Deregulation of cell death in cancer: Recent highlights

The aim of this Special Issue on the deregulation of cell death in cancer is to bring together recent perspectives on the relationship between tumorigenesis and programmed cell death (PCD) [...]

Fault slip rates for the active External Dinarides thrust-and-fold belt

We present estimates of slip rates for active faults in the External Dinarides. This thrust-and-fold belt formed in the Adria-Eurasia collision zone by the progressive formation of NE-dipping thrusts in the footwalls of older structures. We calculated the long-term horizontal velocity field, slip rates and related uncertainties for active faults using a thin-shell finite element method. We incorporated active faults with different effective fault frictions, rheological properties, appropriate geodynamic boundary conditions, laterally varying heat flow and topography. The results were obtained by comparing the modeled maximum compressive horizontal stress orientations with the World Stress Map database. The calculated horizontal velocities decrease from the southeastern External Dinarides to the northwestern parts of the thrust-and-fold belt. This spatial pattern is also evident in the long-term slip rates of active faults. The highest slip rate was obtained for the Montenegro active fault, while the lowest rates were obtained for active faults in northwestern Slovenia. Low slip rates, influenced by local active diapirism, are also characteristic for active faults in the offshore central External Dinarides. These findings are contradictory to the concept of Adria as an internally rigid, aseismic lithospheric block because the faults located in its interior release a part of the regional compressive stress. We merged the modeling results and available slip rate estimates to obtain a composite solution for slip rates

Earthquake rates inferred from active faults and geodynamics: the case of the External Dinarides

The goal of earthquake rate models is to define the long-term rate of seismicity above an established magnitude threshold. No earthquake rate models exist for the External Dinarides, although this area is prone to frequent earthquakes that have significant impacts on natural and human environments. In this study, we apply a tectonic/geodynamic approach to build a fault-based and a deformation-based earthquake rate model for the External Dinarides. The main difference between the two models is the inclusion of off-fault seismicity in the deformation-based earthquake rate model. We explore the impact of the moment-balancing uncertainties on the expected number of earthquakes above an established magnitude. The results show comparable earthquake rates for both input models. The slip rate, the elastic modulus and the seismogenic depth play important roles in the variability of earthquake rates, whereas the effects of the corner magnitude and the Gutenberg-Richter β parameter are insignificant. A comparison with the available historical seismic catalogue shows good agreement for MW>5.8 earthquakes

Micro-Raman characterizations of Pompei'smortars

The ancient town of Pompei offers a unique opportunity to study in detail many aspects of the every day life during the Roman early imperial age. The application of micro-Raman spectroscopy can be of great help in performing a reasonably rapid comparative analysis of the mortars, quite useful to ascertain the degree of uniformity of the technical recipes among the various building firms and the eventual technical evolution in the time; moreover, the individuation of minerals of specific geographical origins can give useful information about the extension of commercial intercourses. An example of a micro-Raman investigation on building materials is reported in this work, concerning the analysis of the mortars coming from different points of the wall in the 'The House of the Wedding of Hercules'. Remarkable differences between ancient and modern mortars are found, allowing a discrimination that can be useful in the case of historical building which underwent several restoration works. Copyright © 2008 John Wiley & Sons, Ltd

SHINE: Web Application for Determining the Horizontal Stress Orientation

Interpolating the orientation of the maximum horizontal compressive stress with a well-established procedure is fundamental in understanding the present-day stress field. This paper documents the design principles, strategies and architecture of SHINE (http://shine.rm.ingv.it/), a web-based application for determining the maximum horizontal compressive stress orientation. The interpolation using SHINE can be carried out from a global database or from a custom file uploaded by the user. SHINE satisfies the usability requirements by striving for effectiveness, efficiency and satisfaction as defined by the International Organization for Standardization (ISO) covering ergonomics of human-computer interactions. Our main goal was to build a web-based application with a strong “outside-in” strategy in order to make the interpolation technique available to a wide range of Earth Science disciplines. SHINE is an easy-to-use web application with a straightforward interface guaranteeing quick visualization of the results, which are downloadable in several formats. SHINE is offered as an easy and convenient web service encouraging global data sharing and scientific research collaboration. Within this paper, we present a possible use of SHINE, determining fault kinematics compatibility with respect to the present-day stress field

Decoration of nanovesicles with pH (low) insertion peptide (pHLIP) for targeted delivery

Acidity at surface of cancer cells is a hallmark of tumor microenvironments, which does not depend on tumor perfusion, thus it may serve as a general biomarker for targeting tumor cells. We used the pH (low) insertion peptide (pHLIP) for decoration of liposomes and niosomes. pHLIP senses pH at the surface of cancer cells and inserts into the membrane of targeted cells, and brings nanomaterial to close proximity of cellular membrane. DMPC liposomes and Tween 20 or Span 20 niosomes with and without pHLIP in their coating were fully characterized in order to obtain fundamental understanding on nanocarrier features and facilitate the rational design of acidity sensitive nanovectors. The samples stability over time and in presence of serum was demonstrated. The size, ζ-potential, and morphology of nanovectors, as well as their ability to entrap a hydrophilic probe and modulate its release were investigated. pHLIP decorated vesicles could be useful to obtain a prolonged (modified) release of biological active substances for targeting tumors and other acidic diseased tissues

Deliverable # 3.01.2 Slip rate data of seismogenic sources included in DISS

This deliverable contains three different products: one table with reclassified slip rate data from DISS, one table with slip rate values calculated from numerical models, and two study cases that illustrate the applications of original methods to estimate slip rate

Current trends in ATRA delivery for cancer therapy

All-Trans Retinoic Acid (ATRA) is the most active metabolite of vitamin A. It is critically involved in the regulation of multiple processes, such as cell differentiation and apoptosis, by activating specific genomic pathways or by influencing key signaling proteins. Furthermore, mounting evidence highlights the anti-tumor activity of this compound. Notably, oral administration of ATRA is the first choice treatment in Acute Promyelocytic Leukemia (APL) in adults and NeuroBlastoma (NB) in children. Regrettably, the promising results obtained for these diseases have not been translated yet into the clinics for solid tumors. This is mainly due to ATRA-resistance developed by cancer cells and to ineffective delivery and targeting. This up-to-date review deals with recent studies on different ATRA-loaded Drug Delivery Systems (DDSs) development and application on several tumor models. Moreover, patents, pre-clinical, and clinical studies are also reviewed. To sum up, the main aim of this in-depth review is to provide a detailed overview of the several attempts which have been made in the recent years to ameliorate ATRA delivery and targeting in cancer

RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention

The new low-toxic histone deacetylase inhibitor S-(2) induces apoptosis in various acute myeloid leukemia cells

Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4-benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn(++)-chelating group. Here, we explored the anti-leukaemic properties of three novel hybrids, namely the chiral compounds (S)-2 and (R)-2, and their non-chiral analogue 4, which were first comparatively tested in promyelocytic NB4 cells. (S)-2 and partially 4– but not (R)-2 – caused G0/G1 cell-cycle arrest by up-regulating cyclin G2 and p21 expression and down-regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti-oxidant. Moreover, novel HDACi prompted p53 and α-tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S)-2 > 4 > (R)-2, reflecting that of other biological assays and addressing (S)-2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S)-2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ-receptors. Overall, the BDZ-hydroxamate (S)-2 showed to be a low-toxic HDACi with powerful anti-proliferative and pro-apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti-leukaemic therapy