GPER agonist G-1 decreases adrenocortical carcinoma (ACC) cell growth in vitro and in vivo

We have previously demonstrated that estrogen receptor (ER) alpha (ESR1) increases proliferation of adrenocortical carcinoma (ACC) through both an estrogen-dependent and -independent (induced by IGF-II/IGF1R pathways) manner. Then, the use of tamoxifen, a selective estrogen receptor modulator (SERM), appears effective in reducing ACC growth in vitro and in vivo. However, tamoxifen not only exerts antiestrogenic activity, but also acts as full agonist on the G protein-coupled estrogen receptor (GPER). Aim of this study was to investigate the effect of a non-steroidal GPER agonist G-1 in modulating ACC cell growth. We found that G-1 is able to exert a growth inhibitory effect on H295R cells both in vitro and, as xenograft model, in vivo. Treatment of H295R cells with G-1 induced cell cycle arrest, DNA damage and cell death by the activation of the intrinsic apoptotic mechanism. These events required sustained extracellular regulated kinase (ERK) 1/2 activation. Silencing of GPER by a specific shRNA partially reversed G-1-mediated cell growth inhibition without affecting ERK activation. These data suggest the existence of G-1 activated but GPER-independent effects that remain to be clarified. In conclusion, this study provides a rational to further study G-1 mechanism of action in order to include this drug as a treatment option to the limited therapy of ACC

Synthesis and cytotoxic activity evaluation of 2,3-thiazolidin-4-one derivatives on human breast cancer cell lines

It is well known that resveratrol (RSV) displayed cancer-preventing and anticancer properties but its clinical application is limited because of a low bioavailability and a rapid clearance from the circulation. Aim of this work was to synthesize pharmacologically active resveratrol analogs with an enhanced structural rigidity and bioavailability. In particular, we have synthesized a library of 2,3-thiazolidin-4-one derivatives in which a thiazolidinone nucleus connects two aromatic rings. Some of these compounds showed strong inhibitory effects on breast cancer cell growth. Our results indicate that some of thiazolidin-based resveratrol derivatives may become a new potent alternative tool for the treatment of human breast cancer

Relationships between geogenic radon potential and gamma ray maps with indoor radon levels at Caprarola municipality (central Italy)

Exposures to relatively high indoor radon (222Rn) levels represents a serious public health risk because Rn is associated with lung cancer (Darby et al., 2001; WHO, 2009; Oh et al., 2016; Sheen et al., 2016). The risk is high because radon, and its short-lived decay products in the atmosphere, contributes for about 60% of the total annual effective dose (UNSCEAR, 2000; WHO, 2009). Cancer risk is increased by smoking being almost 9 times higher than the risk to non-smokers exposed to similar levels (EPA, 2009). Due to these reasons, it is very important to assess the indoor exposure of public to radon and their daughters. Rn is a natural ubiquitous gas and its abundance is mainly controlled by the geology, and in particular by the soil and rock content of its parent nuclide (238U). Furthermore, bedrock characteristics (i.e. permeability and porosity) and also fault activity can affect the amount of Rn released in the ground (Ciotoli et al., 2007; Barnet et al., 2018). As such, in conditions of permeable and/or fractured bedrock and high uranium content, high indoor radon concentrations are expected (Bossew and Lettner, 2007; Gruber et al., 2013; Cinelli et al., 2015; Ielsch et al., 2017; Ciotoli et al., 2017). A non-natural contribution that controls the indoor Rn levels is home construction type and building materials (Vauptic et al., 2002; Appleton, 2007). Additionally, meteorological factors, such as wind, temperature and humidity, can affect the rate of Rn entry into the buildings (Porstendörfer et al., 1994; Miles et al., 2005; Schubert et al., 2018). In this work, we propose a new geospatial technique to construct the geogenic radon potential (GRP) map of the Caprarola municipality (northern Lazio, central Italy) characterized by recent (about 100 Kyr) volcanic deposits with high content in radon parent nuclides (Ciotoli et al., 2017). GRP map has been obtained by using Empirical Bayesian Kriging Regression (EBKR) technique with soil gas radon, as the response variable, and a number of proxy variables (i.e. content of the radiogenic parent nuclides, the emanation coefficient of the outcropping rocks, the diffusive 222Rn flux from the soil, the soil-gas CO2 concentration, the Digital Terrain Model (DTM), the permeability of the outcropping rocks and the gamma dose radiation of the shallow lithology. Furthermore, possible relationships between predicted soil radon values (i.e. GRP) and gamma radiation distribution with the indoor concentrations measured in private and public buildings has been investigated, respectively. The obtained results confirm that GRP maps provide the local administration of a useful tool for land use planning and that, the mapping of gamma emission, allows to a fast and effective evaluation of indoor radon hazard because it is mainly influenced by the building materials rather than other anthropic controls

Radon Hazard in Central Italy: Comparison among Areas with Different Geogenic Radon Potential

Radon (222Rn) is a natural radioactive gas formed in rocks and soil by the decay of its parent nuclide (238-Uranium). The rate at which radon migrates to the surface, be it along faults or directly emanated from shallow soil, represents the Geogenic Radon Potential (GRP) of an area. Considering that the GRP is often linked to indoor radon risk levels, we have conducted multi-disciplinary research to: (i) define local GRPs and investigate their relationship with associated indoor Rn levels; (ii) evaluate inhaled radiation dosages and the associated risk to the inhabitants; and (iii) define radon priority areas (RPAs) as required by the Directive 2013/59/Euratom. In the framework of the EU-funded LIFE-Respire project, a large amount of data (radionuclide content, soil gas samples, terrestrial gamma, indoor radon) was collected from three municipalities located in different volcanic districts of the Lazio region (central Italy) that are characterised by low to high GRP. Results highlight the positive correlation between the radionuclide content of the outcropping rocks, the soil Rn concentrations and the presence of high indoor Rn values in areas with medium to high GRP. Data confirm that the Cimini–Vicani area has inhalation dosages that are higher than the reference value of 10 mSv/y

LOCAL SEISMIC HAZARD ASSESSMENT IN EXPLOSIVE VOLCANIC SETTINGS BY 1D AND 2D NUMERICAL ANALYSES

In this study, we face the problem of local seismic response in explosive volcanic setting by using an integrated geological-geophysical-geotechnical approach in the test area of Stracciacappa maar (Sabatini Volcanic District, central Italy). Our aim is to understand if the horizontal and vertical chaotic heterogeneity typical of the volcanic deposits influence site response. The Stracciacappa maar is an active eruptive centre characterised by a crater of about 1 km in diameter and a crater floor of about 30-40 m below the rim (De Rita et al. 1983; Sottili et al. 2012). The ring is mainly composed by the pyroclastic succession belonging to the last phreatomagmatic activity. This pyroclastic succession generally bends outward the rim with low angle dip (10-20°). It consists of at least 25 metres thick alternation of decimetre- to centimetre-thick layers of fine-medium ash and small lapilli. The crater depression is filled by epiclastic debris deposits and by recent and present-day lacustrine muds. The epiclastic debris deposits, of alluvial and delta origin, consist of alternation of cm-thick reworked fine-grained and coarse-grained volcaniclastic material, dipping with low-angle (1s) motions, compared to tectonic events of equivalent magnitude (Jousset and Douglas 2007); the unscaled recording at Bronte Station (BNT in ITACA database, http://itaca.mi.ingv.it) of the ML=4.4 October 27, 2002 event was employed; 2) a high magnitude far-field “tectonic” event (tectonic scenario), whose reference spectrum was built with Ground Motion Prediction Equations (Ambraseys et al., 2005) assuming M=6.5 and distance of 70 km. These conditions are compatible with seismogenic sources located in central Apennines of Italy. Three unscaled recordings of events characterised by magnitude and distance in the range of 6-7 and 60-90 km, respectively, were extracted from ITACA database (http://itaca.mi.ingv.it), matching on average the reference spectrum Two subsoil models have been considered: a detailed model (based on distribution of the lithotypes unravelled by the geological survey) and a simplified one (obtained by grouping interfingering lithotypes resting below the lacustrine silty clays). The result show that the two models have similar response in all range of the interesting period (0.1-1.0s); the damping properties of soft clays and sands deposits in the upper meters reduce the difference in the seismic response at the surface of both models. The results suggest the possibility to simplify the heterogeneous distribution of deposits in this volcanic context for assessment of seismic response purposes. Finally, we carried out both linear and equivalent linear analyses in one-dimensional and bi-dimensional conditions, in order to investigate the bidimensional effects and the role of nonlinearity on the seismic response,. In linear case the behaviour of soils was assumed linear visco-elastic with small strain damping ratio values D0; amplification factors higher than 10 were reached at 2 Hz at soft clays surface in correspondence of the centre and western edge of the maar in bi-dimensional analysis, whereas the 2D/1D ratios were in the order of 2-3 around 2 Hz with maximum values at the maar edges. In the nonlinear analyses, the maximum amplifications dropped below 10 and the 2D effects (i.e., 2D/1D ratios) were generally lower than 2 in the whole range of frequency

Local seismic hazard assessment in explosive volcanic settings by 1d and 2d numerical analyses

In this study, we face the problem of local seismic response in explosive volcanic setting by using an integrated geological-geophysical-geotechnical approach in the test area of Stracciacappa maar (Sabatini Volcanic District, central Italy). Our aim is to understand if the horizontal and vertical chaotic heterogeneity typical of the volcanic deposits influence site response. The Stracciacappa maar is an active eruptive centre characterised by a crater of about 1 km in diameter and a crater floor of about 30-40 m below the rim (De Rita et al. 1983; Sottili et al. 2012). The ring is mainly composed by the pyroclastic succession belonging to the last phreatomagmatic activity. This pyroclastic succession generally bends outward the rim with low angle dip (10-20°). It consists of at least 25 metres thick alternation of decimetre- to centimetre-thick layers of fine-medium ash and small lapilli. The crater depression is filled by epiclastic debris deposits and by recent and present-day lacustrine muds. The epiclastic debris deposits, of alluvial and delta origin, consist of alternation of cm-thick reworked fine-grained and coarse-grained volcaniclastic material, dipping with low-angle (1s) motions, compared to tectonic events of equivalent magnitude (Jousset and Douglas 2007); the unscaled recording at Bronte Station (BNT in ITACA database, http://itaca.mi.ingv.it) of the ML=4.4 October 27, 2002 event was employed; 2) a high magnitude far-field “tectonic” event (tectonic scenario), whose reference spectrum was built with Ground Motion Prediction Equations (Ambraseys et al., 2005) assuming M=6.5 and distance of 70 km. These conditions are compatible with seismogenic sources located in central Apennines of Italy. Three unscaled recordings of events characterised by magnitude and distance in the range of 6-7 and 60-90 km, respectively, were extracted from ITACA database (http://itaca.mi.ingv.it), matching on average the reference spectrum Two subsoil models have been considered: a detailed model (based on distribution of the lithotypes unravelled by the geological survey) and a simplified one (obtained by grouping interfingering lithotypes resting below the lacustrine silty clays). The result show that the two models have similar response in all range of the interesting period (0.1-1.0s); the damping properties of soft clays and sands deposits in the upper meters reduce the difference in the seismic response at the surface of both models. The results suggest the possibility to simplify the heterogeneous distribution of deposits in this volcanic context for assessment of seismic response purposes. Finally, we carried out both linear and equivalent linear analyses in one-dimensional and bi-dimensional conditions, in order to investigate the bidimensional effects and the role of nonlinearity on the seismic response,. In linear case the behaviour of soils was assumed linear visco-elastic with small strain damping ratio values D0; amplification factors higher than 10 were reached at 2 Hz at soft clays surface in correspondence of the centre and western edge of the maar in bi-dimensional analysis, whereas the 2D/1D ratios were in the order of 2-3 around 2 Hz with maximum values at the maar edges. In the nonlinear analyses, the maximum amplifications dropped below 10 and the 2D effects (i.e., 2D/1D ratios) were generally lower than 2 in the whole range of frequency

Biological activity of 3-chloro-azetidin-2-one derivatives having interesting antiproliferative activity on human breast cancer cell lines

Resveratrol (3,40,5 tri-hydroxystilbene), a natural plant polyphenol, has gained interest as a non-toxic agent capable of inducing tumor cell death in a variety of cancer types. However, therapeutic application of these beneficial effects remains very limited due to its short biological half-life, labile properties, rapid metabolism and elimination. Different studies were undertaken to obtain synthetic analogs of resveratrol with major bioavailability and anticancer activity. We have synthesized a series 3-chloro-azetidin-2-one derivatives, in which an azetidinone nucleus connects two aromatic rings. Aim of the present study was to investigate the effects of these new 3-chloro-azetidin-2-one resveratrol derivatives on human breast cancer cell lines proliferation. Our results indicate that some azetidin-based resveratrol derivatives may become new potent alternative tools for the treatment of human breast cance