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As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.
We present the first measurements of charge-dependent correlations on angular difference variables η1 − η2 (pseudorapidity) and φ1 − φ2 (azimuth) for primary charged hadrons with transverse momentum 0.15 <= pt <= 2 GeV/c and |η| <= 1.3 from Au–Au collisions at √sNN = 130 GeV. We observe correlation structures not predicted by theory but consistent with evolution of hadron emission geometry with increasing centrality from one-dimensional fragmentation of color strings along the beam direction to an at least two-dimensional hadronization geometry along the beam and azimuth directions of a hadron-opaque bulk medium.
Results on the production of 4He and Image 1 nuclei in Pb–Pb collisions at √sNN=2.76TeV in the rapidity range |y|<1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0–10% central events are found to be dN/dyHe4=(0.8±0.4(stat)±0.3(syst))×10−6 and Image 2, respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (Tchem=156MeV) as for light hadrons. The measured ratio of Image 3 is 1.4±0.8(stat)±0.5(syst).
Transverse momentum (pT ) spectra of charged particles at mid-pseudorapidity in Xe–Xe collisions at √sNN=5.44TeV measured with the ALICE apparatus at the Large Hadron Collider are reported. The kinematic range 0.15<pT<50GeV/c and |η|<0.8 is covered. Results are presented in nine classes of collision centrality in the 0–80% range. For comparison, a pp reference at the collision energy of √s=5.44 TeV is obtained by interpolating between existing pp measurements at √s=5.02 and 7 TeV. The nuclear modification factors in central Xe–Xe collisions and Pb–Pb collisions at a similar center-of-mass energy of √sNN=5.02 TeV, and in addition at 2.76 TeV, at analogous ranges of charged particle multiplicity density 〈dNch/dη〉 show a remarkable similarity at pT>10 GeV/c. The centrality dependence of the ratio of the average transverse momentum 〈pT〉 in Xe–Xe collisions over Pb–Pb collision at √s=5.02 TeV is compared to hydrodynamical model calculations.
The first measurement of ϕ-meson production in p-Pb collisions at a nucleon-nucleon centre-of-mass energy sNN−−−√ = 5.02 TeV has been performed with the ALICE apparatus at the LHC. The ϕ-mesons have been identified in the dimuon decay channel in the transverse momentum (pT) range 1<pT<7 GeV/c, both in the p-going (2.03<y<3.53) and the Pb-going (−4.46<y<−2.96) directions, where y stands for the rapidity in the nucleon-nucleon centre-of-mass. Differential cross sections as a function of transverse momentum and rapidity are presented. The forward-backward asymmetry for ϕ-meson production is measured for 2.96<|y|<3.53, resulting in a factor ∼0.5 with no significant pT dependence within the uncertainties. The pT dependence of the ϕ nuclear modification factor RpPb exhibits an enhancement up to a factor 1.6 at pT = 3-4 GeV/c in the Pb-going direction. The pT dependence of the ϕ-meson cross section in pp collisions at s√ = 2.76 TeV, which is used to determine a reference for the p-Pb results, is also presented here for 1<pT<5 GeV/c and 2.5<y<4.
We report on results obtained with the Event Shape Engineering technique applied to Pb-Pb collisions at sNN−−−√=2.76 TeV. By selecting events in the same centrality interval, but with very different average flow, different initial state conditions can be studied. We find the effect of the event-shape selection on the elliptic flow coefficient v2 to be almost independent of transverse momentum pT, as expected if this effect is due to fluctuations in the initial geometry of the system. Charged hadron, pion, kaon, and proton transverse momentum distributions are found to be harder in events with higher-than-average elliptic flow, indicating an interplay between radial and elliptic flow.
The correlations between different moments of two flow amplitudes, extracted with the recently developed asymmetric cumulants, are measured in Pb-Pb collisions at √sNN = 5.02 TeV recorded by the ALICE detector at the CERN Large Hadron Collider. The magnitudes of the measured observables show a dependence on the different moments as well as on the collision centrality, indicating the presence of nonlinear response in all even moments up to the eighth. Furthermore, the higher-order asymmetric cumulants show different signatures than the symmetric and lower-order asymmetric cumulants. Comparisons with state-of-the-art event generators using two different parametrizations obtained from Bayesian optimization show differences between data and simulations in many of the studied observables, indicating a need for further tuning of the models behind those event generators. These results provide new and independent constraints on the initial conditions and transport properties of the system created in heavy-ion collisions.
First measurements of hadron(h)−Λ azimuthal angular correlations in p−Pb collisions at sNN−−−√ = 5.02 TeV using the ALICE detector at the LHC are presented. These correlations are used to separate the production of associated Λ baryons into three different kinematic regions, namely those produced in the direction of the trigger particle (near-side), those produced in the opposite direction (away-side), and those whose production is uncorrelated with the jet-axis (underlying event). The per-trigger associated Λ yields in these regions are extracted, along with the near- and away-side azimuthal peak widths, and the results are studied as a function of associated particle pT and event multiplicity. Comparisons with the DPMJET event generator and previous measurements of the ϕ(1020) meson are also made. The final results indicate that strangeness production in the highest multiplicity p−Pb collisions is enhanced relative to low multiplicity collisions in the jet-like regions, as well as the underlying event. The production of Λ relative to charged hadrons is also enhanced in the underlying event when compared to the jet-like regions. Additionally, the results hint that strange quark production in the away-side of the jet is modified by soft interactions with the underlying event.
Measurements of (anti)deuteron and (anti)3He production in the rapidity range |y|< 0.5 as a function of the transverse momentum and event multiplicity in Xe−Xe collisions at a center-of-mass energy per nucleon−nucleon pair of sNN−−−√ = 5.44 TeV are presented. The coalescence parameters B2 and B3 are measured as a function of the transverse momentum per nucleon. The ratios between (anti)deuteron and (anti)3He yields and those of (anti)protons and pions are reported as a function of the mean charged-particle multiplicity density, and compared with two implementations of the statistical hadronization model (SHM) and with coalescence predictions. The elliptic flow of (anti)deuterons is measured for the first time in Xe−Xe collisions and shows features similar to those already observed in Pb−Pb collisions, i.e., the mass ordering at low transverse momentum and the meson−baryon grouping at intermediate transverse momentum. The production of nuclei is particularly sensitive to the chemical freeze-out temperature of the system created in the collision, which is extracted from a grand-canonical-ensemble-based thermal fit, performed for the first time including light nuclei along with light-flavor hadrons in Xe−Xe collisions. The extracted chemical freeze-out temperature Tchem = (154.2 ± 1.1) MeV in Xe−Xe collisions is similar to that observed in Pb−Pb collisions and close to the crossover temperature predicted by lattice QCD calculations.