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BackgroundAnti-PD-1(L1) therapies are less efficacious in patients withEGFR-mutated non-small-cell lung cancer. However, the underlying mechanism is poorly understood.MethodsThe characteristics of T cells inEGFR-mutated and wild-type tumors were analyzed based on The Cancer Genome Atlas database and clinical samples. Plasma levels of 8 T-cell-related cytokines were evaluated and its association with immunotherapy efficacy were explored. Association between EGFR signaling pathway and IL-10 was examined through tumor cell lines and clinical tumor samples.In vitrorestimulation model of human CD8+T cells isolated from peripheral blood was used to analyze the impact of IL-10 on T cells. Doxycycline-inducible transgenicEGFRL858Rmouse models were used to investigate the efficacy of combining recombinant mouse IL-10 protein and PD-1 blockade and its underlying mechanismin vivo.ResultsEGFR-mutated tumors showed a lack of CD8+T cell infiltration and impaired CD8+T cell cytotoxic function. The incompetent CD8+T cells inEGFR-mutated tumors were characterized as absence of CD39 expression, which defined hallmarks of cytotoxic and exhausted features and could not be reinvigorated by anti-PD-1(L1) treatment. Instead, CD39 expression defined functional states of CD8+T cells and was associated with the therapeutic response of anti-PD-1(L1) therapies. Mechanically, IL-10 upregulated CD39 expression and was limited inEGFR-mutated tumors. IL-10 induced hallmarks of CD8+T cells immunity in CD39-dependent manner. Using autochthonousEGFRL858R-driven lung cancer mouse models, combining recombinant mouse IL-10 protein and PD-1 blockade optimized antitumor effects inEGFR-mutated lung tumors.ConclusionsOur study suggested that owing to low level of IL-10 to induce the expression of CD39 on CD8+T cells, fewer phenotypically cytotoxic and exhausted CD39+CD8+T cells inEGFR-mutated tumors could be potentially reinvigorated by anti-PD-1(L1) treatment. Hence, IL-10 could potentially serve as a cytokine-based strategy to enhance efficacy of anti-PD-1(L1) treatment inEGFR-mutated tumors.

Immune checkpoint inhibitors can cause immune-related toxicity in various systems, and myocarditis is the most serious life-threatening toxicity. This report introduces diagnosis and treatment of two cases which developed myocarditis after receiving PD-1 inhibitors therapy. The first case was a 77-year-old male with chordoma, who was treated by third-line sintilimab combined with anlotinib, and presented with symptoms of chest tightness, shortness of breath and upper eyelid ptosis three weeks later. He was diagnosed as immune-checkpoint-inhibitors-related myocarditis and myositis-myasthenia-gravis overlap syndrome based on his clinical symptoms, serum biomarkers, electrocardiogram, echocardiogram, and characteristic findings on cardiac 18F-FDG PET-MRI. Methylprednisolone was given 480 mg/d initially and was gradually reduced to 40 mg/d in 4 weeks, with the myocardial injury biomarkers declined in the same time. The second case was a 69-year-old female with advanced non-small cell lung cancer, who was treated by pemetrexed combined with bevacizumab and camrelizumab, and presented with palpitations 20 days later. She was diagnosed as immune-checkpoint-inhibitors-related myocarditis based on her clinical symptoms, serum biomarkers, electrocardiogram and echocardiogram. Methylprednisolone was given 240 mg/d initially and was gradually reduced to 40 mg/d with good response of myocardial injury biomarkers decline. However, the patient developed fatal myasthenia gravis afterwards, with little response to all treatments. These two cases revealed that, early detection and timely intervention, including discontinuation of immune checkpoint inhibitors and initiation of adequate steroid therapy, can reduce morbidity and mortality and improve prognosis.

Background Resistance is almost inevitable and is still a major obstacle in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Only limited relevant clinical studies evaluated the therapeutic effects by combing metformin and EGFR-TKIs in non-small cell lung cancer (NSCLC) patients. Therefore, we evaluated the efficacy of concurrent use of metformin with EGFR-TKIs, and assessed whether the addition of metformin may improve clinical outcomes and delay the occurrence of EGFR-TKI resistance. Methods We conducted cell proliferation and apoptosis assay for investigation of metformin in combination with EGFR-TKIs to overcome EGFR-TKI resistance in vitro. Furthermore, we retrospectively reviewed clinicopathological characteristics and therapeutic outcomes of EGFR-mutant advanced NSCLC diabetic patients who received EGFR-TKIs with or without concurrent use of metformin. Results In vitro experiment, metformin showed synergistic interaction both with gefitinib in PC9R (CI =0.77) and with osimertinib in PC9R/OR (CI =0.77) in proliferation inhibition assay. Metformin can also augment apoptosis effect of these TKI-resistant cells to EGFR-TKIs. In retrospective cohort, a total of 85 patients were identified (cohort A), in which 28 patients had concurrent use of metformin. The objective response rate in metformin use group was significantly higher (85.7% vs. 47.4%, P=0.001). The median progression-free survival (PFS) and overall survival (OS) in metformin use group were significantly longer (21.6 vs. 9.2 months, P=0.000; 48.4 vs. 36.6 months, P=0.049). Further analysis revealed that metformin obviously prolonged the median PFS2 of osimertinib treatment among patients who progressed to prior line EGFR-TKIs due to secondary EGFR T790M mutation (cohort B). Conclusions Our study suggest that concurrent use of metformin could be beneficial to EGFR-mutant NSCLC patients treated with either first-line EGFR-TKIs or second-line osimertinib.

BACKGROUND Although battlefield first-aid (BFA) training shares many common features with civilian training such as the need to address technical skills and non-technical skills (NTSs), it is more highly scenario-dependent. Studies into extended reality (XR) show clear benefits in medical training; however, the training effects of XR on NTSs, including teamwork and decision-making in BFA, have not been fully proven. OBJECTIVE The current study aimed to create and test a scenario-based, mixed-reality platform suitable for training NTSs in BFA. METHODS First, using next-generation modeling technology and an animation synchronization system, a 10-person offensive battle drill was established. Decision-making training software addressing basic principles of tactical combat casualty care was constructed and integrated into the scenarios with Unreal Engine 4. Large space teamwork and virtual interaction systems that made sense in the proposed platform were developed. Unreal Engine 4 and software engineering technology were used to combine modules to establish a mixed-reality BFA training platform. A total of 20 Grade-4 medical students were recruited to accept BFA training with the platform. Pre-training and post-training tests were carried out in two forms to evaluate the training effectiveness: one was knowledge acquisition regarding the NTSs, and another was a real-world, scenario-based test. In addition, the students were asked to rate their agreement with a series of survey items on a 5-point Likert scale. RESULTS A battlefield geographic environment, tactical scenarios, scenario-based decision software, large space teamwork, and virtual interaction system modules were successfully developed and combined to establish the mixed-reality training platform for BFA. The post-training score of the students’ knowledge acquisition was significantly higher than that of pre-training (t=−12.114, P≤0.001). Furthermore, the NTSs score and the total score that the students obtained in the real-world test were significantly higher than those before training (t=−17.756 and t=−21.354, respectively, P≤0.001). However, there was no significant difference between the scores of technical skills that the students obtained before and after training. Post-training survey revealed that the students found the platform helpful in improving NTSs for BFA, and they were confident in applying BFA skills after training. However, most trainees thought that the platform was not helpful to improve the technical skills of BFA, and 45% of the trainees were not satisfied with the simulation effect. CONCLUSIONS A scenario-based, mixed-reality platform was constructed in this study. In this platform, interaction of the movement of multiplayers in a large space and the interaction of decision-making by the trainees between the real world and the virtual world were accomplished. The platform could improve the NTSs of BFA. Future works, including improvement of the simulation effects and development a training platform that could effectively improve both technical and NTSs of BFA, will be carried out. CLINICALTRIAL Non-applicable.

Zhong, Xin, Zhao Ye, Xiaolin Zhou, Renqing Jiang, Yijun Jia, Wenqiong Du, Haoyang Yang, Lin Zhang, Bai Lu, and Zhaowen Zong. Time course of coagulo-fibrinolytic derangements during acclimatization to high altitude in rabbits and a preliminary study on the possible mechanisms.

DNA vaccines, as an effective prophylactic technology to induce both humoral and cellular immune responses, have already been widely studied to prevent and control viral and bacterial infections in aquaculture. To find a more effective and safer way to control Micropterus salmoides rhabdovirus (MSRV) infection in largemouth bass, two different DNA vaccines expressing partial (pcDNA3.1-G2) and full-length (pcDNA3.1-G) of the MSRV G protein were developed and injected intramuscularly with different doses. The immune effect was comprehensively compared and evaluated by detecting immune-related parameters including serum antibody levels, immune-related physiological indexes, immune-related gene expression and relative survival rates in this study. The results showed that compared with the pcDNA3.1-G vaccine, the pcDNA3.1-G2 vaccine induced higher serum antibody levels, a lower nonspecific immune response in serum (ACP, SOD and T-AOC activities), higher immune-related gene expression and a higher relative survival rate. Moreover, the immune effect of pcDNA3.1-G2-vaccinated fish showed gradually higher with the increasing pcDNA3.1-G2 concentration, especially in pcDNA3.1-G2 (10μg/per fish) group, the relative survival rate reached to 82.5%, which was significant higher (p 0.05) than pcDNA3.1-G (10μg/per fish) group. This study indicated that screening the potential core part of an antigen is an achievable strategy to improve the immunogenicity and immunoprotective effect of DNA vaccine.

Background A strong association between M descriptors and prognosis of non-small cell lung cancer (NSCLC) has been demonstrated recently. However, its predictive and prognostic significance for advanced NSCLC patients treated with immune checkpoint inhibitors (ICIs) remain unclear. In this study, we aimed at investigating the impact of M descriptors on clinical outcomes in those patients. Methods A retrospective analysis was conducted. Patients treated with more than two cycles of ICIs were included. Detailed characteristics and clinical response after immunotherapy were recorded. M descriptors were classified into M1a, M1b, and M1c according to the 8th TNM classification. Results A total of 103 patients were enrolled, including 42 with M1a disease, 16 with M1b disease and 45 with M1c disease. Patients with M1a disease demonstrated significant longer median progress-free survival (PFS) (11.9 vs. 4.1 and 3.2 months, respectively, P=0.0002) and overall survival (OS) (35 vs. 22.1 and 12 months, P=0.02) than those with M1b and M1c disease. Patients with M1a disease showed higher objective response rate (ORR) (28.6% vs. 14.8%, P=0.08) and disease control rate (DCR) (81% vs. 59%, P=0.02) compared with those with M1b and M1c disease. Multivariate analysis identified M1a stage as being independently associated with prolonged PFS and had better OS than those with M1c disease (P=0.05) but not M1b disease (P=0.06). Conclusions The current study demonstrated a clear association between M descriptors and the therapeutic response to ICIs and confirmed its prognostic role in advanced patients treated with ICIs monotherapy. M descriptors may need to be stratified in future study design.

Purpose Our previous study demonstrated that cytological specimens can be used as alternative samples for detecting anaplastic lymphoma kinase (ALK) fusion with the method of reverse transcriptase PCR (RT-PCR) in patients with advanced non-small-cell lung cancer (NSCLC). The current study aimed to investigate the feasibility of cytological specimens for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion detection by RT-PCR in advanced NSCLC patients. Patients and methods A total of 2,538 patients with advanced NSCLC, including 2,101 patients with cytological specimens and 437 patients with tumor tissues, were included in this study. All patients were screened for ROS1 fusion status by RT-PCR. The efficacy of crizotinib treatment was evaluated in ROS1 fusion-positive NSCLC patients. Results Among 2,101 patients with cytological specimens, the average concentration of RNA acquired from cytological specimens was 47.68 ng/μL (95% CI, 43.24-52.62), which was lower than the average of 66.54 ng/μL (95% CI, 57.18-76.60, P=0.001) obtained from 437 tumor tissues. Fifty-five patients harbored ROS1 fusion gene that was detected by RT-PCR, and 14 of them were treated with crizotinib. The incidence of ROS1 fusion was 1.95% (41/2,101) in 2,101 patients with cytological specimens, similar to the rate of 3.20% (14/437, P=0.102) for the 437 patients with tumor tissue. Regarding crizotinib treatment, no statistically significant differences were observed in the objective response rate (ORR) (81.8% vs 100%, P=0.604) between the cytological and tissue subgroups of ROS1-positive patients. Conclusion This study shows that cytological specimens can be utilized as alternative samples for ROS1 fusion detection by RT-PCR in advanced NSCLC patients.

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway have profoundly improved the clinical management of non-small-cell lung cancer (NSCLC). Nevertheless, the superiority of single-agent PD-1/PD-L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR-driven lung tumor models to investigate dynamic microenvironmental responses to EGFR-TKI treatment. We observed that at an early stage, sensitive EGFR-TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8+ T cells and dendritic cells, eradication of Foxp3+ Tregs, and inhibition of M2-like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune-mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid-derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR-TKIs increased the levels of IL-10 and CCL-2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR-TKIs in vivo. The results have implications for combination therapy using EGFR-TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.

Rail transit has become an indispensable part of urban development, but the rail corrugation in the process of vehicle running seriously affects the smooth and safe operation of vehicles. The rail grinding car can significantly reduce the impact of corrugation. The existing rail grinding equipment is heavy and not light enough. This paper mainly analyzes the design structure of the rail grinding unit based on statics, and optimizes the weight reduction of the connecting linkage.

Programmed cell death ligand 1 (PD-L1) expressed on tumor tissues is a vital molecule for immune suppression and its impact on the response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been reported. The significance of soluble PD-L1 (sPD-L1) for lung cancer patients remains unknown. This study investigated whether sPD-L1 could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to EGFR-targeted therapy. We retrospectively evaluated patients who received first-line treatment with EGFR-TKIs for advanced NSCLC with EGFR mutations. Pre-treatment plasma concentrations of PD-L1 and on-treatment (1 month after treatment initiation) plasma concentrations of PD-L1 were measured using the R-plex Human PD-L1 assay. The association between the sPD-L1 level and the clinical outcome was analyzed. Among 66 patients who were eligible for the study, patients with high pre-treatment or on-treatment sPD-L1 levels had decreased objective response rate (ORR) compared with that of patients with low sPD-L1 levels (39.4 vs. 66.7%, p = 0.026 for pre-treatment sPD-L1 level, and 43.5 vs. 73.9%, p = 0.025 for on-treatment sPD-L1 level). A high baseline sPD-L1 level was associated with a shortened progression-free survival (PFS) rate (9.9 vs. 16.1 months, p = 0.005). Both univariate and multivariate analyses showed that a high baseline sPD-L1 level was an independent factor associated with the PFS (hazard ratio [HR] 2.56, p = 0.011). Our study revealed that the sPD-L1 level was strongly related to the outcome of EGFR-TKIs in NSCLC patients harboring EGFR mutations.

Some histone deacetylases (HDACs) promote tumor cell growth and pan- or selective HDAC inhibitors are active in some cancers; however, the pivotal HDAC enzyme and its functions in human diffuse large B-cell lymphoma (DLBCL) remain largely unknown. Using NanoString nCounter assays, we profiled HDAC mRNA expression and identified HDAC6 as an upregulated HDAC family member in DLBCL tissue samples. We then found that HDAC6 plays an oncogenic role in DLBCL, as evidenced by its promotion of cell proliferation in vitro and tumor xenograft growth in vivo. Mechanistically, the interaction between HDAC6 and HR23B downregulated HR23B expression, thereby reducing the levels of casitas B-lineage lymphoma (c-Cbl), an E3 ubiquitin ligase for hepatocyte growth factor receptor (MET), which resulted in the inhibition of MET ubiquitination-dependent degradation. In addition, enhanced HDAC6 expression and decreased HR23B expression were correlated with poor overall survival rates among patients with DLBCL. Taken together, these results establish an HDAC6-HR23B-MET axis and indicate that HDAC6 is a potent promoter of lymphomagenesis in DLBCL. Thus, a therapeutic strategy based on HDAC6 inhibitors in combination with MET inhibitors is promising. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Aiming at the problem that it is difficult to realize the synchronization of motor speed under the electromechanical coupling condition of DC motor and vibrating mass in double machine drive vibration system, the PID parameters of DC motor are optimized by using master-slave control mode and genetic algorithm. Firstly, the electromechanical coupling model of the vibration system is established, and the differential equation of motion of the system is obtained by using Lagrange equation; Using master-slave control structure and genetic PID control algorithm, a controller based on master motor speed difference and slave motor phase difference is designed; The MATLAB/Simulink simulation model is established to verify the effectiveness of the control system. The experimental results show that the genetic PID algorithm based on master-slave control structure can better realize the synchronous control of dual machine driven vibration system. The research content can provide a theoretical basis for the design, control and application of this type of vibration system.

The synchronization characteristics of the circularly symmetrical four-vibrators vibration system are studied. Firstly, the dynamic model of this type of vibration system is established, and the Lagrange equation is used to derive the differential equation of motion. Secondly, the steady-state solution of the vibration system is obtained by averaging the phase of the eccentric rotor of the four exciters in the vibration system, and Hami is used. The frame principle deduces the synchronization conditions and stability conditions for the four vibration exciters of this type of vibration system to achieve synchronous motion. Finally, the correctness of the theoretical analysis is verified by numerical simulation. The relevant research results can provide a theoretical basis for the design of the circularly symmetrical four-vibrators vibration machine.

The sliding mode variable structure synchronous control of vibration pile driving system driven by double DC motors is studied. Firstly, the model of double machine driven vibratory pile driving system is established, and the theoretical derivation of system synchronization and stability is carried out. Secondly, the sliding mode variable structure control method is used to realize the phase speed synchronous control of two motors in the vibration system. Finally, Simulink is used to verify the correctness of the theoretical derivation, and the vibration displacement of the pile driving system is simulated and analyzed. The research shows that the sliding mode variable structure control can realize the synchronous control of the double machine driven vibratory pile driving system, which provides a theoretical and practical engineering basis for the design of this type of vibratory pile driving system.

In the working process of vibration machinery, as the output device of power source, the synchronous running state of motor has a decisive influence on the working efficiency of vibration machinery. This paper mainly studies the control synchronization of the double-mass vibration system driven by two motors. Firstly, the dynamic model of the vibration system is established and the vertical displacement equation of the vibration system is derived. Secondly, using adaptive model and PD control algorithm, the controller of motor in vibration system is designed to achieve accurate control of motor and eccentric block motion. Finally, the vibration synchronization effect of the control system and the effectiveness of the control system are verified by modeling and simulation with MATLAB/Simulink software. The test results show that when the main motor is in different initial phases, the variable parameter controller can achieve the control synchronization of the main motor and the slave motor in a short time and achieve a better control synchronization effect. Relevant research results can provide theoretical basis for the design of double-motor vibration machinery.

Objectives Small-cell lung cancer (SCLC) has been viewed as a smoking-related disease, with only 2% to 5% patients being never-smokers. This study aimed to investigate the clinical characteristics of never-smoking and its association with treatment outcomes in Chinese SCLC patients in real world. Methods We performed a retrospective study of 303 patients with SCLC and grouped into smokers and never-smokers. The clinical characteristics and treatment outcomes of two groups were collected and compared. Results In total, 113 patients with limited-stage (LS) SCLC and 190 patients with extensive-stage (ES) SCLC were enrolled. Sixty-nine (22.8%) patients were never-smokers. Both the median progression-free survival (PFS) and overall survival (OS) were significantly longer in never-smokers than in smokers (PFS, 8.37 vs. 7.10 months, P = 0.036; OS, 19.73 vs. 14.40 months, P = 0.044) in all populations. Multivariate analysis suggested that never-smoking was a significant favorable prognostic factor for PFS (HR = 0.753; P = 0.047) instead of OS (HR = 0.780; P = 0.236) in patients with SCLC. The objective response rate (ORR) to first-line therapy were similar between two group (52.6% vs. 59.4%, P = 0.315). Moreover, prophylactic cranial irradiation (PCI) resulted in marginally significantly longer PFS than observation in patients with ES-SCLC who obtained objective response after first-line therapy (10.57 vs. 7.73 months, P = 0.075). Conclusion The current study indicated that never-smokers are increasingly prevalent in Chinese patients with SCLC. Never-smokers with SCLC had significantly longer PFS and OS compared with smokers, and smoking was an independent poor prognostic factor for PFS in patients with SCLC.

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin’s lymphoma with limited data. In this study, a population-based study of primary breast DLBCL in the United States was performed to determine its incidence trends, prognostic factors, survival, the role of surgery as well as the comparison with nodal DLBCL. 1021 patients diagnosed with breast DLBCL were identified in the Surveillance, Epidemiology, and End Results (SEER) cancer registries from 1973–2014. The incidence of both breast and nodal DLBCL increased over time. Patients with breast DLBCL were older, mainly women, diagnosed at earlier stages and had lower prevalence in white and black races compared with nodal DLBCL. Multivariate analysis revealed older age (≥ 70 years old) and advanced stage as independent predictors of worse OS. Independent predictor of better DSS were younger age (< 70 years old), early stage and diagnosis after 2000. When analyzed according to age, stage, race, tumor laterality and year of diagnosis, the overall survival did not benefit from surgery except in patients diagnosed between 2001–2010 and the surgery rate decreased overtime. Compared with nodal DLBCL, breast DLBCL patients exhibited a better outcome. In conclusion, breast DLBCL is a rare tumor with increasing incidence and improved survival over the last four decades. The introduction of rituximab seems to improve the outcome of breast DLBCL. Further studies are needed to advance our understanding of breast DLBCL and optimize the treatment strategy.

To investigate the prognostic value of PD-L1 expression combined with CD8+ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD-L1, CD8+ TILs, and oncogenic alterations. PD-L1+ was detected in 71 (39.9%) and CD8high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR- were associated with both PD-L1+ and CD8high TILs. Patients with CD8high TILs had longer OS (P = 0.012). PD-L1- was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8high TILs (HR = 0.411; 95% CI, 0.177-0.954; P = 0.038), rather than PD-L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD-L1+ /CD8high and PD-L1+ /CD8low , respectively (P = 0.025). Inconsistent PD-L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD-L1 expression (P = 0.017 and 0.049, respectively). The combination of PD-L1 and CD8+ TILs density, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions. The level of PD-L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

BACKGROUND The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non–small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib. METHODS A total of 55 patients with ALK-positive NSCLC and 14 patients with ROS1-positive NSCLC who were treated with crizotinib were enrolled into the current study. The Bim deletion polymorphism was analyzed by polymerase chain reaction. The clinical features of the Bim deletion polymorphism and its impact on the effect of crizotinib were investigated. RESULTS The Bim deletion polymorphism was present in 9 of 69 patients with ALK-positive or ROS1-positive NSCLC (13.0%). There were no differences noted with regard to clinicopathological features between patients with and without the Bim deletion polymorphism. Patients with the Bim deletion polymorphism had a significantly shorter progression-free survival (PFS) and lower objective response rate compared with those without (median PFS, 182 days vs 377 days [P = .008]) (objective response rate, 44.4% vs 81.7% [P =.041]) in all populations. The significant difference in PFS was observed in patients with ALK-positive NSCLC (83 days vs 305 days [P =.0304]) compared with those with ROS1-positive NSCLC (218 days vs not reached [P =.082]). Multivariate analysis indicated that the Bim deletion polymorphism was an independent predictive factor for patients with ALK-positive NSCLC who were treated with crizotinib (hazard ratio, 4.786 [P =.006]). CONCLUSIONS The Bim deletion polymorphism was found to be associated with poor clinical response to crizotinib in patients with ALK fusion-positive NSCLC. Cancer 2017;123:2927–35. © 2017 American Cancer Society.

In this study 2D numerical simulation for two-stage entrained flow dry feed coal gasification performance was developed. The detailed operational characteristics of O/C distribution between the two stages of the gasifier were examined in standard CFD software FLUENT®14 to analyze their effects on the gasification performance. Furthermore the different reaction mechanisms were investigated for validation of the model with experimental results. The results show that H 2 and CO composition at the exit of gasifier are increased at O/C ratio 0.8 as compared to other simulation cases, and the temperature gradually decreases from 2nd injection level because of water-shift reaction. Maximum CO% was observed when 40% of oxygen injected at the lower level, overall range of H 2 % at the exit of gasifier was 10–45% but maximum H 2 % was found when 50% O 2 % and 30% of coal injected at a lower level. The maximum temperature about 2300 K when 40% O 2 and 40% of coal was injected at a lower level. Overall optimized results for CO, H 2 , and minimum CO 2 formation was observed when 60% O 2 and 40% of coal was injected at a lower level of the gasifier. The gasification performance can be controlled with the optimized coal/oxidant distribution between the stages.

Objectives EGFR-targeted tyrosine kinase inhibitors (TKIs) have been the standard treatment for non-small cell lung cancer patients with EGFR mutations. However, most patients eventually develop resistance. With the development of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1), there is a growing interest in developing combination strategies. However, there are concerns that the combination of a PD-(L)1 inhibitor and EGFR-TKI may be associated with an increased risk of pneumonitis. Therefore, we utilized an established EGFR-driven tumor-bearing mouse model to investigate whether the combination would induce pneumonitis in mouse lung tissue. Materials and Methods Mice were treated with monotherapy or combined therapy of PD-L1 antibody and EGFR-TKIs including first-generation gefitinib and third-generation osimertinib. Bronchoalveolar lavage fluids (BALFs) and lung tissues were collected for analysis at the end of treatment. Results and Conclusion The osimertinib and anti-PD-L1 combined treatment group had the highest inflammation scores in pathologic grades of H&E staining of lung tissue and had the highest percentages of myeloperoxidase positive cells. However, combining gefitinib and anti-PD-L1 treatment appeared to not increase the level of pneumonitis in mice. Total cell counts, neutrophil counts and total protein concentration in BALFs were also significantly increased in the osimertinib and anti-PD-L1 combined treatment group. We next evaluated proinflammatory factors in BALFs. The levels of IFN-γ, IL-2, IL-5, TNF-α and IL-12p70 were increased in osimertinib and anti-PD-L1 combined treatment group. Comparison of different sequences of drug administration demonstrated that mice treated with osimertinib followed by PD-L1 antibody did not show evident lung inflammation. Our findings indicate that osimertinib, rather than gefitinib combined with anti-PD-L1 treatment could lead to lung injury in an EGFR mutated tumor-bearing mouse model. The sequence and timing of combining EGFR-TKI and PD-L1 antibody may influence the severity of pneumonitis.

Purpose Our previous study demonstrated that cytological specimens can be used as alternative samples for detecting anaplastic lymphoma kinase (ALK) fusion with the method of reverse transcriptase PCR (RT-PCR) in patients with advanced non-small-cell lung cancer (NSCLC). The current study aimed to investigate the feasibility of cytological specimens for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion detection by RT-PCR in advanced NSCLC patients. Patients and methods A total of 2,538 patients with advanced NSCLC, including 2,101 patients with cytological specimens and 437 patients with tumor tissues, were included in this study. All patients were screened for ROS1 fusion status by RT-PCR. The efficacy of crizotinib treatment was evaluated in ROS1 fusion-positive NSCLC patients. Results Among 2,101 patients with cytological specimens, the average concentration of RNA acquired from cytological specimens was 47.68 ng/μL (95% CI, 43.24–52.62), which was lower than the average of 66.54 ng/μL (95% CI, 57.18–76.60, P=0.001) obtained from 437 tumor tissues. Fifty-five patients harbored ROS1 fusion gene that was detected by RT-PCR, and 14 of them were treated with crizotinib. The incidence of ROS1 fusion was 1.95% (41/2,101) in 2,101 patients with cytological specimens, similar to the rate of 3.20% (14/437, P=0.102) for the 437 patients with tumor tissue. Regarding crizotinib treatment, no statistically significant differences were observed in the objective response rate (ORR) (81.8% vs 100%, P=0.604) between the cytological and tissue subgroups of ROS1-positive patients. Conclusion This study shows that cytological specimens can be utilized as alternative samples for ROS1 fusion detection by RT-PCR in advanced NSCLC patients.

Emerging evidence has shown that exosomes derived from drug‐resistant tumour cells are able to horizontally transmit drug‐resistant phenotype to sensitive cells. However, whether exosomes shed by EGFR T790M‐mutant–resistant NSCLC cells could transfer drug resistance to sensitive cells has not been investigated. We isolated exosomes from the conditioned medium (CM) of T790M‐mutant NSCLC cell line H1975 and sensitive cell line PC9. The role and mechanism of exosomes in regulating gefitinib resistance was investigated both in vitro and in vivo. Exosome‐derived miRNA expression profiles from PC9 and H1975 were analysed by small RNA sequencing and confirmed by qRT‐PCR. We found that exosomes shed by H1975 could transfer gefitinib resistance to PC9 both in vitro and in vivo through activating PI3K/AKT signalling pathway. Small RNA sequencing and RT‐PCR confirmed that miR‐3648 and miR‐522‐3p were the two most differentially expressed miRNAs and functional study showed that up‐regulation of miR‐522‐3p could induce gefitinib resistance in PC9 cell. The findings of our study reveal an important mechanism of acquired resistance to EGFR‐TKIs in NSCLC.

Based on the dynamic model of the double-mass vibrating mechanical system, the adaptive control theory is introduced to study the motor control synchronization problem in the vibrating mechanical system. First, the dynamic model of the dual-mass nonlinear vibration system is studied, and the overall relationship between the motor motion and the vibration system is analyzed. Then, a dual-motor adaptive control strategy is designed, so that the parameters in the control system can be intelligently adjusted with the synchronization state of the motors, and the synchronization stability and motion trajectory between the motors are studied. Lyapunov stability criterion is used to verify the stability of the synchronous control system. Finally, MATLAB/Simulink is used to simulate the effectiveness of the dual-motor adaptive control system, which proves that the system has good robustness. Through research, it is found that the dual-motor vibration synchronization adaptive control strategy can keep the motors in the dual-mass nonlinear vibration system with good synchronization effects, and the system has good robustness. The research content can provide a certain theoretical reference for the research and design of multi-motor synchronous machinery.

Objective Data on the clinical activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR mutations remain insufficient. This study aimed to investigate the effect of first-line EGFR-TKIs or platinum-based chemotherapy in NSCLC patients with uncommon EGFR mutations. Methods We retrospectively enrolled 504 patients with EGFR-mutant NSCLC. The clinical characteristics and treatment outcomes were collected and compared between patients with common and uncommon EGFR-mutant NSCLC. Results Seventy patients (13.9%) harboring uncommon EGFR mutations were included. Thirty of these patients received EGFR-TKIs and 40 received platinum-based chemotherapy as first-line therapy. The objective response rate (ORR) and median progression-free survival (mPFS) of patients treated with TKIs in the uncommon mutation group was significantly inferior to that in the common mutation group (ORR: 23.3% vs. 51.8%, P=0.003; mPFS: 7.1 vs. 10.9 months, P

Hypoxia is a major cause of treatment resistance in breast cancer. Single-walled carbon nanotubes (SWCNTs) exhibit unique properties that make them promising candidates for breast cancer treatment. In the present study, a new functionalized single-walled carbon nanotube carrying oxygen was synthesized; it was determined whether this material could increase chemosensitivity and radiosensitivity of human breast cancer cell lines, and the underlying mechanisms were investigated. MDA-MB-231 cells growing in folic acid (FA) free medium, MDA-MB-231 cells growing in medium containing FA and ZR-75-1 cells were treated with chemotherapy drugs or radiotherapy with or without tombarthite-modified-FA-chitosan (R-O2-FA-CHI)-SWCNTs under hypoxic conditions, and the cell viability was determined by water-soluble tetrazolium salts-1 assay. The cell surviving fractions were determined by colony forming assay. Cell apoptosis induction was monitored by flow cytometry. Expression of B-cell lymphoma 2 (Bcl-2), survivin, hypoxia-inducible factor 1-α (HIF-1α), multidrug resistance-associated protein 1 (MRP-1), P-glycoprotein (P-gp), RAD51 and Ku80 was monitored by western blotting. The novel synthesized R-O2-FA-CHI-SWCNTs were able to significantly enhance the chemosensitivity and radiosensitivity of human breast cancer cell lines and the material exhibited its expected function by downregulating the expression of Bcl-2, survivin, HIF-1α, P-gp, MRP-1, RAD51 and Ku80.

The prognostic and clinicopathological value of regulatory T cells (Tregs) infiltration in patients with non-small cell lung cancer (NSCLC) remains undetermined. A comprehensive literature search of electronic databases (up to December 2015) was conducted. Relationship between Tregs infiltration and clinicopathological features, recurrence-free survival (RFS) and overall survival (OS) was investigated by synthesizing the qualified data. A total of 1303 NSCLC patients from 11 studies were included. The pooled hazard ratio (HR) for survival showed that high Tregs infiltration had no effect on RFS (HR = 2.03, 95% CI: 0.61-3.44, P = 0.708) and OS (HR = 1.20, 95% CI: 0.58-1.62, P = 0.981). High FoxP3+ Tregs infiltration was significantly associated with poor OS in NSCLC (HR = 3.88, 95% CI: 2.45-5.40, P = 0.000). Test methods, ethnicity and types of specimens had no effect on predicting prognosis of Tregs infiltration. While high Tregs infiltration was significantly correlated with smoking status [odds ratios (ORs) = 1.54, 95% CI: 1.15-2.08; P = 0.004], none of other clinicopathological characteristics such as gender, histological type, lymph node metastasis status, tumor size, vascular invasion, lymphatic invasion and pleural invasion were associated with Tregs infiltration. The present study demonstrated that high FoxP3+ Tregs infiltration was significantly associated with poor prognosis in NSCLC and smoking status.

Objective. To comprehensively compare the effects of conventional therapy combined with intravenous vitamin C and conventional therapy on viral myocarditis in children through a meta-analysis. Methods. Relevant articles including clinical trials of normal treatment combined with intravenous vitamin C and conventional therapy for viral myocarditis in children that were published between January 2000 and February 2018 were selected from PubMed, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, and WANFANG database. The quality of the included studies was assessed using the Cochrane systematic review method (version 5.1.0); data quality was evaluated by two independent researchers. The total effective rate; LDH, CK, and CK-MB levels; and other indicators were analyzed using Rev Man 5.3 software. Results. Eight studies were eligible for this meta-analysis, which included a total of 426 patients in the treatment group and 363 patients in the control group. The meta-analysis results of six studies showed that the total effective rate of intravenous vitamin C combined with conventional therapy was higher than that of conventional therapy alone [Z = 5.46, 95% confidence interval (CI): 1.21 (1.13 to 1.30), P < 0.00001]; that of five studies showed that LDH levels were lower in children receiving intravenous vitamin C combined with conventional therapy than in those receiving conventional therapy alone [Z = 3.70, 95% CI: −1.88 (−2.88 to −0.88), P = 0.0002]; that of three studies showed that CK levels were lower in children receiving intravenous vitamin C combined with conventional therapy than in those receiving conventional therapy alone [Z = 4.21, 95% CI: −0.55 (−0.81 to −0.30), P < 0.0001]; that of four studies showed that CK-MB levels were lower in children receiving intravenous vitamin C combined with conventional therapy than in those receiving conventional therapy alone [Z = 13.64, 95% CI: −1.44 (−1.65 to −1.24), P < 0.00001]; that of two studies showed that CD3 levels were higher in children receiving intravenous vitamin C combined with conventional therapy than in those receiving conventional therapy alone [Z = 2.45, 95% CI: 0.41 (0.08–0.73), P = 0.01]; that of two studies showed no significant difference in changes in CD4 levels between children receiving intravenous vitamin C combined with conventional therapy and those receiving conventional therapy alone [Z = 0.28, 95% CI: −0.21 (−1.69 to 1.28), P = 0.78]; and that of two studies showed no significant difference in changes in CD4/CD8 between children receiving intravenous vitamin C combined with conventional therapy and those receiving conventional therapy alone [Z = 0.07, 95% CI: −0.03 (−0.73 to 0.67), P = 0.94]. Conclusion. The meta-analysis results showed that intravenous vitamin C combined with conventional therapy is better than the simple, conventional therapy for the treatment of viral myocarditis in children in terms of the total effective rate and LDH, CK, and CK-MB levels.

Background Osimertinib demonstrates superior efficacy in patients with non-small cell lung cancer (NSCLC) who acquired EGFR T790M mutation as resistant mechanism to upfront EGFR tyrosine kinase inhibitors (TKIs). Not all the T790M-positive tumors are homogeneously sensitive to osimertinib, however, and the duration of response often varies. Previous studies suggest that loss of T790 M at osimertinib resistance is correlated with shortened survival benefit of osimertinib. The aim of this study is to investigate the prevalence of T790 M loss after progression to osimertinib in Chinese patients with NSCLC harboring EGFR T790 M mutation and to compare their clinical outcomes and characteristics when stratified by T790 M mutational status at osimertinib resistance. Patients and methods All patients with a secondary T790 M mutation after progression to prior-line EGFR TKIs and received single-agent osimertinib were reviewed. The patients who were reassessed for T790 M mutation post-osimertinib resistance were included in final analysis. Detailed clinicopathologic characteristics and response data were collected. Results Of the patients with confirmed T790 M mutation as acquired resistance to early-generation EGFR TKIs and subsequently received single-agent osimertinib, 84 patients experienced clinical progression after osimertinib treatment and were eligible for analysis. Among them, 31 patients underwent repeated T790 M mutation testing on osimertinib resistance. Sixteen patients had maintained T790 M mutation, whereas 15 patients lost T790 M at resistance. Loss of T790 M at resistance was remarkably correlated with shorter duration of response to osimertinib (P = 0.0005). Furthermore, the overall survival after osimertinib treatment was also decreased in T790M-loss group (P=0.021). The objective response rates were comparable between T790M-maintain and T790M-loss group (31.3% and 26.7%, respectively). In multivariate analysis, loss of T790M remained statistically associated with early progression to osimertinib. Conclusion Loss of T790 M mutation at resistance was correlated with early progression and overall survival in response to osimertinib treatment in Chinese patients with NSCLC harboring acquired T790 M mutation.

Gut microbiome plays a dominant role in modulating therapeutic efficacy of immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor/ligand-1 (PD-1/PD-L1) pathway, suggesting that co-administration of antibiotics (Abx), which might result in dysbacteriosis, can attenuate the clinical outcomes of ICIs. The current study aimed to investigate the predictive role of Abx on ICIs treatment in patients with advanced non-small cell lung cancer (NSCLC). The impact of proton pump inhibitors (PPIs), another medication that can induce dysbacteriosis, was also investigated.We retrospectively reviewed the medical records of eligible patients who received anti-PD-1-based therapies in our hospital. Tumor responses, patients' survival, the incidence of immune-related adverse events (irAEs) and other baseline variables were examined. The application of Abx or PPIs treatment were also collected. Clinical outcomes and clinicopathologic features were compared according to the status of Abx or PPIs co-administration.A total of 109 patients were included. Of them, 20 (18.3%) patients were categorized in Abx-treated group. No major difference in baseline characteristics was observed between Abx-treated and -untreated groups. Concomitant Abx treatment was significantly associated with shorter progression-free survival (PFS) (p 0.0001) and overall survival (OS) (p = 0.0021). And primary disease progression tended to increase in Abx-treated group (p = 0.092). Yet, the occurrence and grades of irAEs were comparable between two groups. In multivariable analysis, Abx treatment was markedly associated with worse PFS (HR=0.32, 95%CI 0.18-0.59, p 0.0001) and OS (HR=0.35, 95%CI 0.16-0.77, p = 0.009). Regarding the use of PPIs, no significant difference was observed in clinical outcomes between the patients with or without concomitant PPIs treatment.Abx treatment was significantly associated with attenuated clinical outcomes derived from anti-PD-1-based ICIs in a Chinese cohort of patients with advanced NSCLC.