With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations ("target-dependent resistance") and in the parallel and downstream pathways ("target-independent resistance"). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Tumor Microenvironment/genetics*

BACKGROUND: The expression of programmed cell death ligand 1 (PD-L1) as a biomarker for immunotherapy in non-small cell lung cancer (NSCLC) is routinely detected in clinical pathology department. However, the spatial heterogeneity of PD-L1 expression in intrapulmonary tumors and extrapulmonary metastases is still a challenge for the clinical testing. This study aims to explore the differences of PD-L1 expression in test samples obtaining from different sites of NSCLC. This study may contribute to the detection strategy of PD-L1 in patients with advanced lung cancer. METHODS: One hundred and thirty-one cases of consecutively detected PD-L1 (22c3 assay, Dako) staining in metastatic NSCLC and 972 cases of non-paired intrapulmonary NSCLC were collected. The discrepancies of tumor proportion score (TPS) of PD-L1 expression in intrapulmonary samples and extrapulmonary metastatic samples of different sites were compared. RESULTS: The positive expression rate of PD-L1 in extrapulmonary metastatic NSCLC (TPS ≥ 1%) was 61.83%, and the TPS was significantly higher than that in intrapulmonary tumors (P=0.03). The PD-L1 scores of the specimens obtained from different sites were significantly different (P=0.007). The positive rates of PD-L1 in liver and adrenal metastases were 85.71% and 77.78% respectively, and their TPS were significantly higher than that of the intrapulmonary samples (P<0.05). The positive rates of PD-L1 in lymph node, bone, brain, soft tissue, and pleural metastases was 40.00%-66.67%, with no significant differences compared to intrapulmonary tumors. The analysis of histological subtype and sample type showed that the PD-L1 score of extrapulmonary samples of adenocarcinoma subtype or surgical specimen was significantly higher than that of intrapulmonary tumors. The analysis of clinicopathological parameters showed that the PD-L1 positive expression or high expression were significantly correlated with male patients, smoking history, and epidermal growth factor receptor (EGFR) wild type. CONCLUSIONS The expression of PD-L1 in metastatic NSCLC is generally higher than that in intrapulmonary tumor, and the positive rate of PD-L1 expression was discrepant in different sites of specimen. The differences of PD-L1 score between extrapulmonary metastatic samples and intrapulmonary samples may be associated with different metastatic sites, histological subtype, and specimen type.
B7-H1 Antigen/metabolism* ; Biomarkers, Tumor/metabolism* ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Humans ; Immunohistochemistry ; Lung Neoplasms/drug therapy* ; Male

OBJECTIVE: To report on a family which has two siblings with SCN2A mutation caused by germline mosaicism suffering from autism spectrum disorder/development delay (ASD/DD). METHODS: Clinical data was collected for the proband and his parents. Next generation sequencing (NGS) was carried out on the proband and his parents. Suspected mutations were verified by Sanger sequencing of the proband, his parents and brother. To detect whether there is a low proportion of somatic mosaicism in the parents, a droplet digital PCR was conducted. The result of ddPCR showed that the father was germline mosaicism (0.233%). RESULTS: NGS has identified a de novo splicing mutation of the SCN2A gene, c.605+1G>A, in the proband and his brother. Combined with its clinical phenotype and inheritance pattern, SCN2A was judged to be the pathogenic gene. Above findings strongly suggested parental germline mosaicism. CONCLUSION ASD/DD in siblings with SCN2A mutations caused by germline mosaicism. Paternal mosaicism should be considered as one of the important inheritance patterns for counseling parents with a child carrying SCN2A mutation. The ddPCR can help to reveal very low proportion of germline mosaicism.
Autism Spectrum Disorder ; Germ Cells ; Humans ; Male ; Mosaicism ; Mutation ; NAV1.2 Voltage-Gated Sodium Channel/genetics* ; Siblings

Objective:To investigate the distribution of the spherical aberration in age-related cataractous eyes using the Pentacam HR.Methods:A cross-sectional study was performed in Shanxi Eye Hospital from December 2014 to December 2015.The preoperative corneal spherical aberration of 1 319 eyes of 1 319 patients with age-related cataract over 40-years-old was analyzed.The mean average keratometry (Km value), and corneal posterior surface Km corneal astigmatism, posterior corneal astigmatism, and corneal thickness were measured with.Pentacam, and the Zernike coefficients of corneal spherical aberration were calculated.A correlation between spherical aberration and corneal parameters was evaluated by Pearson correlation analysis.The proportion of eyes qualifying for spherically neutral or negatively aspheric intraocular lens targeted residual spherical aberration level was evaluated.This study protocol was approved by Ethics Committee of Shanxi Eye Hospital and complied with Declaration of Helsinki.Results:The average age of all patients was (68.00±11.12) years old with an average spherical aberration (0.34±0.17)μm.The spherical aberration was lower than 0 μm in 22 eyes (1.67%), 0~0.4 μm in 842 eyes (63.84%), and greater than 0.4 μm in 455 eyes (34.50%). There was a weak positive correlation between spherical aberration and age ( r=0.398, P<0.001). There were very weak correlations between spherical aberration and corneal Km, posterior corneal surface Km, corneal thickness ( r=0.129, P<0.001; r=0.240, P<0.001; r=-0.068, P<0.05). No significant correlations were found between spherical aberration and corneal astigmatism or posterior corneal astigmatism ( r=-0.025, P=0.365; r=-0.008, P=0.771). Seven hundred and ten eyes (53.83%) could be qualified for implantation of negatively or neutrally aspheric intraocular lens based on postoperative targets of (0.10±0.05)μm residual spherical aberration. Conclusions:Corneal spherical aberration in Chinese patients is greater than that in other populations (+ 0.27 μm) in literature and shows individual differences.The appropriate aspheric intraocular lens should be selected according to individual corneal spherical aberration before cataract operation.

Objective:To explore the role of small molecule glycoprotein Serglycin (SRGN) in chemotherapy resistance of non-small cell lung cancer (NSCLC).Methods:In NSCLC H1299 cell line, shRNA technology was used to interfere with the expression of SRGN and establish stable interfering cell line. Western blot and real time fluorescence quantitative polymerase chain reaction (qRT-PCR) were used to verify the knockdown efficiency; MTS was used to detect the knockdown cell line′s drug sensitivity to cDDP and Oxaliplatin; enzyme linked immunosorbent assay (ELISA), Western blot and qRT-PCR were used to explore the effect of transforming growth factor β (TGFβ) on SRGN and vice versa; Western blot was used to detect the effect of SRGN on epithelial-mesenchymal transition (EMT) related molecules, and online data bioinformatics was used to analyze the correlation between SRGN and EMT related molecules expression; in addition, online prognostic analysis software (kmplot) was used to analyze the correlation between SRGN, TGFβ and prognosis of lung cancer patients.Results:Comparing with the control group, the test group, knocking down SRGN can obviously improve the drug sensitivity of NSCLC cell to cDDP ( P=0.032 7) or Oxaliplatin ( P=0.014 2). TGFβ can enhance the experission of SRGN in NSCLC and SRGN also can help TGFβ secreted from cells. SRGN promotes the epithelial mesenchyme transition by modulating Snail1. By analyzing TCGA database, we found that the expression of SRGN was negatively correlated with the expression of CDH1 (coding for Ecadherin protein) ( r=-0.25) and there was a positive correlation with Snai1 expression ( r=0.37). These results suggest that SRGN can promote the change of EMT in lung cancer cells through TGF β 1 and snail 1. The overall survival time of NSCLC patients with low expression of SRGN was much longer than the patients with high expression of SRGN ( P=0.007 7). The overall survival time of NSCLC patient with low expression in both SRGN and TGFβ1 or TGFβ2 was 73months or 42.8 months longer than that with high expression in both SRGN and TGFβ1/2. Conclusions:Intercting with TGFβ1, SRGN promotes EMT of NSCLC cells, which facilitates the chemoresistence of NSCLC. The simultaneous low expression of SRGN and TGFβ1 or TGFβ2 can significantly prolong the overall survival of patients with NSCLC.

Objective To evaluate the role of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in remote ischemic preconditioning-induced reduction of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice.Methods Sixty-eight healthy male C57BL/6 mice,aged 6-8 weeks,weighing 22-26 g,were divided into 4 groups (n =17 each) using a random number table:control group (group C),ALI group,remote ischemic preconditioning group (group RIPC) and brusatol plus remote ischemic preconditioning group (group B+RIPC).Normal saline 100 μl was intratracheally instilled in group C.ALI was induced by intratracheal instillation of LPS 5 mg/kg in group ALI.Mice in group RIPC were subjected to 6 cycles of 5-min ischemia followed by 5-min reperfusion in the right hindlimbs using a tourniquet,and 1 h later the model of ALI was established.Nrf2 inhibitor brusatol 2 mg/kg (in 100 μl of 1％ dimethyl sulfoxide) was intraperitoneally injected every other day for 10 days prior to establishment of the ALI model in group B.Brusatol 2 mg/kg was intraperitoneally injected every other day for 10 days prior to establishment of the ALI model,and remote ischemic preconditioning was performed at 1 h before establishment of the ALI model in group B+RIPC.Seven mice in each group were selected at 24 h after establishment of the ALI model,and bronchoalveolar lavage fluid (BALF) was collected for determination of protein concentrations and neutrophil count.Mice were then sacrificed and lungs were removed for determination of lung water content,myeloperoxidase (MPO) activity,contents of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α),and expression of Nrf2,HO-1 and high-mobility group box 1 protein (HMGB1) in lung tissues (by Western blot) and for examination of pathological changes (with a light microscope).Results Compared with group C,the lung water content,MPO activity,contents of IL-1β and TNF-α,and neutrophil count and protein concentrations in BALF were significantly increased,and the expression of Nrf2,HO-1 and HMGB1 was up-regulated in group ALI (P＜ 0.05).Compared with group ALI,the lung water content,MPO activity,contents of IL-1β and TNF-α,and neutrophil count and protein concentrations in BALF were significantly decreased,the expression of Nrf2 and HO-1 was up-regulated,and the expression of HMGB1 was down-regulated (P＜0.05),and the pathological changes were significantly attenuated in group RIPC.Compared with group RIPC,the lung water content,MPO activity,contents of IL-1β and TNF-α,and neutrophil count and protein concentrations in BALF were significantly increased,the expression of Nrf2 and HO-1 was down-regulated,and the expression of HMGB1 was up-regulated (P＜0.05),and the pathological changes were aggravated in group B+RIPC.Conclusion The activation of Nrf2/HO-1 signaling pathway is involved in remote ischemic preconditioning-induced reduction of LPS-induced ALI in mice.

Objective To investigate the prevalence of thyroid nodules and thyroid dysfunction in southern mountainouss areas of Ningxia.Methods A cross-sectional study was conducted among a representative sample of 10 639 adults in Jingyuan county with a population proportionate sampling method.High-resolution ultrasound was used to examine the thyroid and fasting blood specimens were collected in the morning for measurement of TSH,FT4,FT3.Chi-square test and spearman rank correlation analysis were used for statistical analysis.Results The prevalence of thyroid nodules was 29.08％,the sex-and age-adjusted rate was 27.17％.The prevalence of thyroid nodules was higher in women than in men (32.68％ vs.24.88％,x2=76.029 2,P＜0.001) and age was positively associated with thyroid nodules (r=0.272,P＜0.001).The rate of thyroid dysfunetion,subclinical hypothyroidism,subclinical hyperthyroidism,hypothyroidism,hyperthyroidism were 17.39％,13.00％,0.42％,0.96％,3.01％,respectively.The prevalence of thyroid nodules was higher in abnormal TSH group than in normal TSH group (39.44％ vs.27.24％,x2=95.624 0,P＜0.001).The level of THS,FT3,FT4 in thyroid nodules group differed fromn control group (Z=-9.144,P＜0.001;Z=-6.140,P＜0.001;Z=-1.997,P=0.046).Conclusion The prevalence of thyroid nodules and thyroid dysfunction were higher in southern mountainous areas of Ningxia.The relationship between thyroid nodules and thyroid function needs further research.We should pay attention to the early screening and diagnosis of thyroid nodules in mountainous areas.

Objective The method for detecting expression of human CDK14 gene with Real-time quantitative PCR was developed.Methods To establish a method for detecting expression of human CDK14 gene with Real-time quantitative PCR by designing and synthesis of the primers of CDK14 target gene andβ-Actin reference gene and extracting total RNA from different lung cancer cell lines.Then the specificity,detection range and repeatability of this method were evaluated.At last,the expression level of CDK14 gene in different cell lines,which were with or without siRNA interference,were carried out by using this method.Results The method for detecting expression of human CDK14 gene with Real-time quantitative PCR,which had good specificity,good repeatability (CV=7.3 ％) and wide detection range (Ct value range of CDK14 and β-Actin amplification curve were 22.47～32.96 and 15.14～ 27.55 respectively,r2 =0.9844),was developed and it was verified by electrophoresis analysis,melting curve,PCR product sequencing.And CDK14 gene expression level,which was detected by this method,increased in HCC827 D5,H1650 and number 1 siRNA segment was effective interference segment.Conclusion The method for detecting expression of human CDK14 gene with Real-time quantitauve PCR was established successfully.

Objective    To investigate the effect and mechanism of epigallocatechin-3-gallate (EGCG) on restenosis of the vein graft. Methods    Totally 90 Sprague-Dawley rats were randomly divided a the control group, a vein graft group and an EGCG+vein graft group. At week 1, 2 and 4, the intimal and tunica thickness of the venous graft wall was evaluated by hematoxylin-eosin staining, and the expression of Ki-67 was assessed by immunohistochemistry analysis, and then the expression of hairy and enhancer of split-1 (HES1) was measured by Western blot assay. Results    At week 2, the intimal thickness (46.76±4.89 μm vs. 8.93±0.82 μm, 46.76±4.89 μm vs. 34.24±3.57 μm), tunica thickness (47.28±4.37 vs. 16.33±1.52 μm, 47.28±4.37 vs. 36.27±3.29 μm), positive cell rate of Ki-67 (21.59%±2.29% vs. 1.12%±0.22%, 21.59%±2.29%vs. 15.38%±1.30%), expression of HES1 respectively increased in the experimental group than those in the control group and the EGCG+vein graft group (P<0.05, respectively). At week 4, the intimal thickness (66.38±6.23 μm vs. 8.29±0.79 μm,   66.38±6.23 μm vs. 48.39±4.23 μm), tunica thickness (63.27±6.18 μm vs. 15.29±1.49 μm, 63.27±6.18 μm vs. 44.63±4.49 μm), positive cell rate of Ki-67 (33.19%±3.03% vs. 1.09%±0.19%, 33.19%±3.03% vs. 24.37%±2.73%), expression of HES1 increased in the experimental group than those in the control group and EGCG+vein graft group (P<0.05, respectively). Conclusion    EGCG may inhibite restenosis of vein graft by inhibiting Notch signal pathway.