Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective as first-line treatment of advanced non-small-cell lung cancer patients with EGFR mutations (EGFR-M+).
We ...conducted a literature-based meta-analysis to quantify the magnitude of benefit with upfront EGFR TKI in EGFR-M+ patients. Meta-regression and sensitivity analyses were also carried out to identify additional predictors of outcome and to assess the influence of trial design.
Five trials (805 patients) were identified (three trials prospectively enrolling EGFR-M+ patients and two retrospective analyses of EGFR-M+ patients). TKI significantly increased progression-free survival (PFS) hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.36–0.58, P < 0.0001 and overall response rate (ORR) (HR 2.08, 95% CI 1.75–2.46, P < 0.0001) over chemotherapy, while significantly decreasing neutropenia. No significant difference was observed in overall survival. The rate of exon-19 mutations, female gender, and nonsmoking status were identified as additional predictors of outcome at meta-regression analysis. A significant interaction with trial design was found for both PFS (P = 0.028) and ORR (P = 0.008), suggesting a larger advantage for patients treated within prospective trials.
In EGFR-M+ patients, first-line TKI increase both PFS and ORR by ∼25%, while significantly decreasing toxicity. The role of additional predictive factors and the influence of trial design on the magnitude of the observed benefit warrant further investigation.
The resistive wall impedance of a vacuum chamber with elliptic cross section is of particular interest for circular particle accelerators as well as for undulators in free electron lasers. By using ...the electric field of a point charge and of a small dipole moving at arbitrary speed in an elliptical vacuum chamber, expressed in terms of Mathieu functions, in this paper we take into account the finite conductivity of the beam pipe walls by means of the surface impedance, and evaluate the longitudinal and transverse driving and detuning impedances for any beam velocity. We also extend the definition of the Yokoya form factors, valid in the thick wall regime, at any beam energy, and show that, in the ultra-relativistic limit, they coincide with the ones that are found in literature. The method is also extended to the multilayer vacuum chamber case. Under conditions generally satisfied with particle accelerator beam pipes, the classical transmission line theory can be used to modelling the impedance seen by a bunch in a vacuum chamber with several layers as an equivalent circuit with the same number of load impedances, giving, as result, a surface impedance that can be used in combination with the fields of the elliptic geometry to obtain the resistive wall impedance in an elliptical multilayer vacuum chamber. The results are also compared with a more time consuming 3D electromagnetic code and with solutions for known cases of circular and flat beam pipe.
The accurate calculation of the beam coupling impedance for particle accelerators is necessary to carefully assess the machine stability against impedance-driven collective effects. A first order ...evaluation of the beam coupling impedance is often done by means of analytical formulas and/or 2D numerical codes. The infinite length approximation is often used to simplify the calculation of the beam coupling impedance of accelerator elements. This is expected to be a reasonable assumption for devices whose length is greater than the transverse dimension but may be a less accurate approximation for segmented devices. In this work, we present the application of the mode matching method to the calculation of the transverse dipolar impedance of a cylindrical cavity loaded with a toroidal insert. By choosing different insert electromagnetic properties (permittivity, permeability, and conductivity) and dimensions, the model can represent a beam pipe, a thin insert, a lossy cavity, or a collimator for which the effect of the finite length is investigated. The method is successfully benchmarked against available analytical formulas, field-matching codes, and 3D commercial solvers. The proposed model allows for performing wide parametric scans and reaching accurate results, therefore becoming an essential tool for the impedance evaluation of accelerator devices.
Starting from the electric fields produced by a point charge and a dipole traveling inside a circular vacuum chamber, in this paper we derive a formalism for a complete set of equations that describe ...the electromagnetic fields and the longitudinal and transverse coupling impedances arising by the interaction of a beam with a perfectly conducting pipe in the case of elliptic geometry. The expressions, which are valid for any frequency and beam energy, are written in terms of expansions of Mathieu functions, allow to range from a circular geometry to the parallel plates, and show an interesting parallelism with the well-known expressions for a circular pipe. We also obtain that, under the approximation of low frequency, the formalism allows us to derive the Laslett coefficients for parallel plates, circular and elliptic beam pipe.
In this paper, we discuss the electromagnetic interaction between a point charge travelling inside a waveguide of elliptical cross section, and the waveguide itself. By using a convenient expansion ...of the Mathieu functions, useful in particular for treating a variety of problems in applied mathematics and physics with elliptic geometry, we first obtain the longitudinal electromagnetic field of a point charge (Green’s function) in free space in terms of elliptical coordinates. This expression allows, then, to calculate the scattered field due to the boundary conditions in our geometry. By summing the contribution of the direct or primary field and the indirect field scattered by the boundary, after a careful choice of some expansion expressions, we derive a novel formula of the longitudinal electric field, in any transverse position of the elliptical cross section, generated by the charge moving along the longitudinal axis of the waveguide. The obtained expression is represented in a closed form, it can be differentiated and integrated, it can be used to fully describe the radiation process of a particle beam travelling inside a waveguide of elliptical cross section, and it is valid for any elliptic geometry. The equations are used to evaluate the coupling impedance due to indirect space charge in case of elliptical geometry. In addition, they are useful as preliminary studies for the determination of the coupling impedance in different cases involving elliptic vacuum chambers, as, for example, the effect of the finite conductivity of the beam pipe wall or the geometrical variation of the vacuum chamber due to elliptic step transitions existing in some accelerators.
In particle accelerators, the beam quality can be strongly affected by the interaction with self-induced electromagnetic fields excited by the beam in the passage through the elements of the ...accelerator. The beam coupling impedance quantifies this interaction and allows predicting the stability of the dynamics of high intensity, high brilliance beams. The coupling impedance can be evaluated with finite element methods or using analytical approaches, such as field matching or mode matching. In this paper we present an application of the mode matching technique for an azimuthally uniform structure of finite length: a cylindrical cavity loaded with a toroidal slab of lossy dielectric, connected with cylindrical beam pipes. In order to take into account the finite length of the structure, with respect to the infinite length approximation, we decompose the fields in the cavity into a set of orthonormal modes. We obtain a complete set of equations using the magnetic field matching and the nonuniform convergence of the electric field on the cavity boundaries. We present benchmarks done with CST Particle Studio simulations and existing analytical formulas and codes, pointing out the effect of different material conductivities, finite length, and nonultrarelativistic particle beam velocity.
The TIARA (Test Infrastructure and Accelerator Research Area) project funded by the European Union 7th framework programme made a survey of provision of education and training in accelerator science ...in Europe. This survey highlighted the need for more training opportunities targeting undergraduate-level students. This need is now being addressed by the European Union H2020 project ARIES (Accelerator Research and Innovation for European Science and Society) via the preparation of a Massive Open Online Course (MOOC) on particle accelerator science and engineering. We present here the current status of this project, the main elements of the syllabus, how it will be delivered, and the schedule for providing the course.
The need for dynamic loading of overhead lines requires reliable assessment models that should be able to predict both the evolution of the hot-spot temperature and the associated maximum allowed ...duration at any load level and on the basis of actual conductor thermal state and forecasted environmental conditions. In order to address this problem, a novel identification semi-physical modelling architecture that combines the knowledge coming from expertise with empirical evidence provided by observations is proposed. This is performed by integrating an analytical thermal model, which estimates qualitatively the conductor hot-spot temperature, and an adaptive corrective algorithm, based on a local learning theory and aimed at enhancing the estimation accuracy. The corrective algorithm is continuously adjusted by the field data acquired through distributed fibre-optic sensor based on stimulated Brillouin scattering. To assess the performances of the proposed methodology, the main results of the experimental studies obtained on a laboratory overhead lines are presented and discussed.
To characterize the emergency program set up by pancreatic cells in response to pancreatitis, we established the phenotype of the pancreatitis-affected pancreas by characterizing a large number of ...its transcripts. In this report, we describe the cloning, sequencing, and expression pattern of a new gene, named VMP1 (vacuole membrane protein 1). The VMP1 mRNA codes for a putative protein of 406 amino acids. In situ hybridization studies revealed that pancreatic expression of VMP1 mRNAs was restricted to the acinar cells. Interestingly, VMP1 mRNA was also overexpressed in kidney after transient ischemic injury. However, many healthy tissues express VMP1 mRNA. Structure analysis suggested that VMP1 is a transmembrane protein with six hydrophobic regions. VMP1/EGFP fusion protein was located to the Golgi apparatus and the endoplasmic reticulum area. Expression of this protein promoted the formation of intracytoplasmatic vacuoles and VMP1/EGFP was located to the membranes of these vacuoles. Cells overexpressing this protein died after 48 h. In conclusion, we have identified a new stress-induced gene which codes for a transmembrane protein that, when overexpressed, promotes formation of intracellular vacuoles followed by cell death.
p8 is a nuclear DNA-binding protein, which was identified because its expression is strongly activated in response to several stresses. Biochemical and biophysical studies revealed that despite a ...weak sequence homology p8 is an HMG-I/Y-like protein, suggesting that p8 may be involved in transcription regulation. Results reported here strongly support this hypothesis. Using a pull-down approach, we found that p8 interacts with the general co-activator p300. We also found that, similar to the HMG proteins, p300 was able to acetylate recombinant p8 in vitro, although the significance of such modification remains to be determined. Then a screening by the two-hybrid system, using p8 as bait, allowed us to identify the Pax2 trans-activation domain-interacting protein (PTIP) as another partner of p8. Transient transfection studies revealed that PTIP is a strong inhibitor of the trans-activation activities of Pax2A and Pax2B on the glucagon gene promoter, which was chosen as a model because it is a target of the Pax2A and Pax2B transcription factors. This effect is completely abolished by co-transfection of p8 in glucagon-producing InRIG9 cells, indicating that p8 binding to PTIP prevents inhibition of the glucagon gene promoter. This was not observed in NIH3T3 fibroblasts that do not express glucagon. Finally, expression of p8 enhances the effect of p300 on Pax2A and Pax2B trans-activation of the glucagon gene promoter. These observations suggest that in glucagon-producing cells p8 is a positive cofactor of the activation of the glucagon gene promoter by Pax2A and Pax2B, both by recruiting the p300 cofactor to increase the Pax2A and Pax2B activities and by binding the Pax2-interacting protein PTIP to suppress its inhibition.
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