Co-occurring EGFR p.E709X mutation Mediates Primary Resistance to the Third-generation EGFR-TKIs in EGFR p.G719X-mutant Patients with Advanced NSCLC.

PURPOSE: Current NCCN guidelines recommend afatinib or osimertinib as the preferred first-line treatment strategy for patients with advanced NSCLC harboring EGFR p.G719X mutation. However, in the absence of head-to-head trials comparing afatinib with osimertinib in EGFR p.G719X mutant patients, it is unclear which regimen is the preferred treatment option. EXPERIMENTAL DESIGN: A large cohort of 4228 treatment-naïve patients with lung cancer who underwent targeted NGS testing was screened for EGFR p.G719X mutation. A multicenter cohort involving 68 EGFR p.G719X-mutant patients with advanced NSCLC and NGS profiling was retrospectively enrolled to evaluate clinical responses to afatinib(n=37) and the third-generation EGFR-TKIs(n=31). Ba/F3 cells stably expressing the EGFR p.G719A mutation were created to investigate the response to EGFR-TKIs in vitro. RESULTS: Concurrent EGFR p.E709X mutations, being the most frequent co-occurring EGFR mutation in EGFR p.G719X-mutant NSCLC(~30%), exerted a detrimental effect on outcomes in patients treated with third-generation EGFR-TKI(G719X/E709X vs. G719X; ORR:0.00% vs. 47.62%, P<0.001; mPFS:7.18 vs. 14.2 months, P=0.04; respectively). Conversely, no significant difference was found in the treatment efficacy of afatinib between EGFR p.G719X/E709X and EGFR p.G719X patients(G719X/E709X vs. G719X; ORR:71.43% vs. 56.67%, P=0.99; mPFS:14.7 vs. 15.8 months, P=0.69; respectively). In vitro experiments elucidated a resistant drug sensitivity and poor inhibition of EGFR phosphorylation in Ba/F3 cells expressing EGFR p.G719A/E709K mutation upon the third-generation EGFR-TKIs treatment. CONCLUSION: Co-occurring EGFR p.E709X mutation mediates primary resistance to the third-generation EGFR-TKIs in EGFR p.G719X-mutant patients but remained sensitive to afatinib. A personalized treatment strategy should be undertaken based on the co-existing EGFR p.E709X mutation status.

Study of Mass Transfer Enhancement of Electrolyte Flow Field by Rotating Cathode in Through-Mask Electrochemical Micromachining.

To solve the problem of the nonuniform distribution of temperature and electrolytic products in the electrolyte flow field during through-mask electrochemical micromachining, the use of a rotating cathode with surface structures is proposed. The rotation of the cathode increases the efficiency of heat and mass transfer by the electrolyte flow. Simulations are performed to analyze the influence of the type of surface structure, the number of surface structures, and the rotational speed of the cathode on the electrolyte flow field. The results show that the use of a rotating cathode with surface structures significantly improves the mass transfer efficiency of the electrolyte flow field in comparison with a conventional cathode structure, and, in particular, a grooved rotating cathode can increase the outlet flow velocity by about 23%. An experimental demonstration of micropit array processing shows that the use of a grooved rotating cathode increases the mass transfer efficiency by 34% and the processing efficiency by nearly 40% compared with a smooth-surfaced rotating cathode. The grooved rotating cathode also gives the highest machining accuracy. Using this cathode, a uniform micropit array with an average micropit diameter of 201.83 µm, a diameter standard deviation of 3.49 µm, and a depth standard deviation of 0.87 µm is processed.

High-efficiency and low-energy ship recognition strategy based on spiking neural network in SAR images.

Ship recognition using synthetic aperture radar (SAR) images has important applications in the military and civilian fields. Aiming at the problems of the many model parameters and high-energy losses in the traditional deep learning methods for the target recognition in the SAR images, this study has proposed a high-efficiency and low-energy ship recognition strategy based on the spiking neural network (SNN) in the SAR images. First, the visual attention mechanism is used to extract the visual saliency map from the SAR image, and then the Poisson encoder is used to encode it into a spike train, which can suppress the background noise while retaining the visual saliency feature of the SAR image. Besides, an SNN model integrating the time-series information is constructed by combining the leaked and integrated firing spiking neurons with the convolutional neural network (CNN), which can use the firing frequency of the spiking neurons to realize the ship recognition in SAR images. Finally, to solve the problem that SNN model is difficult to train, the arctangent function is used as the surrogate gradient function of the spike emission function during the backpropagation. Hence, applying this backpropagation method to the training process can optimize the SNN model. The experimental results show the following: (1) the proposed strategy can more accurately recognize the ship in the SAR image, and the F1 score can reach 98.55%, which has a better recognition performance than the other traditional deep learning methods; (2) the proposed strategy has the least amount of model parameters (only 3.11MB), which is far less than the model parameters of the other traditional deep learning methods; (3) the proposed strategy has fewer operations (only 17.97M) and can reach 1/30 time of operands of the other traditional deep learning methods, which shows the high efficiency of the proposed strategy using the spike emission signals; (4) the proposed strategy has the energy loss of 1.38 × 10-6J, which can achieve the low energy advantage of nearly three orders of the magnitude compared to the other traditional deep learning methods, indicating that the proposed strategy has a significant energy efficiency.

Influence of Different Tool Electrode Materials on Electrochemical Discharge Machining Performances.

Electrochemical discharge machining (ECDM) is an emerging method for developing micro-channels in conductive or non-conductive materials. In order to machine the materials, it uses a combination of chemical and thermal energy. The tool electrode's arrangement is crucial for channeling these energies from the tool electrode to the work material. As a consequence, tool electrode optimization and analysis are crucial for efficiently utilizing energies during ECDM and ensuring machining accuracy. The main motive of this study is to experimentally investigate the influence of different electrode materials, namely titanium alloy (TC4), stainless steel (SS304), brass, and copper-tungsten (CuW) alloys (W70Cu30, W80Cu20, W90Cu10), on electrodes' electrical properties, and to select an appropriate electrode in the ECDM process. The material removal rate (MRR), electrode wear ratio (EWR), overcut (OC), and surface defects are the measurements considered. The electrical conductivity and thermal conductivity of electrodes have been identified as analytical issues for optimal machining efficiency. Moreover, electrical conductivity has been shown to influence the MRR, whereas thermal conductivity has a greater impact on the EWR, as characterized by TC4, SS304, brass, and W80Cu20 electrodes. After that, comparison experiments with three CuW electrodes (W70Cu30, W80Cu20, and W90Cu10) are carried out, with the W70Cu30 electrode appearing to be the best in terms of the ECDM process. After reviewing the research outcomes, it was determined that the W70Cu30 electrode fits best in the ECDM process, with a 70 µg/s MRR, 8.1% EWR, and 0.05 mm OC. Therefore, the W70Cu30 electrode is discovered to have the best operational efficiency and productivity with performance measures in ECDM out of the six electrodes.

Ultrasound-Assisted Through-Mask Electrochemical Machining of Hole Arrays in ODS Superalloy.

Micro-hole arrays have found wide applications in aerospace, precision instruments, and biomedicine. Among various methods of their production, including mechanical, laser, and electrical discharge, electrochemical machining (ECM) is considered the most lucrative due to its wide processing range, high surface quality, and excellent productivity. In particular, ultrasound-assisted through-mask ECM exhibits an enhanced machining precision due to ultrasonic cavitation, which promotes the removal of the electrolytic products and bubbles. In this study, the equation of cavitation bubble oscillation was derived and numerically solved to study the influence of six different parameters on the ultrasonic cavitation and electrolysis process, and their optimal values were determined. The feasibility of the proposed ultrasound-assisted through-mask ECM technology with the optimized parameters was experimentally corroborated by the fabrication of a high-quality hole array in an oxide dispersion strengthened (ODS) MA956 superalloy.

Ganoderma Lucidum Polysaccharide Peptide Alleviates Hepatoteatosis via Modulating Bile Acid Metabolism Dependent on FXR-SHP/FGF.

BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) encompasses a series of pathologic changes ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma. The purpose of this study was to determine whether ganoderma lucidum polysaccharide peptide (GLPP) has therapeutic effect on NAFLD. METHODS: Ob/ ob mouse model and ApoC3 transgenic mouse model were used for exploring the effect of GLPP on NAFLD. Key metabolic pathways and enzymes were identified by metabolomics combining with KEGG and PIUmet analyses and key enzymes were detected by Western blot. Hepatosteatosis models of HepG2 cells and primary hepatocytes were used to further confirm the therapeutic effect of GLPP on NAFLD. RESULTS: GLPP administrated for a month alleviated hepatosteatosis, dyslipidemia, liver dysfunction and liver insulin resistance. Pathways of glycerophospholipid metabolism, fatty acid metabolism and primary bile acid biosynthesis were involved in the therapeutic effect of GLPP on NAFLD. Detection of key enzymes revealed that GLPP reversed low expression of CYP7A1, CYP8B1, FXR, SHP and high expression of FGFR4 in ob/ob mice and ApoC3 mice. Besides, GLPP inhibited fatty acid synthesis by reducing the expression of SREBP1c, FAS and ACC via a FXR-SHP dependent mechanism. Additionally, GLPP reduced the accumulation of lipid droplets and the content of TG in HepG2 cells and primary hepatocytes induced by oleic acid and palmitic acid. CONCLUSION: GLPP significantly improves NAFLD via regulating bile acid synthesis dependent on FXR-SHP/FGF pathway, which finally inhibits fatty acid synthesis, indicating that GLPP might be developed as a therapeutic drug for NAFLD.

A Study of Electrochemical Machining of Ti-6Al-4V in NaNO3 solution.

The titanium alloy Ti-6Al-4V is used in many industries including aviation, automobile manufacturing, and medical equipment, because of its low density, extraordinary corrosion resistance and high specific strength. Electrochemical machining (ECM) is a non-traditional machining method that allows applications to all kinds of metallic materials in regardless of their mechanical properties. It is widely applied to the machining of Ti-6Al-4V components, which usually takes place in a multicomponent electrolyte solution. In this study, a 10% NaNO3 solution was used to make multiple holes in Ti-6Al-4V sheets by through-mask electrochemical machining (TMECM). The polarization curve and current efficiency curve of this alloy were measured to understand the electrical properties of Ti-6Al-4V in a 10% NaNO3 solution. The measurements show that in a 10% NaNO3 solution, when the current density was above 6.56 A·cm-2, the current efficiency exceeded 100%. According to polarization curve and current efficiency curve, an orthogonal TMECM experiment was conducted on Ti-6Al-4V. The experimental results suggest that with appropriate process parameters, high-quality holes can be obtained in a 10% NaNO3 solution. Using the optimized process parameters, an array of micro-holes with an aperture of 2.52 mm to 2.57 mm and maximum roundness of 9 µm were produced using TMECM.