717 research outputs found
Effects of fluctuations on the initial eccentricity from the Color Glass Condensate in heavy ion collisions
We introduce a modified form of the Kharzeev-Levin-Nardi (KLN) approach for
nuclear collisions. The new ansatz for the unintegrated gluon distribution
function preserves factorization, and the saturation scale is bound from below
by that for a single nucleon. It also reproduces the correct scaling with the
number of collisions at high transverse momentum. The corresponding Monte Carlo
implementation allows us to account for fluctuations of the hard sources
(nucleons) in the transverse plane. We compute various definitions of the
eccentricity within the new approach, which are relevant for the interpretation
of the elliptic flow. Our approach predicts breaking of the scaling of the
eccentricity with the Glauber eccentricity at the level of about 30%.Comment: 9 pages, 10 figures, Updated version as accepted by Phys.Rev.
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Oxaliplatin-DNA adduct formation in white blood cells of cancer patients
In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m−2 oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials
A stochastic flow rule for granular materials
There have been many attempts to derive continuum models for dense granular
flow, but a general theory is still lacking. Here, we start with Mohr-Coulomb
plasticity for quasi-2D granular materials to calculate (average) stresses and
slip planes, but we propose a "stochastic flow rule" (SFR) to replace the
principle of coaxiality in classical plasticity. The SFR takes into account two
crucial features of granular materials - discreteness and randomness - via
diffusing "spots" of local fluidization, which act as carriers of plasticity.
We postulate that spots perform random walks biased along slip-lines with a
drift direction determined by the stress imbalance upon a local switch from
static to dynamic friction. In the continuum limit (based on a Fokker-Planck
equation for the spot concentration), this simple model is able to predict a
variety of granular flow profiles in flat-bottom silos, annular Couette cells,
flowing heaps, and plate-dragging experiments -- with essentially no fitting
parameters -- although it is only expected to function where material is at
incipient failure and slip-lines are inadmissible. For special cases of
admissible slip-lines, such as plate dragging under a heavy load or flow down
an inclined plane, we postulate a transition to rate-dependent Bagnold
rheology, where flow occurs by sliding shear planes. With different yield
criteria, the SFR provides a general framework for multiscale modeling of
plasticity in amorphous materials, cycling between continuum limit-state stress
calculations, meso-scale spot random walks, and microscopic particle
relaxation
Protein Tyrosine Phosphatase Receptor Type O Inhibits Trigeminal Axon Growth and Branching by Repressing TrkB and Ret Signaling
Axonal branches of the trigeminal ganglion (TG) display characteristic growth and arborization patterns during development. Subsets of TG neurons express different receptors for growth factors, but these are unlikely to explain the unique patterns of axonal arborizations. Intrinsic modulators may restrict or enhance cellular responses to specific ligands and thereby contribute to the development of axon growth patterns. Protein tyrosine phosphatase receptor type O (PTPRO), which is required for Eph receptor-dependent retinotectal development in chick and for development of subsets of trunk sensory neurons in mouse, may be such an intrinsic modulator of TG neuron development. PTPRO is expressed mainly in TrkB-expressing (TrkB(+)) and Ret(+) mechanoreceptors within the TG during embryogenesis. In PTPRO mutant mice, subsets of TG neurons grow longer and more elaborate axonal branches. Cultured PTPRO(-/-) TG neurons display enhanced axonal outgrowth and branching in response to BDNF and GDNF compared with control neurons, indicating that PTPRO negatively controls the activity of BDNF/TrkB and GDNF/Ret signaling. Mouse PTPRO fails to regulate Eph signaling in retinocollicular development and in hindlimb motor axon guidance, suggesting that chick and mouse PTPRO have different substrate specificities. PTPRO has evolved to fine tune growth factor signaling in a cell-type-specific manner and to thereby increase the diversity of signaling output of a limited number of receptor tyrosine kinases to control the branch morphology of developing sensory neurons. The regulation of Eph receptor-mediated developmental processes by protein tyrosine phosphatases has diverged between chick and mouse
On the Importance of Countergradients for the Development of Retinotopy: Insights from a Generalised Gierer Model
During the development of the topographic map from vertebrate retina to superior colliculus (SC), EphA receptors are expressed in a gradient along the nasotemporal retinal axis. Their ligands, ephrin-As, are expressed in a gradient along the rostrocaudal axis of the SC. Countergradients of ephrin-As in the retina and EphAs in the SC are also expressed. Disruption of any of these gradients leads to mapping errors. Gierer's (1981) model, which uses well-matched pairs of gradients and countergradients to establish the mapping, can account for the formation of wild type maps, but not the double maps found in EphA knock-in experiments. I show that these maps can be explained by models, such as Gierer's (1983), which have gradients and no countergradients, together with a powerful compensatory mechanism that helps to distribute connections evenly over the target region. However, this type of model cannot explain mapping errors found when the countergradients are knocked out partially. I examine the relative importance of countergradients as against compensatory mechanisms by generalising Gierer's (1983) model so that the strength of compensation is adjustable. Either matching gradients and countergradients alone or poorly matching gradients and countergradients together with a strong compensatory mechanism are sufficient to establish an ordered mapping. With a weaker compensatory mechanism, gradients without countergradients lead to a poorer map, but the addition of countergradients improves the mapping. This model produces the double maps in simulated EphA knock-in experiments and a map consistent with the Math5 knock-out phenotype. Simulations of a set of phenotypes from the literature substantiate the finding that countergradients and compensation can be traded off against each other to give similar maps. I conclude that a successful model of retinotopy should contain countergradients and some form of compensation mechanism, but not in the strong form put forward by Gierer
Overpopulation of in pp collisions: a way to distinguish statistical hadronization from string dynamics
The ratio originating from string decays is predicted
to be larger than unity in proton proton interactions at SPS energies (=160 GeV). The anti-omega dominance increases with decreasing beam energy.
This surprising behavior is caused by the combinatorics of quark-antiquark
production in small and low-mass strings. Since this behavior is not found in a
statistical description of hadron production in proton proton collisions, it
may serve as a key observable to probe the hadronization mechanism in such
collisions.Comment: 4 pages, 4 figure
Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial
Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents.
Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients.
Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60.
Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients
Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses
<p>Abstract</p> <p>Background</p> <p>Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells.</p> <p>Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells.</p> <p>Methods</p> <p>We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays.</p> <p>Results</p> <p>The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4<sup>+</sup>, activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested) could be observed.</p> <p>Conclusion</p> <p>Cellular fusions of MSI<sup>+ </sup>carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These hybrid cells may have great potential for cellular immunotherapy and this approach should be further analyzed in preclinical as well as clinical trials. Moreover, this is the first report on the induction of frameshift-specific T cell responses without the use of synthetic peptides.</p
Active Brownian Particles. From Individual to Collective Stochastic Dynamics
We review theoretical models of individual motility as well as collective
dynamics and pattern formation of active particles. We focus on simple models
of active dynamics with a particular emphasis on nonlinear and stochastic
dynamics of such self-propelled entities in the framework of statistical
mechanics. Examples of such active units in complex physico-chemical and
biological systems are chemically powered nano-rods, localized patterns in
reaction-diffusion system, motile cells or macroscopic animals. Based on the
description of individual motion of point-like active particles by stochastic
differential equations, we discuss different velocity-dependent friction
functions, the impact of various types of fluctuations and calculate
characteristic observables such as stationary velocity distributions or
diffusion coefficients. Finally, we consider not only the free and confined
individual active dynamics but also different types of interaction between
active particles. The resulting collective dynamical behavior of large
assemblies and aggregates of active units is discussed and an overview over
some recent results on spatiotemporal pattern formation in such systems is
given.Comment: 161 pages, Review, Eur Phys J Special-Topics, accepte
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