Slow and fast micro-field components in warm and dense hydrogen plasmas

The aim of this work is the investigation of the statistical properties of local electric fields in an ion-electron two component plasmas for coupled conditions. The stochastic fields at a charged or at a neutral point in plasmas involve both slow and fast fluctuation characteristics. The statistical study of these local fields based on a direct time average is done for the first time. For warm and dense plasma conditions, typically $N_{e}\approx 10^{18}cm^{-3}$, $$, well controlled molecular dynamics (MD) simulations of neutral hydrogen, protons and electrons have been carried out. Relying on these \textit{ab initio} MD calculations this work focuses on an analysis of the concepts of statistically independent slow and fast local field components, based on the consideration of a time averaged electric field. Large differences are found between the results of these MD simulations and corresponding standard results based on static screened fields. The effects discussed are of importance for physical phenomena connected with stochastic electric field fluctuations, e.g., for spectral line broadening in dense plasmas.Comment: 4 pages, 4 figures, submitted to Phys. Rev. Let

Pion production in deeply virtual Compton scattering

Using a soft pion theorem based on chiral symmetry and a $\Delta(1232)$ resonance model we propose an estimate for the production cross section of low energy pions in the deeply virtual Compton scattering (DVCS) process. In particular, we express the $e p \to e \gamma \pi N$ processes in terms of generalized parton distributions. We provide estimates of the contamination of the $e p \to e \gamma p$ DVCS observables due to this associated pion production processes when the experimental data are not fully exclusive, for a set of kinematical conditions representative of present or planned experiments at JLab, HERMES and COMPASS.Comment: 50 pages, 22 figure

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988

Inhibition of N-linked glycosylation impairs ALK phosphorylation and disrupts pro-survival signaling in neuroblastoma cell lines

<p>Abstract</p> <p>Background</p> <p>The Anaplastic Lymphoma Kinase (ALK) is an orphan receptor tyrosine kinase, which undergoes post-translational N-linked glycosylation. The catalytic domain of ALK was originally identified in the t(2;5) translocation that produces the unglycosylated oncogenic protein NPM-ALK, which occurs in Anaplastic Large Cell Lymphoma (ALCL). Recently, both germline and somatic activating missense mutations of ALK have been identified in neuroblastoma (NB), a pediatric cancer arising from neural crest cells. Moreover, we previously reported that ALK expression is significantly upregulated in advanced/metastatic NB. We hypothesized that ALK function may depend on N-linked glycosylation and that disruption of this post-translational modification would impair ALK activation, regardless the presence of either gene mutations or overexpression.</p> <p>Methods</p> <p>We employed tunicamycin to inhibit N-linked glycosylation. The following ALK-positive NB cell lines were used: SH-SY5Y and KELLY (ALK mutation F1174L), UKF-NB3 (ALK mutation R1275Q) and NB1 (ALK amplification). As a control, we used the NB cell lines LA1-5S and NB5 (no ALK expression), and the ALCL cell line SU-DHL1 (NPM-ALK).</p> <p>Results</p> <p>Tunicamycin treatment of ALK-positive NB cells resulted in a hypoglycosylated ALK band and in decreased amounts of mature full size receptor. Concomitantly, we observed a marked reduction of mature ALK phosphorylation. On the contrary, tunicamycin had no effects on NPM-ALK phosphorylation in SU-DHL1 cells. Moreover, phosphorylation levels of ALK downstream effectors (AKT, ERK1/2, STAT3) were clearly impaired only in ALK mutated/amplified NB cell lines, whereas no significant reduction was observed in both ALK-negative and NPM-ALK-positive cell lines. Furthermore, inhibition of N-linked glycosylation considerably impaired cell viability only of ALK mutated/amplified NB cells. Finally, the cleavage of the Poly-ADP-ribose-polymerase (PARP) suggested that apoptotic pathways may be involved in cell death.</p> <p>Conclusions</p> <p>In this study we showed that inhibition of N-linked glycosylation affects ALK phosphorylation and disrupts downstream pro-survival signaling, indicating that inhibition of this post-translational modification may be a promising therapeutic approach. However, as tunicamycin is not a likely candidate for clinical use other approaches to alter N-linked glycosylation need to be explored. Future studies will assess whether the efficacy in inhibiting ALK activity might be enhanced by the combination of ALK specific small molecule and N-linked glycosylation inhibitors.</p

Experience with model-based performance, reliability and adaptability assessment of a complex industrial architecture

In this paper, we report on our experience with the application of validated models to assess performance, reliability, and adaptability of a complex mission critical system that is being developed to dynamically monitor and control the position of an oil-drilling platform. We present real-time modeling results that show that all tasks are schedulable. We performed stochastic analysis of the distribution of task execution time as a function of the number of system interfaces. We report on the variability of task execution times for the expected system configurations. In addition, we have executed a system library for an important task inside the performance model simulator. We report on the measured algorithm convergence as a function of the number of vessel thrusters. We have also studied the system architecture adaptability by comparing the documented system architecture and the implemented source code. We report on the adaptability findings and the recommendations we were able to provide to the system’s architect. Finally, we have developed models of hardware and software reliability. We report on hardware and software reliability results based on the evaluation of the system architecture

Laser-driven strong magnetostatic fields with applications to charged beam transport and magnetized high energy-density physics

Powerful nanosecond laser-plasma processes are explored to generate discharge currents of a few 100 kA in coil targets, yielding magnetostatic fields (B-fields) in excess of 0.5 kT. The quasi-static currents are provided from hot electron ejection from the laser-irradiated surface. According to our model, which describes the evolution of the discharge current, the major control parameter is the laser irradiance Ilasλlas2. The space-time evolution of the B-fields is experimentally characterized by high-frequency bandwidth B-dot probes and proton-deflectometry measurements. The magnetic pulses, of ns-scale, are long enough to magnetize secondary targets through resistive diffusion. We applied it in experiments of laser-generated relativistic electron transport through solid dielectric targets, yielding an unprecedented 5-fold enhancement of the energy-density flux at 60 μm depth, compared to unmagnetized transport conditions. These studies pave the ground for magnetized high-energy density physics investigations, related to laser-generated secondary sources of radiation and/or high-energy particles and their transport, to high-gain fusion energy schemes, and to laboratory astrophysics