new treatments for children with HR disease usually depends on an inadequate response to induction chemotherapy, assessed using imaging modalities. In this study, we sought to identify circulating biomarkers that might be detected in a simple blood sample to predict patient response to induction chemotherapy. Since exosomes released by tumor cells can drive tumor growth and chemoresistance, we tested the hypothesis that exosomal microRNA (exo-miRNAs) in blood might predict response to induction chemotherapy. The exo-miRNAs expression profile in plasma samples collected from children treated in HR-NBL-1/SIOPEN before and after induction chemotherapy was compared to identify a three exo-miRs signature that could discriminate between poor and good responders. Exo-miRNAs expression also provided a chemoresistance index predicting the good or poor prognosis of HR-NB patients

Induction of Epithelial Mesenchimal Transition and Vasculogenesis in the Lenses of Dbl Oncogene Transgenic Mice

BACKGROUND: The Dbl family of proteins represents a large group of proto-oncogenes involved in cell growth regulation. The numerous domains that are present in many Dbl family proteins suggest that they act to integrate multiple inputs in complicated signaling networks involving the Rho GTPases. Alterations of the normal function of these proteins lead to pathological processes such as developmental disorders and neoplastic transformation. We generated transgenic mice introducing the cDNA of Dbl oncogene linked to the metallothionein promoter into the germ line of FVB mice and found that onco-Dbl expression in mouse lenses affected proliferation, migration and differentiation of lens epithelial cells. RESULTS: We used high density oligonucleotide microarray to define the transcriptional profile induced by Dbl in the lenses of 2 days, 2 weeks, and 6 weeks old transgenic mice. We observed modulation of genes encoding proteins promoting epithelial-mesenchymal transition (EMT), such as down-regulation of epithelial cell markers and up-regulation of fibroblast markers. Genes encoding proteins involved in the positive regulation of apoptosis were markedly down regulated while anti-apoptotic genes were strongly up-regulated. Finally, several genes encoding proteins involved in the process of angiogenesis were up-regulated. These observations were validated by histological and immunohistochemical examination of the transgenic lenses where vascularization can be readily observed. CONCLUSION: Onco-Dbl expression in mouse lens correlated with modulation of genes involved in the regulation of EMT, apoptosis and vasculogenesis leading to disruption of the lens architecture, epithelial cell proliferation, and aberrant angiogenesis. We conclude that onco-Dbl has a potentially important, previously unreported, capacity to dramatically alter epithelial cell migration, replication, polarization and differentiation and to induce vascularization of an epithelial tissue