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Abstract Background The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. Methods The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment. Results Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment. Conclusions Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment. Graphical abstract

Abstract Background We aimed to explore the correlation between blood lipids (high density lipoprotein cholesterol [HDL‐C] and apolipoprotein A1 [ApoA1]) and epidermal growth factor receptor (EGFR) T790M mutation, as well as its predictive role in clinical efficacy and progression‐free survial (PFS) in advanced non‐small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (EGFR‐TKI). Methods We retrospectively collected information of 153 patients with advanced NSCLC harboring exon EGFR mutation and receiving EGFR‐TKI. Results The best cutoff value for HDL‐C and ApoA1 was determined to be 1.15 and 1.14 mmol/l. The overall response rate (ORR) was 67.7% in the high HDL‐C group and 46.6% in the low HDL‐C group, respectively. The ORR of the high ApoA1 group showed a significant increase than that of the low ApoA1 group (68.1% vs. 38.5%). The mean ApoA1 level of the EGFR T790M mutation‐positive group was significantly higher than that of the EGFR T790M mutation‐negative group (1.13 g/l vs. 1.01 g/l). Patients with high ApoA1 levels were related to the EGFR T790M mutation (r = 0.324). (3) The median progression‐free survival (PFS) of the high HDL‐C group and low HDL‐C group were 13.00 months and 10.20 months. The median PFS of the high ApoA1 group and the low ApoA1 group were 12.10 and 10.00 months, respectively. Multivariate Cox stepwise regression model analysis demonstrated ECOG PS, pathological type and HDL‐C were confirmed as critical and independent predictors of PFS. Conclusions Patients with EGFR T790M mutations often show higher ApoA1 levels. Peripheral serum HDL‐C and ApoA1 before treatment can be used as potential significant factors for predicting clinical efficacy and PFS in advanced NSCLC patients treated with EGFR‐TKI.

Background In a previous study, a total of 568 differentially expressed proteins including the signal peptidase SPC21 were identified from lung adenocarcinoma (LUAD) and paired normal lung tissues. In this study, the role of SPC21 in LUAD progression was investigated. Methods The relationships and protein-protein interaction network of proteins differentially expressed between paired LUAD samples and adjacent normal tissues samples were identified via the String and Pajek software, respectively. The expression levels of the hub protein SPC21 were analyzed in 84 LUAD-normal paired tissues via immunohistochemistry. The prognostic value of SPC21 mRNA was investigated in 478 LUAD patients from TCGA and GTEx datasets. siRNAs were used in A549 and NCI-H1299 cells to knockdown SPC21. The SPC21 biological function was evaluated using the CCK-8, EdU, plate colony formation, transwell, wound healing, and adhesion assays. Results Patients with lower SPC21 mRNA levels tended to have worse prognosis (overall survival) than those with higher mRNA levels. SPC21 expression was significantly downregulated in LUAD tumor tissues compared with that in paired normal tissues (P

Background: Previous studies suggested that myocardial work (MW) may identify abnormalities in the left ventricular (LV) function and establish a more sensitive index for LV dysfunction at the early stage. This study aimed to explore the value of global and regional MW parameters in predicting high-risk stable coronary artery disease (SCAD) patients with normal wall motion and preserved LV function.Patients and Methods: A total of 131 patients, who were clinically diagnosed as SCAD with normal wall motion and LV function, were finally included in this study. Global MW parameters, including global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE) were measured with non-invasive LV pressure-strain loops constructed from speckle-tracking echocardiography. Regional myocardial work index (RWI) and work efficiency (RWE) were also calculated according to the perfusion territory of each major coronary artery. All patients underwent coronary angiography and were divided into the high-risk SCAD group, the non-high-risk SCAD group, and the No SCAD group according to the range and degrees of coronary arteries stenosis.Results: The global longitudinal strain (GLS), GWI and GCW were statistically different (P < 0.001) among the three groups. In the high-risk SCAD group, GLS, GWI, and GCW were significantly lower than the other two groups (P < 0.05). Receiver operating characteristic analysis demonstrated GWI and GCW could predict high-risk SCAD at a cutoff value of 1,808 mm Hg% (sensitivity, 52.6%; specificity, 87.8%; predictive positive value, 76.3%; predictive negative value, 69.9%) and 2,308 mm Hg% (sensitivity, 80.7%; specificity, 64.9%; predictive positive value, 63.3%; predictive negative value, 80.0%), respectively. Multivariate analyses showed that carotid plaque, decreased GWI, and GCW was independently related to high-risk SCAD. The cutoff values of RWILAD, RWILCX, and RWIRCA were 2,156, 1,929, and 1,983 mm Hg% in predicting high-risk SCAD, respectively (P < 0.001). When we combined RWI in two or three perfusion regions, the diagnostic performance of SCAD was improved (P < 0.001).Conclusions: Both global and regional MW parameters have great potential in non-invasively predicting high-risk SCAD patients with normal wall motion and preserved LV function, contributing to the early identification of high-risk patients who may benefit from revascularization therapy.

Background Desmoglein-2 (DSG2), a desmosomal adhesion molecule, is found to be closely related to tumorigenesis in recent years. However, the clinical value of DSG2 in lung adenocarcinoma remains unclear. Methods Real-time reverse transcription-quantitative polymerase chain reaction (qRT-PCR) was utilized to detect the expression of DSG2 in 40 paired lung adenocarcinoma tissues and corresponding non-cancerous tissues. Data from The Cancer Genome Atlas (TCGA) and Oncomine datasets were also downloaded and analyzed. The correlation between DSG2 and clinicopathological features was investigated. The expression of DSG2 protein by immunohistochemical was also detected from tissue microarray and the Human Protein Atlas database. Integrated meta-analysis combining the three sources (qRT-PCR data, TCGA data and Oncomine datasets) was performed to evaluate the clinical value of DSG2. Univariate and multivariate Cox regression analyses were used to explore the prognostic value of DSG2. Then, co-expressed genes were calculated by Pearson correlation analysis. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to investigate the underlying molecular mechanism. The expression level in lung adenocarcinoma and prognostic significance of the top ten co-expressed genes were searched from Gene Expression Profiling Interactive Analysis (GEPIA) online database. Results DSG2 was highly expressed in lung adenocarcinoma tissues based on qRT-PCR, TCGA and Oncomine datasets. The protein expression of DSG2 was also higher in lung adenocarcinoma. According to qRT-PCR and TCGA, high DSG2 expression was positively associated with tumor size (p = 0.027, p = 0.001), lymph node metastasis (p = 0.014, p < 0.001) and TNM stage (p = 0.023, p

Growing evidence indicates that the cross-linked N-telopeptide of type I collagen (NTx) is likely to be involved in the development of bone metastasis among lung cancer patients. We perform a meta-analysis to disclose the correlation between bone metastasis and NTx and also to evaluate its value in diagnosis of bone metastasis (BM) in lung cancer.Electronic databases were searched and calculated the weighted mean difference (WMD) with 95% confidence interval (CI) to assess the expression difference of NTx between BM+ and BM- lung cancer patients. Moreover, we conducted a sensitivity and specificity test and drew a summary receiver operating characteristic curve (SROC) to assess the diagnostic value of NTx in discerning bone metastasis.A total of eleven studies with 1108 individuals were included in this analysis. The results showed an increased NTx was correlated with the incidence of lung cancer (P < 0.001). The overall sensitivity and specificity of serum NTx (sNTx) for discerning bone metastasis was 0.74 (95% CI = 0.67 to 0.79) and 0.85 (95% CI = 0.80 to 0.89), respectively. As for urine NTx (uNTx) the pooled sensitivity and specificity was 0.77(95% CI = 0.67 to 0.86) and 0.81(95% CI = 0.76 to 0.86). The area under the SROC curve was 0.8889(SE = 0.0255) and 0.8655(SE = 0.0254) for sNTx and uNTx respectively.The elevation of NTx in lung cancer was positively related with the development and progression of bone metastasis. A higher specificity over sensitivity of NTx suggested that it is a more accurate biomarker to distinguish patients without bone metastasis. Regarding SROC curve, sNTx may be a better choice.

The upregulation of vascular cell adhesion molecule-1(VCAM-1) on vascular endothelium plays a great role in the progression of atherosclerosis (AS). In this study, ultrasound molecular imaging was performed to monitor the inflammation injuries in the onset and progression of atherosclerosis with microbubbles targeted to VCAM-1.Mice deficient for the apolipoprotein E (ApoE-/-mice) with high-cholesterol diet were studied as an age-dependent model of atherosclerosis. At 8, 16, 24, and 32 weeks of age, contrast enhanced ultrasound (CEU) molecular imaging of proximal ascending aorta was performed with microbubbles targeted to VCAM-1. Plaque size, monocytes infiltration and the expression of VCAM-1 in the proximal ascending aorta were assessed by histology and western blot analysis, separately.In ApoE-/- mice, molecular imaging for VCAM-1 detected selective signal enhancement (P

A condition for exclusive Z-control in the oxidative ring-opening reaction of 3-cyclohexene-1,2-diols via use of NaI[O.sub.4] without any acid treatment is demonstrated. The process complemented the ring-contraction protocol from 3-cyclohexene-1,2-diols via the E-controlled oxidative ring-opening reaction followed by the intramolecular Baylis-Hillman reaction to produce cyclopentenols.

Long non-coding RNAs (lncRNAs) have been involved in occurrence and progression of multiple cancers. In the present study, we investigated the role of lncRNA Gm15290 in the proliferation and invasion of non-small cell lung cancer (NSCLC) cells. First, we found that lncRNA Gm15290 was markedly up-regulated in tumor tissues from NSCLC patients and NSCLC cell lines, compared with adjacent normal tissues and normal lung cell line HBE respectively. Then, different concentrations of pcDNA-Gm15290 expression vector and Gm15290 siRNA were respectively transfected into A549 NSCLC cells. Our results showed that overexpression of Gm15290 significantly increased the proliferation and invasion of A549 cells and suppressed cell apoptosis. Knockdown of Gm15290 suppressed A549 cell proliferation and invasion and promoted cell apoptosis. Subsequently, we explored the underlying mechanism through which Gm15290 promoted cell proliferation and invasion. The output of RNA hybrid bioinformatic tool revealed that Gm15290 potentially interacted with tumor suppressor miR-615-5p which displayed an opposite expression pattern in the cell lines and a strong negative correlation with the levels of Gm15290 in NSCLC patients (r2 = 0.9677, P<0.0001). The results of RNA pull-down assays confirmed that Gm15290 directly bound with miR-615-5p. Gm15290 negatively regulated the expression of miR-615-5p and increased the protein levels of miR-615-5p target genes, including IGF2, AKT2, and SHMT2. Moreover, miR-615-5p mimic could antagonize the promoting effect of Gm15290 on cell proliferation and invasion. [ABSTRACT FROM AUTHOR]