Simultaneous perturbation of the MAPK and the PI3K/mTOR pathways does not lead to increased radiosensitization

Background The mitogen-activated protein kinases (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways are intertwined on various levels and simultaneous inhibition reduces tumorsize and prolonges survival synergistically. Furthermore, inhibiting these pathways radiosensitized cancer cells in various studies. To assess, if phenotypic changes after perturbations of this signaling network depend on the genetic background, we integrated a time series of the signaling data with phenotypic data after simultaneous MAPK/ERK kinase (MEK) and PI3K/mTOR inhibition and ionizing radiation (IR). Methods The MEK inhibitor AZD6244 and the dual PI3K/mTOR inhibitor NVP-BEZ235 were tested in glioblastoma and lung carcinoma cells, which differ in their mutational status in the MAPK and the PI3K/mTOR pathways. Effects of AZD6244 and NVP-BEZ235 on the proliferation were assessed using an ATP assay. Drug treatment and IR effects on the signaling network were analyzed in a time-dependent manner along with measurements of phenotypic changes in the colony forming ability, apoptosis, autophagy or cell cycle. Results Both inhibitors reduced the tumor cell proliferation in a dose-dependent manner, with NVP-BEZ235 revealing the higher anti-proliferative potential. Our Western blot data indicated that AZD6244 and NVP-BEZ235 perturbed the MAPK and PI3K/mTOR signaling cascades, respectively. Additionally, we confirmed crosstalks and feedback loops in the pathways. As shown by colony forming assay, the AZD6244 moderately radiosensitized cancer cells, whereas NVP-BEZ235 caused a stronger radiosensitization. Combining both drugs did not enhance the NVP-BEZ235-mediated radiosensitization. Both inhibitors caused a cell cycle arrest in the G1-phase, whereas concomitant IR and treatment with the inhibitors resulted in cell line- and drug-specific cell cycle alterations. Furthermore, combining both inhibitors synergistically enhanced a G1-phase arrest in sham-irradiated glioblastoma cells and induced apoptosis and autophagy in both cell lines. Conclusion Perturbations of the MEK and the PI3K pathway radiosensitized tumor cells of different origins and the combination of AZD6244 and NVP-BEZ235 yielded cytostatic effects in several tumor entities. However, this is the first study assessing, if the combination of both drugs also results in synergistic effects in terms of radiosensitivity. Our study demonstrates that simultaneous treatment with both pathway inhibitors does not lead to synergistic radiosensitization but causes cell line-specific effects

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Evidence for the Higgs-boson Yukawa coupling to tau leptons with the ATLAS detector

Results of a search for H → τ τ decays are presented, based on the full set of proton-proton collision data recorded by the ATLAS experiment at the LHC during 2011 and 2012. The data correspond to integrated luminosities of 4.5 fb−1 and 20.3 fb−1 at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV respectively. All combinations of leptonic (τ → `νν¯ with ` = e, µ) and hadronic (τ → hadrons ν) tau decays are considered. An excess of events over the expected background from other Standard Model processes is found with an observed (expected) significance of 4.5 (3.4) standard deviations. This excess provides evidence for the direct coupling of the recently discovered Higgs boson to fermions. The measured signal strength, normalised to the Standard Model expectation, of µ = 1.43 +0.43 −0.37 is consistent with the predicted Yukawa coupling strength in the Standard Model

Low-energy Calibration of XENON1T with an Internal 37^{37}Ar Source

A low-energy electronic recoil calibration of XENON1T, a dual-phase xenontime projection chamber, with an internal $^{37}$Ar source was performed. Thiscalibration source features a 35-day half-life and provides two mono-energeticlines at 2.82 keV and 0.27 keV. The photon yield and electron yield at 2.82 keVare measured to be (32.3$\pm$0.3) photons/keV and (40.6$\pm$0.5) electrons/keV,respectively, in agreement with other measurements and with NEST predictions.The electron yield at 0.27 keV is also measured and it is(68.0$^{+6.3}_{-3.7}$) electrons/keV. The $^{37}$Ar calibration confirms thatthe detector is well-understood in the energy region close to the detectionthreshold, with the 2.82 keV line reconstructed at (2.83$\pm$0.02) keV, whichfurther validates the model used to interpret the low-energy electronic recoilexcess previously reported by XENON1T. The ability to efficiently remove argonwith cryogenic distillation after the calibration proves that $^{37}$Ar can beconsidered as a regular calibration source for multi-tonne xenon detectors.<br

Low-energy calibration of XENON1T with an internal 37^{{\textbf {37}}}Ar source

A low-energy electronic recoil calibration of XENON1T, a dual-phase xenon time projection chamber, with an internal 37Ar source was performed. This calibration source features a 35-day half-life and provides two mono-energetic lines at 2.82 keV and 0.27 keV. The photon yield and electron yield at 2.82 keV are measured to be (32.3±0.3) photons/keV and (40.6±0.5) electrons/keV, respectively, in agreement with other measurements and with NEST predictions. The electron yield at 0.27 keV is also measured and it is (68.0+6.3−3.7) electrons/keV. The 37Ar calibration confirms that the detector is well-understood in the energy region close to the detection threshold, with the 2.82 keV line reconstructed at (2.83±0.02) keV, which further validates the model used to interpret the low-energy electronic recoil excess previously reported by XENON1T. The ability to efficiently remove argon with cryogenic distillation after the calibration proves that 37Ar can be considered as a regular calibration source for multi-tonne xenon detectors

Low-energy Calibration of XENON1T with an Internal 37^{37}Ar Source

A low-energy electronic recoil calibration of XENON1T, a dual-phase xenon time projection chamber, with an internal $^{37}$Ar source was performed. This calibration source features a 35-day half-life and provides two mono-energetic lines at 2.82 keV and 0.27 keV. The photon yield and electron yield at 2.82 keV are measured to be (32.3$\pm$0.3) photons/keV and (40.6$\pm$0.5) electrons/keV, respectively, in agreement with other measurements and with NEST predictions. The electron yield at 0.27 keV is also measured and it is (68.0$^{+6.3}_{-3.7}$) electrons/keV. The $^{37}$Ar calibration confirms that the detector is well-understood in the energy region close to the detection threshold, with the 2.82 keV line reconstructed at (2.83$\pm$0.02) keV, which further validates the model used to interpret the low-energy electronic recoil excess previously reported by XENON1T. The ability to efficiently remove argon with cryogenic distillation after the calibration proves that $^{37}$Ar can be considered as a regular calibration source for multi-tonne xenon detectors

Searching for Heavy Dark Matter near the Planck Mass with XENON1T

Multiple viable theoretical models predict heavy dark matter particles with a mass close to the Planck mass, a range relatively unexplored by current experimental measurements. We use 219.4 days of data collected with the XENON1T experiment to conduct a blind search for signals from multiply interacting massive particles (MIMPs). Their unique track signature allows a targeted analysis with only 0.05 expected background events from muons. Following unblinding, we observe no signal candidate events. This Letter places strong constraints on spin-independent interactions of dark matter particles with a mass between 1×10$^{12}$ and 2×10$^{17}$  GeV/c$^2$. In addition, we present the first exclusion limits on spin-dependent MIMP-neutron and MIMP-proton cross sections for dark matter particles with masses close to the Planck scale

Detector signal characterization with a Bayesian network in XENONnT

We developed a detector signal characterization model based on a Bayesian network trained on the waveform attributes generated by a dual-phase xenon time projection chamber. By performing inference on the model, we produced a quantitative metric of signal characterization and demonstrate that this metric can be used to determine whether a detector signal is sourced from a scintillation or an ionization process. We describe the method and its performance on electronic-recoil (ER) data taken during the first science run of the XENONnT dark matter experiment. We demonstrate the first use of a Bayesian network in a waveform-based analysis of detector signals. This method resulted in a 3% increase in ER event-selection efficiency with a simultaneously effective rejection of events outside of the region of interest. The findings of this analysis are consistent with the previous analysis from XENONnT, namely a background-only fit of the ER data

Cosmogenic background simulations for neutrinoless double beta decay with the DARWIN observatory at various underground sites

Xenon dual-phase time projections chambers (TPCs) have proven to be a successful technology in studying physical phenomena that require low-background conditions. With 40t of liquid xenon (LXe) in the TPC baseline design, DARWIN will have a high sensitivity for the detection of particle dark matter, neutrinoless double beta decay (0 ν β β), and axion-like particles (ALPs). Although cosmic muons are a source of background that cannot be entirely eliminated, they may be greatly diminished by placing the detector deep underground. In this study, we used Monte Carlo simulations to model the cosmogenic background expected for the DARWIN observatory at four underground laboratories: Laboratori Nazionali del Gran Sasso (LNGS), Sanford Underground Research Facility (SURF), Laboratoire Souterrain de Modane (LSM) and SNOLAB. We present here the results of simulations performed to determine the production rate of 137 Xe, the most crucial isotope in the search for 0 ν β β of 136 Xe. Additionally, we explore the contribution that other muon-induced spallation products, such as other unstable xenon isotopes and tritium, may have on the cosmogenic background