Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08–4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.This clinical trial was approved and supported by Merck S.L., an affiliate of Merck KGaA, Darmstadt. Germany [research project number 2010-023580-18, date: 05-06-2014

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection

Overview of JET results for optimising ITER operation

The JET 2019–2020 scientific and technological programme exploited the results of years of concerted scientific and engineering work, including the ITER-like wall (ILW: Be wall and W divertor) installed in 2010, improved diagnostic capabilities now fully available, a major neutral beam injection upgrade providing record power in 2019–2020, and tested the technical and procedural preparation for safe operation with tritium. Research along three complementary axes yielded a wealth of new results. Firstly, the JET plasma programme delivered scenarios suitable for high fusion power and alpha particle (α) physics in the coming D–T campaign (DTE2), with record sustained neutron rates, as well as plasmas for clarifying the impact of isotope mass on plasma core, edge and plasma-wall interactions, and for ITER pre-fusion power operation. The efficacy of the newly installed shattered pellet injector for mitigating disruption forces and runaway electrons was demonstrated. Secondly, research on the consequences of long-term exposure to JET-ILW plasma was completed, with emphasis on wall damage and fuel retention, and with analyses of wall materials and dust particles that will help validate assumptions and codes for design and operation of ITER and DEMO. Thirdly, the nuclear technology programme aiming to deliver maximum technological return from operations in D, T and D–T benefited from the highest D–D neutron yield in years, securing results for validating radiation transport and activation codes, and nuclear data for ITER

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Neutral pathways and heat flux widths in vertical- and horizontal-target EDGE2D-EIRENE simulations of JET

This paper further analyses the EDGE2D-EIRENE simulations presented by Chankin et al (2017 Nucl. Mater. Energy 12 273), of L-mode JET plasmas in vertical-vertical (VV) and Vertical-horizontal (VH) divertor configurations. As expected, the simulated outer divertor ionisation source peaks near the separatrix in VV and radially further out in VH. We identify the reflections of recycled neutrals from lower divertor tiles as the primary mechanism by which ionisation is concentrated on the outer divertor separatrix in the VV configuration. These lower tile reflection pathways (of neutrals from the outer divertor, and to an even greater extent from the inner divertor) dominate the outer divertor separatrix ionisation. In contrast, the lower-tile-reflection pathways are much weaker in the VH simulation and its outer divertor ionisation is dominated by neutrals which do not reflect from any surfaces. Interestingly, these differences in neutral pathways give rise to strong differences in the heat flux density width λq at the outer divertor entrance: λq = 3.2 mm in VH compared to λq = 11.8 mm in VV. In VH, a narrow channel exists in the near scrape-off-layer (SOL) where the convected heat flux, driven by strong Er × B flow and thermoelectric current, dominates over the conducted heat flux. The width of this channel sets λq and is determined by the radial distance between the separatrix and the ionisation peak in the outer divertor

Investigation into the formation of the scrape-off layer density shoulder in JET ITER-like wall L-mode and H-mode plasmas

The low temperature boundary layer plasma (Scrape-Off-Layer or SOL) between the hot core and the surrounding vessel determines the level of power-loading, erosion and implantation of material surfaces, and thus the viability of tokamak-based fusion as an energy source. This study explores mechanisms affecting the formation of flattened density profiles, so-called ‘density shoulders’, in the low-field side (LFS) SOL, which modify ion and neutral fluxes to surfaces – and subsequent erosion. There is evidence against local enhancement of ionization inducing shoulder formation. We find that increases in SOL parallel resistivity, Λdiv (=[L||νei Ωi ]/cs Ωe), postulated to lead to shoulder growth through changes in SOL turbulence characteristics, correlates with increases in upstream SOL shoulder amplitude, As only under a subset of conditions (D2-fuelled L-mode density scans with outer strike point on the horizontal target). Λdiv fails to correlate with As for cases of N2 seeding or during sweeping of the strike point across the horizontal target. The limited correlation of Λdiv with As was also found for H-mode discharges. Thus, while Λdiv above a threshold of ~1 may be necessary for shoulder formation and/or growth, another shoulder mechanism is required. More significantly we find that in contrast to parallel resistivity, outer divertor recycling as quantified by the total outer divertor Balmer Dα emission, I-Dα, does scale with shoulder amplitude where Λdiv does and even where Λdiv fails. Divertor recycling could lead to SOL density shoulder formation through: a) reducing the parallel to the field flow (loss) of ions out of the SOL to the divertor; and b) changes in radial electric fields which lead to ExB poloidal flows as well as potentially affecting the SOL turbulence birth characteristics. Thus changes in divertor recycling may be the sole process in bringing about SOL density shoulders or in tandem with parallel resistivity

Observations and modelling of ion cyclotron emission observed in JET plasmas using a sub-harmonic arc detection system during ion cyclotron resonance heating

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