ERBB2 is the most prominent therapeutic target in gastroesophageal adenocarcinoma (GEA). For two decades, trastuzumab was the only treatment available for GEA overexpressing ERBB2. Several drugs ...showing evidence of efficacy over or in complement to trastuzumab in breast cancer failed to show clinical benefit in GEA. This resistance to anti-ERBB2 therapy is peculiarly recurrent in GEA and is mostly due to tumor heterogeneity with the existence of low expressing ERBB2 tumor clones and loss of ERBB2 over time. The development of new ERBB2 testing strategies and the use of antibody-drug conjugates having a bystander effect are providing new tools to fight heterogeneity in ERBB2-positive GEA. Co-amplifications of tyrosine kinase receptors, alterations in mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways and in proteins controlling cell cycle are well known to contribute resistance to anti-ERBB2 therapy, and they can be targeted by dual therapy. Recently described, NF1 mutations are responsible for Ras phosphorylation and activation and can also be targeted by MEK/ERK inhibition along with anti-ERBB2 therapy. Multiple lines of evidence suggest that immune mechanisms involving antibody-dependent cell-mediated cytotoxicity are preponderant over intracellular signaling in anti-ERBB2 therapy action. A better comprehension of these mechanisms could leverage immune action of anti-ERBB2 therapy and elucidate efficacy of combinations associating immunotherapy and anti-ERBB2 therapy, as suggested by the recent intermediate positive results of the KEYNOTE-811 trial.
•ERBB2 biology complexity in gastroesophageal cancer has hampered the development of new drugs in the last two decades.•ERBB2 status determination is more challenging in gastroesophageal cancer than in breast cancer.•Antibody-drug conjugates and (89)Zr-trastuzumab positron emission tomography imaging can help target tumor heterogeneity.•Dual therapy (immune plus anti-ERBB2) can leverage immune mechanisms involved in anti-ERBB2 therapy.
Nitrous oxide emissions from a network of agricultural experiments in Europe were used to explore the relative importance of site and management controls of emissions. At each site, a selection of ...management interventions were compared within replicated experimental designs in plot-based experiments. Arable experiments were conducted at Beano in Italy, El Encin in Spain, Foulum in Denmark, Logården in Sweden, Maulde in Belgium, Paulinenaue in Germany, and Tulloch in the UK. Grassland experiments were conducted at Crichton, Nafferton and Peaknaze in the UK, Gödöllö in Hungary, Rzecin in Poland, Zarnekow in Germany and Theix in France. Nitrous oxide emissions were measured at each site over a period of at least two years using static chambers. Emissions varied widely between sites and as a result of manipulation treatments. Average site emissions (throughout the study period) varied between 0.04 and 21.21 kg N2O-N ha−1 yr−1, with the largest fluxes and variability associated with the grassland sites. Total nitrogen addition was found to be the single most important determinant of emissions, accounting for 15% of the variance (using linear regression) in the data from the arable sites (p < 0.0001), and 77% in the grassland sites. The annual emissions from arable sites were significantly greater than those that would be predicted by IPCC default emission factors. Variability of N2O emissions within sites that occurred as a result of manipulation treatments was greater than that resulting from site-to-site and year-to-year variation, highlighting the importance of management interventions in contributing to greenhouse gas mitigation.
Medicanes are cyclones over the Mediterranean Sea having a tropical-like structure but a rather small size, that can produce significant damage due to the combination of intense winds and heavy ...precipitation. Future climate projections, performed generally with individual atmospheric climate models, indicate that the intensity of the medicanes could increase under climate change conditions. The availability of large ensembles of high resolution and ocean–atmosphere coupled regional climate model (RCM) simulations, performed in MedCORDEX and EURO-CORDEX projects, represents an opportunity to improve the assessment of the impact of climate change on medicanes. As a first step towards such an improved assessment, we analyze the ability of the RCMs used in these projects to reproduce the observed characteristics of medicanes, and the impact of increased resolution and air-sea coupling on their simulation. In these storms, air-sea interaction plays a fundamental role in their formation and intensification, a different mechanism from that of extra-tropical cyclones, where the baroclinic instability mechanism prevails. An observational database, based on satellite images combined with high resolution simulations (Miglietta et al. in Geophys Res Lett 40:2400–2405,
2013
), is used as a reference for evaluating the simulations. In general, the simulated medicanes do not coincide on a case-by-case basis with the observed medicanes. However, observed medicanes with a high intensity and relatively long duration of tropical characteristics are better replicated in simulations. The observed spatial distribution of medicanes is generally well simulated, while the monthly distribution reveals the difficulty of simulating the medicanes that first appear in September after the summer minimum in occurrence. Increasing the horizontal resolution has a systematic and generally positive impact on the frequency of simulated medicanes, while the general underestimation of their intensity is not corrected in most cases. The capacity of a few models to better simulate the medicane intensity suggests that the model formulation is more important than reducing the grid spacing alone. A negative intensity feedback is frequently the result of air-sea interaction for tropical cyclones in other basins. The introduction of air-sea coupling in the present simulations has an overall limited impact on medicane frequency and intensity, but it produces an interesting seasonal shift of the simulated medicanes from autumn to winter. This fact, together with the analysis of two contrasting particular cases, indicates that the negative feedback could be limited or even absent in certain situations. We suggest that the effects of air-sea interaction on medicanes may depend on the oceanic mixed layer depth, thus increasing the applicability of ocean–atmosphere coupled RCMs for climate change analysis of this kind of cyclones.
Beam test performance of the SKIROC2 ASIC Amjad, M.S.; Anduze, M.; Augustin, J.-E. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2015, Letnik:
778
Journal Article
Recenzirano
Beam tests of the first layers of CALICE silicon tungsten ECAL technological prototype were performed in April and July 2012 using 1–6GeV electron beam at DESY. This paper presents an analysis of the ...SKIROC2 readout ASIC performance under test beam conditions.
Biomarkers of food intake (BFIs) are a promising tool for limiting misclassification in nutrition research where more subjective dietary assessment instruments are used. They may also be used to ...assess compliance to dietary guidelines or to a dietary intervention. Biomarkers therefore hold promise for direct and objective measurement of food intake. However, the number of comprehensively validated biomarkers of food intake is limited to just a few. Many new candidate biomarkers emerge from metabolic profiling studies and from advances in food chemistry. Furthermore, candidate food intake biomarkers may also be identified based on extensive literature reviews such as described in the guidelines for Biomarker of Food Intake Reviews (BFIRev). To systematically and critically assess the validity of candidate biomarkers of food intake, it is necessary to outline and streamline an optimal and reproducible validation process. A consensus-based procedure was used to provide and evaluate a set of the most important criteria for systematic validation of BFIs. As a result, a validation procedure was developed including eight criteria, plausibility, dose-response, time-response, robustness, reliability, stability, analytical performance, and inter-laboratory reproducibility. The validation has a dual purpose: (1) to estimate the current level of validation of candidate biomarkers of food intake based on an objective and systematic approach and (2) to pinpoint which additional studies are needed to provide full validation of each candidate biomarker of food intake. This position paper on biomarker of food intake validation outlines the second step of the BFIRev procedure but may also be used as such for validation of new candidate biomarkers identified, e.g., in food metabolomic studies.
An improved design for an integrated polarization converter is presented. The device is designed for monolithic integration with active and passive components on InP-InGaAsP. A novel simplified ...fabrication process is demonstrated. Measured polarization conversion >97% over a wavelength range of >35 nm agrees well with simulations.
A tolerant single etch-step passive polarization splitter on InP/InGaAsP is designed and fabricated. The device consists of a directional coupler with a wide and a narrow waveguide. Modal ...birefringence of the third-order modes for transverse electric (TE) and transverse magnetic (TM) polarizations is employed to selectively couple one polarization. Tapering is applied to increase the tolerances. The devices are characterized, and the measurement results show good agreement with the beam-propagation-method simulations: a splitting ratio larger than 95% for a width range of around 100 nm and over a large wavelength range, covering at least the C-band
Abstract
Background
Extracellular volume (ECV) determined by magnetic resonance imaging (MRI) is considered a marker of myocardial fibrosis and a predictor of mortality. In addition to diffuse ...fibrosis, aortic stenosis (AS) patients present increased ECV. However, the impact of regional ECV differences on arrhythmia vulnerability in AS patients has not been assessed.
Purpose
To investigate regional ECV differences in AS patients and to determine their impact on ventricular arrhythmia vulnerability.
Methods
MRI was performed in 51 AS patients (32 males, 19 females) before and 3 months after aortic valve replacement (AVR). Regional differences in ECV were measured between mid-ventricular and basal planes. To investigate their impact on arrhythmia vulnerability, a computational biventricular model was developed from MRI data of the patient who presented the highest ECV difference between the planes in absence of a scar determined by late gadolinium enhancement (male 75y, post-AVR, ECV mid 25.5%, ECV base 31.3%, Figure A). The model was divided in two regions and extracellular conductivities (GE) were adjusted in each region as described previously (1), with additional GE reduction in the high ECV region representing increased interstitial fibrosis. This approach resulted in GE being 26.4% lower for ECV of 31.3% when compared to ECV of 25.5%. A model with uniform ECV of 25.5% was used as a control. Myocardial tissue was modelled with a cell radius of 16 micrometers, as reported in AS patients (2). The right ventricular apex was paced with S1=750 ms for 10 beats, followed by rapid pacing with different cycle lengths spanning the 20 ms window before the loss of stimulus capture to test arrhythmia inducibility. The simulations were repeated with an additional GE reduction by 30% and 60% in both regions to mimic conduction delays from diffuse fibrosis.
Results
Cardiac MRI showed significantly higher ECV in the basal plane of AS patients when compared to the mid-ventricular plane, both before and after AVR (Figure B), with the largest ECV found after AVR (mid-ventricular: p<0.0001; basal: p=0.0011). No sex-specific differences were found. Simulations in the model with patient-derived ECV showed slightly longer QRS and lower CV than the model with uniform ECV (Table). By contrast, myocardial fibrosis had a larger impact on CV slowing. Arrhythmia was inducible when either diffuse fibrosis was present or ECV at the ventricular base was increased (Table).
Conclusion
Regional differences in ECV were found in the ventricles of AS patients. Computer simulations suggest that these differences have a minimal effect on ventricular conduction when compared to diffuse fibrosis. However, they might increase arrhythmia vulnerability even in the absence of diffuse fibrosis. Additional studies are necessary to investigate the effects of each on arrhythmia maintenance and cardiac mechanics.
The excellent jet energy resolution required for precise physics measurements at ILC is achievable using a Particle Flow Method and highly granular calorimeters. As it was shown by CALICE ...international R&D collaboration, the silicon-tungsten imaging electromagnetic calorimeter provides the best granularity, stability and resolution of jet energy measurement. After proving the calorimeter concept with physical prototypes in 2005–2011, an emphasis is now moved to building a technological prototype satisfying challenging requirements. All chosen technologies should be reliable and scalable for a mass production of a future detector. We report on the current status of R&D, in particular, on beam and charge injection tests of the technological prototype and on the tests of ECAL mechanical structure. We also report on our plans to build a realistic prototype detector and test it together with an existing carbon fiber-tungsten mechanical structure. A similar silicon-tungsten calorimeter technology has been recently proposed for the Phase 2 upgrade of CMS end-cap calorimeter and future high energy circular collider projects.
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