A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine

Continuous-distribution puddle model for conduction in trilayer graphene

An insulator-to-metal transition is observed in trilayer graphene based on the temperature dependence of the resistance under different applied gate voltages. At small gate voltages the resistance decreases with increasing temperature due to the increase in carrier concentration resulting from thermal excitation of electron-hole pairs. At large gate voltages excitation of electron-hole pairs is suppressed, and the resistance increases with increasing temperature because of the enhanced electron-phonon scattering. We find that the simple model with overlapping conduction and valence bands, each with quadratic dispersion relations, is unsatisfactory. Instead, we conclude that impurities in the substrate that create local puddles of higher electron or hole densities are responsible for the residual conductivity at low temperatures. The best fit is obtained using a continuous distribution of puddles. From the fit the average of the electron and hole effective masses can be determined.Comment: 18 pages, 5 figure

Four dimensional "old minimal" N=2 supersymmetrization of R^4

We write in superspace the lagrangian containing the fourth power of the Weyl tensor in the "old minimal" d=4, N=2 supergravity, without local SO(2) symmetry. Using gauge completion, we analyze the lagrangian in components. We find out that the auxiliary fields which belong to the Weyl and compensating vector multiplets have derivative terms and therefore cannot be eliminated on-shell. Only the auxiliary fields which belong to the compensating nonlinear multiplet do not get derivatives and could still be eliminated; we check that this is possible in the leading terms of the lagrangian. We compare this result to the similar one of "old minimal" N=1 supergravity and we comment on possible generalizations to other versions of N=1,2 supergravity.Comment: 31 pages, no figures. Minor corrections. Details of the full calculation included as an appendix. Reference adde

Central Pb+Pb Collisions at 158 A GeV/c Studied by Pion-Pion Interferometry

Two-particle correlations have been measured for identified negative pions from central 158 AGeV Pb+Pb collisions and fitted radii of about 7 fm in all dimensions have been obtained. A multi-dimensional study of the radii as a function of kT is presented, including a full correction for the resolution effects of the apparatus. The cross term Rout-long of the standard fit in the Longitudinally CoMoving System (LCMS) and the vl parameter of the generalised Yano-Koonin fit are compatible with 0, suggesting that the source undergoes a boost invariant expansion. The shapes of the correlation functions in Qinv and Qspace have been analyzed in detail. They are not Gaussian but better represented by exponentials. As a consequence, fitting Gaussians to these correlation functions may produce different radii depending on the acceptance of the experimental setup used for the measurement.Comment: 13 pages including 10 figure

Search for Disoriented Chiral Condensates in 158 AGeV Pb+Pb Collisions

The restoration of chiral symmetry and its subsequent breaking through a phase transition has been predicted to create regions of Disoriented Chiral Condensates (DCC). This phenomenon has been predicted to cause anomalous fluctuations in the relative production of charged and neutral pions in high-energy hadronic and nuclear collisions. The WA98 experiment has been used to measure charged and photon multiplicities in the central region of 158 AGeV Pb+Pb collisions at the CERN SPS. In a sample of 212646 events, no clear DCC signal can be distinguished. Using a simple DCC model, we have set a 90% C.L. upper limit on the maximum DCC production allowed by the data.Comment: 20 Pages, LaTeX, uses elsart.cls, 8 eps figures included, submitted to Physics Letters

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters