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Background Data on treatable traits (TTs) in different populations are limited. Objective To assess TTs in elderly patients with asthma and compare them to younger patients, to evaluate the association of TTs with future exacerbations, and to develop an exacerbation prediction model. Methods We consecutively recruited 521 participants at West China Hospital, Sichuan University based on the Australasian Severe Asthma Network, classified as elderly (n = 62) and nonelderly (n = 459). Participants underwent a multidimensional assessment to characterize the TTs and were then followed up for 12 months. TTs and their relationship with future exacerbations were described. Based on the TTs and asthma control levels, an exacerbation prediction model was developed, and the overall performance was externally validated in an independent cohort. Results A total of 38 TTs were assessed. Elderly patients with asthma had more chronic metabolic diseases, fixed airflow limitation, emphysema, and neutrophilic inflammation, whereas nonelderly patients with asthma exhibited more allergic characteristics and psychiatric diseases. Nine traits were associated with increased future exacerbations, of which exacerbation prone, upper respiratory infection–induced asthma attack, cardiovascular disease, diabetes, and depression were the strongest. A model including exacerbation prone, psychiatric disease, cardiovascular disease, upper respiratory infection–induced asthma attack, noneosinophilic inflammation, cachexia, food allergy, and asthma control was developed to predict exacerbation risk and showed good performance. Conclusions TTs can be systematically assessed in elderly patients with asthma, some of which are associated with future exacerbations, proving their clinical utility of evaluating them. A model based on TTs can be used to predict exacerbation risk in people with asthma.

Purpose: To explore disease-causing gene mutations of epilepsy with febrile seizures plus (EFS+) in Southern Chinese Han population. Methods: Blood samples and clinical data were collected from 49 Southern Han Chinese patients with EFS+. Gene screening was performed using whole-exome sequencing and panel sequencing for 485 epilepsy-related genes. The pathogenicity of variants was evaluated based on ACMG scoring and assessment of clinical concordance. Results: We identified 10 putatively causative sodium channel gene variants in 49 patients with EFS+, including 8 variants in SCN1A (R500Q appeared twice), one in SCN3A and one in SCN9A. All these missense mutations were inherited from maternal or paternal and were evaluated to be of uncertain significance according to ACMG. The clinical features of patients were in concordance with the EFS+ phenotype of the mutated SCN1A, SCN3A and SCN9A gene. The clinical phenotypes of 11 probands with these gene variants included febrile seizures plus (FS+, n=7), Dravet Syndrome (n=3), FS+ with focal seizures (n=1). Three probands with SCN1A variants (R500Q located in the non-voltage areas, or G1711D in the pore-forming domain) developed severe Dravet syndrome. The affected individuals with the other 6 SCN1A variants located outside the pore-forming domain showed mild phenotypes. Novel SCN3A variant ((D1688Y) and SCN9A variant (R185H) were identified in two probands respectively and both of the probands had FS+. Conclusion: The SCN1A, SCN3A, and SCN9A gene mutations might be a pathogenic cause of EFS+ in Southern Chinese Han population.

Yu-Xiong Guo,1,2,* Hong-Xia Ma,1– 3,* Yu-Xin Zhang,2 Zhi-Hong Chen,2 Qiong-Xiang Zhai1,2 1The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of Pediatrics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 3Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiong-Xiang ZhaiDepartment of Pediatrics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, People’s Republic of ChinaTel +86-2083827812-76222Fax +86-20-8328480Email zhaiqx_241@163.comBackground: Intellectual developmental disorders (IDD) generally refers to the persistent impairment of cognitive activities and mental retardation caused by physical damage to the brain or incomplete brain development. We aimed to explore its genetic causes.Methods: In this study, 21 IDD patients were recruited. The Gesell developmental scales (GDS) and Wechsler intelligence scale for children (WISC) were used to assess the impaired level of intellectual development for all probands. A superconducting MRI scanner (Philips AcsNT 3.0 T Philips, Best, The Netherlands) was used to perform a plain MRI scan of the skull on the probands. The whole-exome sequencing was carried out using next-generation sequencing in all probands and their families.Results: Eight had seizures and four had typical characteristics of autism. Pregnancy and delivery were uneventful except for three patients. Moderate IDD (52.4%) accounted for the majority. The abnormal MRI results included ventriculomegaly, pachygyria, broadening external cerebral space, abnormal signal change and agenesis of corpus callosum. Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASKgenes. The function areas result of gene-positive group were compared to that of gene-negative group. Not significant (p> 0.05) items were revealed after this analysis.Conclusion: Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASK genes. The function areas result of gene-positive group were not significantly different from the gene-negative group.Keywords: intellectual developmental disorders, gene variant, whole-exome sequencing

With the rapidly increasing number of Internet of Things (IoT) devices, various interconnected devices have become targets of growing cyberattacks. Keeping the firmware of an IoT device up-to-date is one feasible way to protect the device against cyberattacks. The existing approaches of firmware update (including distribution and validation) are not scalable in distribution to increasing numbers of devices, however, let alone able to provide reliable validation. To address the above issues, this study proposes a hybrid update scheme, including distributed membership-based firmware sharing for firmware distribution and smart-contract-enabled firmware validation via a blockchain (BC). This hybrid update approach leverages the advantages of a peer-to-peer network and a blockchain. Evaluation of the study has shown that the proposed distributed membership-based firmware sharing is more secure and scalable to an increasing number of devices. The proposed smart-contract-enabled firmware validation is more efficient than the firmware validation in existing studies since it can effectively reduce unwanted repeat validation via a smart contract in a blockchain. In addition, it can help make sure all members of an IoT-enabled service having the right firmware before providing the service to users. Such designs can improve service quality and also reduce as much human intervention to leverage the strengths of an IoT-enabled application or system.

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.

Background Tyrosine kinase domain (TKD) mutation and particularly exon 20 insertion mutations of ERBB2 have been extensively reported in non-small cell lung cancer (NSCLC). Due to the increased accessibility of next-generation sequencing, more ERBB2 mutations within the non-TKD can be detected in clinical practice. Nevertheless, the clinical significance of non-TKD mutations remains unknown. Hence, this study was designed to comprehensively outline the landscape and characteristics of ERBB2 mutations in NSCLC. Methods A total of 1934 patients with NSCLC from cBioPortal were included in the study. An ERBB2 mutation cohort was identified, while subsequent analyses revealed clinical and genomic characteristics. Results The frequency of ERBB2 mutation was 4.5%, and it was determined to be more likely to occur in never-smokers. ERBB2 mutations occurring in the non-TKD accounted for 57.5% of ERBB2 mutations. In the non-TKD, missense mutation was the most recurrent mutation type, and S310F was the most recurrent mutation variant. ERBB2 mutations within non-TKD also had a strong oncogenic ability where up to 37.5% of ERBB2 oncogenic mutations were within non-TKD. The co-mutation of EGFR or KRAS was higher in the non-TKD mutation compared to the TKD mutation. Shorter overall survival was observed in ERBB2-mutant patients compared with ERBB2 wild-type patients. There was no significant difference in overall survival between patients with non-TKD mutations and TKD mutations. Conclusions The present study showed that a considerable portion of non-TKD mutations were oncogenic. ERBB2 mutation was a poor prognostic factor. The non-TKD mutation might also be used as a therapeutic target in ERBB2-directed target therapy. Key points • Significant findings of the study ERBB2 mutations were more abundant within a nontyrosine domain than those within the tyrosine domain. Up to 37.5% of ERBB2 oncogenic mutations were within the nontyrosine domain. ERBB2 mutation was a poor prognostic factor. • What this study adds The frequency of EGFR or KRAS co-mutations were significantly higher in ERBB2 mutations within the nontyrosine kinase domain compared to ERBB2 mutations within the tyrosine kinase domain. Nontyrosine domain mutations confer equal overall survival to tyrosine domain mutations.

Background Inflammatory pseudotumor-like follicular dendritic cell (IPT-like FDC) tumors of the liver is an uncommon tumor with extremely low incidence. To date, the radiologic findings of this tumor in multiphase computed tomography (CT) and magnetic resonance imaging (MRI) imaging have not been described. Case summary Patient 1 is a 31-year-old Chinese female, whose complaining incidentally coincided with the finding of multiple liver masses. In the local hospital, an abdominal enhanced CT found two hypo-dense solid lesions, with heterogeneous sustained hypoenhancement, in the upper segment of the liver's right posterior lobe. In our hospital, enhanced magnetic resonance imaging (MRI) with hepatocyte-specific contrast agents showed a similar enhanced pattern of lesions with patchy hyperintensity in the hepatobiliary phase (HBP). The patient underwent surgery and recovered well. The final pathology confirmed an IPT-like FDC tumor. No recurrence was found on the regular re-examination. Patient 2 is a 48-year-old Chinese male admitted to our hospital for a huge unexpected hepatic lesion. A dynamic enhanced abdominal CT revealed a huge heterogeneous enhanced solid tumor in the right lobe of the liver with a size of 100 mm × 80 mm, which showed a heterogeneous sustained hypoenhancement. In addition, enlarged lymph nodes were found in the hilum of the liver. This patient underwent a hepatic lobectomy and lymph node dissection. The final pathology confirmed an IPT-like FDC tumor. No recurrence was found upon regular re-examination. Conclusion When a hepatic tumor shows heterogeneous sustained hypoenhancement with a patchy enhancement during HBP, an IPT-like FDC tumor should be considered in the differential diagnosis.

BACKGROUND Follicular dendritic cell (FDC) sarcoma/tumor is a rare malignant tumor of follicular dendritic cells, which is considered a low-grade sarcoma that can involve lymph nodes or extranodal sites. Conventional FDC sarcomas are negative for Epstein-Barr virus (EBV), whereas the inflammatory pseudotumor-like variant consistently shows EBV in the neoplastic cells. CASE SUMMARY We report two cases of inflammatory pseudotumor-like FDC sarcoma in the liver that received 3D laparoscopic right hepatectomy and open right hepatectomy separately. CONCLUSION EBV probe-based in situ hybridization and detection of immunohistochemical markers of FDC play an important role in the diagnosis and differential diagnosis of inflammatory pseudotumor-like FDC sarcoma. Complete surgical excision combined with regional lymphadenectomy may be effective in reducing the postoperative recurrence and metastasis and improving long-term survival rates.

The interest-driven creator (IDC) theory is being developed as a group endeavor by Asian researchers to articulate a holistic learning design theory for future education in Asia. The theory hypothesizes that students, driven by interest, can be engaged in the creation of knowledge (generating ideas and artifacts). By repeating this creation process in their daily learning routines, they will excel in learning performance, develop twenty-first-century competencies, and form creation habits. We hope that with such practices in education, our future generations will ultimately become lifelong interest-driven creators. In IDC Theory, there are three anchored concepts, namely, interest, creation, and habit. Each anchored concept comprises three component concepts which form a concept loop. For example, the creation loop consists of three component concepts—imitating, combining, and staging. Imitating is concerned with taking in (or inputting) an abundant amount of existing knowledge from the outside world to form one’s background knowledge. Combining refers to delivering (or outputting) new ideas or artifacts prolifically by synthesizing existing information encountered in the world and thoughts arising from the students’ background knowledge. Staging relates to frequently demonstrating the generated ideas or artifacts to the relevant communities and receiving feedback from these communities to improve the novelty and value of the demonstrated outcomes while gaining social recognition and nurturing positive social emotions. This paper focuses on describing the three components of the creation loop. We provide three case studies to illustrate the creation loop at work, as well as how it intertwines with both the interest and habit loops in supporting students to develop their creation capabilities. In presenting this iteration of the creation concept, an anchored concept in IDC theory, we acknowledge the roles played of imitation, combination, and staging in different learning and education contexts—indeed, there are multiple theories that inform and intersect with it.

BackgroundEchinoderm microtubule-associated protein-like 4 (EML4) is the canonical anaplastic lymphoma kinase (ALK) fusion partner in non-small cell lung cancer (NSCLC), and ALK-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking.MethodsNinety-eight ALK-positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their ALK fusion patterns. Non-canonical ALK fusions were validated using RNA-sequencing.Results54.1% of patients had pure canonical EML4-ALK fusions, 19.4% carried only non-canonical ALK fusions, and 26.5% harbored complex ALK fusions with coexisting canonical and non-canonical ALK fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex ALK fusion group. Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical EML4-ALK fusion group (p = 0.010). The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.ConclusionOur results suggest NSCLC patients with complex ALK fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis.

Background Epidermal growth factor receptor (EGFR) exon 20 insertion (EGFR ex20ins) is a common mutation in non-small cell lung cancer (NSCLC). Patients with EGFR ex20ins generally respond poor to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR ex20ins are often co-occurring with EGFR amplification. However, the impact of EGFR amplification on the survival of patients with EGFR ex20ins mutations has not been determined. Methods This is an observational longitudinal cohort study. A prospectively managed database included consecutive treatment-naive adult patients with advanced NSCLC and EGFR ex20ins confirmed by next-generation sequencing (NGS) at Guangdong Provincial People's Hospital between November 2017 and February 2019. The participants were enrolled from the database and extracted their clinical characteristics, treatment and clinical outcomes. NGS was used to establish whether EGFR amplification was present in tumor tissue. Overall survival (OS) and progression-free survival (PFS) were compared between EGFR amplification and non-EGFR amplification groups using the Kaplan-Meier method and log-rank test. Subgroup analyses were performed based on the treatment used (EGFR-TKI or chemotherapy). Results Fifteen different EGFR ex20ins mutation subtypes were identified in the 39 patients included in the analysis, and the most common subtypes were p.A767_D770dup (25.6%), p.S768_D770dup (23.1%) and p.N771_H773dup (10.3%). Among 31 patients with EGFR ex20ins mutations and NGS data for tumor tissue, EGFR amplification was identified in 12 patients (38.7%) and there were no significant differences in clinical characteristics. Among 26 patients, there were no significant differences between the EGFR amplification (n=11) and non-EGFR amplification (n=15) groups in median OS (715 vs. 452 days, P=0.912). Among 20 patients administered chemotherapy, there were no significant differences between the EGFR amplification and non-EGFR amplification groups in median PFS (206 vs. 112 days, P=0.425). Among 24 patients administered an EGFR-TKI, median PFS was longer in the non-EGFR amplification group than in the EGFR amplification group (110 vs. 31 days, P=0.030). Conclusions There is a tendency that EGFR amplification might be a poor predictor in EGFR ex20ins-positive NSCLC patients treated with EGFR-TKIs.

Asthma, a heterogeneous disease, can be divided into 4 inflammatory phenotypes using induced sputum cell counts-eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma, and paucigranulocytic asthma (PGA). Although research has focused on EA and NA, there is little known about PGA.To study the heterogeneity of PGA and identify possible PGA clusters to guide clinical treatment.Patients with PGA were grouped by hierarchical cluster analysis and enrolled into a prospective cohort study to validate the clusters, relative to future risk of asthma exacerbations in a real-world setting. Clusters were validated by tree analysis in a separate population. Finally, we explored PGA stability.Cluster analysis of 145 patients with PGA identified 3 clusters: cluster 1 (n = 110, 75.9%) was "mild PGA," cluster 2 (n = 20, 13.8%) was "PGA with psychological dysfunction and rhinoconjunctivitis and other allergic diseases," and cluster 3 (n = 15, 10.3%) was "smoking-associated PGA." Cluster 3 had significantly increased risk of severe exacerbation (relative risk [RR] = 6.43, P = .01), emergency visit (RR = 8.61, P = .03), and hospitalization (RR = 12.94, P .01). Results of the cluster analysis were successfully validated in an independent PGA population classified using decision tree analysis. Although PGA can transform into or develop from other phenotypes, 70% were stable over time.Among 3 identified PGA clusters, cluster 3 had a higher risk of severe exacerbation. PGA heterogeneity indicates the requirement of novel targeted interventions.

Highlights • Predictive power of PD response for ICIs was superior than traditional biomarkers; • Predictive efficacy was improved by integrating tumor-immune-related features; • When tumor-specific feature was replaced, the model has pan-cancer applicability. • NRAS and PDPK1 have the potential to induce primary resistance to ICIs., Background Treatment by immune checkpoint blockade (ICB) provides a remarkable survival benefit for multiple cancer types. However, disease aggravation occurs in a proportion of patients after the first couple of treatment cycles. Methods RNA sequencing data was retrospectively collected. 6 tumour-immune related features were extracted and combined to build a lung cancer-specific predictive model to distinguish responses as progression disease (PD) or non-PD. This model was trained by 3 public pan-cancer datasets and a lung cancer cohort from our institute, and generated a lung cancer-specific integrated gene expression score, which we call LITES. It was finally tested in another lung cancer dataset. Results LITES is a promising predictor for checkpoint blockade (area under the curve [AUC]=0.86), superior to traditional biomarkers. It is independent of PD-L1 expression and tumour mutation burden. The sensitivity and specificity of LITES was 85.7% and 70.6%, respectively. Progression free survival (PFS) was longer in high-score group than in low-score group (median PFS: 6.0 vs. 2.4 months, hazard ratio=0.45, P=0.01). The mean AUC of 6 features was 0.70 (range=0.61-0.75), lower than in LITES, indicating that the combination of features had synergistic effects. Among the genes identified in the features, patients with high expression of NRAS and PDPK1 tended to have a PD response (P=0.001 and 0.01, respectively). Our model also functioned well for patients with advanced melanoma and was specific for ICB therapy. Conclusions LITES is a promising biomarker for predicting an impaired response in lung cancer patients and for clarifying the biological mechanism underlying ICB therapy.

This study evaluated whether tumor expression of programmed death ligand 1 (PD-L1) could predict the response of EGFR-mutated NSCLC to EGFR tyrosine kinase inhibitor (TKI) therapy.We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC at the Guangdong Lung Cancer Institute between April 2016 and September 2017 and were not enrolled in clinical studies. The patients' EGFR and PD-L1 statuses were simultaneously evaluated.Among the 101 eligible patients, strong PD-L1 expression significantly decreased objective response rate, compared with weak or negative PD-L1 expression (35.7% versus 63.2% versus 67.3%, p = 0.002), and shortened progression-free survival (3.8 versus 6.0 versus 9.5 months, p0.001), regardless of EGFR mutation type (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% versus 30.2%, p = 0.009). Notably, we found a high proportion of PD-L1 and cluster of differentiation 8 (CD8) dual-positive cases among patients with de novo resistance (46.7%, 7 of 15). Finally, one patient with de novo resistance to EGFR-TKIs and PD-L1 and CD8 dual positivity experienced a favorable response to anti-programmed death 1 therapy.This study revealed the adverse effects of PD-L1 expression on EGFR-TKI efficacy, especially in NSCLC patients with de novo resistance. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1 and CD8 dual positivity and suggest potential therapeutic sensitivity to programmed death 1 blockade.

Background ALK-tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK-positive non-small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. Methods Targeted next-generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. Results ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK -positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post-treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK-TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. Conclusions Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes.

To discuss the effect and mechanism of adenovirus-mediated OX40Ig gene transfer in inducing long-term survival of liver allografts in rats.Orthotopic liver transplantation was performed from Lewis to Brown Norway (BN) rats through the modified two-cuffed technique, and all rats were randomly divided equally into four groups: control, AdEGFP, AdOX40Ig, and FK506. The survival times of the rats were recorded. The rats' liver function, serum cytokines, hepatocyte pathology, OX40Ig protein level, and mixed lymphocyte reaction (MLR) with or without recombinant interleukin-2 (rIL-2) were evaluated.Compared with the control and AdEGFP groups, the rats in the AdOX40Ig and FK506 groups survived longer (P 0.05), experienced less damage to hepatic function (P 0.05), and showed milder hepatic cellular rejection and less hepatic cellular apoptosis. Interferon (IFN)-γ and IL-2 content in the serum were lower after operation (P .05) in the AdOX40Ig and FK506 groups. On the contrary, IL-4 and IL-10 content in the serum was higher after operation (P 0.05) in the AdOX40Ig and FK506 groups. OX40Ig protein was significantly expressed in the AdOX40Ig group and reached the highest level on the 7th day after operation. With respect to the MLR between BN and Lewis rats, the AdOX40Ig group showed a lighter reaction for the same strain than the control and AdEGFP groups (P 0.05), which is different from the MLR between BN and F344 rats. After adding rIL-2 to the MLR system between BN rats in the AdOX40Ig group and Lewis rats, MLR was aggravated.Through OX40/OX4OL pathways, OX40Ig created an immunosuppressive effect after liver transplantation in rats. This immunosuppressive effect is associated with reduced IL-2 and can be reversed by adding IL-2 with antigen specificity.

Purpose: Leptomeningeal metastases are more common in non–small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of leptomeningeal metastases. Experimental Design: We compared the CellSearch Assay, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected leptomeningeal metastases. Next-generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTC) of 19 patients. Results: Twenty-one patients were diagnosed with leptomeningeal metastases, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27–14,888). CellSearch had a sensitivity of 95.2% for leptomeningeal metastases diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2–4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was detected in only 1 of 14 CSFCTC samples. Other potential resistant mutations, such as MET amplification and ERBB2 mutation, were also identified in CSFCTCs. Conclusions: CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose leptomeningeal metastases, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with leptomeningeal metastases. Clin Cancer Res; 23(18); 5480–8. ©2017 AACR.

Although the learning of programming language is critical in science and technology education, it might be difficult for some students, especially novices. One possible reason might be the fact that programming language, especially for three-dimensional (3D) applications, is too complex and abstract for these students to understand. Programming for 3D applications requires understanding the spatial relationship of 3D objects and hence needs a visualization technique more. In view of this, this article presents an augmented reality (AR)-enhanced learning system that offers visual representation and interactivity to help students learn programming for 3D applications. To examine the influences of such an AR-enhanced system on student learning, a within-group experiment with 34 college students was conducted. All students used both of an AR-enhanced version and an ordinary version. The findings revealed that the AR-enhanced version made students have better learning efficiency than the ordinary system. In addition, the AR-enhanced system also made students have enhanced perceptions in terms of system usability, flow experience, and usage perception. Based on the results, further development of AR-enhanced learning systems is also suggested and discussed.

This paper proposes an approach for developing curriculum-level open student models. This approach entails evaluating student core competencies using the correspondence between courses and core competencies in a competency-based curriculum and students’ taken courses and grades. On the basis of this approach, a curriculum-level, competency-based visualized analytic system, called visualized analytics of core competencies (VACCs), was implemented. Course-competency diagnostic tools, course work performance radar charts, and peer-based ranking tables were developed as part of the VACC analytic system for student reflection and to position their levels of core competencies. These curriculum-level open student models revealed multiple aspects of students’ core competencies by monitoring the quantity and quality of courses taken by students, and evaluating students’ ranks regarding core competencies compared with their classmates and graduates. VACC evaluation was conducted in this paper. The results showed that more than 70% of students reported that VACC helped in reflecting on their core competencies, assisting them in understanding the correspondence between their taken courses and core competencies, and helping them to set goals regarding taking additional courses. In addition, this paper discusses potential analytics and applications of open student models of core competencies.

Background Intratumoral epidermal growth factor receptor (EGFR) mutational heterogeneity is yet controversial in non-small cell lung cancer (NSCLC) patients. Single-cell analysis provides the genetic profile of single cancer cells and an in-depth understanding of the heterogeneity of a tumor. Methods Firstly, single H1975 cells harboring the EGFR L858R mutation were submitted to flow cytometry isolation, nested polymerase chain reaction (nested-PCR) amplification, and direct DNA sequencing to assess the feasibility of single-cell direct DNA sequencing. Then, the single cells of patients with lung adenocarcinoma receiving gefitinib were captured by laser capture microdissection and analyzed by the above methods to identify the intratumoral heterogeneity of the EGFR L858R mutant. Three patients with progression-free survival (PFS) > 14 months were categorized as the long PFS group, and 3 patients with PFS

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.

The measurement of hole shape and size of large plate parts has always been a technical problem. The article proposes a technology to use non-contact photoelectric detection technology for online detection of the shape and position of large plate-shaped workpieces. The detection principle is: the control system controls the photoelectric detection system to move in a straight line along the guide rail at a uniform speed, and the large plate-shaped workpiece the hole shape and size are measured, and the lighting system moves synchronously with the photoelectric detection system to provide the light source for it. The images collected by the photoelectric detection system are processed through digital image processing and image splicing technology to realize the hole shape and size of large plate workpieces. Non-contact measurement.

Epidermal growth factor receptor (EGFR) T790M mutation has shown to be associated with the clinical outcomes of patients after initial EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy in EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, its predictive role in EGFR-TKI re-challenge remains unknown. The present study was aimed to explore the correlation between T790M mutation and any benefits from EGFR-TKI re-challenge. We retrospectively reviewed 922 consecutive patients with EGFR-mutant non-small cell lung cancer (NSCLC) patients administered with gefitinib/erlotinib at Guangdong General Hospital. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were analyzed respectively. In total, 66 EGFR-mutant patients with stage IV adenocarcinoma were eligible, of whom 51 underwent re-biopsy upon initial progression. Among them, 18 (35.3%) harbored T790M mutation. No statistical significant differences were seen between T790M-positive and T790M-negative patients in PFS, OS, ORR or DCR. The median PFS, median OS, ORR, and DCR of the overall 66 patients were 2.0 months, 6.8 months, 6.1% and 39.4%, respectively. Good performance status (PS) was found to be independent favorable prognostic factor and long TKI-free interval to be associated with superior PFS. In conclusion, T790M mutation might not predict the clinical outcomes in first-generation EGFR-TKI re-challenge. Based on the poor efficacy from our data, re-challenge of first-generation EGFR-TKIs could not be recommended routinely, but for those with good PS and long TKI-free interval, it might be an alternative option.

The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively. Immunohistochemistry was used to evaluate the activation of associated proteins. We found that nine in ten patients with EGFR/ALK co-alterations had good response with first-line EGFR TKI, and the objective response rate (ORR) of EGFR TKIs was 80% (8/10) for EGFR/ALK co-altered and 65.5% (55/84) for EGFR-mutant (P = 0.57), with a median progression-free survival (PFS) of 11.2 and 13.2 months, (hazard ratio [HR]=0.95, 95% [CI], 0.49-1.84, P= 0.87). ORR of crizotinib was 40% (2/5) for EGFR/ALK co-altered and 73.9% (17/23) for ALK-rearranged (P= 0.29), with a median PFS of 1.9 and 6.9 months (hazard ratio [HR], 0.40; 95% [CI] 0.15-1.10, P = 0.08). The median overall survival (OS) was 21.3, 23.7, and 18.5 months in EGFR-mutant, ALK-rearranged, and EGFR/ALK co-altered (P= 0.06), and there existed a statistically significant difference in OS between ALK-rearranged and EGFR/ALK co-altered (P=0.03). Taken together, the first-line EGFR-TKI might be the reasonable care for advanced NSCLC harbouring EGFR/ALK co-alterations, whether or nor to use sequential crizotinib should be guided by the status of ALK rearrangement and the relative level of phospho-EGFR and phospho-ALK.

// Hong-Fei Gao 1,2 , Jin-Ji Yang 2 , Zhi-Hong Chen 2 , Xu-Chao Zhang 2 , Hong-Hong Yan 2 , Wei-Bang Guo 2 , Qing Zhou 2 , Lou-Ying Gou 2 , Zhong-Yi Dong 2 and Yi-Long Wu 2 1 Guangdong Cardiovascular Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China 2 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Correspondence to: Yi-Long Wu, email: // Keywords : soluble c-Met, EGFR-TKI, NSCLC Received : December 07, 2015 Accepted : April 16, 2016 Published : May 18, 2016 Abstract Background: The activation of c-Met has been associated with both primary and acquired resistance to EGFR-TKI therapy in NSCLC patients. Thus, c-Met status during EGFR-TKI therapy should receive much attention. Results: Forty-nine patients were selected as training cohort and 52 cases as validation cohort. With disease progression, IHC results showed that 37 (75.5%) of the patients were tissue c-Met-negative, and 12 (24.5%) were tissue c-Met-positive. There was a statistically significant difference in the dynamic change in soluble c-Met between the tissue c-Met-negative and c-Met-positive groups ( P = 0.002). Patients with a baseline soluble c-Met level >766 ng/ml showed inferior median progression-free survival (PFS; 10.2 vs . 14.0 months; P = 0.003) after EGFR-TKI treatment. Multivariate Cox proportional hazards model analyses demonstrated that the soluble c-Met level was an independent prognostic factor for PFS after EGFR-TKI treatment ( P = 0.009; hazard ratio: 3.583; 95% confidence interval: 1.379-9.312). In the validation cohort, patients with soluble c-Met levels >766 ng/ml were also determined to have significant short median PFS after EGFR-TKI treatment (6.8 vs . 14.5 months, P < 0.001). Patients and Methods: We retrospectively investigated the dynamic change in the soluble c-Met level in plasma and its relationship with clinical outcomes of EGFR-TKI therapy in advanced NSCLC. Immunohistochemistry (IHC) was used to assess the expression of c-Met in the resistant tissue. Plasma c-Met levels were assayed in duplicate using a human soluble c-Met quantitative enzyme-linked immunosorbent assay (ELISA) kit. Conclusions: Quantitatively determining the soluble c-Met level in plasma by ELISA might provide a non-invasive and sensitive method to predict EGFR-TKI prognosis.

Background Our previous study identified rs9387478 as a new susceptibility locus associated with lung cancer in never-smoking women in Asia; however, the clinical and prognostic significance of this finding is not known. Methods We analyzed the relationship between the rs9387478 single nucleotide polymorphism and i) clinical parameters and ii) overall survival time in 505 female nonsmoking lung cancer patients, using the chi-square test and Kaplan-Meier analysis with the log-rank test, respectively. We further established the epidermal growth factor receptor (EGFR) mutation status and assessed its association with rs9387478 genotypes as well as the efficacy of EGFR tyrosine kinase inhibitors. Results The frequency of the AA genotype was significantly higher in the EGFR-mutation-negative group than in the EGFR-mutation-positive group (32% vs. 16%, χ 2 = 13.025, p = 0.011). Patients with the CC genotype had a better overall survival time than patients with the AA/AC genotype (median survival time: 54.2 vs. 32.9 months, χ 2 = 4.593, p = 0.032). The distribution of rs9387478 genotypes differed according to the clinical disease stage. Conclusions This study indicates that the rs9387478 genotype was associated with overall survival in nonsmoking female patients with lung cancer, although it was not significant after adjusting for multiple testing. The identification of the location of the rs9387478 single nucleotide polymorphism in the genomic interval containing the DCBLD1 and ROS1 genes, together with the finding that the rs9387478 polymorphism correlates with EGFR mutation status, may have important implications for therapeutic approaches targeting EGFR or ROS1 in patients with lung cancer.

In-depth analysis of the current shortcomings in the detection of large board parts, a photoelectric detection method based on image processing technology is proposed, the overall structure of the detection system is designed in detail, the mechanical transmission system and the photoelectric detection system are specifically designed, and at the same time, the analysis the implementation steps of image processing for large-scale class parts using photoelectric detection technology are given. The specific implementation process is given, including: image acquisition, image stitching and image edge extraction, and finally the photoelectric online detection of large-scale board parts is completed.

BackgroundImmunotherapy has become an important treatment option for patients with advanced non-small cell lung cancer (NSCLC). At present, none of these existing biomarkers can effectively stratify true responders and there is an urgent need for identifying novel biomarkers. Exosomes derived from the serum of patients with cancer have been proven to be reliable markers for cancer diagnosis. Here, we explored the possibility of using plasma-derived exosomal microRNAs as potential biomarkers for optimal selection of patients with advancedEGFR/ALKnegative NSCLC to immunotherapy.MethodsFrom June 2017 to February 2019, 30 patients with advancedEGFR/ALKwild-type (WT) NSCLC who received PD-1/PD-L1 inhibitors were enrolled. The efficacy evaluation was conducted after every three cycles of treatment according to RECIST 1.1. Plasma samples of these patients were collected before the administration of PD-1/PD-L1 inhibitors as baseline, and after every three cycles if the patients achieved partial response (PR) or complete response. Plasma from seven healthy individuals was also collected as normal control. Exosomes were prepared by ultracentrifugation followed by total RNA extraction, and exosome-derived miRNAs were profiled using small RNA next-generation sequencing followed by differential expression analysis.ResultsIn order to identify biomarker for better response, all five patients who achieved PR and four patients with progressive disease (PD) at efficacy evaluation were included for differential expression analysis. Based on unsupervised hierarchical clustering, exosomal miRNA expression profile was significantly altered in patients with NSCLC compared with normal controls with a total of 155 differentially expressed exosomal miRNAs. Interestingly, hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified significantly upregulated in the PD groups compared with the PR group at baseline before the treatment. In addition, we identified that hsa-miR-125b-5p, a T-cell suppressor, showed a trend of increased expression in the PD group at baseline and was significantly downregulated in the post-treatment plasma exosomes compared with pre-treatment samples of the PR patients.ConclusionPatients with NSCLC represent unique plasma exosomal miRNA profiles. Hsa-miR-320d, hsa-miR-320c, and hsa-miR-320b were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLCs. When T-cell suppressor hsa-miR-125b-5p was downregulated during the treatment, the patients may obtain increased T-cell function and respond well to immunotherapy.

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.

Background: Abivertinib is a novel, third-generation EGFR tyrosine kinase inhibitor. We investigated the safety and efficacy of abivertinib in Chinese patients with EGFR T790Mpositive non-small cell lung cancer (NSCLC) and determined the recommended Phase II dose (RP2D). Methods: This open-label, single-arm, dose-escalation study enrolled patients (18–75 years) with disease progression on prior EGFR TKIs from 8 centers in China. Patients received abivertinib 50–350 mg BID in sequential cohorts using a dose escalation/expansion protocol which determined dose-limiting toxicities (DLTs) in Cycle 1 and evaluated the clinical activity of abivertinib. RP2D (primary endpoint) was based on DLTs along with available safety, efficacy and pharmacokinetic data. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. This study is registered with ClinicalTrials.gov (NCT02330367). Findings: Between January 2015 and March 2018, 140 patients received abivertinib for a median (range) of 21·7 (1·3–148) weeks. Median relative dose intensity was 99%. Maximum tolerated dose was not reached with only 3 DLTs observed across all doses. RP2D was 300 mg BID based on a median (range) PFS of 6·9 (3·0, 9·0) months, ORR of 40% and broadly comparable safety profile to the 50–300 mg BID doses. Grade 3/4 treatment-related adverse events were more frequent with abivertinib 350 mg BID (4/6 patients, 67%) versus 300 mg BID (12/45, 27%) and lower doses. Minimal accumulation of abivertinib was observed at steady state across the studied doses and exposure rose proportionally with increasing dose. Interpretation: Abivertinib 150–300 mg BID represented the efficacious range while 350 mg BID dose had the least favorable safety profile, suggesting 300 mg BID as the RP2D. This novel study design which considered efficacy, pharmacokinetics, and safety beyond Cycle 1 in addition to DLTs may facilitate RP2D determination for drugs with favorable toxicity profiles. Clinical Trial Number: This study is registered with ClinicalTrials.gov (NCT02330367). Funding Statement: This study was funded by ACEA Therapeutics Inc. Declaration of Interests: W-HX is an employee of ACEA Pharmaceutical Research, Hangzhou, China. FL, LX and XX are employees of ACEA Therapeutics Inc. QZ declares speaker fees from AstraZeneca and Roche. LW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. YLW declares speaker fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. X-QL, PH, J-YZ, LZ, T-TA, YC, JJ, Z-HC, and BG declare no competing interests. Ethics Approval Statement: The study was conducted according to the ethical principles established in the Declaration of Helsinki and was consistent with the Chinese Good Clinical Practice Guidelines. The study protocol was approved by the institutional review board or independent ethics committee at each study center.

This paper describes a learning system, named My-Bookstore, where students buy (make records of) books (paper books) which they have read, and then sell (recommend) the books they like to others. This system is designed to encourage elementary students' classroom reading and book recommendation. The long-term influence of the My-Bookstore system on students' reading in terms of word usage and perception among 204 first-grade students who had used the system for three semesters was investigated. The results indicated that (a) the students borrowed a large number of books and were willing to recommend their favorite books in My-Bookstore; (b) most of the students felt that the overall use experience of the My-Bookstore was attractive, and the goal of the game was relevant to their reading. They also had confidence in recommending books and felt satisfaction when other students accepted their recommendations.

This paper presents studies on the theories aimed at using the technologies of Internet of Things in the domain of the emergency management of ponded water on road surface. It first introduces an emergency management model based on the Internet of Things to solve the problem of ponded water on road surface. It discusses a few critical technologies related to this model including monitoring the condition of the ponded water on road surface and the condition of the traffic simultaneously, the framework of data interfacing using multiple sources including the heterogeneous data, the analysis of traffic jam spreading pattern at critical locations of ponded water, comprehensive information analysis, and comprehensive demonstrations of monitoring based on GIS. In the end it gives our expectation about the future and development direction of using the technologies of Internet of Things in city traffic emergency management.

The concomitant presence of echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) and epidermal growth factor receptor (EGFR) is extremely rare. Previous studies have shown that EGFR mutation and EML4-ALK fusion are mutually exclusive and that the coexistence of these 2 genes are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) and ALK inhibitors. We report a case of lung adenocarcinoma harboring a concomitant EGFR mutation and EML4-ALK fusion that benefited for a short period from 3 TKIs. Additional study is warranted to clarify the therapeutic strategies in such patients with a concomitant EGFR mutation and EML4-ALK fusion.

Introduction Patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations are a heterogeneous group exhibiting differential responses to EGFR inhibitors. This retrospective study reviews the prevalence of uncommon EGFR mutations in a Chinese NSCLC cohort and the clinical characteristics and efficacy of EGFR tyrosine kinase inhibitors (TKIs) associated with these patients. Materials andmethods A total of 5363 lung cancer patients were screened and underwent EGFR genotyping at the Guangdong Lung Cancer Institute. Of those with uncommon EGFR mutations, the clinical characteristics and responses to EGFR-TKIs were reviewed retrospectively. Results Uncommon EGFR mutations were observed in 218 patients, comprising 11.9% of all patients with documented EGFR mutations. More smokers (30.7% vs. 24.3%, P=0.039) and males (54.1% vs. 44.4%, P=0.007) were among the patients with uncommon mutations compared with common mutations. The most frequent uncommon mutations were exon 20 insertions (30.7%, n=67), followed by G719X mutations (21.1%, n=46) and compound L858R mutations (17.0%, n=37). Favorable efficacy was observed in patients harboring compound L858R or G719X mutations, with a median progression-free survival (PFS) of 15.2 (95% CI: 8.7-21.7) or 11.6 (95% CI: 3.6-19.6) months, respectively. The median PFS of those with the T790M mutation or an exon 20 insertion was 1.0 (95% CI: 0.0-2.2) and 3.0 (95% CI: 1.3-4.7) months, respectively. Conclusion This study reviewed the prevalence of uncommon EGFR mutations and their sensitivity to EGFR-TKIs. Favorable responses were observed in patients with G719X and compound L858R mutations, indicating that they may benefit from EGFR-TKIs as a first-line therapy.

Objectives To investigate the clinical characteristics of anaplastic lymphoma kinase (ALK) rearrangements and sequence complexity of the ALK fusion gene in Chinese lung cancer patients. Methods We prospectively screened ALK rearrangements in 1474 lung cancer specimens, including 1387 cases of non-small cell lung cancer (NSCLC), 54 cases of small cell lung cancer (SCLC), and 33 cases of cancer with lung metastasis from other organs by both standard polymerase chain reaction (PCR) and rapid amplification of cDNA ends (RACE)-coupled PCR. Fifteen cases of ALK-positive RACE-coupled PCR products were transformed into Escherichia coli for molecular cloning and sequenced for complexity analysis. Results The overall frequency of ALK rearrangements was 5.1% (71/1387) in NSCLC. In 71 positive cases, the coexistence of epidermal growth factor receptor (EGFR) and ALK variations was found in 6 cases (8.5%), and the coexistence of different ALK variants was found in 2 cases (2.8%) (1 case with variants 1 and 9; the other case with variants 3 and 2) by PCR analysis. Furthermore, through sequence cloning analysis of 15 cases of non-selective ALK-positive samples, two cases with variants 1 and 3 harbored the coexistence of three subtypes (variant 1 subtypes: E13; A20, E13del63; A20 and E7E12E13; A20 and variant 3 subtypes: E6; A20, E6ins33; A20 and E3E6; A20). Variant 3a and 3b subtypes were always coexistent and had the same proportion of ALK variant 3 rearrangements. ALK rearrangement was associated with young age, female gender, never-smokers, those with adenocarcinoma, advanced stage, and EGFR mutations. No ALK fusion was detected in 54 cases of SCLC or 33 cases of cancer with lung metastasis from other organs. Conclusions The identification of novel ALK variants, the coexistence of EGFR mutations and ALK fusions, the coexistence of ALK variants, and the coexistence of subtypes reveal the diversity and sequence complexity of ALK fusions.

Introduction Subtype classification of lung adenocarcinoma (LUAD) divides different survivals and therapeutic vulnerabilities; however, little is known about the disease's underlying molecular mechanism. This study sought to determine the genetic and immune profiles of histologic subtypes and identify the evidence for adjuvant immunotherapy. Methods We performed an integrated analysis of multidimensional data from a discovery set consisting of cohorts of The Cancer Genome Atlas and the Broad Institute data set from the LUAD public database and a validation set from the Guangdong Lung Cancer Institute. Immunohistochemical staining was carried out to determine the expression of the proteins programmed cell death 1 ligand (PD-L1) and CD8. Results Patients with solid predominant LUAD showed poor disease-free survival and a high frequency of relapse/metastasis compared with those with the nonsolid subtype of LUAD. The solid subtype tended to occur more frequently in those with a history of smoking. Solid predominant LUAD exclusively showed increased expression of PD-L1 and a high proportion of dual positive PD-L1– and tumor-infiltrating lymphocytes. Meanwhile, a notable increase in the tumor mutation burden and higher frequency of GC>TA transversions were specifically identified in tumors of the solid subtype. Furthermore, the solid subtype of tumor displayed an active cytotoxic immune signature and increased incidence of genetic mutations related to immunogenicity. Conclusion Solid predominant LUAD was identified as a subtype with adaptive immune resistance, higher cytotoxic activity, and enhanced immunogenicity. These findings suggest that patients with solid predominant LUAD may represent a potential selective group that will benefit from adjuvant programmed cell death 1 blockade immunotherapy.

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.

The design of educational agents increasingly attracts researchers' attention recently. One of major reasons is that educational agents could enhance student learning in various aspects. Although research in this area has mushroomed, such research mainly emphasizes on students in higher education. It is still unclear how educational agents influence young student learning. In addition, competition is a significant element, but fewer studies take competition into account while designing educational agents. Although some studies have indicated that educational agents in competitive environments has positive effects on students' perception and attribution, its impacts on students' motivation and performance are unclear. Thus, the study develops an integrative agent that combines educational and competitive elements for young students, and further examines its influences, in terms of motivation and learning performance. The results revealed that such competitive educational agents could enhance students' motivation and learning performance.

Based on the technology concept and application of IOT, the technology of IOT is applied to the monitoring and safety early warning of bridge health to improve the level and efficiency of the operation and management in safety of bridge. The article discusses the key issues involved in the application, from the selection and optimized layout of sensors, the acquisition and transmission of monitoring data, the architecture and function of the bridge health monitoring system, safety early warning model research of bridge etc. And the article provides scientific basis for decision making in the safe operation and daily maintenance and management of bridges.

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and Met inhibitors have enabled progress in the management of advanced non–small-cell lung cancer (NSCLC). However, the clinical benefits of these agents are not uniform across the NSCLC spectrum. Thus, we evaluated the prognostic effect of mesenchymal-epithelial transition (MET) expression in Asian NSCLC patients with or without EGFR mutation. Methods: Frozen tumor tissues were collected from 92 patients with surgical resection and 10 with lymph node biopsy. Mutations in exons 18–21 in the EGFR–tyrosine kinase domain and MET expression were analyzed by using sequencing and immunohistochemistry, respectively. Results: The MET overexpression rate was 51% in NSCLC patients. MET-positive patients had poorer overall survival than MET-negative patients (29.8 versus 69.1 months, χ 2 = 7.420, p = 0.006) in patients with wild-type EGFR . However, no statistically significant difference was found in EGFR mutant patients (35.0 versus 35.9 months, χ 2 = 0.114, p = 0.735). Multivariate analysis showed that stage, MET expression, and sex were independent prognostic factors in patients with wild-type EGFR (χ 2 = 32.896, p Conclusions: These results suggest that MET expression has different prognostic significance in patients with differing EGFR mutation status. Whether MET inhibitors should be given early to NSCLC patients with EGFR wild-type needs further investigation.

This document analyzes the current problems brought by the impact of mass passenger flow in Beijing Rail Transit Network. Based on the characteristics of Internet of Things such as real-time sensing, information sharing and intelligence analysis etc., the construction strategy of Internet of Things precautionary systems is proposed to prevent mass passenger rail transit, and defined the selection and deployment policies of passenger flow detection equipment. Practice shows that the system effectively improves the forecasting capacity of mass passenger flow, and provides strong support for the implementation of rail transit sophisticated management.

To determine the inter-regional power replacement, this paper starts from the inter-regional power transmission and out-purchased demands and puts forward the analysis models of power transmission and out-purchased. Then it focuses on the decision problem of inter-regional power transmission and out-purchased where power supply exceeds power demand and provide the corresponding optimization algorithm. The models shows that inter-regional power replacement can reduce the generation pollutants emission, promote the power efficiency, and raise renewable energy grid-connected content like hydropower, wind power and so on, making magnificent economy and environmental effects.

The objective of this study was to analyze the predictive roles of VEGF/KDR/Ras/MAPK gene expression in patients with advanced non-small-cell lung cancer (NSCLC) treated with bevacizumab plus chemotherapy. Twenty-five patients participating in an open-label phase IV trial (SAiL, MO19390) with available tumor tissues were analyzed. The mRNA expression levels of VEGF, kinase insert domain receptor (KDR), Ras, and mitogen-activated protein kinase (MAPK) in tumor tissues were detected using real-time quantitative PCR methods. The relationships between gene expression and disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Patients with lower Ras expression had a longer PFS and OS than patients with higher expression (median PFS, 9.9 vs 5.5 months, χ(2)=3.944, P=0.047; OS, 19.3 vs 7.1 months, χ(2)=9.384, P=0.002). The PFS and OS of patients with lower and higher MAPK expression exhibited a marginal and significant difference (median PFS, 9.9 vs 5.5 months, χ(2)=3.464, P=0.063; OS, 19.3 vs 9.7 months, χ(2)=5.298, P=0.021), respectively. Multivariate analyses using Cox's proportional hazards model showed that Ras is an independent predictor of OS (χ(2)=9.384, P=0.002). No differences in DCR were found according to Ras expression level. The results indicate that Ras is an independent predictor of OS. Thus, patients with lower Ras expression are most likely to benefit from bevacizumab plus chemotherapy treatment regimen. Patients with higher levels of Ras should receive other inhibitors that target Ras. The results also suggest that gene therapies that decrease RAS expression combined with bevacizumab may improve lung cancer treatment. Although there is a very important implication to patient selection in the target therapy, the data in this study are very preliminary owing to the too small sample size. Therefore, further research involving large numbers of patients and a prospective assessment of low and high RAS mRNA expressions getting the same treatments need to be done before conclusions can be made.

Aimed to solve the abandoned wind problem and reduce CO2 emission in the power generation process, this paper put forward a thermal, wind power and pumped storage power station co-operation cost-benefit analysis model. And through a simulation example, found that using pumped storage power station to substitute thermal power as the alternate service for wind power, and absorb underused wind power, can reduce the use of fired units and increase the capacity of grid to absorb wind power, as well as reduce CO2 emission. Then through the sensitivity analysis, found that the amount of grid-connected wind power is a sensitive factor of CO2 emission reduction and the decrease of grid power purchase profit. So when grid implementing wind power grid connection, should use pumped storage power station as the wind power alternate service to promote wind power grid connection.