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Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. FTO is an N6-methyladenosine (m6A) demethylase that participates in various biological events, while its role in DR remains elusive. Herein, we detected elevated FTO expression in retinal proliferative membranes of DR patients. FTO promoted endothelial cell (EC) cell cycle progression and tip cell formation to facilitate angiogenesisin vitro, in mice and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC-microglia interactions to induce retinal inflammation and neurodegenerationin vivoandin vitro. Mechanistically, FTO affected EC features via modulatingCDK2mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate mediated histone lactylation. FB23-2, an inhibitor to FTO’s m6A demethylase activity, suppressed angiogenic phenotypesin vivoandin vitro. Noteworthy, we developed a nanoplatform encapsulating FB23-2 for systemic administration, and confirmed its targeting and therapeutic efficiencies in mice. Collectively, our study demonstrated that FTO coordinates EC biology and retinal homeostasis in DR, providing a promising nanotherapeutic approach for DR.

In this paper, we propose an estimation algorithm for the shape of the road using trails of leading vehicles via a linear mixed model (LMM) approach. A vehicle trail is essentially the motion traje...

Currently, the inflow conditions used in the study of oblique detonation engines are ideal premixed inflow, and there are few studies on non-premixed inflow. The fuel mixing process in the flow field structure and mixing degree for forming oblique blast waves has essential significance. This paper uses a combination of theoretical analysis and numerical simulation to study the inlet section of the oblique detonation engine. The governing equations are the inviscid Euler equations coupled with chemical reaction source terms, and the second-order TVD scheme is used to solve the equations. First, this paper compared the influence of the single hydrogen nozzle parameters on the flow field structure and the hydrogen mole fraction distribution at the outlet, optimized the hydrogen jet structure, and analyzed the coupling effect between the incoming flow and the jet. The closer the nozzle location is to the supersonic inlet, the lower the Mach number, and the higher the equivalence ratio of hydrogen to oxygen, the better the fuel and air mixing effect. And too large or too small hydrogen injection angle will make the hydrogen too concentrated on the wall and insufficient penetration depth, which reduces the mixing of hydrogen. Secondly, while maintaining the same fuel mass flow rate as the single hydrogen nozzle, this paper increases the number of hydrogen nozzles, thereby increasing the obstruction to the incoming flow and improving the fuel mixing effect. Finally, because the physical ramp and aerodynamic ramp as a method of increasing mixing will lead to fuel concentration on the wall, which is not conducive to the subsequent combustion, this paper proposes an optimization model of the strut injection method. The results show that strut injection can effectively improve the mixing degree of hydrogen and air at the exit and solve the problem of fuel concentration at the wall by using the staggered jet and baroclinic effect of hydrogen. This paper reveals the law of fuel injection in the inlet and provides essential data support for studying oblique detonation engines in a non-premixed environment.

This paper put forward the theory of processing behavior through research on conceptual system of advanced manufacturing technologies and production modes such as cloud manufacturing and systematic classification of processing technology, and gave the concept of processing behavior primitive element. The processing behavior was classified and the relationship between different levels of processing behavior was clarified. To realize the standardization of NC processing technology for parts of automatic turning programming. Embed turning behavior into the design elements, realize the combination of design and manufacturing, shorten the time and space of coordination and product cycle, reduce product design and manufacturing costs, and achieve green, low consumption, high quality, high efficiency and effective manufacturing of turning parts.

Purpose Rearranged during transfection (RET) fusions are important genetic drivers in non-small cell lung cancer (NSCLC). Selective RET inhibitors are setting a new paradigm in RET-driven NSCLC. However, the real-world treatment patterns, outcomes and toxicity remain largely unknown. Methods Data from RET fusion-positive NSCLC patients treated in our centre were retrospectively analysed. Of them, patients diagnosed before and after August 2018 were included in analysis of treatment patterns; and patients received selective RET inhibitors were eligible for analysis of adverse events (AEs). Results Patients diagnosed before August 2018 (n = 30) predominantly received chemotherapy and immunotherapy (83%) as initial therapy, while patients diagnosed after August 2018 (n = 39) mainly received selective RET inhibitors (38.5% at first-line; 50.0% at second-line). In the total 69 patients, overall survival (OS) was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients. In the 38 patients received selective RET inhibition, median progression-free survival (PFS) was 11.9 months. AEs ≥ grade 3 occurred in 42.1% patients and were not associated with PFS (p = 0.63) or OS (p = 0.60). Haematological toxicity ≥ grade 3 occurred in 31.6% patients and was the leading cause of drug discontinuation. Conclusion Selective RET inhibitors are increasingly being adopted into clinical practice and are associated with improved OS. However, treatment-related ≥ grade 3 AEs, especially haematologic AEs, occur frequently in real-world setting.

Immune checkpoint inhibitors (ICIs), especially anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies, have made dramatic progress in the treatment of lung cancer, especially for patients with cancers not driven by oncogenes. However, responses are limited to a subset of patients, and which subset of patients will optimally benefit from ICI remains unknown. With the advantage of being minimally invasive and dynamic, noninvasive biomarkers are promising candidates to predict response, monitor resistance, and track the evolution of lung cancer during ICI treatment. In this review, we focus on the application of circulating tumor DNA (ctDNA) in plasma in immunotherapy. We examine the potential of pre- and on-treatment features of ctDNA as biomarkers, and following multiparameter analysis, we determine the potential clinical value of integrating predictive liquid biomarkers of ICIs to optimize patient management. We further discuss the role of ctDNA in monitoring treatment resistance, as well as challenges in clinical translation.

In this paper, we discuss the photonic spin Hall effect (PSHE) in the combined structure of periodic dielectric waveguides (PDWs) and photonic crystal waveguide (PCW). By controlling the polarization of the dipole source, we have successfully achieved the arbitrary manipulation of PSHE for the PDW guided mode in our structure. The advantage of PDW is that it can be designed to different shapes without the geometric constraints, and still maintains a relatively high transmission rate. Therefore, by further changing the structure, including the adjustment of the intersection angle between PDW and PCW, and the alteration of the straight PDW to the bending or bifurcated shapes, we find that the output of highly unidirectional PSHE is mainly determined by the intersection angle between PDW and PCW and almost independent of the detailed shape of PDW.

Discovery of activating mutations in epidermal growth factor receptor (EGFR) as a predictive biomarker for first-generation EGFR tyrosine kinase inhibitors (TKIs) has initiated an era of precision oncology for the treatment of advanced EGFR-mutant non-small cell lung cancer (NSCLC). Despite the robust efficacy of first- and second-generation EGFR TKIs, disease relapse is inevitable. EGFR T790M mutation is the predominant cause of disease relapse and third-generation, irreversible EGFR inhibitors designed for targeting EGFR T790M and activating mutations have demonstrated promising clinical activity and tolerability. Unfortunately, disease progression inevitably occurs and heterogenous resistance mechanisms have been reported with limited subsequent treatment strategies available. Till now, treatment approaches for patients progressed from third-generation EGFR TKIs have not been clearly established. In this review, we summarize the recent findings in resistance mechanisms to third-generation EGFR TKIs and emerging treatment approaches for EGFR-mutant patients after resistance to third-generation EGFR TKIs. We further discuss clinical challenges and future perspectives for management of EGFR-mutant patients resistant to third-generation EGFR TKIs.

In this article, we extended the approach of Dai et al. (2017) to several populations case and compared various other approaches on simulated and real data. The results show that the naive Bayes classifier for functional data is applicable to multi-category classification problems and has preferable finite-sample performance over competitors.

Although the activation method of permonosulfate has been gradually developed, its practical application is severely restricted by the high cost and difficult recovery of the catalyst, thereby resulting in secondary pollution. In this study, the application potential of self-decolorization of dyes and degradation of other pollutants through persulfate(PS) activation was examined by building a self-decolorization system. The results showed that the dyes could activate PS under visible light irradiation, which could realize not only the self-decolorization of dyes, but also the degradation of other pollutants. The degradation rates of rhodamine B and bisphenol A could reach 80% and 90%, respectively. This process included both free radical reaction pathways and nonradical reaction pathways. The active oxidants produced in the system included superoxide radicals, sulfate radicals, hydroxyl radicals, and singlet oxygen. The self-decolorization efficiency of dyes was related to the type of dyes, initial concentration of the dyes, dosage of PS, and initial pH of the solution. Meanwhile, the initial concentrations of the dyes and other pollutants had a great influence on the degradation of other pollutants. This study provides a new idea for economic and environmental protection in the PS activation method, and has broad application prospects in the treatment of printing and dyeing wastewater.

Via enlarging the specific surface area of sludge biochar to enhance the close contact of multiple reactants may be a simple route to improve the catalytic performance with reduced dosage of biochar and oxidant, benefitting for cost-effectiveness and eco-friendliness. Herein, PS activation ability of a reported sludge-derived biochar adsorbent was investigated. 80% TOC of 100 mL 10 mg/L BPA was removed within 40 min by 7 mg biochar and 0.5 mM PS mixed, with a relatively high PS activation efficiency close to 50%. Expectedly, the desired mineralization efficiency of complex actual wastewater was also identified. Eco-friendliness of the application mode was confirmed by the leaching toxicity and acute bio-toxicity tests. Physicochemical properties of the sludge biochar were comprehensively characterized by various techniques. Combined with a series of mechanism analysis, ·OH, SO4·-, ·O2-, 1O2, free electron all participated in pollutants removal process and the non-radical pathway of electron transfer dominated the reaction. The generated metastable complex [SBC-PS*] confirmed by in situ FT-IR and Raman spectra was the most important active species for electron transfer and PS decomposition. Due to the high efficiency and stability, the sludge biochar adsorbent/PS catalytic system provides a promising way for waste reuse and advanced wastewater treatment.

To explore the difference in the emission of air pollutants from coal stoves, five new and common residential coal stoves (square briquette, baffled heat exchange, heating and cooking integrated gasification positive burning, and gasification reverse burning stove) were selected. The emission level of major air pollutants was determined using simulated combustion in the laboratory for quantitatively evaluating the environmental effects of different coal stoves. Moreover, the factors and reasons for the differences were identified, and suggestions for the reduction of emission were proposed. The results showed that: ① the emissions of air pollutants from different coal stoves were significantly different; the heating and cooking integrated stove had the largest emission intensity (2.9 kg ·t

Inflammation constitutes an important component of non-alcoholic fatty liver disease. STAT3 is a direct target of inflammatory cytokines, but also mediates glycolipid metabolism in the liver. As a potent inhibitor of STAT3, the effect of Nifuroxazide (Nifu) on glycolipid metabolism in liver has not been reported. In this study, we used palmitic acid (PA)-induced HepG2 cells to examine the expression of inflammatory factors and apoptosis-related proteins and the content of triglyceride (TG), total cholesterol (TC), and glycogen. The expression of hepatic lipogenic proteins (ACCα, SREBP-1c, FAS), gluconeogenesis enzymes (PEPCK, G6Pase, and IRS2), the IL-6/STAT3/SOCS3 inflammatory axis, and the insulin signaling pathway was determined. Our study shows that Nifu significantly improves lipid metabolism disorders in the PA-induced HepG2 cells, whereas, it remarkably reduced intracellular free fatty acid (FFA), TG, and TC content, suppressed lipid synthesis, and increased lipid decomposition. Our results also showed that Nifu significantly improved dysregulated glucose metabolism in the PA-treated HepG2 cells, increased glycogen content, and inhibited gluconeogenesis. Further research indicated that Nifu markedly inhibited activation of the IL-6/STAT3/SOCS3 signaling pathway. Finally, due to anti-inflammatory stress, Nifu enhanced insulin signaling in the PA-induced HepG2 cells. Therefore, Nifu can improve glucose and lipid metabolism in the PA-induced HepG2 cells, which provides new evidence that Nifu has a positive effect on PA-induced cellular hepatic steatosis and improves glucose metabolism in HepG2 cells, providing a new perspective for studying drug treatment of glucose and lipid metabolism disorders.

2591 Background: Immune checkpoint inhibitors (ICIs) have suboptimal efficacy in non-small cell lung cancer (NSCLC) patients with ERBB2 mutations, including ERBB2 exon 20 insertions. This study aims to investigate the efficacy of ICIs and immune characteristics in NSCLC patients harboring ERBB2 ex20ins and non-ex20ins mutations. Methods: Advanced NSCLC patients harboring ERBB2 mutations were recruited from January 2016 to December 2020. Pre-ICI tumor tissue samples were collected and performed with targeted next-generation sequencing. Patients received ICIs were followed up every 3 months until November 2021. Genomic features were compared between patients with ERBB2 ex20ins and non-ex20ins mutations. Progression-free survival (PFS), overall survival (OS), and tumor immune microenvironment (TIME) features characterized by multiplex immunohistochemistry (IHC) were further analyzed in patients receiving ICIs. Two-sample T-tests were performed to compare means; Cox models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Two external datasets of ERBB2-mutant NSCLC patients, including TCGA (n = 23) and META (n = 33), were used for validation. Results: A total of 117 eligible patients were enrolled (median age: 59 [range: 24-82], males 57.3%, stage IV 68.4%, adenocarcinoma 93.2%), of whom 37 received subsequent ICI treatment. similar PD-L1 tumor proportion score (mean: 8.1% vs. 13.2%, p = 0.25) and significantly lower mutation number (mean: 3.0 vs. 6.2 muts/person, p < 0.01) were detected in patients with ERBB2 ex20ins, compared to patients with ERBB2 mutations other than ex20ins. Similarly, in the TCGA cohort, tumor mutation burden was significantly lower in ERBB2 ex20ins patients (mean: 2.2 vs. 10.3 muts/Mb, p = 0.02). Of 37 patients receiving ICIs, ERBB2 non-ex20ins patients displayed superior PFS (mPFS: 13.5 vs. 4.4 months, HR: 0.31, 95% CI: 0.14-0.71), relatively long OS (mOS: 27.5 vs. 8.1 months, HR: 0.47, 95% CI: 0.20-1.14), and a relatively high rate of durable clinical benefit (64.3% vs. 34.8%, p = 0.10) than ex20ins patients, consistent with what was observed in the META cohort (PFS, mPFS: 13.2 vs. 2.5 months, HR: 0.20, 95% CI: 0.06-0.68; OS, mOS: 23.3 vs. 8.0 months, HR: 0.32, 95% CI: 0.11-0.90). Moreover, the CD4+ T cell density appeared to be lower in the tumor stroma of ERBB2 ex20ins patients than that of non-ex20ins patients (300.5 vs. 1288.0 /mm2, p = 0.08), even though the general TIME features of ex20ins patients were similar to those of non-ex20ins patients. Conclusions: NSCLC patients carrying ERBB2 ex20ins demonstrated worse clinical outcome under ICI treatment, similar PD-L1 expression and lower mutation number when compared to those with non-ex20ins mutations. Genomic and TIME characteristics should be further investigated to elucidate the efficacy of ICIs in lung cancer patients carrying ERBB2 mutations.

Ionization source based on thruster of anode layer using on the spacecraft has been investigated greatly recently. Based on the principle and structure model of the ionization source, we introduce the Particle-In-Cell Monte-Carlo-Collision (PIC-MCC) plasma simulation method into the vacuum discharge process and study on the discharge characteristics of the ionization source. The comparison results show that the discharge characteristics of anode layer ionization source such as the beam energy, beam density change with the discharge voltage, working pressure and gas type. The discharge characteristics from simulation get a good agreement with experimental results. The simulation is instructive for further research on the optimization design and characteristics research of ionization source in the material modification process.

A general mathematical model of the AMTEC/TEG hybrid system consisting of alkali metal thermal electric converter (AMTEC) and thermoelectric generator (TEG) has been developed, in which the load parameters and main geometric parameters were considered. Instead of specifying some parameters, the evaporating temperature and condensing temperature of the AMTEC as well as the operating temperature of the TEG subsystem were determined by solving energy balance equations. Results show that electrode current density has a quite noticeable influence on both AMTEC subsystem and TEG subsystem. The maximum conversion efficiencies for AMTEC and AMTEC/TEG are 27.42% and 31.33%, respectively. Besides, it is interesting to note that the optimal value of the ratio of thermoelectric module area to electrode area is always near 0.2 regardless of the ratio of evaporator heat transfer area to electrode area. The length of thermoelectric arms l and the ratio of the thermoelectric couple area to the total area of the thermoelectric module b are critical factors, b ≥ 0.55 and l ≤ 11 mm should be satisfied to obtain a compact and low-cost system.

The performance of solar photovoltaic-thermoelectric generation hybrid system (PV-TGS) and solar photovoltaic-thermoelectric cooling hybrid system (PV-TCS) under different conditions were theoretic...

Objective Endoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism. Methods The triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα, SREBP-1c, LXRα, CPT-1α, PGC-1α and PPARα), ER stress and mitochondrial function related genes (GRP78, eIF2α, ATF4, BCL-2, and SDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKβ/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice. Results ACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenous ACE2 improved lipid metabolism through the IKKβ/NFκB/IRS-1 pathway in skeletal muscle. Conclusions ACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.

Inflammation and oxidative stress are important factors that cause islet β-cell dysfunction. STAT3 is not only a major factor in cell proliferation and differentiation, but also plays an important role in mediating inflammation. As a potent inhibitor of STAT3, the effect of Nifuroxazide (Nifu) on pancreatic islet cells in a high glucose environment has not been reported. In the present study, we used high concentration glucose-induced INS-1 cells to examine the effects of Nifu on high glucose-induced cell function by glucose-stimulated insulin secretion (GSIS). The effects of Nifu on high glucose-induced oxidative stress were recorded by oxidative factors and antioxidant factors. Simultaneously, the effect of Nifu on the inflammatory response, apoptosis, and STAT3/SOCS3 signal pathway were validated by quantitative real-time PCR (qRT-PCR) and Western blot. Our study indicated that Nifu significantly improved cell vitality and insulin secretion of INS-1 cells induced by high glucose. We found Nifu significantly inhibited pro-oxidative factors (ROS, MDA) and promoted anti-oxidative factors (SOD, GSH-PX, CAT). Meanwhile, qRT-PCR and Western blot results showed that inflammatory and apoptosis factors were remarkably inhibited by Nifu. Further research indicated that Nifu clearly suppressed the activation of the STAT3/SOCS3 signaling pathway. In conclusion, Nifu can significantly improve the insulin secretion function, protect oxidative stress injury, and reduce inflammatory response and apoptosis in high glucose-induced INS-1 cells. Therefore, Nifu has a new positive effect on maintaining the normal function of pancreatic islet cells in a high glucose environment and provides new drug candidates for the treatment and prevention of diabetes.

The treatment of advanced non-small cell lung cancer (NSCLC) has evolved from palliative cytotoxic chemotherapy to precise medicine based on genetic alternations over the last decade. Anaplastic lymphoma kinase (ALK) rearrangement characterizes a molecular subset of NSCLC with an impressive response to crizotinib.To analyze the efficacy of crizotinib in first-line treatment of adults with advanced ALK-positive NSCLC, updated data on development and recent advances of first-line crizotinib in this subset population are reviewed.To date, crizotinib should be established as a standard of care in previously untreated advanced NSCLC with ALK-rearrangement. However, the efficacy of first-line crizotinib is limited by acquired resistance. Second generation ALK inhibitors have demonstrated clinical activity in both crizotinib-refractory and crizotinib naïve setting. How to maximize first-line benefit for advanced ALK-positive NSCLC remains challenging. Combinational strategy, advances in companion diagnostics and optimization of ALK inhibitors might contribute to improve outcome in this subset of patients in future.

Background: Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC). Here, we report resistance mechanisms to abivertinib, a novel third-generation EGFR TKI, from a phase I dose-escalation/expansion study (NCT02330367). Methods: Patients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR TKIs received abivertinib in dose escalation (50–350 mg twice daily [BID]) or expansion (300 mg BID) cohorts. Patients enrolled at Guangdong Lung Cancer Institute who underwent next-generation sequencing (NGS)-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis. Findings: Thirty of 73 patients enrolled were eligible for resistance analysis. Upon abivertinib progression, 27 patients provided plasma samples (six patients also provided paired samples from the progression sites) and three patients only provided tissue samples from the progression sites for NGS. A heterogeneous landscape of resistance to abivertinib was observed: 15% (4/27) experienced EGFR T790M loss and 13% (4/30) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (37%), and considered a putative resistance mechanism in seven (23%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation. Interpretation: Our findings reveal a heterogenous pattern of resistance mechanisms to abivertinib which is distinct from that previously reported with osimertinib. EGFR amplification was the most common resistance mechanism in this cohort. Fund: The National Key R&D Program of China (Grant No. 2016YFC1303800), Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120). Keywords: Abivertinib, Resistance mechanisms, EGFR T790M mutation, NSCLC, EGFR amplification

Background: Resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a major clinical challenge in advanced non-small cell lung cancer (NSCLC). Here, we report resistance mechanisms to abivertinib, a novel third-generation EGFR TKI, from a phase I dose-escalation/expansion study (NCT02330367), and describe clinical strategies to overcome EGFR amplification-mediated resistance. Methods: Patients with EGFR T790M-positive advanced NSCLC and progression on prior EGFR TKIs received abivertinib in dose escalation (50-350 mg twice daily [BID]) or expansion (300 mg BID) cohorts. Patients enrolled at Guangdong Lung Cancer Institute who underwent next-generation sequencing-based genomic profiling upon abivertinib progression (prior to October 30, 2018) were enrolled in this exploratory analysis. Findings: Thirty-two of 73 patients enrolled were eligible for resistance analysis. A heterogeneous landscape of resistance mechanisms to abivertinib was observed with 14% (4/28) experiencing EGFR T790M loss and 13% (4/32) developing EGFR tertiary mutations including C797S. EGFR amplification was observed in 11 patients (34%), and considered a putative resistance mechanism in seven (22%) patients. Other EGFR-independent resistance mechanisms involved CDKN2A, MET, PIK3CA, HER2, TP53, Rb1 and small-cell lung cancer transformation. We demonstrated that abivertinib plus nimotuzumab or afatinib is effective and tolerable in overcoming EGFR amplification-mediated resistance to abivertinib. Interpretation: Our findings reveal a heterogenous pattern of resistance mechanisms to abivertinib which is distinct from that previously reported with osimertinib. EGFR amplification was the most common resistance mechanism in this cohort and may be overcome by combining abivertinib with an EGFR monoclonal antibody or afatinib. Funding: This work was supported by The National Key R&D Program of China (Grant No. 2016YFC1303800, to Q Zhou), Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Lab of Translational 447 Medicine in Lung Cancer (Grant No. 2012A061400006/2017B030314120, to YL WU). Medical writing support was provided by Siân Marshall PhD, SIANTIFIX Inc., Cambridge, UK, funded by ACEA Therapeutics Inc. Declaration of Interest: QZ declares grants from National Key R&D Program of China, speaker fees from AstraZeneca and Roche. Y-LW declares grants from Key Lab System Project of Guangdong Science and Technology Department, speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. XX is the CEO and stock owner of ACEA Therapeutics Inc. WT, FRL are employees of ACEA Therapeutics Inc. S-KC, J-YY, H-ZH, ZZ are employees of Burning Rock Biotech. Other authors declare no competing interests. Ethical Approval: This study was approved by the ethics committee at Guangdong General Hospital, and all patients provided written, informed consent. The study adhered to the principles of Declaration of Helsinki and the Good Clinical Practice guidelines.

Background The third-generation EGFR tyrosine kinase inhibitor osimertinib has been approved in many countries to treat advanced NSCLC in patients with the EGFR T790M mutation. As the development of acquired resistance is inevitable, it is urgent that the mechanisms of such resistance be clarified. Methods DNA samples from a cohort of 340 patients with lung adenocarcinoma who were taking osimertinib were subjected to next-generation sequencing and screened in terms of the frequencies of the L792H and G796R mutations. Ba/F3 cells stably expressing the EGFR L858R/T790M mutations (in cis) with either the L792H or G796R mutation were created to investigate the impact of the two novel mutations on EGFR tyrosine kinase inhibitors and other potential drug combinations in vitro. Structural analyses were performed by using Schrodinger/Maestro software (version 11.1.012, Schrodinger LLC, Cambridge, MA). Results L792H and G796R were detected in 1.76% (six of 340) and 0.56% (two of 340) patients with lung adenocarcinoma treated with osimertinib, respectively. The introduction of L792H or G796R mutations against an L858R/T790M background caused dramatic reductions in osimertinib sensitivity. Structural modeling showed that mutations in cis with T790M either forced the ligand (osimertinib) to rotate out (breaking the binding) or pulled the hinge loop (breaking the hinge). Various other drug combinations. including cetuximab with EAI045, failed to inhibit either cis mutant effectively. Conclusions The EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations conferred resistance to osimertinib both in vitro and in silico. For patients in whom the two resistance mutations occur at low frequency, more precise treatment strategies and additional combinational approaches are required.

During persistent antigen stimulation, CD8(+) Tcells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of Tcell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished Tcell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) Tcells to protect against Listeria infection and attenuate tumor growth invivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) Tcells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) Tcells invivo. Our data show that NFAT promotes Tcell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.

Liquid biopsies, especially the analysis of circulating tumor DNA (ctDNA), as a novel and non-invasive method for the diagnosis and monitoring of non-small cell lung cancer (NSCLC) have already been implemented in clinical settings. The majority of ctDNA is released from apoptotic or necrotic tumor cells, thus reflecting the genetic profile of a tumor. Numerous studies have reported a high concordance in mutation profiles derived from liquid biopsy and tissue biopsy, especially in driver genes. Liquid biopsy could overcome the clonal heterogeneity of tumour biopsy, as it provides a single snapshot of a tumour tissue. Moreover, non-invasiveness is the biggest advantage for liquid biopsy, and the procedure can be repeatedly performed during the treatment for the purpose of monitoring. Therefore, ctDNA could act as a potential complementary method for tissue biopsies in diagnosis, prognostic, treatment response and resistance. Areas covered: This review summarizes the recent advancements in liquid biopsy with a focus on NSCLC, including its applications and technologies associated with assessing ctDNA. The authors conclude the review by discussing the challenges associated with liquid biopsy. Expert commentary: The analysis of ctDNA represents a promising method for liquid biopsy, which will be a novel and potentially complementary method in diagnosis, treatment and prognostic in NSCLC at all stages.

The treatment paradigm of non-small cell lung cancer (NSCLC) has evolved into oncogene-directed precision medicine. Identifying actionable genomic alterations is the initial step towards precision medicine. An important scientific progress in molecular profiling of NSCLC over the past decade is the shift from the traditional piecemeal fashion to massively parallel sequencing with the use of next-generation sequencing (NGS). Another technical advance is the development of liquid biopsy with great potential in providing a dynamic and comprehensive genomic profiling of NSCLC in a minimally invasive manner. The integration of NGS with liquid biopsy has been demonstrated to play emerging roles in genomic profiling of NSCLC by increasing evidences. This review summarized the potential applications of NGS-based liquid biopsy in the diagnosis and treatment of NSCLC including identifying actionable genomic alterations, tracking spatiotemporal tumor evolution, dynamically monitoring response and resistance to targeted therapies, and diagnostic value in early-stage NSCLC, and discussed emerging challenges to overcome in order to facilitate clinical translation in future.

Introduction Increasing evidence has demonstrated that exon 19 deletions (Del19) and L858R mutation in EGFR have different prognostic and predictive roles in NSCLC. We aimed to investigate whether these two mutations produced differences in mechanisms of resistance to EGFR tyrosine kinase inhibitors. Methods Consecutive patients with advanced EGFR -mutant NSCLC who acquired resistance to EGFR tyrosine kinase inhibitors and underwent postprogression biopsy were enrolled. Mechanisms including T790M mutation, mesenchymal-epithelial transition proto-oncogene ( MET ) amplification, and histological transformation, as well as KRAS , phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene ( PIK3CA ) mutation, and anaplastic lymphoma receptor tyrosine kinase gene ( ALK ) fusion, were analyzed. Results The prevalence of T790M mutation was significantly higher in the Del19 subgroup than that in L858R subgroup (50.4% versus 36.5%, p = 0.043). Apart from this, there was no difference in other mechanisms including MET amplification and histological transformation. The median overall survival (OS) of patients with T790M mutation was 36.0 months (95% confidence interval [CI]: 30.9–41.2), which was significantly longer than the 26.5 months (95% CI: 24.0–29.0) in MET -positive patients, 19.7 months (95% CI: 18.2–21.2) in patients with histological transformation, and 23.0 months (95% CI: 17.4–28.6) in the KRAS/PIK3CA/ALK -altered population ( p = 0.021). The hazard ratios of the MET -amplification subgroup and subgroup with histological transformation were 1.809-fold and 2.370-fold higher than that in T790M-positive subgroup. The median OS times were months 33.3 (95% CI: 28.9–37.7) in the Del19 subgroup and 26.4 months (95% CI: 23.2–29.6) in the L858R subgroup ( p = 0.028). However, in multivariable analysis adjusted for T790M genotype, the EGFR mutation subtype was no longer found to be significant. Conclusions Significant OS benefit was observed in patients with T790M mutation, suggesting that a larger proportion of T790M mutation might contribute to the better survival of patients with Del19.

Plasma Optical Emission Spectroscopy was employed to investigate hysteresis process of reactive sputtering with high purity Zn target in the presence of Ar plus O2 plasma. An optimal working point was obtained through analyzing hysteretic curve in order to deposit high quality ZnO film. Scanning Electron Microscope was used to characterize effects of various O2 flow rate on surface crystal structure of samples. The SEM results indicate that the structure of ZnO film is strongly dependent on O2 flow rate at constant pressure and power. Specially, At 1.6 sccm O2 flow rate, the sample with best crystallite structure has been observed. Energy-dispersive X-ray Spectroscopy also demonstrates the relationship between the chemical compositions of ZnO films and O2 flow rate. The film to 1.6 sccm O2 shows the optimal atom ratio of Zn to O and the mass ratio of Zn to O. The water contact angle measurement also shows various O2 flow rate strongly affects wettability.

In order to solve the traditional problems such as long designing cycle and high designing cost, the research applies the virtual simulation technology to the design of cathode target on magnetron sputtering vacuum coater. Through analyzing, modeling and simulating, the process model of a typical cathode target on magnetron sputtering coater is proposed. The virtual design of cathode target framework based on distributed collaborative simulation is constructed, which provides a theorial basis for the research of virtual design on cathode target.Using Solidworks software, parts modeling and assembly modeling of cathode target are realized. Using ADAMS, the movements of charged particles in magnetic field and high frequency alternating electric field are simulated, and the visual animation simulation of particles movement is achieved. The research demonstrates the feasibility of virtual simulation technology on vacuum coater design.

The Ta2O5/SiO2 Multi-layer Antireflection Coating Is Prepared on K9 Glass by RF Magnetron Sputtering Technology in the Experiment. the Growth Parameters Are Changed to Get Multi-layer Antireflection Film with Good Optical Properties. in the Technical Research, the Influence of Various Growth Parameters, Including Working Pressure, Oxygen Content, Substrate Temperature, Etc., on the Optical Properties and Structures of the Coatings Are Studied. Optical Properties and Morphological Features such as Surface, Structure Are Investigated by UV-VIS Spectrophotometer and AFM, Respectively. the Detecting Results Further Verify the Important Influences of Proper Growth Parameters on Optical Properties of Antireflection Coating.

During the reactive sputtering process, due to the hysteresis effect, the sputtering state should be maintained in the transition region of the hysteresis curve which can used to obtain stoichiometric compound films at a high deposition rate. If sputtering state changes, it is impossible to make the sputtering state step back to the original point by manually control the process parameters, because the hysteresis is irreversible. Thus it requires a method of fast feedback to control the sputtering power and the reaction gas flow rate into the chamber. In this paper the PEM (plasma emission monitor) control system and the single neuron self-adaptive PID algorithm have been designed to maintain the sputtering state in proper condition, namely preventing the target from poisoned in the reactive sputtering. The signal acquisition and the controller design were the major parts of the PEM system. The signal acquisition was realized by the optical emission spectrometer. And the single neuron self-adaptive PID controller has been designed in the paper. Using the MATLAB software, the simulation experiments have been done. The output waveforms showed that using traditional non-adaptive PID control algorithm, the overshoot is over 6% and the regulation time is over 1.8s, but using single neuron self-adaptive PID algorithm the overshoot 0 and regulation time 0.5s. Monitoring the target spectral intensity at various reaction gas flow rate, several conclusions could be obtained. The overshoot 6% indicated that the reactive gas flow into the chamber was excessive, the target was poisoned and the sputtering state in chemical mode. And while the overshoot was zero which indicated that the target poisoned was avoided and the reaction ran in defined condition. The PEM using the single neuron self-adaptive PID algorithm responded faster than that using the traditional PID algorithm. The PEM system designed in the paper can effectively avoid the target poisoned and make the reactive sputtering maintain at an ideal state.

Background Previous works indicated that the stress on the endoplasmic reticulum (ER) affected nonalcoholic fatty liver disease (NAFLD). However, there is no clear evident on the effect of the regulation of ER stress by angiotensin-converting enzyme 2 (ACE2) on the prevention of NAFLD. Methods HepG2 cells were treated with thapsigargin (Tg) or palmitic acid (PA). We analysed ACE2 expression using Western-blotting analyses. ER stress-related proteins were detected in ACE2 knockout mice and Ad-ACE2-treated db/db mice by immunofluorescence or Western-blotting analyses. In ACE2-overexpression HepG2 cells, the triglyceride (TG), total cholesterol (TC), and glycogen content were detected by assay kits. Meanwhile, the expression of hepatic lipogenic proteins (ACCα, SREBP-1c, FAS, and LXRα), enzymes for gluconeogenesis (PEPCK, G6Pase, and IRS2), and IKKβ/NFκB/IRS1/Akt pathway were analysed by Western-blotting analyses. Results ACE2 was significantly increased in Tg/PA-induced cultured hepatocytes. Additionally, ACE2 knockout mice displayed elevated levels of ER stress, while Ad-ACE2-treated db/db mice showed reduced ER stress in liver. Furthermore, activation of ACE2 can ameliorate ER stress, accompanied by decreased TG content, increased intracellular glycogen, and downregulated expression of hepatic lipogenic proteins and enzymes for gluconeogenesis in Tg/PA-induced hepatocytes. As a consequence of anti-ER stress, the activation of ACE2 led to improved glucose and lipid metabolism through the IKKβ/NFκB/IRS1/Akt pathway. Conclusions This is the first time documented that ACE2 had a notable alleviating role in ER stress-induced hepatic steatosis and glucose metabolism via the IKKβ/NFκB/IRS1/Akt-mediated pathway. This study may further provide insight into a novel underlying mechanism and a strategy for treating NAFLD.

We followed 103 patients for 6-16 months after discharge from elective long-term video/EEG monitoring to compare clinical outcomes and quality of life between patients diagnosed with epileptic (ES) and those diagnosed with psychogenic nonepileptic (PNES) seizures. Outcome measures determined at telephone or mail follow-up included seizure frequency, antiepileptic drug use, and self-reported quality of life using the Quality of Life in Epilepsy inventory. Of the 62 responders, 41 were diagnosed with ES and 11 with PNES, using strictly applied criteria. Those with ES reported significant improvement in Seizure Worry (P=0.003), Medication Side Effects (P0.001), and Social Function (P0.001). In addition, both groups showed a decrease in seizure frequency. Furthermore, both groups showed a significant decrease in antiepileptic drug use at follow-up, with a greater, and sustained, decrease for the PNES group. Approximately half the patients in each group reported an improvement in overall condition.

BACKGROUND: Previously, tachyplesin gene (tac) has been successfully transferred into Undaria pinnatifida gametophytes using the method of microprojectile bombardment transformation. The objectives of this study were to compare and evaluate the performance of bubble-column and airlift bioreactors to determine a preferred configuration of bioreactor for vegetative propagation of transgenic U. pinnatifida gametophytes, and to then investigate the influence of light on vegetative propagation of these gametophytes, including incident light intensity, photoperiod and light quality to resolve the problems of rapid vegetative propagation within the selected bioreactor.

The life cycle of seaweed Laminaria japonica involves a generation alternation between diploid sporophyte and haploid gametophte. The expression of foreign genes in sporophte has been proved. In this research, the recombinant expression in gametophyte was investigated by particle bombardment with the rt-PA gene encoding the recombinant human tissue-type plasminogen activator (Reteplase), which is a thrombolytic agent for acute myocardial infarction (AMI). Transgenic gametophytes were selected by their resistance to herbicide phosphiothricin (PPT), and proliferated in an established bubble column photo-bioreactor. According to the results from quantitative ELISA, Southern blotting, and fibrin agarose plate assay (FAPA) for bioactivity, it was showed that the rt-PA gene had been integrated into the genome of gametophytes of L. japonica, and the expression product showed the expected bioactivity, implying the proper post-transcript modification in haploid gametophyte.