Identification of an Exosome-relevant SNHG6-hsa-miR-429- CHRDL1/CCNA2 Axis for Lung Adenocarcinoma Prognosis Evaluation.

AIM: To explore an exosome-relevant molecular classification in lung adenocarcinoma (LUAD). BACKGROUND: Exosome genes or relevant non-coding RNAs are regulators of cancer treatment and prognosis, but their function in LUAD has not yet been determined. OBJECTIVE: Unraveling a molecular classification applying exosome-related RNA networks for LUAD prognosis evaluation. METHODS: MicroRNA sequencing data (miRNAs-seq) and RNA sequencing data (RNA- seq) were derived from The Cancer Genome Atlas (TCGA). The ConsensusCluster- Plus package was used for molecular typing in LUAD based on 121 Exosome-related genes. Then, a limma package was conducted to explore differentially expressed mRNAs (DEmRNAs), differentially expressed miRNAs (DEmiRNAs) and differentially expressed lncRNAs (DElncRNAs) in molecular typing for constructing an Exosome-driven competing endogenous RNA network (ceRNA). Dominant miRNAs, as well as target mRNAs, were identified by COX modeling and Kaplan-Meier survival analysis. RESULTS: Two Exosome-associated molecular clusters classified in LUAD. The C2 cluster favored high clinicopathology and showed a trend toward poor prognosis. 29 lncRNA- miRNA and 12 miRNA-mRNA interaction pairs were identified. The hsa-miR-429 was the pivotal miRNA in the network that affected the prognosis of LUAD. According to the interaction relationship and LUAD prognostic role, SNHG6-hsa- miR-429-CHRDL1/CCNA2 was identified. SNHG6-hsa-miR-429-CHRDL1 exerts oncogenic effects, and SNHG6-hsa-miR-429- CCNA2 exerts pro-oncogenic effects. CONCLUSION: Overall, our study identified an Exosome-driven ceRNA network in LUAD, and the SNHG6-hsa-miR-429-CHRDL1/CCNA2 axis could be a new therapeutic target for LUAD and our study provides new insights into the molecular mechanisms of LUAD.

A benchmarking framework for the accurate and cost-effective detection of clinically-relevant structural variants for cancer target identification and diagnosis.

BACKGROUND: Accurate clinical structural variant (SV) calling is essential for cancer target identification and diagnosis but has been historically challenging due to the lack of ground truth for clinical specimens. Meanwhile, reduced clinical-testing cost is the key to the widespread clinical utility. METHODS: We analyzed massive data from tumor samples of 476 patients and developed a computational framework for accurate and cost-effective detection of clinically-relevant SVs. In addition, standard materials and classical experiments including immunohistochemistry and/or fluorescence in situ hybridization were used to validate the developed computational framework. RESULTS: We systematically evaluated the common algorithms for SV detection and established an expert-reviewed SV call set of 1,303 tumor-specific SVs with high-evidence levels. Moreover, we developed a random-forest-based decision model to improve the true positive of SVs. To independently validate the tailored 'two-step' strategy, we utilized standard materials and classical experiments. The accuracy of the model was over 90% (92-99.78%) for all types of data. CONCLUSION: Our study provides a valuable resource and an actionable guide to improve cancer-specific SV detection accuracy and clinical applicability.

Modeling nutrient flows from land to rivers and seas - A review and synthesis.

Water quality modeling facilitates management of nutrient flows from land to rivers and seas, in addition to environmental pollution management in watersheds. In the present paper, we review advances made in the development of seven water quality models and highlight their respective strengths and weaknesses. Afterward, we propose their future development directions, with distinct characteristics for different scenarios. We also discuss the practical problems that such models address in the same region, China, and summarize their different characteristics based on their performance. We focus on the temporal and geographical scales of the models, sources of pollution considered, and the main problems that can be addressed. Summary of such characteristics could facilitate the selection of appropriate models for resolving practical challenges on nutrient pollution in the corresponding scenarios globally by stakeholders. We also make recommendations for model enhancement to expand their capabilities.

ITGA9-AS1 up-regulates ITGA9 by targeting miR-4765 and recruiting HNRNPU to affect the proliferation and apoptosis of non-small cell lung cancer cells.

Long non-coding RNAs (lncRNAs) have been regarded as promising biomarkers in the regulation of various biological and pathological processes of non-small cell lung cancer (NSCLC). LncRNAITGA9-AS1 has been reported to be down-regulated in elderly patients with lung cancer, but how it may influence NSCLC remains to be identified. Therefore, we aim to explore the specific mechanism involving ITGA9-AS1 and ITGA9 in NSCLC. A functional assay was conducted to verify ITGA9-AS1's proliferative effects on NSCLC cells. Mechanism experiments with bioinformatics predictions were performed to explore the interaction of ITGA9-AS1 and ITGA9 in NSCLC cells. ITGA9-AS1 inhibited NSCLC cell proliferation while enhancing cell apoptosis. It up-regulated ITGA9 by competitively sponging miR-4765, and it stabilizedITGA9 mRNA by recruiting a RNA-binding protein (RBP)-HNRNPU (heterogeneous nuclear ribonucleoprotein U) in NSCLC cells. ITGA9-AS1 suppressed NSCLC progression by the up-regulation of ITGA9 via targeting miR-4765 and recruiting HNRNPU.

Exosome-mediated transfer of SNHG7 enhances docetaxel resistance in lung adenocarcinoma.

Long noncoding RNA (lncRNA) small nucleolar RNA host gene 7 (SNHG7) has been widely reported in various cancers, including lung adenocarcinoma (LUAD). However, it is largely unknown whether SNHG7 is involved in docetaxel resistance of LUAD. In the current study, we identified the high expression of SNHG7 in docetaxel-resistant cells. Through functional assays, we determined that silencing of SNHG7 decreased IC50 value of LUAD cells to docetaxel and suppressed proliferation and autophagy in LUAD cells, and reversed M2 polarization in macrophages. Mechanistically, we uncovered that SNHG7 promoted autophagy via recruiting human antigen R (HuR) to stabilize autophagy-related genes autophagy related 5 (ATG5) and autophagy related 12 (ATG12). Moreover, exosomal SNHG7 was transmitted from docetaxel-resistant LUAD cells to parental LUAD cells and thus facilitated docetaxel resistance. Additionally, exosomal SNHG7 activated the phosphatidylinositol 3-kinase (PI3K)/AKT pathway to promote M2 polarization in macrophages via recruiting cullin 4A (CUL4A) to induce ubiquitination and degradation of phosphatase and tensin homolog (PTEN). Taken together, we concluded that exosomal SNHG7 enhances docetaxel resistance of LUAD cells through inducing autophagy and macrophage M2 polarization. All findings in the study suggested that SNHG7 may be a promising target for relieving docetaxel resistance in LUAD.

Long-Chain Non-Coding RNA (lncRNA) MT1JP Suppresses Biological Activities of Lung Cancer by Regulating miRNA-423-3p/Bim Axis.

BACKGROUND This study aimed to explain the effects and mechanism of MT1JP in lung cancer development and treatment. MATERIAL AND METHODS Thirty non-small cell lung cancer (NSCLC) (stages I-II, 17 cases; stages III-IV, 13 cases) and adjacent normal tissues were obtained. MT1JP and miRNA-423-3p levels were assessed by in situ hybridization and Bim protein expression by immunohistochemistry, and the correlations determined were analyzed. Cell proliferation was determined using MTT and colony formation assay, and cell apoptosis was measured using flow cytometry. A549 cell invasion and migration were assessed by Transwell migration and scratch wound healing assays. Relative mRNA and protein expressions were assessed using real-time polymerase chain reaction and western blotting. Correlations between miRNA-423-3p and Bim protein were investigated using luciferase activity assay, and Bim protein expression was evaluated using western blotting. RESULTS MT1JP, miRNA-423-3p, and Bim expressions in NSCLC cancer tissues and those in adjacent cancer tissues were significantly different (P<0.01 or P<0.001) with increasing stage. Compared with those in the normal control (NC) group, cell proliferation rates were significantly suppressed (P<0.01 or P<0.001) and cell apoptosis rates significantly increased (P<0.01 or P<0.001) in the miRNA inhibitor and lncRNA+miRNA inhibitor groups. Invasion cell numbers and wound healing rates were also significantly inhibited in the miRNA inhibitor and lncRNA+miRNA inhibitor groups (P<0.01 or P<0.001) compared with those in the NC group. CONCLUSIONS The lncRNA MT1JP suppresses NSCLC biological activities by regulating the miRNA-423-3p/Bim axis.

Liver X receptors agonist T0901317 downregulates matrix metalloproteinase-9 expression in non-small-cell lung cancer by repressing nuclear factor-κB.

The liver X receptors (LXRs) is an important component of the nuclear receptor (NR) superfamily. Previous studies have shown that the LXRs possessed antitumor activity in various types of tumor cells. However, the complicated mechanisms underlying the antitumor activity remain largely unexplored. In this study, we incubated A549 cells with the compound T0901317, a specific LXRs agonist, for 24 h. The MTT assay was used to assess cell viability. Transwell assays were used to evaluate cell migration and invasion. The shRNA was utilized for RNA interference. The target gene and protein expression levels were assessed using reverse transcription-PCR and western blot assay. The DNA-binding activity of nuclear factor κB (NF-κB) was examined using electrophoretic mobility shift assays. Luciferase reporter assay was used to detect the binding of NF-κB to the matrix metalloproteinase-9 (MMP-9) promoter. We found that T0901317 inhibited the invasion and migration of A549 cells in a dose-dependent manner. Meanwhile, we further indicated that activation of LXRß, one subtype of LXRs, can downregulate MMP-9 expression. More importantly, activation of LXRß triggered by T0901317 inhibited the invasion and metastasis of A549 cells by repressing NF-κB/MMP-9 signaling pathway. Taken together, our study shows that activation of LXRs triggered by T0901317 inhibits the invasion and metastasis of human non-small-cell lung cancer by repressing the NF-κB/MMP-9 signaling pathway.

Association between BIM deletion polymorphism and clinical outcome of EGFR-mutated NSCLC patient with EGFR-TKI therapy: A meta-analysis.

AIM: BIM deletion polymorphism was deemed to be associated with downregulation of BIM, resulting in a decreased apoptosis induced by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutation-positive non-small cell lung cancer (NSCLC). However, accumulating evidences concerning the association between BIM deletion polymorphism and efficacy of EGFR-TKI and survival in EGFR-mutation-driven NSCLC patient reported contradictory results. MATERIALS AND METHODS: A meta-analysis was conducted by combing six original eligible studies including 871 NSCLC patients. RESULTS: Our study showed that BIM deletion polymorphism was significantly associated with poor response to EGFR-TKI therapy in mutant EGFRNSCLC patients (P(h) = 0.309, P(z) = 0.001, OR = 0.39, 95% confidence interval (CI) = 0.23-0.67). Disease control rate (DCR) in mutant EGFRNSCLC patient with treatment of EGFR-TKI was significantly decreased in patients with BIM deletion polymorphism comparing to patients harbored BIM wild variant (P(h) = 0.583, P(Z) = 0.007, OR = 0.46, 95%CI = 0.25-0.85). EGFR mutation-derived NSCLC patient carrying BIM deletion polymorphism had a shorter progression-free survival (PFS; P(h) < 0.001, P(z) < 0.001, hazard ratio (HR) = 1.37, 95%CI = 1.09-1.71) and overall survival (OS; P(h) = 0.90, P(z) = 0.003, HR = 1.25, 95%CI = 1.08-1.45), than those harbored BIM wild variant. CONCLUSION: These results suggested that BIM deletion polymorphism might be a cause that contributes to primary EGFR-TKI resistance, and it could be used as a genetic predictor for EGFR-TKI outcome and an independent prognostic factor of EGFR mutation-driven NSCLC patient.

IBS: an illustrator for the presentation and visualization of biological sequences.

UNLABELLED: Biological sequence diagrams are fundamental for visualizing various functional elements in protein or nucleotide sequences that enable a summarization and presentation of existing information as well as means of intuitive new discoveries. Here, we present a software package called illustrator of biological sequences (IBS) that can be used for representing the organization of either protein or nucleotide sequences in a convenient, efficient and precise manner. Multiple options are provided in IBS, and biological sequences can be manipulated, recolored or rescaled in a user-defined mode. Also, the final representational artwork can be directly exported into a publication-quality figure. AVAILABILITY AND IMPLEMENTATION: The standalone package of IBS was implemented in JAVA, while the online service was implemented in HTML5 and JavaScript. Both the standalone package and online service are freely available at http://ibs.biocuckoo.org. CONTACT: renjian.sysu@gmail.com or xueyu@hust.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Rs895819 within miR-27a might be involved in development of non small cell lung cancer in the Chinese Han population.

MicroRNA-27a (miR-27a) is deemed to be an oncogene that plays an important role in development of various cancers, and single nucleotide polymorphism (SNP) of miR-27a can influence the maturation or aberrant expression of hsa-miR27a, resulting in increased risk of cancer and poor prognosis for non-small cell lung cancer (NSCLC). This study aimed to assess the effects of rs895819 within miR-27a on susceptibility and prognosis of NSCLC patients in 560 clinical confirmed cases and 568 healthy check-up individuals. Adjusted odds/hazard ratios (ORs/HRs) and 95% confidential intervals (CIs) were calculated to evaluate the association between rs895819 and the risk and prognosis of NSCLC. The results showed that allele A and genotype GG of rs895819 were significantly associated with an increased risk of NSCLC (38.9% vs 30.8%, adjusted OR=1.26, 95%CI=1.23-1.29 for allele G vs A; 18.1% vs 11.7%, adjusted OR=1.67, 95%CI=1.59-1.75 for genotype GG vs AA). Moreover, positive associations were also observed in dominant and recessive models (53.7% vs 49.9%, adjusted OR=1.17, 95%CI=1.13-1.20 for GG/AG vs AA; 18.1% vs 11.7%, adjusted=1.65, 95%CI=1.58-1.73). However, no significant association was found between rs895819 and the prognosis of NSCLC in genotype, dominant and recessive models. These results suggested that miR-27a might be involved in NSCLC carcinogenesis, but not in progression of NSCLC. The allele G, genotype GG and allele G carrier (GG/AG vs AA) of rs895819 might be genetic susceptible factors for NSCLC. Further multi-central, large sample size and well-designed prospective studies as well as functional studies are warranted to verify our findings.

Expression and significance of circulating microRNA-31 in lung cancer patients.

BACKGROUND: The aim of this study was to investigate the expression level of circulating microRNA-31(miRNA-31) in lung cancer patients and its clinical significance. MATERIAL AND METHODS: Real-time fluorescent quantitative PCR was utilized to detect the circulating miRNA-31 expression levels in 300 lung cancer patients and 300 health control subjects. The ROC curve was drawn to evaluate the diagnostic value of the circulating miRNA-31 expression levels in lung cancer. The 300 lung cancer patients were divided into a miRNA-31 low-expression group and a miRNA-31 high-expression group. A survival curve was drawn according to the Kaplan-Meier method to evaluate the prognostic value of the circulating microRNA-31 expression levels for lung cancer. RESULTS: The circulating miRNA-31 expression levels in the lung cancer patients (l.88±0. 67) increased significantly (P<0.001) compared to the healthy controls (0.58±0. 44). The area under the ROC curve drawn according to the circulating miRNA-31 expression levels was 0.785 (95% CI=0.486-0.763). When the critical value was 1.27, the sensitivity and specificity for lung cancer diagnosis according to the circulating miRNA-31 expression levels were 0.769 and 0.745, respectively. The difference in the survival curve between the miRNA-31 low-expression group (123 cases) and high-expression group (177 cases) was statistically significant (P=0.004). Median survival period of the low-expression group (38.44 months) was longer than that of the high-expression group (25.23 months). CONCLUSIONS: miRNA-31 may be a molecular marker for the diagnostic and prognostic evaluation of primary lung cancer.

[Clinical analysis of the rare causes of hemoptysis: a report of 4 cases].

OBJECTIVE: To improve the diagnosis of hemoptysis caused by rare lung diseases. METHODS: Four cases of hemoptysis caused by rare diseases which were diagnosed by angiography or operation were reported and related literature were reviewed. RESULTS: The 4 cases of hemoptysis were caused by intercostal-to-pulmonary arterial fistula (IPAF), pulmonary hamartoma (PH), congenital unilateral absence of the left pulmonary artery (ALPA) and primary pulmonary hypertension (PPH). Bronchial arteriography and bronchial artery embolization were performed for IPAF. For PH, a benign tumor, the diagnosis was based on the history and radiography examination, and operation was the choice for therapy. ALPA was confirmed by radiography, if massive hemoptysis occurred, surgical intervention was the best choice. The diagnosis of PPH was firstly evaluated by chest film and echocardiogram, and the final diagnosis relied on right cardiac catheter examination. CONCLUSIONS: Hemoptysis is a common symptom of respiratory diseases, including some rare cases which are easy to be misdiagnosed. The correct diagnosis and therapy rely on comprehensive thinking, careful history collection and reasonable examinations.

Accurate visible speech synthesis based on concatenating variable length motion capture data.

We present a novel approach to synthesizing accurate visible speech based on searching and concatenating optimal variable-length units in a large corpus of motion capture data. Based on a set of visual prototypes selected on a source face and a corresponding set designated for a target face, we propose a machine learning technique to automatically map the facial motions observed on the source face to the target face. In order to model the long distance coarticulation effects in visible speech, a large-scale corpus that covers the most common syllables in English was collected, annotated and analyzed. For any input text, a search algorithm to locate the optimal sequences of concatenated units for synthesis is desrcribed. A new algorithm to adapt lip motions from a generic 3D face model to a specific 3D face model is also proposed. A complete, end-to-end visible speech animation system is implemented based on the approach. This system is currently used in more than 60 kindergarten through third grade classrooms to teach students to read using a lifelike conversational animated agent. To evaluate the quality of the visible speech produced by the animation system, both subjective evaluation and objective evaluation are conducted. The evaluation results show that the proposed approach is accurate and powerful for visible speech synthesis.