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The improvement of treatment for patients with 'driver-gene-negative' lung adenocarcinoma (LUAD) remains a critical problem to be solved. We aimed to explore the role of methylation of N6 adenosine (m6A)-related long noncoding RNA (lncRNA) in stratifying 'driver-gene-negative' LUAD risk. Patients negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as 'driver-gene-negative' cases. RNA sequencing was performed in 46 paired tumors and adjacent normal tissues from patients with 'driver-gene-negative' LUAD. Twenty-three m6A regulators and relevant lncRNAs were identified using Pearson's correlation analysis. K-means cluster analysis was used to stratify patients, and a prognostic nomogram was developed. The CIBERSORT and pRRophetic algorithms were employed to quantify the immune microenvironment and chemosensitivity. We identified two clusters highly consistent with the prognosis based on their unique expression profiles for 46 m6AlncRNAs. A risk model constructed from nine m6A lncRNAs could stratify patients into high- and low-risk groups with promising predictive power (C-index = 0.824), and the risk score was an independent prognostic factor. The clusters and risk models were closely related to immune characteristics and chemosensitivity. Additional pan-cancer analysis using the nine m6AlncRNAs showed that the expression of DIO3 opposite strand upstream RNA (DIO3OS) is closely related to the immune/stromal score and tumor stemness in a variety of cancers. Our results show that m6AlncRNAs are a reliable prognostic tool and can aid treatment decision-making in 'driver-gene-negative' LUAD. DIO3OS is associated with the development of various cancers and has potential clinical applications.

Background To study the role of computed tomography (CT)-derived radiomics features and clinical characteristics on the prognosis of “driver gene-negative” lung adenocarcinoma (LUAD) and to explore the potential molecular biological which may be helpful for patients’ individual postoperative care. Methods A total of 180 patients with stage I-III “driver gene-negative” LUAD in the First Affiliated Hospital of Sun Yat-Sen University from September 2003 to June 2015 were retrospectively collected. The Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model was used to screen radiomics features and calculated the Rad-score. The prediction performance of the nomogram model based on radiomics features and clinical characteristics was validated and then assessed with respect to calibration. Gene set enrichment analysis (GSEA) was used to explore the relevant biological pathways. Results The radiomics and the clinicopathological characteristics were combined to construct a nomogram resulted in better performance for the estimation of OS (C-index: 0.815; 95% confidence interval [CI]: 0.756–0.874) than the clinicopathological nomogram (C-index: 0.765; 95% CI: 0.692–0.837). Decision curve analysis demonstrated that in terms of clinical usefulness, the radiomics nomogram outperformed the traditional staging system and the clinicopathological nomogram. The clinical prognostic risk score of each patient was calculated based on the radiomics nomogram and divided by X-tile into high-risk (> 65.28) and low-risk (≤ 65.28) groups. GSEA results showed that the low-risk score group was directly related to amino acid metabolism, and the high-risk score group was related to immune and metabolism pathways. Conclusions The radiomics nomogram was promising to predict the prognosis of patients with “driver gene-negative” LUAD. The metabolism and immune-related pathways may provide new treatment orientation for this genetically unique subset of patients, which may serve as a potential tool to guide individual postoperative care for those patients.

Objectives: Assessing the prognosis of patients with “driver-gene-negative” lung adenocarcinoma (LUAD patients negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET and ROS1 were identified as “driver-gene-negative”) is of significant clinical importance. We aimed to devise a prognostic nomogram for this LUAD subgroup and to define its biological basis.Materials and methods: Prognostic nomogram were established based on a retrospective study of 294 patients with surgical resected “driver-gene-negative” LUAD at The First Affiliated Hospital of Sun Yat-sen University between September 2003 and June 2015. The concordance index (C-index) and calibration curve were used to determine its predictive accuracy and discriminatory capacity. Patients were classified into low- and high-risk subgroups according to nomogram scores. To define the biological basis, we carried out gene set enrichment analysis in an independent dataset of 49 “driver-gene-negative” LUAD patients.Results: The nomogram built on the independent factors including CTC, age and stage achieved C-index of 0.785 [95% confidence interval (CI) 0.753-0.817] for predicting OS of “driver-gene-negative” LUAD. The calibration curves for OS probabilities showed a good agreement between the nomogram prediction and actual observation. High-risk patients had shorter OS [hazard ratio (HR) = 7.43, 95% CI 5.20-10.42, pConclusions: The prognostic nomogram showed promising prediction efficacy and is expected to predict the prognosis of “driver-gene-negative” LUAD. The easy-to-use nomogram and the enriched pathways can help clinical decision-making, guide follow-up planning, and develop new therapeutic targets.

Objectives: Thymoma-associated myasthenia gravis (TAMG) is the most common paraneoplastic syndromeof thymoma. The screening of TAMG before thymoma resection is required to avoid severe perioperative complications, especiallyrespiratory failure. Herein, we developed a 3D DenseNet deep learning (DL) model based on preoperative computed tomography (CT) to detect TAMGin thymoma patients.Methods:A large cohort of 230 thymoma patientswere enrolled. 182 thymoma patients (81 with TAMG, 101 without TAMG) were used for training and model building. 48 cases from another hospital were used for external validation. A 3D-DenseNet-DL model and five machine learning models with radiomics features were performed to detectTAMG in thymoma patients. A comprehensive analysis by integrating 3D-DenseNet-DL model and general CT image features,named 3D-DenseNet-DL-based multi-model, was also performed to establish a more effective prediction model.Results: By elaborately comparing the prediction efficacy,the 3D-DenseNet-DL effectively identified TAMG patients, with a mean area under ROC curve (AUC), accuracy, sensitivity and specificity of 0.734, 0.724, 0.787 and 0.672, respectively. The effectiveness of the 3D-DenseNet-DL-based multi-model was further improved as evidenced bythe following metrics: AUC 0.766, accuracy 0.790, sensitivity 0.739 and specificity 0.801. External verification results confirmed the feasibility of this DL-based multi-model with metrics: AUC 0.730, accuracy 0.732, sensitivity 0.700 and specificity 0.690,respectively.Conclusions: Our 3D-DenseNet-DL model can effectively detect TAMG in patients with thymoma based on preoperative CT images. This model may serve as a non-invasive screening method or as a supplement to the conventional diagnostic criteria for identifyingTAMG.Key points:Thymoma-associated myasthenia gravis (TAMG) is a common paraneoplastic syndrome.3D-DenseNet-DL model can effectively detect TAMG based on preoperative CT images.This model may serve as a supplement for identifying TAMG.

Background Previous genomic studies revealed phosphotidylinositol-3-kinase (PI3K)/Akt pathway mutation in human salivary gland adenoid cystic carcinoma (ACC). No validation of its prognostic value has been reported. Methods P-Akt, pan-Akt, phosphorylated-mammalian target of rapamycin (p-mTOR), PI3K, and insulin-like growth factor-1 receptor beta (IGF-1Rβ) were detected on 120 salivary gland ACC/adjacent salivary gland pairs immunohistochemically and were correlated with clinicopathological data. Results Expression of cytoplasmic and nuclear p-Akt, cytoplasmic p-mTOR, nuclear pan-Akt, and nuclear IGF-1Rβ were higher in ACC than in adjacent salivary glands. P-Akt, p-mTOR, PI3K, and IGF-1Rβ expression were correlated with one another in both cytoplasm and nucleus. Low p-mTOR expression in both subcellular compartments was associated with locoregional recurrence, poor disease-free survival (DFS), and overall survival (OS). Low nuclear p-Akt (Ser473) and p-mTOR expression were independent predictors for poor OS and DFS, respectively. Conclusion High level of Akt/mTOR activation in ACC is correlated with a significantly improved survival. P-mTOR and nuclear p-Akt are prognostic biomarkers of salivary gland ACC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1145-1154, 2017.

Additional file 1. Supplementary data.

Background/Aims: Golgi phosphoprotein 3 (GOLPH3) is a newly reported oncogene that plays a significant role in regulating cell growth. Recent research has shown that overexpression of GOLPH3 is correlated with patient survival and M classification in breast cancer and other cancers. However, the mechanisms by which GOLPH3 contributes to metastasis in non-small cell lung cancer (NSCLC) have not been previously clarified and are therefore the focus of this work. Methods: Immunohistochemistry (IHC) and western blotting analysis were performed to assess the GOLPH3 protein level, small interfering RNA (siRNA) and transwell assays were conducted to investigate the role of GOLPH3 in migration and invasion, and real-time PCR was performed to estimate the level of GOLPH3 mRNA expression. Results: GOLPH3 was significantly correlated with clinicopathological variables, such as the clinical stage (P=0.012), T classification (P=0.002) and metastasis (M classification) (P=0.008), in NSCLC patients and was negatively correlated with the prognosis. Knockdown of GOLPH3 significantly suppressed the migratory and invasive ability of NSCLC cell lines and downregulated the enzyme activity and protein levels of MMP-2 and MMP-9. Conclusions: The expression level of GOLPH3 is correlated with metastasis and prognosis in NSCLC, and GOLPH3 mediates metastasis by regulating the protein levels of MMP-2 and MMP-9 in vitro.

Previous genomic studies revealed phosphotidylinositol-3-kinase (PI3K)/Akt pathway mutation in human salivary gland adenoid cystic carcinoma (ACC). No validation of its prognostic value has been reported.P-Akt, pan-Akt, phosphorylated-mammalian target of rapamycin (p-mTOR), PI3K, and insulin-like growth factor-1 receptor beta (IGF-1Rβ) were detected on 120 salivary gland ACC/adjacent salivary gland pairs immunohistochemically and were correlated with clinicopathological data.Expression of cytoplasmic and nuclear p-Akt, cytoplasmic p-mTOR, nuclear pan-Akt, and nuclear IGF-1Rβ were higher in ACC than in adjacent salivary glands. P-Akt, p-mTOR, PI3K, and IGF-1Rβ expression were correlated with one another in both cytoplasm and nucleus. Low p-mTOR expression in both subcellular compartments was associated with locoregional recurrence, poor disease-free survival (DFS), and overall survival (OS). Low nuclear p-Akt (Ser473) and p-mTOR expression were independent predictors for poor OS and DFS, respectively.High level of Akt/mTOR activation in ACC is correlated with a significantly improved survival. P-mTOR and nuclear p-Akt are prognostic biomarkers of salivary gland ACC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1145-1154, 2017.

Podocyte injury plays an important role in glomerulosclerosis in IgA nephropathy (IgAN). Eepithelial-to-mesenchymal transition (EMT) caused by different factors is the main reason for podocyte damage. This study hypothesized that conditioned mesangial medium may induced EMT process of podocytes and thereby lead to glomerular injury or sclerosis.Podocytes were incubated in medium from mesangial cells incubated with aggregated IgA1(aIgA1) isolated from IgAN patients. Wortmannin were used to inhibit phosphatidylinositol-3-kinase (PI3-K) in podocytes.Western blot analysis, real-time PCR and confocal fluorescent microscopy demonstrated that reduced expression of P-Cadherin, Zonula occludens-1 (ZO-1) and podocin, increased expression of fibroblast -specific protein (FSP-1), α-smooth muscle action(α-SMA) and desmin in podocytes exposed to medium from mesangial cells incubated with aIgA1 isolated from IgAN patients compared with podocytes cultured in RPMI 1640 medium containing 0.5% fetal bovine serum ( FBS) (p0.05). Mesangial medium resulted in a greater albumin influx across the podocyte monolayer (p0.05). Phosphorylation of Akt increased with this medium, as indicated by an increase in the p-Akt/Akt ratio. Treatment with wortmannin partly restored the changes in epithelial and mesenchymal markers and albumin influx. IgAN patients with massive proteinuria showed remarkable α-SMA and FSP-1 expression in podocytes.Our findings indicated that mesangial medium from cells incubated with aIgA1 isolated from IgAN patients induced EMT in podocytes and the PI3-K/ Akt-signaling pathway was involved in the process.

Lung cancer is the leading cause of mortality among malignant diseases in humans worldwide. During the last decade, molecular targeted therapies for non-small cell lung cancer using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib, have been shown to be a promising approach for patients harboring activating mutations in EGFR. The current study reports a 77-year-old patient diagnosed with adenocarcinoma harboring L858R and T790M point mutations in the EGFR gene. The patient was treated with gefitinib as the second-line therapy, but no clinical benefit was observed. As the majority of patients with lung cancer receiving EGFR-TKI therapy acquire resistance, repeated biopsies and detection of the EGFR mutation state are beneficial for selecting appropriate treatments.

Heparanase (HPA) influences tumourigenesis and tumour progression by various mechanisms, including angiogenesis. Cyclooxygenase-2 (COX-2) was strongly correlated with microvessel density, and that COX-2 expression is up-regulated by HPA in esophageal cancer. In this study, we examined the relationship between HPA expression and that of COX-2 in colon carcinoma. The aim of this study was to determine whether the expression of HPA is related to the angiogenesis in colorectal cancer and whether it could be involved in clinical behaviour of colon carcinoma.HPA and COX-2 was analyzed with Immunohistochemistry and Western blot. Microvessels in colon carcinoma were examined by using anti-CD34 antibody. Statistical analysis was applied to test for the prognostic and diagnostic associations.Immunohistochemistry revealed that HPA was expressed at low level in normal colonic mucosa (4/78, 5.1%), but at higher level in tumor tissues (63/78, 80.7%) and closely correlated with tumor lymph node metastasis (p0.05). This result was further confirmed by Western blot analysis. Furthermore, carcinomas with high HPA expression demonstrated high COX-2 expression and high MVD (microvesseldensity) labelled with CD34. In addition, mortality was higher in patients with HPA+ phenotype and HPA was an independent predictor of overall survival (p0.05).Our findings indicated that HPA might be an important biomarker for malignant transformation and be involved in promoting colon carcinoma metastasis by increasing angiogenesis.

The purpose of the present study was to investigate the electrolyte alterations of submandibular/sublingual saliva in submandibular sialolithiasis patients compared with saliva from healthy controls.Submandibular/sublingual saliva was collected from 10 submandibular sialolithiasis patients and from 10 sex- and age-matched healthy controls. Ion chromatography was performed to determine the concentrations of inorganic cations (potassium, calcium, magnesium, and sodium), inorganic anions (chloride, phosphate, nitrate, and sulphate) and organic anions (thiocyanate, lactate, acetate, and citrate).The calcium concentration was significantly higher in sialolithiasis patients than in controls (P0.05). In contrast, the levels of magnesium and citrate in the saliva of sialolithiasis patients were significantly reduced compared to the values obtained in controls (P0.05). No significant differences were detected among other ions.Our findings indicate that saliva electrolyte composition of sialolithiasis patients is substantially altered with respect to crystallisation mechanisms. Increased calcium ion as a crystallisation substance and decreased magnesium and citrate ions as crystallisation inhibitors may be involved in the etiopathology of calculi formation.