DNA methylation-based prediction of response to immune checkpoint inhibition in metastatic melanoma

Background Therapies based on targeting immune checkpoints have revolutionized the treatment of metastatic melanoma in recent years. Still, biomarkers predicting long-term therapy responses are lacking. Methods A novel approach of reference-free deconvolution of large-scale DNA methylation data enabled us to develop a machine learning classifier based on CpG sites, specific for latent methylation components (LMC), that allowed for patient allocation to prognostic clusters. DNA methylation data were processed using reference-free analyses (MeDeCom) and reference-based computational tumor deconvolution (MethylCIBERSORT, LUMP). Results We provide evidence that DNA methylation signatures of tumor tissue from cutaneous metastases are predictive for therapy response to immune checkpoint inhibition in patients with stage IV metastatic melanoma. Conclusions These results demonstrate that LMC-based segregation of large-scale DNA methylation data is a promising tool for classifier development and treatment response estimation in cancer patients under targeted immunotherapy

Depletion of Trypanosome CTR9 Leads to Gene Expression Defects

The Paf complex of Opisthokonts and plants contains at least five subunits: Paf1, Cdc73, Rtf1, Ctr9, and Leo1. Mutations in, or loss of Paf complex subunits have been shown to cause defects in histone modification, mRNA polyadenylation, and transcription by RNA polymerase I and RNA polymerase II. We here investigated trypanosome CTR9, which is essential for trypanosome survival. The results of tandem affinity purification suggested that trypanosome CTR9 associates with homologues of Leo1 and Cdc73; genes encoding homologues of Rtf1 and Paf1 were not found. RNAi targeting CTR9 resulted in at least ten-fold decreases in 131 essential mRNAs: they included several that are required for gene expression and its control, such as those encoding subunits of RNA polymerases, exoribonucleases that target mRNA, RNA helicases and RNA-binding proteins. Simultaneously, some genes from regions subject to chromatin silencing were derepressed, possibly as a secondary effect of the loss of two proteins that are required for silencing, ISWI and NLP1

A Novel, Non-Apoptotic Role for Scythe/BAT3: A Functional Switch between the Pro- and Anti-Proliferative Roles of p21 during the Cell Cycle

BACKGROUND: Scythe/BAT3 is a member of the BAG protein family whose role in apoptosis has been extensively studied. However, since the developmental defects observed in Bat3-null mouse embryos cannot be explained solely by defects in apoptosis, we investigated whether BAT3 is also involved in cell-cycle progression. METHODS/PRINCIPAL FINDINGS: Using a stable-inducible Bat3-knockdown cellular system, we demonstrated that reduced BAT3 protein level causes a delay in both G1/S transition and G2/M progression. Concurrent with these changes in cell-cycle progression, we observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21, which is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Our findings indicate that in Bat3-knockdown cells, p21 continues to be synthesized during cell-cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent delay in cell-cycle progression. Finally, we showed that BAT3 co-localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression. CONCLUSION: Our study reveals a novel, non-apoptotic role for BAT3 in cell-cycle regulation. By maintaining a low p21 protein level during the G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 to S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation by cyclin A/Cdk2, an event required for G2/M progression. BAT3 modulates these pro- and anti-proliferative roles of p21 at least in part by regulating cyclin A abundance, as well as p21 translocation between the cytoplasm and the nucleus to ensure that it functions in the appropriate intracellular compartment during each phase of the cell cycle.Dissertatio

Performance of missing transverse momentum reconstruction with the ATLAS detector using proton–proton collisions at √s = 13 TeV

The performance of the missing transverse momentum (EmissT) reconstruction with the ATLAS detector is evaluated using data collected in proton–proton collisions at the LHC at a centre-of-mass energy of 13 TeV in 2015. To reconstruct EmissT, fully calibrated electrons, muons, photons, hadronically decaying τ -leptons, and jets reconstructed from calorimeter energy deposits and charged-particle tracks are used. These are combined with the soft hadronic activity measured by reconstructed charged-particle tracks not associated with the hard objects. Possible double counting of contributions from reconstructed charged-particle tracks from the inner detector, energy deposits in the calorimeter, and reconstructed muons from the muon spectrometer is avoided by applying a signal ambiguity resolution procedure which rejects already used signals when combining the various EmissT contributions. The individual terms as well as the overall reconstructed EmissT are evaluated with various performance metrics for scale (linearity), resolution, and sensitivity to the data-taking conditions. The method developed to determine the systematic uncertainties of the EmissT scale and resolution is discussed. Results are shown based on the full 2015 data sample corresponding to an integrated luminosity of 3.2 fb−1

Search for heavy neutral Higgs bosons produced in association with b-quarks and decaying into b-quarks at root s=13 TeV with the ATLAS detector

A search for heavy neutral Higgs bosons produced in association with one or two b -quarks and decaying to b -quark pairs is presented using 27.8  fb − 1 of √ s = 13  TeV proton-proton collision data recorded by the ATLAS detector at the Large Hadron Collider during 2015 and 2016. No evidence of a signal is found. Upper limits on the heavy neutral Higgs boson production cross section times its branching ratio to b ¯ b are set, ranging from 4.0 to 0.6 pb at 95% confidence level over a Higgs boson mass range of 450 to 1400 GeV. Results are interpreted within the two-Higgs-doublet model and the minimal supersymmetric Standard Model

Dijet azimuthal correlations and conditional yields in pp and p plus Pb collisions at √{S}^NN=5.02 TeV with the ATLAS detector

This paper presents a measurement of forward-forward and forward-central dijet azimuthal angular correlations and conditional yields in proton-proton (pp) and proton-lead (p + Pb) collisions as a probe of the nuclear gluon density in regions where the fraction of the average momentum per nucleon carried by the parton entering the hard scattering is low. In these regions, gluon saturation can modify the rapidly increasing parton distribution function of the gluon. The analysis utilizes 25 pb^{-1} of pp data and 360 mp^{-1} of p + Pb data, both at {S}^NN=5.02 TeV, collected in 2015 and 2016, respectively, with the ATLAS detector at the Large Hadron Collider. The measurement is performed in the center-of-mass frame of the nucleon-nucleon system in the rapidity range between -4.0 and 4.0 using the two highest transverse-momentum jets in each event, with the highest transverse-momentum jet restricted to the forward rapidity range. No significant broadening of azimuthal angular correlations is observed for forward-forward or forward-central dijets in p + Pb compared to pp collisions. For forward-forward jet pairs in the proton-going direction, the ratio of conditional yields in p + Pb collisions to those in pp collisions is suppressed by approximately 20%, with no significant dependence on the transverse momentum of the dijet system. No modification of conditional yields is observed for forward-central dijets

Study of the rare decays of B_{s}^{0} and B^{0} mesons into muon pairs using data collected during 2015 and 2016 with the ATLAS detector

A study of the decays B_{s}^{0} → μ⁺μ⁻ and B_{0} → μ⁺μ⁻ has been performed using 26.3 fb⁻¹ of 13 TeV LHC proton-proton collision data collected with the ATLAS detector in 2015 and 2016. Since the detector resolution in μ⁺μ⁻ invariant mass is comparable to the B_{s}^{0} - B^{0} mass difference, a single fit determines the signal yields for both decay modes. This results in a measurement of the branching fraction Β (B^{0} → μ⁺μ⁻) < 4.3 x 10⁻¹⁰ at 95% confidence level. The result is combined with the Run 1 ATLAS result, yielding Β (B_{s}^{0} → μ⁺μ⁻) = (2.8_{-0.7}^{+0.8}) x 10⁻⁹ and Β (B^{0} → μ⁺μ⁻) < 2.1 x 10⁻¹⁰ at 95% confidence level. The combined result is consistent with the Standard Model prediction within 2.4 standard deviations in the B (B^{0} → μ⁺μ⁻) - Β (B_{s}^{0} → μ⁺μ⁻) plane

Measurement of jet-substructure observables in top quark, W boson and light jet production in proton-proton collisions at √s=13 TeV with the ATLAS detector

A measurement of jet substructure observables is presented using data collected in 2016 by the ATLAS experiment at the LHC with proton-proton collisions at s√ = 13 TeV. Large-radius jets groomed with the trimming and soft-drop algorithms are studied. Dedicated event selections are used to study jets produced by light quarks or gluons, and hadronically decaying top quarks and W bosons. The observables measured are sensitive to substructure, and therefore are typically used for tagging large-radius jets from boosted massive particles. These include the energy correlation functions and the N-subjettiness variables. The number of subjets and the Les Houches angularity are also considered. The distributions of the substructure variables, corrected for detector effects, are compared to the predictions of various Monte Carlo event generators. They are also compared between the large-radius jets originating from light quarks or gluons, and hadronically decaying top quarks and W bosons

Measurement of the CP-violating phase ϕ<inf>s</inf> in Bs0→J/ψϕ decays in ATLAS at 13 TeV

A measurement of the Bs0→J/ψϕ decay parameters using 80.5fb-1 of integrated luminosity collected with the ATLAS detector from 13 Te proton–proton collisions at the LHC is presented. The measured parameters include the CP-violating phase ϕs, the width difference Δ Γ s between the Bs0 meson mass eigenstates and the average decay width Γ s. The values measured for the physical parameters are combined with those from 19.2fb-1 of 7 and 8 Te data, leading to the following: ϕs=-0.087±0.036(stat.)±0.021(syst.)radΔΓs=0.0657±0.0043(stat.)±0.0037(syst.)ps-1Γs=0.6703±0.0014(stat.)±0.0018(syst.)ps-1Results for ϕs and Δ Γ s are also presented as 68% confidence level contours in the ϕs–Δ Γ s plane. Furthermore the transversity amplitudes and corresponding strong phases are measured. ϕs and Δ Γ s measurements are in agreement with the Standard Model predictions