Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis

Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.</div

ATLAS

% ATLAS \\ \\ ATLAS is a general-purpose experiment for recording proton-proton collisions at LHC. The ATLAS collaboration consists of 144 participating institutions (June 1998) with more than 1750~physicists and engineers (700 from non-Member States). The detector design has been optimized to cover the largest possible range of LHC physics: searches for Higgs bosons and alternative schemes for the spontaneous symmetry-breaking mechanism; searches for supersymmetric particles, new gauge bosons, leptoquarks, and quark and lepton compositeness indicating extensions to the Standard Model and new physics beyond it; studies of the origin of CP violation via high-precision measurements of CP-violating B-decays; high-precision measurements of the third quark family such as the top-quark mass and decay properties, rare decays of B-hadrons, spectroscopy of rare B-hadrons, and $B ^0 _{s}$-mixing. \\ \\The ATLAS dectector, shown in the Figure includes an inner tracking detector inside a 2~T~solenoid providing an axial field, electromagnetic and hadronic calorimeters outside the solenoid and in the forward regions, and barrel and end-cap air-core-toroid muon spectrometers. The precision measurements for photons, electrons, muons and hadrons, and identification of photons, electrons, muons, $\tau$-leptons and b-quark jets are performed over $| \eta |$ < 2.5. The complete hadronic energy measurement extends over $| \eta |$ < 4.7. \\ \\The inner tracking detector consists of straw drift tubes interleaved with transition radiators for robust pattern recognition and electron identification, and several layers of semiconductor strip and pixel detectors providing high-precision space points. \\ \\The e.m. calorimeter is a lead-Liquid Argon sampling calorimeter with an integrated preshower detector and a presampler layer immediately behind the cryostat wall for energy recovery. The end-cap hadronic calorimeters also use Liquid Argon technology, with copper absorber plates. The end-cap cryostats house the e.m., hadronic and forward calorimeters (tungsten-Liquid Argon sampling). The barrel hadronic calorimeter is an iron-scintillating tile sampling calorimeter with longitudinal tile geometry. \\ \\Air-core toroids are used for the muon spectrometer. Eight superconducting coils with warm voussoirs are used in the barrel region complemented with superconducting end-cap toroids in the forward regions. The toroids will be instrumented with Monitored Drift Tubes (Cathode Strip Chambers at large rapidity where there are high radiation levels). The muon trigger and second coordinate measurement for muon tracks are provide