Checkpoint inhibition reduces the threshold for Drug-Specific T-Cell priming and increases the incidence of sulfasalazine hypersensitivity

An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors (ICIs) and sulfasalazine (SLZ). Thus, the aim of this study was to characterize the T cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in vitro platforms. A regulatory competent human dendritic cell/T-cell coculture assay was used to model the effects of ICIs on de novo nitroso sulfamethoxazole- and sulfapyridine (SP) (the sulfonamide component of SLZ) hydroxylamine-specific priming responses. The role of T cells in the pathogenesis of the observed reactions was explored in 3 patients through phenotypic characterization of SP/sulfapyridine hydroxylamine (SPHA)-responsive T-cell clones (TCC), and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of SP- and SPHA-responsive T cells were isolated from all 3 patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B, and perforin) was identified for SP and SPHA-responsive TCC, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T cells are effectors of hypersensitivity reactions observed in oncology patients administered ICIs and SLZ. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring

Two-hadron semi-inclusive production including subleading twist

We extend the analysis of two-hadron fragmentation functions to the subleading twist, discussing also the issue of color gauge invariance. Our results can be used anywhere two unpolarized hadrons are semi-inclusively produced in the same fragmentation region, also at moderate values of the hard scale Q. Here, we consider the example of polarized deep-inelastic production of two hadrons and we give a complete list of cross sections and spin asymmetries up to subleading twist. Among the results, we highlight the possibility of extracting the transversity distribution with longitudinally polarized targets and also the twist-3 distribution e(x), which is related to the pion-nucleon sigma term and to the strangeness content of the nucleon.Comment: 16 pages, RevTeX4, 5 figures, revised notation of several formulae, added text in Secs. III-V, added reference

Energy Transfer in Multi Field Inflation and Cosmological Perturbations

In cascade inflation and some other string inflation models, collisions of mobile branes with other branes or orbifold planes occur and lead to interesting cosmological signatures. The fundamental M/string-theory description of these collisions is still lacking but it is clear that the inflaton looses part of its energy to some form of brane matter, e.g. a component of tensionless strings. In the absence of a fundamental description, we assume a general barotropic fluid on the brane, which absorbs part of the inflaton's energy. The fluid is modeled by a scalar with a suitable exponential potential to arrive at a full-fledged field theory model. We study numerically the impact of the energy transfer from the inflaton to the scalar on curvature and isocurvature perturbations and demonstrate explicitly that the curvature power spectrum gets modulated by oscillations which damp away toward smaller scales. Even though, the contribution of isocurvature perturbations decays toward the end of inflation, they induce curvature perturbations on scales that exit the horizon before the collision. We consider cases where the scalar behaves like radiation, matter or a web of cosmic strings and discuss the differences in the resulting power spectra.Comment: v1: 25 pages, 7 figures; v2: references added;v3: typo corrected, accepted for publication to JCA

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Exotic ρ±ρ0\rho^\pm\rho^0 state photoproduction

It is shown that the list of unusual mesons planned for a careful study in photoproduction can be extended by the exotic states $X^\pm(1600)$ with $I^G(J ^{PC})=2^+(2^{++})$ which should be looked for in the $\rho^\pm\rho^0$ decay channels in the reactions $\gamma N\to\rho^\pm\rho^0N$ and $\gamma N\to\rho^\pm \rho^0\Delta$. The full classification of the $\rho^\pm\rho^0$ states by their quantum numbers is presented. A simple model for the spin structure of the $\gamma p\to f_2(1270)p$, $\gamma p\to a^0_2(1320)p$, and $\gamma N\to X^\pm (N, \Delta)$ reaction amplitudes is formulated and the tentative estimates of the corresponding cross sections at the incident photon energy $E_\gamma\approx 6$ GeV are obtained: $\sigma(\gamma p\to f_2(1270)p)\approx0.12$ $\mu$b, $\sigma(\gamma p\to a^0_2(1320)p)\approx0.25$ $\mu$b, $\sigma(\gamma N\to X^\pm N\to\rho^\pm\rho^0N)\approx0.018$ $\mu$b, and $\sigma(\gamma p\to X^-\Delta^{++ }\to\rho^-\rho^0\Delta^{++})\approx0.031$ $\mu$b. The problem of the $X^\pm$ signal extraction from the natural background due to the other $\pi^\pm\pi^0 \pi^+\pi^-$ production channels is discussed. In particular the estimates are presented for the $\gamma p\to h_1(1170)\pi^+n$, $\gamma p\to\rho'^{+}n\to \pi^+\pi^0\pi^+\pi^-n$, and $\gamma p\to\omega\rho^0p$ reaction cross sections. Our main conclusion is that the search for the exotic $X^\pm(2^+(2^{++}))$ states is quite feasible at JEFLAB facility. The expected yield of the $\gamma N\to X^\pm N\to\rho^\pm\rho^0N$ events in a 30-day run at the 100% detection efficiency approximates $2.8\times10^6$ events.Comment: 19 pages, revtex, 1 figure in postscipt, some comments and references added, a few minor typos corrected, to be published in Phys. Rev.

Dynamic protein methylation in chromatin biology

Post-translational modification of chromatin is emerging as an increasingly important regulator of chromosomal processes. In particular, histone lysine and arginine methylation play important roles in regulating transcription, maintaining genomic integrity, and contributing to epigenetic memory. Recently, the use of new approaches to analyse histone methylation, the generation of genetic model systems, and the ability to interrogate genome wide histone modification profiles has aided in defining how histone methylation contributes to these processes. Here we focus on the recent advances in our understanding of the histone methylation system and examine how dynamic histone methylation contributes to normal cellular function in mammals

Measurement of the cross section for isolated-photon plus jet production in pp collisions at √s=13 TeV using the ATLAS detector

The dynamics of isolated-photon production in association with a jet in proton–proton collisions at a centre-of-mass energy of 13 TeV are studied with the ATLAS detector at the LHC using a dataset with an integrated luminosity of 3.2 fb−1. Photons are required to have transverse energies above 125 GeV. Jets are identified using the anti- algorithm with radius parameter and required to have transverse momenta above 100 GeV. Measurements of isolated-photon plus jet cross sections are presented as functions of the leading-photon transverse energy, the leading-jet transverse momentum, the azimuthal angular separation between the photon and the jet, the photon–jet invariant mass and the scattering angle in the photon–jet centre-of-mass system. Tree-level plus parton-shower predictions from Sherpa and Pythia as well as next-to-leading-order QCD predictions from Jetphox and Sherpa are compared to the measurements

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat