Synergistic cytotoxic effect of l-asparaginase combined with decitabine as a demethylating agent in pediatric T-ALL, with specific epigenetic signature

T-Acute Lymphoblastic Leukemia (T-ALL) remains a subgroup of pediatric ALL, with a lower response to standard chemotherapy. Some recent studies established the fundamental role of epigenetic aberrations such as DNA hypermethylation, to influence patients' outcome and response to chemotherapy. Moreover, L-asparaginase is an important chemotherapeutic agent for treatment of ALL and resistance to this drug has been linked to ASNS expression, which can be silenced through methylation. Therefore, we tested whether the sensitivity of T-ALL cell lines towards L-asparaginase is correlated to the epigenetic status of ASNS gene and whether the sensitivity can be modified by concurrent demethylating treatment. Hence we treated different T-ALL cell lines with L-asparaginase and correlated different responses to the treatment with ASNS expression. Then we demonstrated that the ASNS expression was dependent on the methylation status of the promoter. Finally we showed that, despite the demethylating effect on the ASNS gene expression, the combined treatment with the demethylating agent Decitabine could synergistically improve the L-asparaginase sensitivity in those T-ALL cell lines characterized by hypermethylation of the ASNS gene. In conclusion, this preclinical study identified an unexpected synergistic activity of L-asparaginase and Decitabine in the subgroup of T-ALL with low ASNS expression due to hypermethylation of the ASNS promoter, while it did not restore sensitivity in the resistant cell lines characterized by higher ASNS expression

The Role of HDACs Inhibitors in Childhood and Adolescence Acute Leukemias

Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs) are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs) are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia

Molecular Signature of Biological Aggressiveness in Clear Cell Sarcoma of the Kidney (CCSK)

: Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms' tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases

Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.A combination of Drosophila dGBA1b loss-of-function models and Gaucher Disease (GD) patient-derived iPSCs reveals an impairment in GD neuronal cell growth and that Hippo pathway hyperactivation contributes to the impairment

Commentaire de Cédric Houdré et Salvatore Serravalle. L’évaluation des dépenses fiscales en France Deux apports de l’économie publique pour rationaliser la fiscalité dérogatoire

Houdré Cédric, Serravalle Salvatore. Commentaire de Cédric Houdré et Salvatore Serravalle. L’évaluation des dépenses fiscales en France Deux apports de l’économie publique pour rationaliser la fiscalité dérogatoire. In: Economie et statistique, n°427-428, 2009. pp. 123-126

Commentaire de Cédric Houdré et Salvatore Serravalle. L’évaluation des dépenses fiscales en France Deux apports de l’économie publique pour rationaliser la fiscalité dérogatoire

Houdré Cédric, Serravalle Salvatore. Commentaire de Cédric Houdré et Salvatore Serravalle. L’évaluation des dépenses fiscales en France Deux apports de l’économie publique pour rationaliser la fiscalité dérogatoire. In: Economie et statistique, n°427-428, 2009. pp. 123-126

The knowledge-based perspective of risk management in healthcare organisations

The aim of this research is to investigate how risk management in a healthcare organisation can be supported by knowledge management. The subject of research is the development and management of existing logs called "risk registers", through specific risk management processes employed in a N.H.S. (Foundation) Trust in England, in the U.K. Existing literature on organisational risk management stresses the importance of knowledge for the effective implementation of risk management programmes, claiming that knowledge used to perceive risk is biased by the beliefs of individuals and groups involved in risk management and therefore is considered incomplete. Further, literature on organisational knowledge management presents several definitions and categorisations of knowledge and approaches for knowledge manipulation in the organisational context as a whole. However, there is no specific approach regarding "how to deal" with knowledge in the course of organisational risk management. The research is based on a single case study, on a N.H.S. (Foundation) Trust, is influenced by principles of interpretivism and the frame of mind of Soft Systems Methodology (S.S.M.) to investigate the management of risk registers, from the viewpoint of people involved in the situation. Data revealed that knowledge about risks and about the existing risk management policy and procedures is situated in several locations in the Trust and is neither consolidated nor present where and when required. This study proposes a framework that identifies required knowledge for each of the risk management processes and outlines methods for conversion of this knowledge, based on the SECI knowledge conversion model, and activities to facilitate knowledge conversion so that knowledge is effectively used for the development of risk registers and the monitoring of risks throughout the whole Trust under study. This study has theoretical impact in the management science literature as it addresses the issue of incomplete knowledge raised in the risk management literature using concepts of the knowledge management literature, such as the knowledge conversion model. In essence, the combination of required risk and risk management related knowledge with the required type of communication for risk management creates the proposed methods for the support of each risk management process for the risk registers. Further, the indication of the importance of knowledge in risk management and the presentation of a framework that consolidates knowledge required for the risk management processes and proposes way(s) for the communication of this knowledge within a healthcare organisation have practical impact in the management of healthcare organisations.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Identification of a cytogenetic and molecular subgroup of acute myeloid leukemias showing sensitivity to L-Asparaginase

L-Asparaginase (L-Asp) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid, and its depletion induces leukemic cell death. L-Asp is an important component of treatment regimens for Acute Lymphoblastic Leukemia (ALL). Sensitivity to L-Asp is due to the absence of L-Asparagine synthetase (ASNS), the enzyme that catalyzes the biosynthesis of L-asparagine. ASNS gene is located on 7q21.3, and its increased expression in ALLs correlates with L-Asp resistance. Chromosome 7 monosomy (-7) is a recurrent aberration in myeloid disorders, particularly in adverse-risk Acute Myeloid Leukemias (AMLs) and therapy-related myeloid neoplasms (t-MN), that leads to a significant downregulation of the deleted genes, including ASNS. Therefore, we hypothesized that -7 could affect L-Asp sensitivity in AMLs. By treating AML cell lines and primary cells from pediatric patients with L-Asp, we showed that -7 cells were more sensitive than AML cells without -7. Importantly, both ASNS gene and protein expression were significantly lower in -7 AML cell lines, suggesting that haploinsufficiency of ASNS might induce sensitivity to L-Asp in AMLs. To prove the role of ASNS haploinsufficiency in sensitizing AML cells to L-Asp treatment, we performed siRNA-knockdown of ASNS in AML cell lines lacking -7, and observed that ASNS knockdown significantly increased L-Asp cytotoxicity. In conclusion, -7 AMLs showed high sensitivity to L-Asp treatment due to low expression of ASNS. Thus, L-Asp may be considered for treatment of AML pediatric patients carrying -7, in order to improve the outcome of adverse-risk AMLs and t-MN patients