Mirna signature to identify lung asbestos-related malignancies

L'associazione tra esposizione all'amianto e neoplasie polmonari è ben consolidata. Tuttavia, precisi dati istopatologici sono scarsamente considerati quando si studia il legame tra cancro e amianto in un approccio compensatorio. L'espressione dei miRNA è precocemente alterata dall'esposizione ad agenti cancerogeni professionali /ambientali, quindi utile per identificare un nuovo profilo correlato all'amianto in grado di distinguere una neoplasia indotta da asbesto rispetto a quella con diversa eziologia. Abbiamo condotto uno studio multifasico per identificare i miRNA associati alle neoplasie indotte dall'amianto. Sono stati inclusi quattro gruppi: pazienti con carcinoma polmonare non a piccole cellule asbesto-correlato e non (NSCLC-Asb e NSCLC), mesotelioma maligno (MM) e soggetti di controllo (CTRL). Successivamente, i miRNA selezionati sono stati valutati in una popolazione esposta all'amianto ed è stato realizzato un modello "in vitro" per identificare il meccanismo di regolazione dei miRNA indotto da asbesto. Quattro miRNA sierici costituiti dal miR-126, miR-205, miR-222 e miR-520g sono risultati coinvolti nelle neoplasie asbesto-correlate. In particolare, l'aumento dell'espressione del miR-126 e del miR-222 è stato trovato in soggetti attualmente esposti all’asbesto ed entrambi i miRNA sono coinvolti nelle principali pathway collegate allo sviluppo tumorale. Un'aumentata espressione dell’EGFR è stata trovata nelle cellule pre-cancerose indotte da asbesto, causando l'attivazione di effettori a valle (AKT e MAPK p38). L'attivazione asbesto-mediata della via EGFR-AKT ha portato alla sovra-espressione del miR-222 e alla sotto-espressione del miR-520g, che sono stati invertiti inibendo l'EGFR, suggerendo il suo coinvolgimento nella regolazione dei miRNA indotta da asbesto. Questo studio evidenzia miRNA che sono potenzialmente coinvolti in neoplasie legate all'amianto e i meccanismi di espressione in cui possono essere coinvolti nella patogenesi indotta da asbesto.The association between asbestos exposure and lung malignancies is well established. Nevertheless, precise histopathological data are poorly considered when investigating the asbestos-cancer link in compensatory approach. MiRNA expression is early altered by exposure to occupational/environmental carcinogens, thus, useful to identify a novel asbestos-related profile able to distinguish asbestos-induced cancer from cancer with different etiology. We performed consequential study phases to identify miRNAs associated with the asbestos-induced malignancies. Four groups have been included: patients with asbestos-related and non-asbestos-related non-small cell lung cancer (NSCLC-Asb and NSCLC), malignant mesothelioma (MM), and disease-free subjects (CTRL). Next, the selected miRNAs were evaluated in an asbestos-exposed population and an ‘in vitro’ model was performed to identify the mechanism of asbestos-induced miRNA regulation. Four serum miRNAs consisting of miR-126, miR-205, miR-222 and miR-520g were found to be involved in asbestos-related malignant diseases. Notably, increased expression of miR-126 and miR-222 were found in currently exposed subjects, and both miRNAs were involved in major pathways linked to cancer development. Increased expression of EGFR was found in the asbestos-induced pre-cancerous cells, causing activation of the down-stream effector AKT and p38 MAPK signalling. Asbestos-mediated activation of EGFR-AKT pathway resulted in miR-222 upregulation and miR-520g downregulation, which were reversed by inhibiting EGFR, suggesting its involvement in asbestos-induced miRNA regulation. This study uncovers miRNAs that are potentially involved in asbestos-related malignancies and their expression outline mechanisms whereby miRNAs may be involved in asbestos-induced pathogenesis

Exosomal transfer of miR-126 promotes the anti-tumour response in malignant mesothelioma: Role of miR-126 in cancer-stroma communication

none11MiR-126 has been shown to suppress malignant mesothelioma (MM) by targeting cancer-related genes without inducing toxicity or histopathological changes. Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. Here, a tumour stromal model composed of endothelial cells (HUVECs), fibroblasts (IMR-90 cells), non-malignant mesothelial cells (Met-5A cells) and MM cells (H28 and MM-B1 cells) was used. The cells were treated with exosomes from HUVECs carrying endogenous (exo-HUVEC) and enriched miR-126 (exo-HUVECmiR-126), and the uptake/turnover of exosomes; miR-126 distribution within the stroma; and effect of miR-126 on cell signalling, angiogenesis and cell proliferation were evaluated. Based on the sensitivity of MM cells to exo-HUVEC miR-126 treatment, miR-126 was distributed differently across stromal cells. The reduced miR-126 content in fibroblasts in favour of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in an miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that transfer of miR-126 via HUVEC-derived exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM.noneMonaco, Federica; Gaetani, Simona; Alessandrini, Federica; Tagliabracci, Adriano; Bracci, Massimo; Valentino, Matteo; Neuzil, Jiri; Amati, Monica; Bovenzi, Massimo; Tomasetti, Marco; Santarelli, LoryMonaco, Federica; Gaetani, Simona; Alessandrini, Federica; Tagliabracci, Adriano; Bracci, Massimo; Valentino, Matteo; Neuzil, Jiri; Amati, Monica; Bovenzi, Massimo; Tomasetti, Marco; Santarelli, Lor

Dal team accoglienza al bed management ospedaliero.

RIASSUNTOLa riduzione dei posti letto negli ospedali laziali, ha ri-disegnato il concetto di servizio sanitario ospedaliero regionale, riconoscendo l'ospedale il solo luogo dove recarsi per curare le malattie acute ed urgenti. L'Azienda Ospedaliera San Camillo-Forlanini di Roma, nel rispetto del piano sanitario regionale, del piano di rientro e della riqualificazione della rete ospedaliera, ha avuto una significativa riduzione di posti letto e ciò, ha comportato una riorganizzazione interna. La Direzione Aziendale per dare una risposta soddisfacente all'utenza, ha dato inizio nel febbraio del 2008 ad un progetto, oggi servizio, con l'istituzione di un gruppo di coordinatori infermieristici, con lo specifico mandato di razionalizzare ed ottimizzare i posti letto dedicati all'emergenza-urgenza. Questo gruppo denominato "Team Accoglienza" è formato da caposala esperti, che conoscono il funzionamento dell'intero ospedale. Il team collabora, quotidianamente, con il personale medico ed infermieristico del Pronto Soccorso, per la definizione del percorso diagnostico, terapeutico ed assistenziale più idoneo al malato. Il progetto è stato sviluppato applicando la metodologia: del Percorso di Massima di Riferimento e l'Analisi Sistemica. Negli anni questo servizio ha contribuito: al miglioramento di alcuni indicatori sistemici di attivití , di alcune Unití  Operative ed alla formazione di personale sanitario di direzione. Nel 2009 la Giunta Regionale del Lazio ha riconosciuto tale progetto come strategico all'interno delle organizzazioni ospedaliere pubbliche e private.Parole Chiave: Bed Manager, ricovero, ottimizzatore.ABSTRACTReduction on number of hospital beds i.e. on patients' admission among hospitals in Lazio has lead to a reformulation of health service framework within Lazio indentifying hospital as the only place to go to treat acute and urgent diseases. San Camillo-Forlanini, the largest hospital in Rome, according to the regional health plan, the recovery plan and the redevelopment of network hospital has had a significant reduction of hospital beds leading, as consequence, to the need of an internal reorganization. In order to correctly address this issue, the management of the Hospital started in February 2008 a project, setting up a group made up by nursing coordinators which had as a main aim to manage the number of hospital beds needed for emergencies. This group has been called "Admission Team" and nurses within the group are familiar with hospital policies and organization. The team collaborates daily with physicians and nurses in emergency room, in order to decide the most appropriate health care protocol for each patient. The project follows a specific methodology i.e. Systemic Analysis. Over the years this project has contributed to the improvement to a number of indicators and more generally to the health care within the hospital together with the enhancement of education of new managerial roles among health professional. In 2009, the Regional Council of Lazio has recognized this project as strategic within private and public hospitals. Keywords: Bed Management, admission, hospital polic

MiR-126 in intestinal-type sinonasal adenocarcinomas: exosomal transfer of MiR-126 promotes anti-tumour responses

Background: Intestinal-type sinonasal adenocarcinomas (ITACs) are aggressive malignancies related to wood dust and leather exposure. ITACs are generally associated with advanced stage at presentation due to the insidious growth pattern and non-specific symptoms. Therefore, biomarkers that can detect the switch from the benign disease to malignancy are needed. Essential for tumour growth, angiogenesis is an important step in tumour development and progression. This process is strictly regulated, and MiR-126 considered its master modulator. Methods: We have investigated MiR-126 levels in ITACs and compared them to benign sinonasal lesions, such as sinonasal-inverted papillomas (SIPs) and inflammatory polyps (NIPs). The tumour-suppressive functions of MiR-126 were also evaluated. Results: We found that MiR-126 can significantly distinguish malignancy from benign nasal forms. The low levels of MiR- 126 in ITACs point to its role in tumour progression. In this context, restoration of MiR-126 induced metabolic changes, and inhibited cell growth and the tumorigenic potential of MNSC cells. Conclusions: We report that MiR-126 delivered via exosomes from endothelial cells promotes anti-tumour responses. This paracrine transfer of MiRs may represent a new approach towards MiR-based therapy

Epigenetic Regulation of miRNA Expression in Malignant Mesothelioma: miRNAs as Biomarkers of Early Diagnosis and Therapy

Asbestos exposure leads to epigenetic and epigenomic modifications that, in association with ROS-induced DNA damage, contribute to cancer onset. Few miRNAs epigenetically regulated in MM have been described in literature; miR-126, however, is one of them, and its expression is regulated by epigenetic mechanisms. Asbestos exposure induces early changes in the miRNAs, which are reversibly expressed as protective species, and their inability to reverse reflects the inability of the cells to restore the physiological miRNA levels despite the cessation of carcinogen exposure. Changes in miRNA expression, which results from genetic/epigenetic changes during tumor formation and evolution, can be detected in fluids and used as cancer biomarkers. This article has reviewed the epigenetic mechanisms involved in miRNA expression in MM, focusing on their role as biomarkers of early diagnosis and therapeutic effects

Prenatal exposure to the cannabinoid receptor agonist WIN 55,212-2 increases glutamate uptake through overexpression of GLT1 and EAAC1 glutamate transporter subtypes in rat frontal cerebral cortex

Prenatal exposure to the CB1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone) mesylate (WIN) at a daily dose of 0.5 mg/kg, and Delta9-tetrahydrocannabinol (Delta9-THC) at a daily dose of 5 mg/kg, reduced dialysate glutamate levels in frontal cerebral cortex of adolescent offspring (40-day-old) with respect to those born from vehicle-treated mothers. WIN treatment induced a statistically significant enhancement of Vmaxl-[3H]glutamate uptake, whereas it did not modify glutamate Km, in frontal cerebral cortex synaptosomes of adolescent rats. Western blotting analysis, performed either in membrane proteins derived from homogenates and in proteins extracted from synaptosomes of frontal cerebral cortex, revealed that prenatal WIN exposure enhanced the expression of glutamate transporter 1 (GLT1) and excitatory amino acid carrier 1 (EAAC1). Moreover, immunocytochemical analyses of frontal cortex area revealed a more intense GLT1 and EAAC1 immunoreactivity (ir) distribution in the WIN-treated group. Collectively these results show that prenatal exposure to the cannabinoid CB1 receptor agonist WIN increases expression and functional activity of GLT1 and EAAC1 glutamate transporters (GluTs) associated to a decrease of cortical glutamate outflow, in adolescent rats. These findings may contribute to explain the mechanism underlying the cognitive impairment observed in the offspring of mothers who used marijuana during pregnanc

A methodology for assessing the spatial distribution of static wildfire risk over wide areas: the case studies of Liguria and Sardinia (Italy)

In Mediterranean areas, some studies suggest universal increases in fire frequency due to climatic warming. However, some authors point out that the universality of these results is questionable. In this study, we try to go beyond the simple analysis of statistical data related with the number of fires and the total burned area, which can be misleading in the context of climate change. The fire perimeters have been used to inquire spatialized climate indexes and the vegetation cover. A statistical analysis of climate indexes has been conducted and a certain number of Type of Homogeneous Areas (THA) defined by introducing information on vegetation cover. The comparison of THA and climatic indexes allowed the definition of an index of risk. Maps of this index highlight risky areas in Liguria and Sardinia (Italy)