LINC00346 Sponges miR-30c-2-3p to Promote the Development of Lung Adenocarcinoma by Targeting MYBL2 and Regulating CELL CYCLE Signaling Pathway.

BACKGROUND: LINC00346 has recently been reported to regulate the development of several cancer types, but its biological functions and underlying mechanisms in lung adenocarcinoma (LUAD) have not been elucidated. The purpose of this study was to investigate the molecular mechanism of LINC00346 in the progression of LUAD. METHODS: Bioinformatics was performed to find the target lncRNA, miRNA and mRNA, and the binding relationship between the target genes was verified by dual luciferase reporter gene and RIP assays. Fluorescence in situ hybridization was used to detect the location of LINC00346 in LUAD tissues. The expressions of LINC00346, miR-30c-2-3p and MYBL2 in each group were detected by qRT-PCR, and western blot was performed to detect expressions of MYBL2 and CELL CYCLE related proteins. Proliferation, metastasis, apoptosis and cell cycle of LUAD cells were detected by CCK-8, colony formation, Transwell and flow cytometry assays, respectively. Mouse xenograft models were established to further determine the effects of LINC00346 on LUAD tumor growth in vivo. RESULTS: LINC00346 was upregulated in LUAD tissues and cells and was mainly localized in the cytoplasm. Knockdown of LINC00346 inhibited tumor growth in vivo, proliferation, metastasis and cell cycle progression, while induced apoptosis. LINC00346 sponged miR-30c-2-3 by targeting MYBL2 and regulating CELL CYCLE signaling pathway. Inhibiting miR-30c-2-3p or overexpressing MYBL2 could reverse the inhibitory effect of LINC00346 knockdown on LUAD process. CONCLUSIONS: LINC00346 as a ceRNA played a carcinogenic role in the development of LUAD via miR-30c-2-3p/MYBL2 axis regulating the CELL CYCLE signaling pathway. The study generally elucidated the mechanism by which LINC00346 regulated the development of LUAD, providing new ideas for the diagnosis and treatment of LUAD guided by lncRNA.

Unraveling the relative impacts of climate change and human activities on grassland productivity in Central Asia over last three decades.

Climate change (CC) and human activities (HA) have severely influenced grassland productivity in Central Asia since the 1980s. However, the relative impacts of CC and HA on grassland productivity are not adequately documented, especially over the past three decades. In this study, we adapted the Ensemble Empirical Mode Decomposition (EEMD) to reveal potential timescales at which grassland productivity varied in Central Asia and to investigate the spatiotemporal variations of grassland productivity during 1982-2015. We developed a quantitative method that incorporated the EEMD, along with six scenarios, to disentangle the effects of CC and HA on grassland productivity in Central Asia. Results showed that grassland productivity in Central Asia trended upward significantly at a rate of 0.66 gC m-2 yr-1 and was dominated by a 3-year time scale oscillation. The impacts of CC and HA on grassland productivity varied significantly over space and time. CC mainly facilitated grassland productivity restoration, whereas HA decreased grassland productivity in Central Asia. Besides, varied HA in six regions of Central Asia were due to different policy implementations across these regions. In particular, HA in Xinjiang significantly promoted grassland restoration, accounting for 22.5% of the total human-affected area, mostly because of the implementation of the Grazing Withdrawal Program (GWP), while HA significantly accelerated grassland productivity degradation in Uzbekistan and Turkmenistan over last three decades. Additionally, HA promoted the restoration of grassland productivity in Kazakhstan in a short period due to the disintegration of the Soviet Union, but degraded it at long-term scale. Further, precipitation was found to be the main climatic factor while grazing be the main human factor for controlling grassland productivity variations in Central Asia, respectively. Overall, our study provides not only a novel way of quantifying the impacts of CC and HA on vegetation variations but also new insights into mechanisms mediating grassland productivity in Central Asia.

miR-196b-5p Promotes Proliferation, Migration and Invasion of Lung Adenocarcinoma Cells via Targeting RSPO2.

OBJECTIVE: To explore the biological role of miR-196b-5p/RSPO2 in the occurrence and development of lung adenocarcinoma (LUAD) and to provide a basis for finding new therapeutic targets for LUAD. METHODS: Differentially expressed genes were analyzed based on LUAD microarray, and the target gene of the target miRNA was predicted. qRT-PCR was used to detect the expression levels of miR-196b-5p and RSPO2 mRNA in normal human bronchial epithelial cell line BEAS-2B and LUAD cell lines A549, NCI-H1792 and NCI-H226. Western blot was used to evaluate protein expression. Cell proliferative, migratory and invasive abilities were detected by CCK-8 and transwell assays. Dual-luciferase assay was conducted to verify the targeting relationship between miR-196b-5p and RSPO2. RESULTS: The results of qRT-PCR showed that miR-196b-5p was significantly highly expressed in LUAD cells, and the expression level of its downstream target gene RSPO2 was significantly decreased. The results of CCK-8 and transwell assays exhibited that miR-196b-5p promoted proliferation, migration and invasion of LUAD cells, while RSPO2 inhibited the malignant progression of LUAD cells. Dual-luciferase assay confirmed the targeted binding relationship between miR-196b-5p and RSPO2. Overexpression of RSPO2 partially reversed the promotion of miR-196b-5p on proliferation, migration and invasion of LUAD cells. CONCLUSION: miR-196b-5p promoted proliferation, migration and invasion of LUAD cells by targeting and down-regulating RSPO2, which provided ideas for searching new targets for the diagnosis and treatment of LUAD.

Assessment of tumor mutation burden calculation from gene panel sequencing data.

Background: High tumor mutation burden (TMB) is an emerging selection biomarker for immune checkpoint blockade in tumors such as melanoma and non-small cell lung cancer. TMB is typically calculated from whole genome sequencing or whole exome sequencing (WES) data. Recently, clinical trials showed that TMB can also be estimated from targeted sequencing of a panel of only a few hundred genes of interest, which can be performed at a high depth for clinical applications.  Materials and methods: In this study, we systematically investigated the distribution of TMB and preferences at the gene and mutation level, as well as the correlation between TMB calculated by WES and panel sequencing data using somatic mutation data from 15 cancer types from The Cancer Genome Atlas (TCGA).  Results: We proposed a pan-cancer TMB panel and demonstrated that it had a higher correlation with WES than other panels. Our panel could serve as a reference data-set for TMB-oriented panel design to identify patients for immunotherapy.

[Efficacy of S-1 in Advanced Non-small Cell Lung Cancer Patients Treated 
with More Than Two Lines of Chemotherapy].

BACKGROUND: There is no standard treatment for advanced non-small cell lung cancer (NSCLC) after the failure of two lines of chemotherapy, S-1 as the third generation of fluorouracil derivate with well safety and low toxicity, presented some efficacy in lung cancer treatment. The aim of this study is to explore the efficacy of S-1 for advanced NSCLC patients treated with two or more prior chemotherapy regimens. METHODS: We performed a retrospective analysis of 105 NSCLC patients treated with S-1 monotherapy or S-1 contained chemotherapy as the third or more line of treatment in our hospital from January 2014 to April 2017. S-1 was administrated orally twice daily for 2 weeks, followed by one week of rest, the dose of drug was determined by body surface area (<1.25 m2, 80 mg/d; 1.25 m2-1.5 m2, 100 mg/d; ≥1.5 m2, 120 mg/d), platinum or the third-generation chemotherapy drugs could be combinedly used. Clinical response was assigned every cycle according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Kaplan-Meier analysis was used to estimate progression-free survival (PFS). RESULTS: 42 patients received S-1 monotherapy, the other 63 patients received combined regimens, the median treatment line was 4 (3-11) and the median treatment cycle was 2 (1-14). No complete response (CR) were observed, there were 4 patients with partial response (PR), 34 patients with stable disease (SD) and 67 patients with progressive disease (PD), the objective response rate (ORR) was 3.81%, disease control rate (DCR) was 36.19%. The median PFS was 1.90 months (0.67 months-10.83 months), no difference between monotherapy and combined group (DCR: 28.56% vs 41.27%, P=0.185), the liver metastasis showed poorer PFS (1.40 months vs 1.93 months , P=0.042). CONCLUSIONS: S-1 presented some activity in advanced NSCLC treated with more than two lines of treatment. The addition of other drugs cannot improve efficacy. S-1 monotherapy can be used as a choice for heavily-treated patients.

[The efficacy and adverse effects of individualized treatment for elderly patients with epidermal growth factor receptor wild-type non-small cell lung cancer under the guidance of molecular markers].

OBJECTIVE: To compare the efficacy and toxicity of chemotherapy under the guidance of molecular markers and with vinorelbine in elderly patients with epidermal growth factor receptor (EGFR) wild-type advanced non-small cell lung cancer (NSCLC). METHODS: A total of 86 elderly patients with pathologically-confirmed advanced NSCLC with EGFR wild-type were recruited between June 2010 to October 2012. There were 69 males and 17 females, aging from 70 to 83 years. They were divided randomly into 2 groups according to the proportion of 1: 1 by SPSS 16.0 software. The study group received chemotherapy (cisplatin, gemcitabine, paclitaxel, and pemetrexed ) under the guidance of molecular markers (excision repair cross-complementing 1 ERCC1, ribonucleotide reductase M1 RRM1, Class III beta-tubulin, thymidylate synthetase TS). The control group received vinorelbine 25 mg/m(2) days 1 and 8 with 21 days as a cycle. RESULTS: The progression-free survival (PFS) of the study group and the control group was 4.0 months (95%CI: 3.1-4.9) and 3.0 months (95% CI: 2.4-3.6 ) respectively, the difference being statistically significant (χ(2) = 4.750, P = 0.029). The objective response rate (ORR) was 23% (10/43) and 19% (8/43) (χ(2) = 0.281, P = 0.596), the disease control rate (DCR) was 79% (34/43) and 77% (33/43) (χ(2) = 0.068, P = 0.795), and the median overall survival (OS) was 8.3 months and 7.5 months (χ(2) = 0.756, P = 0.385), respectively; the differences being not significant. Adverse effects were similar between the study group and the control group. The most commonly seen adverse events were hematological toxicity, nausea, vomiting, fatigue, alopecia, joint and muscle pain. Most of the toxicity was of grade I and grade II. There was no treatment-related death. CONCLUSIONS: The PFS was prolonged in elderly patients with EGFR wild-type advanced NSCLC under the guidance of molecular markers, but there was no improvement in ORR, DCR and OS. Further studies are needed to evaluate the clinical significance of this treatment modality.

[Clinical investigation of efficacy of pemetrexed in 32 patients with pulmonary adenocarcinoma after failure to chemotherapy and gefitinib].

BACKGROUND AND OBJECTIVE: The relapse-free time of gefitinib as the second or third line therapy in patients with advanced non-small cell lung cancer (NSCLC) was not satisfactory. The aim of this study is to evaluate the efficacy and toxicity of pemetrexed in patients with pulmonary adenocarcinoma after failure to chemotherapy and gefitinib. METHODS: A total of 32 relapsed patients with pulmonary adenocarcinoma after failure to chemotherapy and gefitinib received pemetrexed 500 mg/m2 by the intravenous administration on the first day, with 21 days as a cycle. Dexamethasone, folic acid and vitamin B12 were applied to relieve the drug toxicity. The objective response rate was estimated by Response Evaluation Criteria in Solid Tumors (RECIST) and the toxicity was estimated by National Cancer Institute Common Toxicity Criteria (version 3.0). RESULTS: For a total of 32 patients, 4 patients reached partial response (PR), constituting a total of 12.5%; 11 patients reached stable disease (SD), constituting a total of 34.4%; 17 patients reached progressive disease (PD), constituting a total of 53.1%. The median progression free survival (PFS) was 2.7 months. The median overall survival (OS) was 11.0 months. One-year survival rate was 37.5%. The most common adverse events (AEs) were myelosuppression with grade I and grade II toxicity. Other adverse events were tolerated. CONCLUSION: Pemetrexed was clinically beneficial for the patients with pulmonary adenocarcinoma after the failure of chemotherapy and gefitinib.