5-(carbamoylmethylene)-oxazolidin-2-ones as a promising class of heterocycles inducing apoptosis triggered by increased ROS levels and mitochondrial dysfunction in breast and cervical cancer

Oxazolidinones are antibiotics that inhibit protein synthesis by binding the 50S ribosomal subunit. Recently, numerous worldwide researches focused on their properties and possible involvement in cancer therapy have been conducted. Here, we evaluated in vitro the antiproliferative activity of some 5-(carbamoylmethylene)-oxazolidin-2-ones on MCF-7 and HeLa cells. The tested compounds displayed a wide range of cytotoxicity on these cancer cell lines, measured by MTT assay, exhibiting no cytotoxicity on non-tumorigenic MCF-10A cells. Among the nine tested derivatives, four displayed a good anticancer potential. Remarkably, OI compound showed IC50 values of 17.66 and 31.10 µM for MCF-7 and HeLa cancer cells, respectively. Furthermore, we assessed OI effect on the cell cycle by FACS analysis, highlighting a G1 phase arrest after 72 h, supported by a low expression level of Cyclin D1 protein. Moreover, mitochondrial membrane potential was reduced after OI treatment driven by high levels of ROS. These findings demonstrate that OI treatment can inhibit MCF-7 and HeLa cell proliferation and induce apoptosis by caspase-9 activation and cytochrome c release in the cytosol. Hence, 5-(carbamoylmethylene)-oxazolidin-2-ones have a promising anticancer activity, in particular, OI derivative could represent a good candidate for in vivo further studies and potential clinical use

The limits of the rotating wave approximation in the electromagnetic field propagation in a cavity

We consider three two-level atoms inside a one-dimensional cavity, interacting with the electromagnetic field in the rotating wave approximation (RWA), commonly used in the atom-radiation interaction. One of the three atoms is initially excited, and the other two are in their ground state. We numerically calculate the propagation of the field spontaneously emitted by the excited atom and scattered by the second atom, as well as the excitation probability of the second and third atom. The results obtained are analyzed from the point of view of relativistic causality in the atom-field interaction. We show that, when the RWA is used, relativistic causality is obtained only if the integrations over the field frequencies are extended to $-\infty$; on the contrary, noncausal tails remain even if the number of field modes is increased. This clearly shows the limit of the RWA in dealing with subtle problems such as relativistic causality in the atom-field interaction.Comment: 13 pages, 6 figure

Therapeutic sequences in patients with grade 1−2 neuroendocrine tumors (NET): an observational multicenter study from the ELIOS group

Purpose: Many different treatments are suggested by guidelines to treat grade 1−2 (G1−G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1−G2 NET. Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1–G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03). Conclusions: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1−G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy

Lo studio delle deformazioni del suolo nell'area di Bojano nel periodo 2004-2006

In questa nota sono riportati i risultati ottenuti da indagini geodetiche effettuate nell’area del Sannio-Matese nell’ambito di una Convenzione triennale perfezionata tra l’Assessorato ai Lavori Pubblici della Regione Molise e l’INGV-OV, rivolta all’individuazione di eventuali fenomeni deformativi del suolo in atto nel comune di Bojano (CB). Lo studio, condotto nel periodo 2004-2006, ha visto la progettazione di una rete geodetica nell’area del Comune di Bojano, avente come riferimento il Cs 104 della Linea 80 IGMI corrispondente al Cs LBO/AIGM in Carta, e la materializzazione di vertici GPS, caposaldi di livellazione e l’installazione di Dry Tilt. Le misure di livellazione sull’intera rete, relative al caposaldo di riferimento, hanno evidenziato un generale trend in subsidenza nel bacino di Bojano connesso, con buona probabilità, alle oscillazioni stagionali della falda. I risultati dellemisure sui vertici della rete GPS sono in buon accordo con quelli ottenuti dalle misure di livellazione, evidenziando un trend in subsidenza nella piana di Bojano e nell’area delle sorgenti del Biferno. Le stime dell’inclinazione del suolo ottenute attraverso l’applicazione della tecnica dei dry-tilt hanno delineato un quadro deformativo relativo alla zona cittadina di Bojano consistente in una inclinazione del suolo nel quadrante ENE

Machine learning in clinical and epidemiological research: Isn't it time for biostatisticians to work on it?

In recent years, there has been a widespread cross-fertilization between Medical Statistics and Machine Learning (ML) techniques

Ionization Electron Signal Processing in Single Phase LArTPCs II. Data/Simulation Comparison and Performance in MicroBooNE

The single-phase liquid argon time projection chamber (LArTPC) provides a large amount of detailed information in the form of fine-grained drifted ionization charge from particle traces. To fully utilize this information, the deposited charge must be accurately extracted from the raw digitized waveforms via a robust signal processing chain. Enabled by the ultra-low noise levels associated with cryogenic electronics in the MicroBooNE detector, the precise extraction of ionization charge from the induction wire planes in a single-phase LArTPC is qualitatively demonstrated on MicroBooNE data with event display images, and quantitatively demonstrated via waveform-level and track-level metrics. Improved performance of induction plane calorimetry is demonstrated through the agreement of extracted ionization charge measurements across different wire planes for various event topologies. In addition to the comprehensive waveform-level comparison of data and simulation, a calibration of the cryogenic electronics response is presented and solutions to various MicroBooNE-specific TPC issues are discussed. This work presents an important improvement in LArTPC signal processing, the foundation of reconstruction and therefore physics analyses in MicroBooNE.Comment: 54 pages, 36 figures; the first part of this work can be found at arXiv:1802.0870

Research needs towards a resilient community: Vulnerability reduction, infrastructural systems model, loss assessment, resilience-based design and emergency management

Most of the literature on resilience is devoted to its assessment. It seems time to move from analysis to design, to develop the tools needed to enhance resilience. Resilience enhancement, a close relative of the less fashionable risk mitigation, adds to the latter, at least in the general perception, a systemic dimension. Resilience is often paired with community, and the latter is a system. This chapter therefore discusses strategies to enhance resilience, endorses one of prevention rather than cure, and focuses in the remainder on the role played by systemic analysis, i.e. the analysis of the built environment modelled beyond a simple collection of physical assets, with due care to the associated interdependencies. Research needs are identified and include challenges in network modelling, the replacement of generic fragility curves for components, how to deal with evolving state of information

KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth

The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis1,2. Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production2. The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRASmut cell lines display decreased glutaminolysis, lower NADPH/NADP+ and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRASWT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRASmut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRASmut rewired glutamine metabolism2, and thus it should be considered a key metabolic target for the treatment of this refractory tumour

Suppression of adenine nucleotide translocase-2 by vector-based siRNA in human breast cancer cells induces apoptosis and inhibits tumor growth in vitro and in vivo

INTRODUCTION: Adenine nucleotide translocator (ANT) 2 is highly expressed in proliferative cells, and ANT2 induction in cancer cells is known to be directly associated with glycolytic metabolisms and carcinogenesis. In addition, ANT2 repression results in the growth arrest of human cells, implying that ANT2 is a candidate for cancer therapy based on molecular targeting. METHODS: We utilized an ANT2-specific RNA interference approach to inhibit ANT2 expression for evaluating its antitumor effect in vitro and in vivo. Specifically, to investigate the therapeutic potential of ANT2 repression, we used a DNA vector-based RNA interference approach by expressing shRNA to knockdown ANT2 in breast cancer cell lines overexpressing ANT2. RESULTS: ANT2 shRNA treatment in breast cancer cell line MDA-MB-231 repressed cell growth as well as proliferation. In addition, cell cycle arrest, ATP depletion and apoptotic cell death characterized by the potential disruption of mitochondrial membrane were observed from the ANT2 shRNA-treated breast cancer cells. Apoptotic breast cancer cells transfected with ANT2 shRNA also induced a cytotoxic bystander effect that generates necrotic cell death to the neighboring cells. The intracellular levels of TNFalpha and TNF-receptor I were increased in ANT2 shRNA transfected cells and the bystander effect was partly blocked by anti-TNFalpha antibody. Ultimately, ANT2 shRNA effectively inhibited tumor growth in vivo. CONCLUSION: These results suggest that vector-based ANT2 RNA interference could be an efficient molecular therapeutic method for breast cancer with high expression of ANT2.This work was supported in part by the grants from the Cancer Research Center, and the Korean Science & Engineering Foundation through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine

The Making of the NEAM Tsunami Hazard Model 2018 (NEAMTHM18)

The NEAM Tsunami Hazard Model 2018 (NEAMTHM18) is a probabilistic hazard model for tsunamis generated by earthquakes. It covers the coastlines of the North-eastern Atlantic, the Mediterranean, and connected seas (NEAM). NEAMTHM18 was designed as a three-phase project. The first two phases were dedicated to the model development and hazard calculations, following a formalized decision-making process based on a multiple-expert protocol. The third phase was dedicated to documentation and dissemination. The hazard assessment workflow was structured in Steps and Levels. There are four Steps: Step-1) probabilistic earthquake model; Step-2) tsunami generation and modeling in deep water; Step-3) shoaling and inundation; Step-4) hazard aggregation and uncertainty quantification. Each Step includes a different number of Levels. Level-0 always describes the input data; the other Levels describe the intermediate results needed to proceed from one Step to another. Alternative datasets and models were considered in the implementation. The epistemic hazard uncertainty was quantified through an ensemble modeling technique accounting for alternative models’ weights and yielding a distribution of hazard curves represented by the mean and various percentiles. Hazard curves were calculated at 2,343 Points of Interest (POI) distributed at an average spacing of ∼20 km. Precalculated probability maps for five maximum inundation heights (MIH) and hazard intensity maps for five average return periods (ARP) were produced from hazard curves. In the entire NEAM Region, MIHs of several meters are rare but not impossible. Considering a 2% probability of exceedance in 50 years (ARP≈2,475 years), the POIs with MIH >5 m are fewer than 1% and are all in the Mediterranean on Libya, Egypt, Cyprus, and Greece coasts. In the North-East Atlantic, POIs with MIH >3 m are on the coasts of Mauritania and Gulf of Cadiz. Overall, 30% of the POIs have MIH >1 m. NEAMTHM18 results and documentation are available through the TSUMAPS-NEAM project website (http://www.tsumaps-neam.eu/), featuring an interactive web mapper. Although the NEAMTHM18 cannot substitute in-depth analyses at local scales, it represents the first action to start local and more detailed hazard and risk assessments and contributes to designing evacuation maps for tsunami early warning.publishedVersio