Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity

5noopenThe design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity.openPinzi L.; Foschi F.; Christodoulou M.S.; Passarella D.; Rastelli G.Pinzi, L.; Foschi, F.; Christodoulou, M. S.; Passarella, D.; Rastelli, G

Identification of tsunami deposits in south-eastern Sicily: evidence for the 365 A.D. Crete earthquake?

In the past decade, the methodologies and techniques of paleoseismological studies have evolved towards a multidisciplinary approach for the characterization of past earthquakes. Along with traditional geologic and geomorphologic near-fault investigations, off-fault studies of evidence for past earthquakes, such as soft sediment deformation (e.g. Moretti, 2000; Marco and Agnon, 2005), evidence of liquefaction (e.g. Tuttle et al., 2002; Guarnieri et al., 2009) and tsunami deposits (Dawson and Stewart, 2007; Pantosti et al., 2008; De Martini et al., 2009) are considered useful tools in the assessment of paleoearthquakes ages, magnitudes, and earthquake recurrence rates. We present the preliminary results of off-fault paleoseismological studies carried out in south-eastern Sicily, focused to identify evidence of tsunami inundations

Geological evidence for paleotsunamis along eastern Sicily (Italy): an overview

Abstract. We present geological evidence for paleotsunamis along the ~230 km-long coast of eastern Sicily (Italy); combining this information with historical data, we reconstruct a unique history of tsunami inundations. We integrate data on 38 paleotsunami deposits (from fine sand layers to boulders) collected at 11 sites (one offshore). The geological data record traces of large tsunamis which have occurred during the past 4 millennia. Chronological constrains include 14C, 210Pb and 137Cs, OSL and tephrochronology. When compatible, the age of the paleotsunami deposits is associated to historical events, but it is also used to highlight unknown tsunamis. Average tsunami recurrence interval (between 320 and 840 yr) and minimum inland tsunami ingressions (often greater than the historical ones) were estimated at several sites. On the basis of this work, the tsunami catalogue is implemented by two unknown tsunamis which occurred during the first millennium BC and by one unknown regional tsunami, which occurred in 650–770 AD. By including this latter event in the eastern Sicily catalogue, we estimate an average recurrence interval for strong tsunamis of ca. 385 yr. Comparison and merging of historical and geological data can definitely contribute to a better understanding of regional and local tsunami potential and provides robust parameters to be used in tsunami hazard estimates

Discovering the characteristics of the surface faulting ancestors of the L’Aquila April 6, 2009 earthquake by paleoseismological investigations

The occurrence of the Mw 6.3, April 6, 2009 earthquake has highlighted how critical is the development of hazard models that incorporate all the information on the long-term seismic behavior of faults (i.e., individual events rupture length and slip, timing, etc.). Under this light we started a campaign of paleoseismological investigations in the epicentral area. The 2009 earthquake occurred on the Paganica normal fault (PF hereinafter) and produced a max 0.15 m high, 3 km-long continuous surface rupture along its central section, as well as several short, discontinuous cracks along the rest of the fault trace; secondary slip along nearby tectonic structures was observed too. The PF consists of a prominent NW-SE striking and SW dipping long-term morphologic scarp formed by the tectonic juxtaposition of Pliocene-middle Pleistocene and late Pleistocene alluvial deposits, and by smaller compound scarps in late Pleistocene-Holocene deposits. The fault runs for a total length of about 20 km along the NE side of the Aterno River valley, a graben-type basin bounded by marked antithetic faults. The limited extent and the small throw of the 2009 surface ruptures, when compared to the size of the Paganica long-term fault scarp, raise questions about the evolution and rupture history of this fault and suggest that the PF may have experienced larger Magnitude earthquakes than the 2009 seismic event. With the aim of defining the Max Magnitude expected for the PF by determining the size of the individual coseismic surface ruptures occurred in the past and their max extent, their frequency and the average rate of displacement we have been excavating new trenches and studied artificial exposures across the PF fault zone, in most of the cases intersecting the 2009 surface ruptures. Preliminary results show evidence for repeated decimetric surface faulting events during the past 3 millennia with the penultimate likely being the 1461 event (Me 6.4); evidence for possible previous larger slip events is found too. Whether the small ruptures are all related to slip at depth on the PF or would represent sympathetic slip triggered by earthquake occurred on nearby faults should be better investigated. Conversely, provided the “double size” slip behavior of the PF is confirmed, to characterize the seismic hazard of the area we should consider a more complex seismogenic model than that presently applied. In particular, we should include also the scenario that the PF produces relatively frequent (each 4-600 yr) 2009-type earthquakes and rare (each 3-4 millennia) larger events, likely in connection with other nearby active structures (i.e., San Demetrio Fault? Pettino Fault?)

Geological evidence for paleotsunamis along eastern Sicily (Italy): an overview

We present geological evidence for paleotsunamis along the 230 km-long coast of eastern Sicily (Italy); combining this information with historical data, we reconstruct a unique history of tsunami inundations. We integrate data on 38 paleotsunami deposits (from fine sand layers to boulders) collected at 11 sites (one offshore). The geological data record traces of large tsunamis which have occurred during the past 4 millennia. Chronological constrains include 14C, 210Pb and 137Cs, OSL and tephrochronology. When compatible, the age of the paleotsunami deposits is associated to historical events, but it is also used to highlight unknown tsunamis. Average tsunami recurrence interval (between 320 and 840 yr) and minimum inland tsunami ingressions (often greater than the historical ones) were estimated at several sites. On the basis of this work, the tsunami catalogue is implemented by two unknown tsunamis which occurred during the first millennium BC and by one unknown regional tsunami, which occurred in 650–770 AD. By including this latter event in the eastern Sicily catalogue, we estimate an average recurrence interval for strong tsunamis of ca. 385 yr. Comparison and merging of historical and geological data can definitely contribute to a better understanding of regional and local tsunami potential and provides robust parameters to be used in tsunami hazard estimates

Antifungal Activity and DNA Topoisomerase Inhibition of Hydrolysable Tannins from Punica granatum L

Punica granatum L. (pomegranate) fruit is known to be an important source of bioactive phenolic compounds belonging to hydrolysable tannins. Pomegranate extracts have shown antifungal activity, but the compounds responsible for this activity and their mechanism/s of action have not been completely elucidated up to now. The aim of the present study was the investigation of the inhibition ability of a selection of pomegranate phenolic compounds (i.e., punicalagin, punicalin, ellagic acid, gallic acid) on both plant and human fungal pathogens. In addition, the biological target of punicalagin was identified here for the first time. The antifungal activity of pomegranate phenolics was evaluated by means of Agar Disk Diffusion Assay and minimum inhibitory concentration (MIC) evaluation. A chemoinformatic analysis predicted for the first time topoisomerases I and II as potential biological targets of punicalagin, and this prediction was confirmed by in vitro inhibition assays. Concerning phytopathogens, all the tested compounds were effective, often similarly to the fungicide imazalil at the label dose. Particularly, punicalagin showed the lowest MIC for Alternaria alternata and Botrytis cinerea, whereas punicalin was the most active compound in terms of growth control extent. As for human pathogens, punicalagin was the most active compound among the tested ones against Candida albicans reference strains, as well as against the clinically isolates. UHPLC coupled with HRMS indicated that C. albicans, similarly to the phytopathogen Coniella granati, is able to hydrolyze both punicalagin and punicalin as a response to the fungal attack. Punicalagin showed a strong inhibitory activity, with IC50 values of 9.0 and 4.6 µM against C. albicans topoisomerases I and II, respectively. Altogether, the results provide evidence that punicalagin is a valuable candidate to be further exploited as an antifungal agent in particular against human fungal infections

Path replanning for orientation-constrained needle steering

Introduction: Needle-based neurosurgical procedures require high accuracy in catheter positioning to achieve high clinical efficacy. Significant challenges for achieving accurate targeting are (i) tissue deformation (ii) clinical obstacles along the insertion path (iii) catheter control. Objective: We propose a novel path-replanner able to generate an obstacle-free and curvature bounded three-dimensional (3D) path at each time step during insertion, accounting for a constrained target pose and intraoperative anatomical deformation. Additionally, our solution is sufficiently fast to be used in a closed-loop system: needle tip tracking via electromagnetic sensors is used by the path-replanner to automatically guide the programmable bevel-tip needle (PBN) while surgical constraints on sensitive structures avoidance are met. Methods: The generated path is achieved by combining the ”Bubble Bending” method for online path deformation and a 3D extension of a convex optimisation method for path smoothing. Results: Simulation results performed on a realistic dataset show that our replanning method can guide a PBN with bounded curvature to a predefined target pose with an average targeting error of 0.65 ± 0.46 mm in position and 3.25 ± 5.23 degrees in orientation under a deformable simulated environment. The proposed algorithm was also assessed in-vitro on a brain-like gelatin phantom, achieving a target error of 1.81 ± 0.51 mm in position and 5.9 ± 1.42 degrees in orientation. Conclusion: The presented work assessed the performance of a new online steerable needle path-planner able to avoid anatomical obstacles while optimizing surgical criteria. Significance: This method is particularly suited for surgical procedures demanding high accuracy on the desired goal pose under tissue deformations and real-world inaccuracies

Looking for seismites in the Fucino basin: preliminary results from a combined geological geophysical approach.

We present a combined geological-geophysical study on the lacustrine sequence of the Fucino Plain (central Italy). New acquired data on liquefaction features and the recovery of a seismite in the lacustrine sequence are shown. Our preliminary results suggest the occurrence of three seismic events in the last ca. 45 kyr. Moreover, a first attempt to find out the source deposit responsible of the widespread liquefaction phenomena has been performed by means of shallow engine boreholes and ERT profiles

Antifungal Activity and DNA Topoisomerase Inhibition of Hydrolysable Tannins from Punica granatum L

Punica granatum L. (pomegranate) fruit is known to be an important source of bioactive phenolic compounds belonging to hydrolysable tannins. Pomegranate extracts have shown antifungal activity, but the compounds responsible for this activity and their mechanism/s of action have not been completely elucidated up to now. The aim of the present study was the investigation of the inhibition ability of a selection of pomegranate phenolic compounds (i.e., punicalagin, punicalin, ellagic acid, gallic acid) on both plant and human fungal pathogens. In addition, the biological target of punicalagin was identified here for the first time. The antifungal activity of pomegranate phenolics was evaluated by means of Agar Disk Diffusion Assay and minimum inhibitory concentration (MIC) evaluation. A chemoinformatic analysis predicted for the first time topoisomerases I and II as potential biological targets of punicalagin, and this prediction was confirmed by in vitro inhibition assays. Concerning phytopathogens, all the tested compounds were effective, often similarly to the fungicide imazalil at the label dose. Particularly, punicalagin showed the lowest MIC for Alternaria alternata and Botrytis cinerea, whereas punicalin was the most active compound in terms of growth control extent. As for human pathogens, punicalagin was the most active compound among the tested ones against Candida albicans reference strains, as well as against the clinically isolates. UHPLC coupled with HRMS indicated that C. albicans, similarly to the phytopathogen Coniella granati, is able to hydrolyze both punicalagin and punicalin as a response to the fungal attack. Punicalagin showed a strong inhibitory activity, with IC50 values of 9.0 and 4.6 µM against C. albicans topoisomerases I and II, respectively. Altogether, the results provide evidence that punicalagin is a valuable candidate to be further exploited as an antifungal agent in particular against human fungal infections

MedNet status report

MedNet is a network of very broadband seismic stations installed in countries bordering the Mediterranean area. The project started in 1987, with a final goal of 12-15 stations and a spacing of about 1000 km between stations. It was motivated both by research interest and by seismic hazard monitoring. The network presently comprises 23 operating stations, all of them equipped with state of the art seismographic stations. Presently, fully automatic network functions include: - daily monitoring of state of health; - data recover after link failures; - triggered retrieval of event waveforms; - update of web pages (http://mednet.ingv.it) for events and station information.PublishedS. Fernando (SPAIN)1.1. TTC - Monitoraggio sismico del territorio nazionaleope