Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab

Background: Inhibition of the activated epidermal growth factor receptor (EGFR) with either enzymatic kinase inhibitors or anti-EGFR antibodies such as cetuximab, is an effective modality of treatment for multiple human cancers. Enzymatic EGFR inhibitors are effective for lung adenocarcinomas with somatic kinase domain EGFR mutations while, paradoxically, anti-EGFR antibodies are more effective in colon and head and neck cancers where EGFR mutations occur less frequently. In colorectal cancer, anti-EGFR antibodies are routinely used as second-line therapy of KRAS wild-type tumors. However, detailed mechanisms and genomic predictors for pharmacological response to these antibodies in colon cancer remain unclear. Findings: We describe a case of colorectal adenocarcinoma, which was found to harbor a kinase domain mutation, G724S, in EGFR through whole genome sequencing. We show that G724S mutant EGFR is oncogenic and that it differs from classic lung cancer derived EGFR mutants in that it is cetuximab responsive in vitro, yet relatively insensitive to small molecule kinase inhibitors. Through biochemical and cellular pharmacologic studies, we have determined that cells harboring the colon cancer-derived G719S and G724S mutants are responsive to cetuximab therapy in vitro and found that the requirement for asymmetric dimerization of these mutant EGFR to promote cellular transformation may explain their greater inhibition by cetuximab than small-molecule kinase inhibitors. Conclusion: The colon-cancer derived G719S and G724S mutants are oncogenic and sensitive in vitro to cetuximab. These data suggest that patients with these mutations may benefit from the use of anti-EGFR antibodies as part of the first-line therapy

Long-term efficacy, safety and immunogenicity in patients with rheumatoid arthritis continuing on an etanercept biosimilar (LBEC0101) or switching from reference etanercept to LBEC0101: an open-label extension of a phase III multicentre, randomised, double-blind, parallel-group study

Background To evaluate the long-term efficacy, safety and immunogenicity of continuing LBEC0101; the etanercept (ETN) biosimilar; or switching from the ETN reference product (RP) to LBEC0101 in patients with rheumatoid arthritis (RA). Methods This multicentre, single-arm, open-label extension study enrolled patients who had completed a 52-week randomised, double-blind, parallel phase III trial of LBEC0101 vs ETN-RP. Patients treated with ETN-RP during the randomised controlled trial switched to LBEC0101; those treated with LBEC0101 continued to receive LBEC0101 in this study. LBEC0101 (50 mg) was administered subcutaneously once per week for 48 weeks with a stable dose of methotrexate. Efficacy, safety and immunogenicity of LBEC0101 were assessed up to week 100. Results A total of 148 patients entered this extension study (70 in the maintenance group and 78 in the switch group). The 28-joint disease activity scores (DAS28)-erythrocyte sedimentation rate (ESR) were maintained in both groups from week 52 to week 100 (from 3.068 to 3.103 in the maintenance group vs. from 3.161 to 3.079 in the switch group). ACR response rates at week 100 for the maintenance vs. switch groups were 79.7% vs. 83.3% for ACR20, 65.2% vs. 66.7% for ACR50 and 44.9% vs. 42.3% for ACR70. The incidence of adverse events and the proportion of patients with newly developed antidrug antibodies were similar in the maintenance and switch groups (70.0% and 70.5%, 1.4% and 1.3%, respectively). Conclusions Administration of LBEC0101 showed sustained efficacy and acceptable safety in patients with RA after continued therapy or after switching from ETN-RP to LBEC0101. Trial registration ClinicalTrials.gov, NCT02715908. Registered 22 March 2016.This extension study was funded by LG Chem, Ltd. (formerly, LG Life Sciences, Ltd), Mochida Pharmaceutical Co., Ltd. and Korea Health Industry Development Institute

Intense multicycle THz pulse generation from laser-produced nanoplasmas

We present a novel scheme to obtain robust, narrowband, and tunable THz emission using a nano-dimensional overdense plasma target, irradiated by two counter-propagating detuned laser pulses. So far, no narrowband THz sources with a field strength of GV/m-level have been reported from laser-solid interaction (mostly half-or single-cycle THz pulses with only broadband frequency spectrum). From two- and three-dimensional particle-in-cell simulations, we find that the strong plasma current generated by the beat ponderomotive force in the colliding region, produces beat-frequency radiation in the THz range. Here we report intense THz pulses (f???30THz) with an unprecedentedly high peak field strength of 11.9 GV/m and spectral width (?? f/ f??? 5.3 %) , which leads to a regime of an extremely bright narrowband THz source of TW/cm2, suitable for various ambitious applications

Measurement of local density and magnetic field of a magnetized plasma using Raman scattering from a focused laser pulse

We investigated the possibility of pin pointing the local density and magnetic field of an inhomogeneous, magnetized plasma by stimulated Raman scattering of a pump laser pulse focused on a desired position. As the Raman growth rate is proportional to the pump pulse amplitude, the spectral peak shift of the scattered signal is, though it is a spatially integrated one, expected to be determined dominantly by that from the focal position of the pump pulse. From a theoretical estimation, we found a condition of the pulse duration and plasma density for such an expectation to properly work. It was confirmed by two-dimensional particle-in-cell simulations that as long as the pulse duration is long and the length scale of the plasma inhomogeneity is large compared to the Rayleigh length, the spectral bandwidth of the spatially integrated Raman signal can be narrow enough to distinguish the peak position with good enough resolution.close0

Control of High Harmonics Radiation from Plasma Dipole Oscillation

Recently we reported a novel idea of generating a localized bunch of electrons oscillating in-phase, named plasma dipole oscillation (PDO), by colliding two detuned laser pulses in a plasma. From a series of two-dimensional particle-in-cell (PIC) simulations and theoretical analysis, we verified that PDO oscillates with the local plasma frequency and emits a strong dipole radiation at the same frequency. Such a property of PDO enables it to be used as a light source in terahertz band (Kwon et al., Sci. Rep. 2018) and also as a novel diagnostic method of reconstructing non-uniform plasma densities (Kylychbekov et al., PSST 2020). In this paper, we present our new calculation, where we find that the PDO is not just a linear harmonic oscillator as described in the slab-model of the plasma oscillation, but has a high nonlinearity, which yields high harmonic radiations. The second harmonic radiation emitted from the nonlinear PDO can be a new model of 2fp radio-burst from solar plasmas, which is conventionally explained by two-plasmon merger. Since the harmonic radiations are strongly dependent on the shape of PDO, the high harmonics of PDO can be controlled by manipulation of frequency chirp and profiles of the driving laser pulses

Laser pulse compression by a density gradient plasma for exawatt to zettawatt lasers

We propose a new method of compressing laser pulses to ultra-high powers based on spatially varying dispersion of an inhomogeneous plasma. Here, compression is achieved when a long, negatively frequency-chirped laser pulse reflects off the density ramp of an over-dense plasma slab. As the density increases longitudinally, high frequency photons at the leading part of the laser pulse penetrate more deeply into the plasma region than lower frequency photons, resulting in pulse compression in a similar way to that by a chirped mirror. Proof-of-principle simulations carried out using a one-dimensional (1D) and quasi-3D particle-in-cell (PIC) simulation codes predict compression of a 2.35 ps laser pulse to 10.3 fs, a ratio of 225. As plasma is robust and resistant to damage at high intensities, unlike solid-state gratings commonly used in chirped-pulse amplification (CPA), the method could be used as a compressor to reach exawatt or zettawatt peak powers