Fenretinide induces autophagic cell death in caspase-defective breast cancer cells

The elimination of tumor cells by apoptosis is the main mechanism of action of chemotherapeutic drugs. More recently, autophagic cell death has been shown to trigger a nonapoptotic cell death program in cancer cells displaying functional defects of caspases. Fenretinide (FenR), a synthetic derivative of retinoic acid, promotes growth inhibition and induces apoptosis in a wide range of tumor cell types. The present study was designed to evaluate the ability of fenretinide to induce caspase-independent cell death and to this aim we used the human mammary carcinoma cell line MCF-7, lacking functional caspase-3 activity. We demonstrated that in these cells fenretinide is able to trigger an autophagic cell death pathway. In particular we found that fenretinide treatment resulted in the increase in Beclin 1 expression, the conversion of the soluble form of LC3 to the autophagic vesicle-associated form LC3-II and its shift from diffuse to punctate staining and finally the increase in lysosomes/autophagosomes. By contrast, caspase-3 reconstituted MCF-7 cell line showed apoptotic cell death features in response to fenretinide treatment. These data strongly suggest that fenretinide does not invariably elicit an apoptotic response but it is able to induce autophagy when apoptotic pathway is deregulated. The understanding of the molecular mechanisms involved in fenretinide action is important for the future design of therapies employing this retinoid in breast cancer treatment

SuperB: a linear high-luminosity B Factory

This paper is based on the outcome of the activity that has taken place during the recent workshop on "SuperB in Italy" held in Frascati on November 11-12, 2005. The workshop was opened by a theoretical introduction of Marco Ciuchini and was structured in two working groups. One focused on the machine and the other on the detector and experimental issues. The present status on CP is mainly based on the results achieved by BaBar and Belle. Estabilishment of the indirect CP violation in B sector in 2001 and of the direct CP violation in 2004 thanks to the success of PEP-II and KEKB e+e- asymmetric B Factories operating at the center of mass energy corresponding to the mass of the Y(4s). With the two B Factories taking data, the Unitarity Triangle is now beginning to be overconstrained by improving the measurements of the sides and now also of the angles alpha, and gamma. We are also in presence of the very intriguing results about the measurements of sin(2 beta) in the time dependent analysis of decay channels via penguin loops, where b --> s sbar s and b --> s dbar d. Tau physics, in particular LFV search, as well as charm and ISR physics are important parts of the scientific program of a SuperB Factory. The physics case together with possible scenarios for the high luminosity SuperB Factory based on the concepts of the Linear Collider and the related experimental issues are discussed.Comment: 22 pages, 22 figures, INFN Roadmap Repor

CELL DEATH AND AUTOPHAGY: CYTOKINES, DRUGS, AND NUTRITIONAL FACTORS

Cellsmay use multiple pathways to commit suicide. In certain contexts, dying cells generate large amounts of autophagic vacuoles and clear large proportions of their cytoplasm, before they finally die, as exemplified by the treatment of human mammary carcinoma cells with the anti-estrogen tamoxifen (TAM, ≤1 M). Protein analysis during autophagic cell death revealed distinct proteins of the nuclear fraction including GST- and some proteasomal subunit constituents to be affected during autophagic cell death. Depending on the functional status of caspase-3, MCF-7 cells may switch between autophagic and apoptotic features of cell death [Fazi, B., Bursch,W., Fimia, G.M., Nardacci R., Piacentini, M., Di Sano, F., Piredda, L., 2008. Fenretinide induces autophagic cell death in caspase-defective breast cancer cells. Autophagy 4(4), 435–441]. Furthermore, the self-destruction of MCF-7 cells was found to be completed by phagocytosis of cell residues [Petrovski, G., Zahuczky, G., Katona, K., Vereb, G., Martinet,W., Nemes, Z., Bursch,W., Fésüs, L., 2007. Clearance of dying autophagic cells of different origin by professional and non-professional phagocytes. Cell Death Diff. 14 (6), 1117–1128]. Autophagy also constitutes a cell’s strategy of defense upon cell damage by eliminating damaged bulk proteins/organelles. This biological condition may be exemplified by the treatment of MCF-7 cells with a necrogenic TAM-dose (10 M), resulting in the lysis of almost all cells within 24 h. However, a transient (1 h) challenge of MCF-7 cells with the same dose allowed the recovery of cells involving autophagy. Enrichment of chaperones in the insoluble cytoplasmic protein fraction indicated the formation of aggresomes, a potential trigger for autophagy. In a further experimental model HL60 cells were treated with TAM, causing dose-dependent distinct responses: 1–5 MTAM, autophagy predominant; 7–9 M, apoptosis predominant; 15 M, necrosis. These phenomena might be attributed to the degree of cell damage caused by tamoxifen, either by generating ROS, increasing membrane fluidity or forming DNA-adducts. Finally, autophagy constitutes a cell’s major adaptive (survival) strategy in response to metabolic challenges such as glucose or amino acid deprivation, or starvation in general. Notably, the role of autophagy appears not to be restricted to nutrient recycling in order to maintain energy supply of cells and to adapt cell(organ) size to given physiological needs. For instance, using a newly established hepatoma cell line HCC-1.2, amino acid and glucose deprivation revealed a pro-apoptotic activity, additive to TGF- 1. The proapoptotic action of glucose deprivation was antagonized by 2-deoxyglucose, possibly by stabilizing the mitochondrial membrane involving the action of hexokinase II. These observations suggest that signaling cascades steering autophagy appear to provide links to those regulating cell number. Taken together, our data exemplify that a given cell may flexibly respond to type and degree of (micro)environmental changes or cell death stimuli; a cell’s response may shift gradually from the elimination of damaged proteins by autophagy and the recovery to autophagic or apoptotic pathways of cell death, the failure of which eventually may result in necrosis

MEG Upgrade Proposal

We propose the continuation of the MEG experiment to search for the charged lepton flavour violating decay (cLFV) \mu \to e \gamma, based on an upgrade of the experiment, which aims for a sensitivity enhancement of one order of magnitude compared to the final MEG result, down to the $6 \times 10^{-14}$ level. The key features of this new MEG upgrade are an increased rate capability of all detectors to enable running at the intensity frontier and improved energy, angular and timing resolutions, for both the positron and photon arms of the detector. On the positron-side a new low-mass, single volume, high granularity tracker is envisaged, in combination with a new highly segmented, fast timing counter array, to track positron from a thinner stopping target. The photon-arm, with the largest liquid xenon (LXe) detector in the world, totalling 900 l, will also be improved by increasing the granularity at the incident face, by replacing the current photomultiplier tubes (PMTs) with a larger number of smaller photosensors and optimizing the photosensor layout also on the lateral faces. A new DAQ scheme involving the implementation of a new combined readout board capable of integrating the diverse functions of digitization, trigger capability and splitter functionality into one condensed unit, is also under development. We describe here the status of the MEG experiment, the scientific merits of the upgrade and the experimental methods we plan to use.Comment: A. M. Baldini and T. Mori Spokespersons. Research proposal submitted to the Paul Scherrer Institute Research Committee for Particle Physics at the Ring Cyclotron. 131 Page

Measurement of the radiative decay of polarized muons in the MEG experiment

We studied the radiative muon decay $\mu^+ \to e^+\nu\bar{\nu}\gamma$ by using for the first time an almost fully polarized muon source. We identified a large sample (~13000) of these decays in a total sample of 1.8x10^14 positive muon decays collected in the MEG experiment in the years 2009--2010 and measured the branching ratio B($\mu^+ \to e^+\nu\bar{\nu}\gamma$) = (6.03+-0.14(stat.)+-0.53(sys.))x10^-8 for E_e > 45 MeV and E_{\gamma} > 40 MeV, consistent with the Standard Model prediction. The precise measurement of this decay mode provides a basic tool for the timing calibration, a normalization channel, and a strong quality check of the complete MEG experiment in the search for $\mu^+ \to e^+\gamma$ process.Comment: 8 pages, 7 figures. Added an introduction to NLO calculation which was recently calculated. Published versio

New constraint on the existence of the mu+-> e+ gamma decay

The analysis of a combined data set, totaling 3.6 \times 10^14 stopped muons on target, in the search for the lepton flavour violating decay mu^+ -> e^+ gamma is presented. The data collected by the MEG experiment at the Paul Scherrer Institut show no excess of events compared to background expectations and yield a new upper limit on the branching ratio of this decay of 5.7 \times 10^-13 (90% confidence level). This represents a four times more stringent limit than the previous world best limit set by MEG.Comment: 5 pages, 3 figures, a version accepted in Phys. Rev. Let

The MEG detector for μ+→e+γ{\mu}+\to e+{\gamma} decay search

The MEG (Mu to Electron Gamma) experiment has been running at the Paul Scherrer Institut (PSI), Switzerland since 2008 to search for the decay \meg\ by using one of the most intense continuous $\mu^+$ beams in the world. This paper presents the MEG components: the positron spectrometer, including a thin target, a superconducting magnet, a set of drift chambers for measuring the muon decay vertex and the positron momentum, a timing counter for measuring the positron time, and a liquid xenon detector for measuring the photon energy, position and time. The trigger system, the read-out electronics and the data acquisition system are also presented in detail. The paper is completed with a description of the equipment and techniques developed for the calibration in time and energy and the simulation of the whole apparatus.Comment: 59 pages, 90 figure

Measurement of ISR-FSR interference in the processes e+ e- --> mu+ mu- gamma and e+ e- --> pi+ pi- gamma

Charge asymmetry in processes e+ e- --> mu+ mu- gamma and e+ e- --> pi+ pi- gamma is measured using 232 fb-1 of data collected with the BABAR detector at center-of-mass energies near 10.58 GeV. An observable is introduced and shown to be very robust against detector asymmetries while keeping a large sensitivity to the physical charge asymmetry that results from the interference between initial and final state radiation. The asymmetry is determined as afunction of the invariant mass of the final-state tracks from production threshold to a few GeV/c2. It is compared to the expectation from QED for e+ e- --> mu+ mu- gamma and from theoretical models for e+ e- --> pi+ pi- gamma. A clear interference pattern is observed in e+ e- --> pi+ pi- gamma, particularly in the vicinity of the f_2(1270) resonance. The inferred rate of lowest order FSR production is consistent with the QED expectation for e+ e- --> mu+ mu- gamma, and is negligibly small for e+ e- --> pi+ pi- gamma.Comment: 32 pages,29 figures, to be submitted to Phys. Rev.

A Study of Time-Dependent CP-Violating Asymmetries and Flavor Oscillations in Neutral B Decays at the Upsilon(4S)

We present a measurement of time-dependent CP-violating asymmetries in neutral B meson decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at the Stanford Linear Accelerator Center. The data sample consists of 29.7 ${\rm fb}^{-1}$ recorded at the $\Upsilon(4S)$ resonance and 3.9 ${\rm fb}^{-1}$ off-resonance. One of the neutral B mesons, which are produced in pairs at the $\Upsilon(4S)$, is fully reconstructed in the CP decay modes $J/\psi K^0_S$, $\psi(2S) K^0_S$, $\chi_{c1} K^0_S$, $J/\psi K^{*0}$ ($K^{*0}\to K^0_S\pi^0$) and $J/\psi K^0_L$, or in flavor-eigenstate modes involving $D^{(*)}\pi/\rho/a_1$ and $J/\psi K^{*0}$ ($K^{*0}\to K^+\pi^-$). The flavor of the other neutral B meson is tagged at the time of its decay, mainly with the charge of identified leptons and kaons. The proper time elapsed between the decays is determined by measuring the distance between the decay vertices. A maximum-likelihood fit to this flavor eigenstate sample finds $\Delta m_d = 0.516\pm 0.016 {\rm (stat)} \pm 0.010 {\rm (syst)} {\rm ps}^{-1}$. The value of the asymmetry amplitude $\sin2\beta$ is determined from a simultaneous maximum-likelihood fit to the time-difference distribution of the flavor-eigenstate sample and about 642 tagged $B^0$ decays in the CP-eigenstate modes. We find $\sin2\beta=0.59\pm 0.14 {\rm (stat)} \pm 0.05 {\rm (syst)}$, demonstrating that CP violation exists in the neutral B meson system. (abridged)Comment: 58 pages, 35 figures, submitted to Physical Review

Response to electrons and pions of the calorimeter for the CHORUS experiment

We built and tested on charged particle beams the high energy-resolution calorimeter for the CHORUS experiment, which searches for nu(mu)-nu(tau) oscillations in the CERN Wide Band Neutrino Beam. This calorimeter is longitudinally divided into three sectors: one electromagnetic and two hadronic. The first two upstream sectors are made of lead and plastic scintillating fibers in the volume ratio of 4/1, and they represent the first large scale application of this technique for combined electromagnetic and hadronic calorimetry. The third sector is made of a sandwich of lead plates and scintillator strips and complements the measurement of the hadronic energy flow. In this paper, we briefly describe the calorimeter design and we show results on its response to electrons and pions, obtained from tests performed at the CERN SPS and PS. An energy resolution of sigma(E)/E=(32.3+/-2.4)%/root E(GeV)+(1.4+/-0.7)% was achieved for pions, and sigma(E)/E=(13.8+/-0.9)%/root V(GeV)+(-0.2+/-0.4)% for electrons