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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.

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.

Background In previous studies, the predictive role of BIM deletion polymorphism with respect to responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) has been controversial. The potential reasons for these inconsistent findings were unknown. Methods Data from CTONG0901 clinical trial and medical records of Guangdong Lung Cancer Institute (GLCI) were retrospectively pooled. A total of 194 and 141 EGFR‐mutant non‐small cell lung cancer (NSCLC) patients treated with first‐ and second‐generation EGFR‐TKIs were examined in the CTONG0901 and GLCI cohorts, respectively. Sixty‐eight patients were treated with third‐generation EGFR‐TKIs in the GLCI cohort. The BIM gene status was examined by next‐generation sequencing. Results The frequency of BIM deletion polymorphism was 11.3% and 17.0% in CTONG0901 and GLCI cohorts, respectively. For first‐ and second‐generation EGFR‐TKIs in CTONG0901 cohort, objective response (ORR) was 54.5% in BIM deletion group versus 56.4% in wild‐type BIM group (P = .87); disease control rate (DCR) was 90.9% versus 88.4% (P = 1.00); progression‐free survival (PFS) was 10.5 versus 11.2 months (P = .59); and overall survival (OS) was 20.5 versus 20.5 months (P = .73). In GLCI cohort, ORR was 54.2% versus 60.7% (P = .55); DCR was 91.7% versus 96.6% (P = .27); PFS was 10.1 versus 11.6 months (P = .63); and OS was 58.5 versus 45.0 months (P = .93). For third‐generation EGFR‐TKIs, ORR was 18.2% versus 63.2% (P = .02); DCR was 81.8% versus 96.5%, (P = .12); PFS was 5.8 versus 9.0 months (P = .13); and OS was 30.0 versus 24.8 months (P = .85). Cox regression analysis showed that concomitant genetic alterations could adversely affect the response to EGFR‐TKIs, but not BIM deletion. Conclusions The presence of BIM deletion showed no relation to an impaired response to first‐, second‐, and third‐generation EGFR‐TKIs in NSCLC patients. The factors influencing the response of EGFR‐TKIs were concomitant genetic alterations, but not BIM deletion.

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.

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas1 receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. Ace2 knockout mice (Ace2-/y) and Mas1 knockout mice (Mas1-/-) displayed impaired thermogenesis. Mice transplanted with brown adipose tissue from Mas1-/- display metabolic abnormalities consistent with those seen in the Ace2 and Mas1 knockout mice. In contrast, impaired thermogenesis of Leprdb/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of Ace2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids, and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel potential therapeutic targets for the treatment of metabolic disorders.

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.

In this paper, the thermal generation and milling stability of titanium alloy during machining are investigated mainly. A new definition of processing behavior is given based on the principles of minimization, entity expression and combination, and a model of side milling behavior is constructed. Through a series of side milling orthogonal experiments on Ti-6Al-4V titanium alloy, the cutting forces under different process parameters are obtained. Further, the cutting force coefficients of the model is calculated by the complete average algorithm and the peak average algorithm, and the milling stability of the system is analyzed by a stability lobe diagram. The results show that the different cutting parameters have important influences on the milling stability of titanium alloy.

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.

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.