Sphingosine kinase 1 is up-regulated during hypoxia in U87MG glioma cells: Role of hypoxia-inducible factors 1 and 2

Sphingosine 1-phosphate (S1P), a sphingolipid metabolite that plays an important role in the regulation of cell survival, growth, migration, and angiogenesis, acts both inside the cells and as an extracellular mediator through binding to five G protein-coupled receptors (S1P(1-5)). Sphingosine kinase 1 (SK1), the enzyme responsible for S1P production, is overexpressed in many solid tumors, including gliomas. One common feature of these tumors is the presence of "hypoxic regions," characterized by cells expressing high levels of hypoxia-inducible factors HIF-1alpha and HIF-2alpha, two transcription regulators that modulate the levels of proteins with crucial roles in tumor progression. So far, nothing is known about the role and the regulation of SK1 during tumor-induced hypoxia or about SK1 regulation and HIFs. Here we investigated the role of HIF-1alpha and HIF-2alpha in the regulation of SK1 during hypoxic stress in glioma-derived U87MG cells. We report that hypoxia increases SK1 mRNA levels, protein expression, and enzyme activity, followed by intracellular S1P production and S1P release. Interestingly, knockdown of HIF-2alpha by small interfering RNA abolished the induction of SK1 and the production of extracellular S1P after CoCl(2) treatment, whereas HIF-1alpha small interfering RNA resulted in an increase of HIF-2alpha and of SK1 protein levels. Moreover, using chromatin immunoprecipitation analysis, we demonstrate that HIF-2alpha binds the SK1 promoter. Functionally, we demonstrate that conditioned medium from hypoxia-treated tumor cells results in neoangiogenesis in human umbilical vein endothelial cells in a S1P receptor-dependent manner. These studies provide evidence of a link between S1P production as a potent angiogenic agent and the hypoxic phenotype observed in many tumors

A 1 mm Scintillating Fibre Tracker Readout by a Multi-anode Photomultiplier

This note describes a prototype particle tracking detector constructed with 1 mm plastic scintillating fibres with a 64 channel Hamamatsu H8500 flat-panel multi-anode photomultiplier readout. Cosmic ray tracks from an array of 11 gas-filled drift tubes were matched to signals in the scintillating fibres in order to measure the resolution and efficiency of tracks reconstructed in the fibre-based tracker. A GEANT4 detector simulation was also developed to compare cosmic ray data with MC results and is discussed in the note. Using the parameters measured in this experimental setup, modified fibre tracker designs are suggested to improve resolution and efficiency in future prototypes to meet modern detector specifications.Comment: Laboratori Nazionali Di Frascati SIDS-Pubblicazioni LNF - 10 / 21(P) October 26, 201

Optical Link of the Atlas Pixel Detector

The on-detector optical link of the ATLAS pixel detector contains radiation-hard receiver chips to decode bi-phase marked signals received on PIN arrays and data transmitter chips to drive VCSEL arrays. The components are mounted on hybrid boards (opto-boards). We present results from the irradiation studies with 24 GeV protons up to 32 Mrad (1.2 x 10^15 p/cm^2) and the experience from the production.Comment: 9th ICATPP Conference, Como, Ital

Test results of the front-end system for the Silicon Drift Detectors of ALICE

The front-end system of the Silicon Drift Detectors (SDDs) of the ALICE experiment is made of two ASICs. The first chip performs the preamplification, temporary analogue storage and analogue-to-digital conversion of the detector signals. The second chip is a digital buffer that allows for a significant reduction of the connection from the front-end module to the outside world. In this paper, the results achieved on the first complete prototype of the front-end system for the SDDs of ALICE are presented

Ecosystem functioning and ecological status in the Venice lagoon, which relationships?

The implementation of management measures for improving the ecological status within an Ecosystem Based Management approach represents one the of the main challenges in coastal and transitional water environments. In general terms, ecological status and ecosystem functioning are expected to be positively associated, being good ecological processes a sort of prerequisite for the ecosystem health, but often relationships between ecosystem functioning indicators and the metrics used to define ecological status resulted to be rather puzzling. Moreover, the Biological Quality Elements (BQEs) do not show a consistent response to the changes in the ecosystem. This situation does not allow to recognize where interventions are really needed, hindering the definition of effective management strategies. In the present paper, a spatially explicit food web model of the Venice lagoon (with the resolution of 300 m) is used to simulate changes in the ecological status and related them to different management scenarios. Functional changes in the food web were investigated by comparing values of a set of 12 indicators derived by the ecological network analysis. In general, results highlighted on one hand the need for more discussion about the implementation of the WFD, at least in complex and spatially heterogeneous transitional waters environments, as the Venice lagoon; on the other, results remark the opportunity to support the BQEs monitoring with an ecological modelling approach. These models are certainly not the panacea for addressing questions about the environmental management, as they have inherent uncertainties (on parameters, structure, processes etc.); however, they can prove useful for selecting among different policy choices, since they offer the opportunity to simulate the mean effects, preliminarily verifying the efficacy of the proposed interventions

Effect of oral consumption of capsules containing Lactobacillus paracasei LPC-S01 on the vaginal microbiota of healthy adult women: a randomized, placebo-controlled, double-blind crossover study

Oral consumption of probiotics is practical and can be an effective solution to preserve vaginal eubiosis. Here, we studied the ability of orally administered Lactobacillus paracasei LPC-S01 (DSM 26760) to affect the composition of the vaginal microbiota and colonize the vaginal mucosa in nondiseased adult women. A total of 40 volunteers took oral probiotic (24 billion CFU) or placebo capsules daily for 4 weeks, and after a 4-week washout, they switched to placebo or probiotic capsules according to the crossover design. A total of 23 volunteers completed the study according to the protocol. Before and after capsule ingestion, vaginal swabs were collected for qPCR quantification to detect L. paracasei LPC-S01 and for 16S rRNA gene sequencing. Vaginal swabs were grouped according to their bacterial taxonomic structure into nine community state types (CSTs), four of which were dominated by lactobacilli. Lactobacillus paracasei LPC-S01 was detected in the vagina of two participants. Statistical modeling (including linear mixed-effects model analysis) demonstrated that daily intake of probiotic capsules reduced the relative abundance of Gardnerella spp. Quantitative PCR with Gardnerella vaginalis primers confirmed this result. Considering the pathogenic nature of G. vaginalis, these results suggest a potential positive effect of this probiotic capsule on the vaginal microbial ecosystem

Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer

Beam Test Performance and Simulation of Prototypes for the ALICE Silicon Pixel Detector

The silicon pixel detector (SPD) of the ALICE experiment in preparation at the Large Hadron Collider (LHC) at CERN is designed to provide the precise vertex reconstruction needed for measuring heavy flavor production in heavy ion collisions at very high energies and high multiplicity. The SPD forms the innermost part of the Inner Tracking System (ITS) which also includes silicon drift and silicon strip detectors. Single assembly prototypes of the ALICE SPD have been tested at the CERN SPS using high energy proton/pion beams in 2002 and 2003. We report on the experimental determination of the spatial precision. We also report on the first combined beam test with prototypes of the other ITS silicon detector technologies at the CERN SPS in November 2004. The issue of SPD simulation is briefly discussed.Comment: 4 pages, 5 figures, prepared for proceedings of 7th International Position Sensitive Detectors Conference, Liverpool, Sept. 200

Multi-GeV Electron Spectrometer

The advance in laser plasma acceleration techniques pushes the regime of the resulting accelerated particles to higher energies and intensities. In particular the upcoming experiments with the FLAME laser at LNF will enter the GeV regime with almost 1pC of electrons. From the current status of understanding of the acceleration mechanism, relatively large angular and energy spreads are expected. There is therefore the need to develop a device capable to measure the energy of electrons over three orders of magnitude (few MeV to few GeV) under still unknown angular divergences. Within the PlasmonX experiment at LNF a spectrometer is being constructed to perform these measurements. It is made of an electro-magnet and a screen made of scintillating fibers for the measurement of the trajectories of the particles. The large range of operation, the huge number of particles and the need to focus the divergence present unprecedented challenges in the design and construction of such a device. We will present the design considerations for this spectrometer and the first results from a prototype.Comment: 7 pages, 6 figures, submitted to NIM

Performance of ALICE pixel prototypes in high energy beams

The two innermost layers of the ALICE inner tracking system are instrumented with silicon pixel detectors. Single chip assembly prototypes of the ALICE pixels have been tested in high energy particle beams at the CERN SPS. Detection efficiency and spatial precision have been studied as a function of the threshold and the track incidence angle. The experimental method, data analysis and main results are presented.Comment: 10 pages, 9 figures, contribution to PIX2005 Workshop, Bonn (Germany), 5-8 September 200