Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by ...onset of resistance.
We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.
Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET-dependent pathways, which were upregulated in GEO-CR cells. Furthermore, activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenous activation of MET by HGF stimulation in cetuximab-sensitive GEO and SW48 cells induced resistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-α, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-α overexpression induced the EGFR-MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.
These results suggest that overexpression of TGF-α through induction of EGFR-MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer.
The bioactive compounds in myrtle berries, such as phenolic compounds and anthocyanins, have shown a potentially positive effect on human health. Efficient extraction methods are to be used to obtain ...maximum amounts of such beneficial compounds from myrtle. For that reason, this study evaluates the effectiveness of a rapid ultrasound-assisted method (UAE) to extract anthocyanins and phenolic compounds from myrtle berries. The influence of solvent composition, as well as pH, temperature, ultrasound amplitude, cycle and solvent-sample ratio on the total phenolic compounds and anthocyanins content in the extracts obtained were evaluated. The response variables were optimized by means of a Box-Behnken design. It was found that the double interaction of the methanol composition and the cycle, the interaction between methanol composition and temperature, and the interaction between the cycle and solvent-sample ratio were the most influential variables on the extraction of total phenolic compounds (92.8% methanol in water, 0.2 s of cycle, 60 °C and 10:0.5 mL:g). The methanol composition and the interaction between methanol composition and pH were the most influential variables on the extraction of anthocyanins (74.1% methanol in water at pH 7). The methods that have been developed presented high repeatability and intermediate precision (RSD < 5%) and the bioactive compounds show a high recovery with short extraction times. Both methods were used to analyze the composition of the bioactive compounds in myrtle berries collected from different locations in the province of Cadiz (Spain). The results obtained by UAE were compared to those achieved in a previous study where microwave-assisted extraction (MAE) methods were employed. Similar extraction yields were obtained for phenolic compounds and anthocyanins by MAE and UAE under optimal conditions. However, UAE presents the advantage of using milder conditions for the extraction of anthocyanins from myrtle, which makes of this a more suitable method for the extraction of these degradable compounds.
The region around the Galactic Center (GC) is now well established to be brighter at energies of a few GeV than what is expected from conventional models of diffuse gamma-ray emission and catalogs of ...known gamma-ray sources. We study the GeV excess using 6.5 yr of data from the Fermi Large Area Telescope. We characterize the uncertainty of the GC excess spectrum and morphology due to uncertainties in cosmic-ray source distributions and propagation, uncertainties in the distribution of interstellar gas in the Milky Way, and uncertainties due to a potential contribution from the Fermi bubbles. We also evaluate uncertainties in the excess properties due to resolved point sources of gamma rays. The GC is of particular interest, as it would be expected to have the brightest signal from annihilation of weakly interacting massive dark matter (DM) particles. However, control regions along the Galactic plane, where a DM signal is not expected, show excesses of similar amplitude relative to the local background. Based on the magnitude of the systematic uncertainties, we conservatively report upper limits for the annihilation cross-section as a function of particle mass and annihilation channel.
Amongst the most critical in-service loads to be considered during the design phase to ensure the flight safety the bird strike event plays a key-role. Under this scenario, regulations pay particular ...attention on the wing leading edge component. In this paper, starting by a verified Finite Element (FE) modelling technique, herein discussed, a numerical tendency analysis on the leading edge of a new concept of Tiltrotor has been carried out to support its design and to have indications on the best thickness to strength ratio which is able to satisfy the crashworthiness requirements. Given the bird impact scenarios (impact locations and impact angles), different thicknesses of the metallic component have been investigated, to assess the potential weight saving hence preserving the safety of flight. The results show consistency between the investigated thicknesses and impact scenarios, giving indications for the subsequent phase of the wing design.
Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment ...with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies.
Fue conducida una investigación con el objetivo de evaluar una metodología participativa para el desarrollo de híbridos heteróticos de maíz en condiciones de bajos insumos agroquímicos, en la finca ...de un productor del municipio La Palma, provincia de Pinar del Río. Se utilizaron como progenitores las diez variedades que más votos recibieron durante una feria de diversidad de maíz ejecutada con este fin. Se realizaron dos ciclos de autofecundación, bajo las condiciones fitotécnicas acostumbradas en la región y además se realizaron mediciones de ocho descriptores. Se analizó la carga recesiva en la generación F1 y se calculó depresión consanguínea para cada generación. Se procesaron los datos utilizando Excel y SPSS 11.5. Se encontró, que las líneas no soportaron la depresión consanguínea en F2 bajo el ambiente de manejo de limitados insumos agroquímicos y la generación F1 obtenida de progenitores locales, mostraron menor depresión que las obtenidas de progenitores de otras provincias del país.
An investigation was conducted with the objective to evaluate a participatory methodology for maize_shybrid development, in agricultural low inputs conditions at farmer_s property in La Palma, province of Pinar del Río. Were used as progenitors, ten varieties more votes received duringthe maize diversity_s fair. Two self fecundation cycles was performed as well as the evaluation of eight describers. The recessive charge was analyzed in F1 and consanguineous depression was evaluated for each generation. All data were processed using Excel and SPSS 11.5. It was found that lines didn_t tolerate the consanguineous depression in the second generation from local progenitors, manifest lower depression that those obtained from progenitors from other provinces of the country.
Abstract The aim of this study is to evaluate and quantify the effect of the incoming flow on the coherent structures characterizing the wake of two NREL reference wind turbines with different ...dimensions: the NREL 5-MW and the NREL 15-MW. The Dynamic Mode Decomposition (DMD) approach has been used to detect dynamically-relevant flow structures. We employ the Sparsity-Promoting version of the DMD (SPDMD) algorithm for ranking the most relevant modes, in order to extract a limited subset of relevant flow features that optimally approximate the original data sequence. The dataset on which the SPDMD is based consists of ordered snapshots obtained by Large Eddy Simulations (LES), where the Actuator Line Method (ALM) simulates the rotor and the Immersed Boundary Method (IBM) models the tower and nacelle. To ensure a realistic comparison, the two turbines are subjected to two turbulent inflows with the same mean Atmospheric Boundary Layer (ABL) obtained through a precursor simulation. The results reveal significant differences in the dependence of the absolute value of the DMD amplitudes on the angular frequency for the two turbines. However, the coherent structures appear to have the same shape for the main modes, although the tip vortex structures have a higher dynamic relevance for the NREL 15-MW turbine. This is due to the larger length scales imposed by the rotor and the lower turbulence intensity at the taller rotor height.
Abstract
We report the discovery of four Fast Radio Bursts (FRBs) in the ongoing SUrvey for Pulsars and Extragalactic Radio Bursts at the Parkes Radio Telescope: FRBs 150610, 151206, 151230 and ...160102. Our real-time discoveries have enabled us to conduct extensive, rapid multimessenger follow-up at 12 major facilities sensitive to radio, optical, X-ray, gamma-ray photons and neutrinos on time-scales ranging from an hour to a few months post-burst. No counterparts to the FRBs were found and we provide upper limits on afterglow luminosities. None of the FRBs were seen to repeat. Formal fits to all FRBs show hints of scattering while their intrinsic widths are unresolved in time. FRB 151206 is at low Galactic latitude, FRB 151230 shows a sharp spectral cut-off, and FRB 160102 has the highest dispersion measure (DM = 2596.1 ± 0.3 pc cm−3) detected to date. Three of the FRBs have high dispersion measures (DM > 1500 pc cm−3), favouring a scenario where the DM is dominated by contributions from the intergalactic medium. The slope of the Parkes FRB source counts distribution with fluences >2 Jy ms is $\alpha =-2.2^{+0.6}_{-1.2}$ and still consistent with a Euclidean distribution (α = −3/2). We also find that the all-sky rate is $1.7^{+1.5}_{-0.9}\times 10^3$FRBs/(4π sr)/day above ${\sim }2{\rm \, }\rm {Jy}{\rm \, }\rm {ms}$ and there is currently no strong evidence for a latitude-dependent FRB sky rate.
The phenolic compounds and anthocyanins present in myrtle berries are responsible for its beneficial health properties. In the present study, a new, microwave-assisted extraction for the analysis of ...both phenolic compounds and anthocyanins from myrtle pulp has been developed. Different extraction variables, including methanol composition, pH, temperature, and sample⁻solvent ratio were optimized by applying a Box⁻Behnken design and response surface methodology. Methanol composition and pH were the most influential variables for the total phenolic compounds (58.20% of the solvent in water at pH 2), and methanol composition and temperature for anthocyanins (50.4% of solvent at 50 °C). The methods developed showed high repeatability and intermediate precision (RSD < 5%). Both methods were applied to myrtle berries collected in two different areas of the province of Cadiz (Spain). Hierarchical clustering analysis results show that the concentration of bioactive compounds in myrtle is related to their geographical origin.
•The levels of PAHs were investigated in commercial vegetable oils.•The maximum European limits were exceeded in 28% for total 4 PAHs and 12% for BaP.•43% of vegetable oils were adulterated.•The ...highest levels for PAHs were verified in adulterated samples predominantly.
This study aimed at evaluating the polycyclic aromatic hydrocarbons (PAHs) contamination of commercial vegetable oils and examined the identity through the fatty acids profiles. Coconut, safflower, evening primrose, and linseed oils marketed in São Paulo (Brazil) were investigated totaling 69 samples. Four PAHs, benzoaanthracene (BaA), chrysene (Chr), benzobfluoranthene (BbF), and benzoapyrene (BaP), were detected in 96% of the samples at individual levels ranging from not detected to 14.99 μg kg−1. Chrysene was the abundant hydrocarbon found among all types of oils, with the highest median values. The results of the fatty acid profiles revealed that 43% showed different profiles according to the ones on their labels, with a higher incidence of adulteration of evening primrose oils. The maximum tolerable limits by European Regulation No. 835/2011 were exceeded for BaP in 12%, and for total 4 PAHs in 28%, with a greater contribution of adulterated samples.
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