lba22negative hyper selection of ras wild type wt metastatic colorectal cancer mcrc patients randomized to first line folfox plus panitumumab pan followed by maintenance therapy with either 5fu lv plus pan or single agent pan translational analyses of the valentino study

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Maintenance Therapy with Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients with RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial

Key PointsQuestionIs maintenance therapy with single-agent panitumumab noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment with panitumumab plus FOLFOX-4 in patients with previously untreated RAS wild-type metastatic colorectal cancer? FindingsIn this open-label, phase 2 randomized clinical trial of 229 patients, maintenance therapy with single-agent panitumumab alone was inferior to panitumumab plus fluorouracil-leucovorin in terms of 10-month progression-free survival (49.0% vs 59.9%). MeaningThe continuation of single-agent anti-epidermal growth factor receptor treatment in the maintenance setting will likely achieve inferior progression-free survival compared with the continuation of chemotherapy plus an anti-epidermal growth factor receptor agent in a phase 3 confirmation trial. This open-label, phase 2 randomized clinical trial assesses whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus combined fluorouracil and leucovorin calcium among patients with RAS wild-type metastatic colorectal cancer. ImportanceFew studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. ObjectiveTo determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. Design, Setting, and ParticipantsThis open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m(2) at day 1, leucovorin calcium, 200 mg/m(2), and fluorouracil, 400-mg/m(2) bolus, followed by 600-mg/m(2) continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. InterventionsPatients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. Main Outcomes and MeasuresThe prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. ResultsOverall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n=117) or arm B (n=112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR,1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR,1.51; 95% CI, 1.11-2.07; P=.01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. Conclusions and RelevanceIn patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. Trial RegistrationClinicalTrials.gov identifier: NCT0247604

Measurement of the nuclear modification factor of b-jets in 5.02 TeV Pb+Pb collisions with the ATLAS detector

This paper presents a measurement of b-jet production in Pb+Pb and pp collisions at sqrt(s_NN)=5.02 TeV with the ATLAS detector at the LHC. The measurement uses 260 pb^{−1} of pp collisions collected in 2017 and 1.4 nb^{−1} of Pb+Pb collisions collected in 2018. In both collision systems, jets are reconstructed via the anti-kt algorithm. The b-jets are identified from a sample of jets containing muons from the semileptonic decay of b-quarks using template fits of the muon momentum relative to the jet axis. In pp collisions, b-jets are reconstructed for radius parameters R=0.2 and R=0.4, and only R=0.2 jets are used in Pb+Pb collisions. For comparison, inclusive R=0.2 jets are also measured using 1.7 nb^{−1} of Pb+Pb collisions collected in 2018 and the same pp collision data as the b-jet measurement. The nuclear modification factor, R_{AA}, is calculated for both b-jets and inclusive jets with R=0.2 over the transverse momentum range of 80-290 GeV. The nuclear modification factor for b-jets decreases from peripheral to central collisions. The ratio of the b-jet R_{AA} to inclusive jet R_{AA} is also presented and suggests that the R_{AA} for b-jets is larger than that for inclusive jets in central Pb+Pb collisions. The measurements are compared with theoretical calculations and suggest a role for mass and colour-charge effects in partonic energy loss in heavy-ion collisions

Correlations between flow and transverse momentum in Xe+Xe and Pb+Pb collisions at the LHC with the ATLAS detector: A probe of the heavy-ion initial state and nuclear deformation

The correlations between flow harmonics v_n for n=2, 3, and 4 and mean transverse momentum [pT] in 129Xe+129Xe and 208Pb+208Pb collisions at sqrt(s)=5.44 and 5.02 TeV, respectively, are measured using charged particles with the ATLAS detector. The correlations are potentially sensitive to the shape and size of the initial geometry, nuclear deformation, and initial momentum anisotropy. The effects from nonflow and centrality fluctuations are minimized, respectively, via a subevent cumulant method and an event-activity selection based on particle production at very forward rapidity. The v_n−[pT] correlations show strong dependencies on centrality, harmonic number n, pT, and pseudorapidity range. Current models qualitatively describe the overall centrality- and system-dependent trends but fail to quantitatively reproduce all features of the data. In central collisions, where models generally show good agreement, the v_2−[pT] correlations are sensitive to the triaxiality of the quadruple deformation. Comparison of the model with the Pb+Pb and Xe+Xe data confirms that the 129Xe nucleus is a highly deformed triaxial ellipsoid that has neither a prolate nor oblate shape. This provides strong evidence for a triaxial deformation of the 129Xe nucleus from high-energy heavy-ion collisions

Measurement of muon pairs produced via γγ scattering in nonultraperipheral Pb+Pb collisions at sqrt(s_NN)=5.02 TeV with the ATLAS detector

Results of a measurement of dimuon photoproduction in nonultraperipheral Pb+Pb collisions at sqrt(s_NN)=5.02 TeV are presented. The measurement uses ATLAS data from the 2015 and 2018 Pb+Pb data-taking periods at the LHC with an integrated luminosity of 1.94 nb^{−1}. The γγ→μ+μ− pairs are identified via selections on pair momentum asymmetry and acoplanarity. Differential cross sections for dimuon production are measured in different centrality, average muon momentum, and pair rapidity intervals as functions of acoplanarity and k⊥, the transverse momentum kick of one muon relative to the other. Measurements are also made as a function of the rapidity separation of the muons and the angle of the muon pair relative to the second-order event plane to test whether magnetic fields generated in the quark-gluon plasma affect the measured muons. A prior observation of a centrality-dependent broadening of the acoplanarity distribution is confirmed. Furthermore, the improved precision of the measurement reveals a depletion in the number of pairs having small acoplanarity or k⊥ values in more central collisions. The acoplanarity distributions in a given centrality interval are observed to vary with the mean pT of the muons in the pair, but the k⊥ distributions do not. Comparisons with recent theoretical predictions are made. The predicted trends associated with effects of magnetic fields on the dimuons are not observed

Production of Υ(nS) mesons in Pb+Pb and pp collisions at 5.02 TeV

A measurement of the production of vector bottomonium states, Υ(1S), Y(2S), and Υ(3S), in Pb+Pb and pp collisions at a center-of-mass energy per nucleon pair of 5.02 TeV is presented. The data correspond to integrated luminosities of 1.38 nb^{−1} of Pb+Pb data collected in 2018, 0.44 nb^{−1} of Pb+Pb data collected in 2015, and 0.26 fb^{−1} of pp data collected in 2017 by the ATLAS detector at the Large Hadron Collider. The measurements are performed in the dimuon decay channel for transverse momentum p^{μμ}_T<30 GeV, absolute rapidity |y^{μμ}|<1.5, and Pb+Pb event centrality 0–80%. The production rates of the three bottomonium states in Pb+Pb collisions are compared with those in pp collisions to extract the nuclear modification factors as functions of event centrality, p^{μμ}_T, and |y^{μμ}|. In addition, the suppression of the excited states relative to the ground state is studied. The results are compared with theoretical model calculations

Measurements of the suppression and correlations of dijets in Pb+Pb collisions at sqrt(s_NN)=5.02 TeV

Studies of the correlations of the two highest transverse momentum (leading) jets in individual Pb+Pb collision events can provide information about the mechanism of jet quenching by the hot and dense matter created in such collisions. In Pb+Pb and pp collisions at sqrt(s_NN)=5.02 TeV, measurements of the leading dijet transverse momentum (pT) correlations are presented. Additionally, measurements in Pb+Pb collisions of the dijet pair nuclear modification factors projected along leading and subleading jet pT are made. The measurements are performed using the ATLAS detector at the LHC with 260 pb^{−1} of pp data collected in 2017 and 2.2 nb^{−1} of Pb+Pb data collected in 2015 and 2018. An unfolding procedure is applied to the two-dimensional leading and subleading jet pT distributions to account for experimental effects in the measurement of both jets. Results are provided for dijets with leading jet pT greater than 100 GeV. Measurements of the dijet-yield-normalized xJ distributions in Pb+Pb collisions show an increased fraction of imbalanced jets compared to pp collisions; these measurements are in agreement with previous measurements of the same quantity at 2.76 TeV in the overlapping kinematic range. Measurements of the absolutely normalized dijet rate in Pb+Pb and pp collisions are also presented, and show that balanced dijets are significantly more suppressed than imbalanced dijets in Pb+Pb collisions. It is observed in the measurements of the pair nuclear modification factors that the subleading jets are significantly suppressed relative to leading jets with pT between 100 and 316 GeV for all centralities in Pb+Pb collisions

Measurement of the total cross section and ρ-parameter from elastic scattering in pp collisions at sqrt(s)=13 TeV with the ATLAS detector

In a special run of the LHC with β⋆=2.5 km, proton–proton elastic-scattering events were recorded at sqrt(s)=13 TeV with an integrated luminosity of 340 μb^{−1} using the ALFA subdetector of ATLAS in 2016. The elastic cross section was measured differentially in the Mandelstam t variable in the range from −t=2.5⋅10^{−4} GeV^2 to −t=0.46 GeV^2 using 6.9 million elastic-scattering candidates. This paper presents measurements of the total cross section σ_{tot}, parameters of the nuclear slope, and the ρ-parameter defined as the ratio of the real part to the imaginary part of the elastic-scattering amplitude in the limit t→0. These parameters are determined from a fit to the differential elastic cross section using the optical theorem and different parameterizations of the t-dependence. The results for σ_{tot} and ρ are σ_{tot}(pp→X)=104.7±1.1 mb ρ=0.098±0.011. The uncertainty in σ_{tot} is dominated by the luminosity measurement, and in ρ by imperfect knowledge of the detector alignment and by modelling of the nuclear amplitude

Measurement of substructure-dependent jet suppression in Pb+Pb collisions at 5.02 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider has been used to measure jet substructure modification and suppression in Pb+Pb collisions at a nucleon-nucleon center-of-mass energy sqrt(sNN)=5.02 TeV in comparison with pp collisions at sqrt(sNN)=5.02 TeV. The Pb+Pb data, collected in 2018, have an integrated luminosity of 1.72 nb^{−1}, while the pp data, collected in 2017, have an integrated luminosity of 260 pb^{−1}. Jets used in this analysis are clustered using the anti-kt algorithm with a radius parameter R=0.4. The jet constituents, defined by both tracking and calorimeter information, are used to determine the angular scale rg of the first hard splitting inside the jet by reclustering them using the Cambridge-Aachen algorithm and employing the soft-drop grooming technique. The nuclear modification factor, RAA, used to characterize jet suppression in Pb+Pb collisions, is presented differentially in rg, jet transverse momentum, and in intervals of collision centrality. The RAA value is observed to depend significantly on jet rg. Jets produced with the largest measured rg are found to be twice as suppressed as those with the smallest rg in central Pb+Pb collisions. The RAA values do not exhibit a strong variation with jet pT in any of the rg intervals. The rg and pT dependence of jet RAA is qualitatively consistent with a picture of jet quenching arising from coherence and provides the most direct evidence in support of this approach

Modular antibodies reveal DNA damage-induced mono-ADP-ribosylation as a second wave of PARP1 signaling

PARP1, an established anti-cancer target that regulates many cellular pathways, including DNA repair signaling, has been intensely studied for decades as a poly(ADP-ribosyl)transferase. Although recent studies have revealed the prevalence of mono-ADP-ribosylation upon DNA damage, it was unknown whether this signal plays an active role in the cell or is just a byproduct of poly-ADP-ribosylation. By engineering SpyTag-based modular antibodies for sensitive and flexible detection of mono-ADP-ribosylation, including fluorescence-based sensors for live-cell imaging, we demonstrate that serine mono-ADP-ribosylation constitutes a second wave of PARP1 signaling shaped by the cellular HPF1/PARP1 ratio. Multilevel chromatin proteomics reveals histone mono-ADP-ribosylation readers, including RNF114, a ubiquitin ligase recruited to DNA lesions through a zinc-finger domain, modulating the DNA damage response and telomere maintenance. Our work provides a technological framework for illuminating ADP-ribosylation in a wide range of applications and biological contexts and establishes mono-ADP-ribosylation by HPF1/PARP1 as an important information carrier for cell signaling. © 2023 The Author(s