Hyperactive Akt1 Signaling Increases Tumor Progression and DNA Repair in Embryonal Rhabdomyosarcoma RD Line and Confers Susceptibility to Glycolysis and Mevalonate Pathway Inhibitors

In pediatric rhabdomyosarcoma (RMS), elevated Akt signaling is associated with increased malignancy. Here, we report that expression of a constitutively active, myristoylated form of Akt1 (myrAkt1) in human RMS RD cells led to hyperactivation of the mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) pathway, resulting in the loss of both MyoD and myogenic capacity, and an increase of Ki67 expression due to high cell mitosis. MyrAkt1 signaling increased migratory and invasive cell traits, as detected by wound healing, zymography, and xenograft zebrafish assays, and promoted repair of DNA damage after radiotherapy and doxorubicin treatments, as revealed by nuclear detection of phosphorylated H2A histone family member X (γH2AX) through activation of DNA-dependent protein kinase (DNA-PK). Treatment with synthetic inhibitors of phosphatidylinositol-3-kinase (PI3K) and Akt was sufficient to completely revert the aggressive cell phenotype, while the mTOR inhibitor rapamycin failed to block cell dissemination. Furthermore, we found that pronounced Akt1 signaling increased the susceptibility to cell apoptosis after treatments with 2-deoxy-D-glucose (2-DG) and lovastatin, enzymatic inhibitors of hexokinase, and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), especially in combination with radiotherapy and doxorubicin. In conclusion, these data suggest that restriction of glucose metabolism and the mevalonate pathway, in combination with standard therapy, may increase therapy success in RMS tumors characterized by a dysregulated Akt signaling

Un approccio morfometrico per l’analisi delle evidenze di neotettonica nella Liguria occidentale

Lo sviluppo e l’interpretazione di mappe a carattere morfometrico sono strumenti importanti per studi di carattere neotettonico e geomorfologico. I sistemi informativi geografici (GIS) consentono in queste tipologie di analisi velocità d’esecuzione, precisione di calcolo e facile ripetibilità. Questo lavoro illustra la metodologia e le necessarie routines di calcolo sviluppate in ambiente GIS per la stima dei principali parametri morfometrici utilizzati in geomorfologia per la caratterizzazione delle influenze neo-tettoniche e tettoniche del reticolo idrografico, con esempi di applicazioni nella Liguria Occidentale. Development and interpretation of morphometric maps are important tools in studies related to neotectonics and geomorphology. Geographic Information System (GIS) allows speed, precision and repeatability to this process. This work presents a methodology and the relative computation routines for GIS environment to evaluate commonly morphometric parameters used in geomorphology to estimate the influences on the drainage evolution by the structure applied in a study area located in Western Ligurian Alps

Predictive Power Evaluation of a Physically Based Model for Shallow Landslides in the Area of Oltrepò Pavese, Northern Italy

The use of real-time landslide early warning systems is attracting the attention of the scientific community, since it allows to assess "where" and "when" a shallow rainfall-induced landslide might occur by coupling rainfall amounts, hydrological models and slope-stability analysis. The paper deals with the main results of a back analysis, which refers to the application of a physically based stability model [Shallow Landslides Instability Prediction (SLIP)] on regional scale. The analysis concerns the occurrence of some recent rainfall-induced shallow landslides in the municipal territory of Broni, in the area of Oltrepò Pavese (Northern Italy). The study area is a hilly region 2.4 km2 wide, where more than 40 % of the territory has slopes steeper than 15° and altitudes are between 90 and 250 m a.s.l. As regards the geologic setting, clayey-silty shallow colluvial deposits, with a maximum thickness of about 3 m, overlap a bedrock made of clayey shales, calcareous flysch and marls. The SLIP model is based on the limit equilibrium method applied to an infinite slope and on the Mohr-Coulomb strength criterion for the soil. By assuming that the main hydro-geotechnical process that leads to failure is the saturation of parts of the soil, the model allows to take into account the condition of partial saturation of the soil. The safety factor (FS) of a slope is also function of previous rainfalls. After the implementation of the model at territory scale, the input data have been introduced through a geographic information systems platform. In the current paper we mainly intend to evaluate the performance of SLIP at catchment scale, by comparison to (1) observed landslide events and (2) another well-established physically based model (TRIGRS). Further, we want to assess the suitability of the model as early warning tool. The results produced by the model are analyzed both in terms of safety factor maps, corresponding to some particular rainfall events, and in terms of the time-varying percentage of unstable areas over a 2-year span period. The paper shows the comparison between observed landslide localizations and model predictions. A quantitative comparison between the SLIP model and TRIGRS is presented, only for the most important event that occurred during the analyzed period. Overall, the results of the stability analyses based on observed rainfalls show the capability of the SLIP model to predict, in real-time and on a wide area, the occurrence of the analyzed phenomena

Monitoring of a slope susceptibility to shallow landslides: preliminary results

Le frane superficiali indotte da piogge intense e concentrate sono annoverabili tra i fenomeni franosi che causano il maggior numero di danni. Al fine di identificare, a scala di versante, i processi idrologici e geotecnici che controllano il loro innesco \ue8 stata installata una stazione sperimentale in un\u2019area campione dell\u2019Oltrepo Pavese per il monitoraggio del contenuto in acqua del terreno, della pressione interstiziale negativa, delle precipitazioni, della direzione ed intensit\ue0 del vento e della radiazione netta. Il lavoro presenta i risultati preliminari ottenuti nel corso dei primi mesi di monitoraggio

A REPORT ON THE 2012 SEISMIC SEQUENCE IN EMILIA (NORTHERN ITALY)

Since mid-May 2012, an energetic seismic sequence has affected the northern part of Italy and specifically a wide sector of the Po River Plain. The sequence has been dominated by two main events: a) Mw = 5.9 occurred near Finale Emilia on May 20th at a depth of 6.3 km, and b) Mw=5.8 occurred near Cavezzo on May 29th at a depth of 10.2 km (earthquake location are obtained Istituto Nazionale di Geofisica e Vulcanologia, http://iside.rm.ingv.it/). The effects of the two main shocks can be summarized as follows: - damage to infrastructures (roads, pipelines) essentially because of the occurrence of liquefaction phenomena or soil failure; - damage to very old constructions (especially churches and bell towers – masonry and brickworks); - recent constructions such as barns and industrial premises have collapsed. These constructions were mainly isostatic structures not designed to withstand earthquakes. The paper deals with the following arguments: - seismological aspects, mainly related to the seismo - tectonic framework, the source mechanisms, and the comparison between the observed seismic motion and that expected on the basis of the National Map of Seismic Hazard; - identification and mapping of the soil failures (liquefaction) and induced damage with special emphasis on the geomorphologic structures showing the presence of ancient riverbeds; - description of the structural damage regarding the historical buildings and the modern industrial buildings. In conclusion the report will try to explain the reasons for the large damage observed in the case of both ancient and modern constructions

Cytotoxic effects of targeted agent alone or with chemotherapy in the treatment of adenoid cystic carcinoma: a preclinical study

Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by high incidence of relapse. When relapsing, ACC has an indolent but relentless behaviour, thus leading to a poor long-term prognosis. The treatment of choice of relapsing ACC remains surgery followed by radiotherapy, whenever feasible. Therapeutic weapons are limited to systemic drugs. The most widely used chemotherapy regimen is the combination of cisplatin and doxorubicin, however with low response rate and not long lasting; there is also a lack of alternatives for second line therapies in case of disease progression. Therefore, a more comprehensive strategy aimed at identifying at preclinical level the most promising drugs or combination is clearly needed. In this study, the cytotoxic effects of two standard chemotherapy drugs, cisplatin and doxorubicin, and of five targeted therapy-drugs was tested in vitro, on an h-TERT immortalized ACC cell line, and in vivo, on zebrafish embryos with ACC tumoral cell xenograft. Then, combinations of one standard chemotherapy drug plus one targeted therapy drug were also evaluated, in order to find the best treatment strategy for ACC. Data obtained demonstrated that both vorinostat and olaparib significantly increased the standard chemotherapy cytotoxic effects, suggesting new interesting therapeutic options for ACC