Doxorubicin chemoresistance in pediatric glioblastoma: role of microRNA-21 (miR-21) and Breast Cancer Resistance Protein (BCRP)

Various signal transduction pathways, and various proteins of the blood-brain barrier (BBB) seem to be involved in chemoresistance of pediatric glioblastoma multiforme (GBM). MicroRNA-21 (miR-21) is an important oncogenic microRNA (miRNA) which modulates drug resistance of tumor cells. Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are ATP-binding cassette (ABC) transporters that also remove drugs through BBB, limiting brain penetration and accumulation. These proteins are also expressed by cancer cells, but their role in chemoresistance is unclear. In GBM and in other brain tumors, miR-21 seems regulate the expression levels of BCRP and P-gp with an indirect regulation mechanism. It has already been shown that doxorubicin (DOX) is an effective anti-glioma agent with antitumor activity also against GBM stem cells. However clinical trials disappointed these data. Preclinical studies suggest that chemoresistance is a multi-levels, dynamic reality, that can be modulated. In particular, in animal models, Morphine (Morph) temporarily alters the permeability of BBB for large molecules, such as DOX. However, its role is unknown in cellular resistance. Moreover, prolonged exposure to DOX showed a significant induction of apoptosis in GBM stem cells while the commonly used etoposide and temozolomide were not quite effective. We analyzed the expression of 5 miRNAs, previously found to be dysregulated in high grade gliomas (HGG), in 9 pediatric GBM samples. Furthermore, we selected a DOX resistant GBM cell line with similar miRNA expression profile, in order to study mechanisms of chemoresistance (miRNAs and ABC trasporters). Analysis on pediatric GBM samples showed an overexpression of miR-21 and a reduced or lack of expression of miR-7, miR-124, miR-128 and miR-137. Analysis of sensitivity to DOX in 3 GBM cell lines (A172, U87MG and T98G) showed a cytotoxic effect after 48h of treatment in A172 and U87MG, but not in T98G cells. TUNEL assay verified also that DOX induced apoptosis in A172 and U87MG but not in T98G. About miRNA expression profile in this cell line, miR-21 in T98G cells was over-expressed likely pediatric GBM samples. We evaluated both the role of Morph and prolonged exposure to DOX, on chemoresistance of T98G. In our experience, treatment with Morph plus DOX did not interfere with the cytotoxic effect of chemotherapy that was observed only after prolonged exposure to anthracycline (96h). Moreover we evaluated the role of miR-21 and ABC transporters in DOX chemoresistance of T98G cells. To validate the possible association of miR-21 with drug resistance of T98G cells, we transfected anti-miR-21 inhibitor into the cells. The expression level of miR-21 was significantly lower in T98G transfected cells (than in the parental control ones). Transfected cells showed a high apoptotic rate compared to control after DOX treatment by TUNEL assay, suggesting a key role of miR-21 in DOX chemoresistance. Finally, we evaluated the cellular expression (basal and after treatment) of P-gp and BCRP in T98G cells. T98G cells constitutively express BCRP, but not P-gp. After treatment with DOX or DOX plus Morph we have seen that both DOX and Morph down-regulate BCRP expression. In conclusion, we have demonstrated that miR-21 was over-expressed in T98G GBM cells and in our pediatric GBM samples. miR-21 could play an important role in DOX chemoresistance of T98G cells. However, DOX chemoresistance seems to be independent from BCRP expression and Morph co-treatment. Only prolonged exposure (96h) to DOX makes T98G cells sensible to DOX

How to become a Multinational Association of Supportive Care in Cancer-designated center of excellence in supportive care in cancer

Purpose of reviewAim of this review is to encourage and involve more doctors to take care of supportive care in cancer patients and to become centers of excellence.Recent findingsIn 2019, MASCC initiated a certification program to recognize oncology centers that demonstrate best practices in supportive cancer care but literature on how to become MASCC-designated center of Excellence in Supportive Care in Cancer is scarce and will be bulleted.Becoming centers of excellence means not only the recognition of the clinical and managerial requirements to provide good supportive care but also the creation of a network of centers to participate in multicenter scientific projects and thus improve knowledge in the field of supportive care in cancer patients

URPINSIEME: un progetto pilota di comunicazione integrata tra URP

Available only in italian.URPINSIEME ? un progetto pilota di comunicazione integrata tra URP nato nel 2002 da un\u27idea dell\u27Ufficio Relazioni con il Pubblico del CNR in collaborazione con l\u27Istituto di Ricerca sull\u27Impresa e lo Sviluppo dello stesso CNR. Il progetto ha visto coinvolti nove1 Uffici per le Relazioni con il Pubblico (URP), o strutture analoghe, che hanno deciso di perseguire gli stessi obiettivi, ovvero: ? l\u27individuazione di interventi congiunti per ottimizzare le azioni comunicative; ? la creazione di un sistema di energie permanenti tra servizi; ? l\u27attuazione di comunicazioni a vari livelli e realizzazione di una rete interattiva; ? la creazione di comunicazione attiva ed integrata tra Amministrazioni ed Enti. Il gruppo di lavoro partecipante al progetto ha realizzato un opuscolo nel quale sono stati strutturati i prodotti e i servizi di tutti gli Organismi coinvolti. In questo modo ? stato possibile avere una visione completa dell\u27offerta delle diverse organizzazioni, suddivisa sia per aree tematiche che per tipologie. I risultati positivi ottenuti con la realizzazione dell\u27opuscolo cartaceo hanno spinto i coordinatori di URPINSIEME a studiare e progettare un sistema dinamico che permettesse ai cittadini e alle imprese interessate di accedere, via Internet, alle stesse informazioni. Il World Wide Web ? oggi il pi? vasto sistema distribuito, eterogeneo e collaborativo per la gestione delle informazioni. Per questo motivo, e proprio in base alla riconosciuta esperienza nel campo delle tecnologie Internet dello IIT, ? stata chiesta all\u27Istituto di Informatica e Telematica (IIT) la collaborazione per la progettazione e realizzazione di un portale Web idoneo alle aspettative dei partecipanti a URPINSIEME. In questo documento sono descritte le diverse fasi che il personale dello IIT ha svolto nella consulenza, progettazione e realizzazione di un sistema informatico in grado di raccogliere le informazioni provenienti dai vari partecipanti a URPINSIEME, fino a renderle fruibili in un portale Web dedicato. Per studiare e affrontare le specifiche problematiche di progettazione, che si sarebbero presentate durante le varie fasi dell\u27attivit?, ? stato creato un gruppo di lavoro ad hoc che coinvolgesse lo IIT e le rappresentanze dei diversi organismi presenti in URPINSIEME. I continui e proficui scambi avuti all\u27interno del gruppo hanno portato alla realizzazione di un primo prototipo del portale e, successivamente, al portale vero e proprio, che ? stato messo in linea il 26 luglio 2004 (http://www.urpinsieme.it). Nei capitoli che seguono sono state prese in considerazione sia le metodologie di progettazione utilizzate, che le soluzioni tecniche adottate

Archele, a web based acquisition, search and retrieval system

The problem of filing and storing paper and electronic documents is of great concern for public administration as well as private companies. We introduce a system that allows acquisition of images by means of one or more computer equipped with scanners, and associated with metadata for the subsequent search for and storage of data in a Document Repository protected by a system of access control lists (ACL).The system we describe here allows filing, search and retrieval of millions of documents by means of web interfaces. The architecture is fully compliant with web standards and with its design principles. The system we describe is called ArchEle (in Italian, Archiviazione Elettronica)

The EPP server of the .it Registry: main features and functionalities

This document outlines a method for the various registries for implementing their EPP client so that it interacts correctly with the synchronous server of the Italian registry. There are three categories of such EPP commands. Commands for: - managing sessions (login, logout, hello) - querying the server without modifying the status of the Contact and Domain objects - for modifying the status of the Contact and Domain objects For each command you will see an example of a request and how the server responds. There are also some examples of responses to errors for cases where the EPP command has not been correctly submitted or submitted in a status in which the command itself is not permitted

Eurid Public Web Site Content Management System Manual ver 1.1

The document describes the features and the use of Plone customized to manage the .eu website through a Web management interface. The document explains how to use the system and in particular how to manage Web contents

Molecular characterization of paediatric glioneuronal tumours with neuropil-like islands: a genome-wide copy number analysis.

Paediatric glioneuronal tumour with neuropil-like islands (GTNI) is a rare neoplasm of neuronal differentiation and diffusely infiltrating astroglial and oligodendrocyte-like components. The 2007 World Health Organization classification of central nervous system tumours considered it as a pattern variation of anaplastic astrocytoma. There are few data on paediatric GTNI probably both for their rarity and variable clinical aggressiveness. We studied by SNP/CGH array four tumour samples of GTNI from two males and two females (one new-born and three children aged from 4 to 8 years), in order to identify any possible common genomic alteration. All patients received chemo- and radiotherapy after their surgical treatment. No genomic instability nor recurrent alterations have been demonstrated in two of our GTNI cases. In the remaining two, we detected a mosaic trisomy 8 (15-20%) in one case, and an amplification at 5q14.1 involving DMGDH (partially), BHMT2 and BHMT genes, with the distal breakpoint falling at 23 Kbp from the 5’UTR of JMY, a p53 cofactor. Although the smallness of the sample impairs any clinical-histological correlation, GTNI appear different at the molecular level, with genomic imbalances playing a possible role in at least part of them. Our work gives an important contribution in knowledge and classification of this family of tumours