FGF17 protects cerebral ischemia reperfusion-induced blood-brain barrier disruption via FGF receptor 3-mediated PI3K/AKT signaling pathway.

Maintaining blood-brain barrier (BBB) integrity is critical components of therapeutic approach for ischemic stroke. Fibroblast growth factor 17 (FGF17), a member of FGF8 superfamily, exhibits the strongest expression throughout the wall of all major arteries during development. However, its molecular action and potential protective role on brain endothelial cells after stroke remains unclear. Here, we observed reduced levels of FGF17 in the serum of patients with ischemic stroke, as well as in the brains of mice subjected to middle cerebral artery occlusion (MCAO) injury and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cells (bEnd.3) cells. Moreover, treatment with exogenous recombinant human FGF17 (rhFGF17) decreased infarct volume, improved neurological deficits, reduced Evans Blue leakage and upregulated the expression of tight junctions in MCAO-injured mice. Meanwhile, rhFGF17 increased cell viability, enhanced trans-endothelial electrical resistance, reduced sodium fluorescein leakage, and alleviated reactive oxygen species (ROS) generation in OGD/R-induced bEnd.3 cells. Mechanistically, the treatment with rhFGF17 resulted in nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and upregulation of heme oxygenase-1 (HO-1) expression. Additionally, based on in-vivo and in-vitro research, rhFGF17 exerted protective effects against ischemia/reperfusion (I/R) -induced BBB disruption and endothelial cell apoptosis through the activation of the FGF receptor 3/PI3K/AKT signaling pathway. Overall, our findings indicated that FGF17 may hold promise as a novel therapeutic strategy for ischemic stroke patients.

The optimal intravesical maintenance chemotherapy scheme for the intermediate-risk group non-muscle-invasive bladder cancer.

OBJECTIVE: Although the current European Association of Urology(EAU) guideline recommends that patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC) should accept intravesical chemotherapy or Calmette-Guerin (BCG) for no more than one year after transurethral resection of bladder tumor(TURBT), there is no consensus on the optimal duration of chemotherapy. Hence, we explored the optimal duration of maintenance intravesical chemotherapy in patients with intermediate-risk NMIBC. SUBJECTS AND METHODS: This was a real-world single-center retrospective cohort study. In total 158 patients with pathologically confirmed intermediate-risk NMIBC were included, who were divided into 4 subgroups based on the number of instillations given. We used Cox regression analysis and survival analysis chart to explore the 3-yr recurrence outcomes of tumor.The optimal duration was determined by receive operating characteristic curve (ROC). RESULTS: The median follow-up was 5.2 years. Compared with instillation for 1-2 months, the Hazard Ratios(HR) values of instillation for less than 1 month, maintenance instillation for 3-6 months and > 6 months were 3.57、1.57 and 0.22(95% CI 1.27-12.41;0.26-9.28;0.07-0.80, P = 0.03;0.62;0.02, respectively). We found a significant improvement in 3-yr relapse-free survival in intermediate-risk NMIBC patients who maintained intravesical instillation chemotherapy for longer than 6 months, and the best benefit was achieved with 10.5 months of maintenance chemotherapy by ROC. CONCLUSIONS: In our scheme, the optimal duration of intravesical instillation with pirrubicin is 10.5 months. This new understanding provides valuable experience for the precise medical treatment model of intermediate-risk NMIBC.

[Spatio-temporal Variation and Multi-dimensional Detection of Driving Mechanism of PM2.5 Concentration in the Chengdu-Chongqing Urban Agglomeration from 2000 to 2021].

Studies on the spatio-temporal variation and driving mechanism of PM2.5 concentration in the Chengdu-Chongqing urban agglomeration are of great significance for regional atmospheric environment protection and national economic sustainable development. Based on PM2.5 remote sensing data, DEM data, in situ meteorological data, MODIS NDVI data, population density data, nighttime lighting data, road network data, and land use type data, a series of mathematical methods such as Theil-Sen Medium analysis and Mann-Kendall significance test, combined with the Geo-detector model were used to analyze the spatio-temporal variation and multi-dimensional detection of the driving mechanism of PM2.5 concentration in the Chengdu-Chongqing urban agglomeration. The results showed that the overall PM2.5 concentration showed a fluctuating downward trend in the Chengdu-Chongqing urban agglomeration from 2000 to 2021, and the PM2.5 pollution was the most prominent in winter. PM2.5 concentration exhibited obvious spatial heterogeneity with "high in the middle and low in the surrounding areas." The high-PM2.5 concentration areas were mainly concentrated in Zigong, Neijiang, Ziyang, and Guang'an, and the areas with a PM2.5 concentration decrease were mainly concentrated in the west of Chongqing. Influencing detection results showed that the spatial heterogeneity of PM2.5 concentration in the Chengdu-Chongqing urban agglomeration was influenced by the combined effects of climate factors, topographic factors, vegetation cover, and anthropogenic factors. Furthermore, elevation, slope, and road network density were regarded as the dominant factors influencing the spatial heterogeneity of PM2.5 concentration in the study area. Topographic factors and climate factors showed the highest and lowest contribution rate to the spatial heterogeneity of PM2.5 concentration, respectively. The contribution rate of topographic factors and anthropogenic factors had gradually increased, and the contribution rate of climate factors and vegetation cover had gradually decreased in the study area from 2000 to 2021. Interaction detection results showed that the spatial heterogeneity of PM2.5 concentration in the Chengdu-Chongqing urban agglomeration was mostly affected by the interaction effects of elevation and road network density, slope, precipitation, sunshine duration, and land use type. The interaction detection results exhibited obvious regional differences on the city level. For instance, the spatial heterogeneity of PM2.5 concentration in Chengdu, Deyang, and Leshan was mostly affected by the interaction between different influencing types, and the spatial heterogeneity of PM2.5 concentration in Dazhou, Meishan, Ya'an, Ziyang, Neijiang, and Zigong was mostly affected by the interaction within a single influencing type.

Rapid weaning from mechanical ventilation and bronchial thermoplasty for near-fatal asthma: A case report.

Background: The action mechanism of bronchial thermoplasty (BT) is poorly understood. Generally, patients with severe asthma who are in desperate need of treatment have relatively low baseline values. In this paper, we describe the case of an asthmatic patient who was saved by a combination of therapy and bronchial thermoplasty. Case information: A patient with near-fatal asthma was initially treated in our hospital with conventional medication, but his condition did not improve. The patient was next subjected to invasive mechanical ventilation, which did not provide significant relief. Additionally, he was treated with BT in conjunction with mechanical ventilation, which promptly reversed his status asthmaticus and stabilized his condition. Conclusion: Patients with near-fatal asthma who do not react effectively to aggressive therapy may benefit from BT.

[Spatio-temporal Variation in PM2.5 Concentration and Its Relationship with Vegetation Landscape Patterns in Typical Economic Zones in China from 2000 to 2020].

This study explored the temporal and spatial variation in PM2.5 concentration and its relationship with the vegetation landscape pattern in three typical economic zones in China, which is of great significance for regional PM2.5pollution control and atmospheric environmental protection. In this study, the pixel binary model, Getis-Ord Gi* analysis, Theil-Sen Median analysis, Mann-Kendall significance test, Pearson correlation analysis, and multiple correlation analysis were used to explore the spatial cluster and spatio-temporal variation in PM2.5 and its correlation with the vegetation landscape index in the three economic zones of China on the basis of PM2.5 concentration data and MODIS NDVI data set. The results showed that PM2.5 in the Bohai Economic Rim was mainly dominated by the expansion of hot spots and the reduction in cold spots from 2000 to 2020. The proportion of cold spots and hot spots in the Yangtze River Delta showed insignificant changes. Both cold and hot spots in the Pearl River Delta had expanded. PM2.5 showed a downward trend in the three major economic zones from 2000 to 2020, and the magnitudes of increasing rates were higher in the Pearl River Delta, followed by those in the Yangtze River Delta and Bohai Economic Rim. From 2000 to 2020, PM2.5 exhibited a downward trend in the context of all vegetation coverage grades, and PM2.5 had most significantly improved within extremely low vegetation coverage in the three economic zones. On the landscape scale, PM2.5 values were mostly correlated with aggregation index in the Bohai Economic Rim, with the largest patch index in the Yangtze River Delta and Shannon's diversity in the Pearl River Delta, respectively. Under the context of different vegetation coverage levels, PM2.5showed the highest correlation with aggregation index in the Bohai Economic Rim, landscape shape index in the Yangtze River Delta, and percent of landscape in the Pearl River Delta, respectively. PM2.5 showed significant differences with vegetation landscape indices in the three economic zones. The combined effect of multiple vegetation landscape pattern indices on PM2.5 was stronger than that of the single vegetation landscape pattern index. The above results indicated that the spatial cluster of PM2.5 in the three major economic zones had changed, and PM2.5 showed a decreasing trend in the three economic zones during the study period. The relationship between PM2.5 and vegetation landscape indices exhibited obvious spatial heterogeneity in the three economic zones.

[Detecting Influencing Factor of Vegetation NPP in Southwest China Based on Spatial Scale Effect].

Vegetation net primary productivity (NPP) is an important parameter for evaluating the quality of terrestrial ecosystems. It is of great importance to study the spatio-temporal evolution of vegetation NPP and its driving force for regional ecological environment protection and sustainable development. On the basis of MODIS NPP data, meteorological data, DEM data, population density data, GDP data, and land use type data, this study used linear regression analysis, R/S analysis, and a Geodetector model to analyze the spatio-temporal variation in vegetation NPP and its future changing trend on both regional and landform scales and to detect the influencing factors that affect the spatial differentiation of vegetation NPP. The results showed that the vegetation NPP exhibited an extremely significant upward trend in southwest China from 2000 to 2020. On the landform scale, the vegetation NPP had showed an upward trend in all landforms, except for the southern Tibet Plateau; among them, the vegetation NPP in the Sichuan Basin showed the most obvious upward trend. The variation in vegetation NPP exhibited obvious spatial heterogeneity in southwest China, with the changing rate of "high in the east and low in the west." The areas with an upward trend of vegetation NPP were greater than the areas with a downward trend, but the changing trend was dominated by a decreasing trend in the future, both in southwest China and each landform unit. The Geodetector results showed that elevation was the dominant factor controlling the spatial differentiation of vegetation NPP in southwest China and all landform units, except for the Yunan-Guizhou Plateau, in which the spatial differentiation of vegetation NPP was mostly dominated by temperature. The interaction detection results showed that the interaction between the influencing factors was manifested as two-factor enhancement or nonlinear enhancement. The interaction between elevation and temperature showed the highest impact on vegetation NPP distribution. On the landform scale, the spatial differential of vegetation NPP was dominated by the interaction between elevation and climate factors or elevation and GDP in the Guangxi Hills, Sichuan Basin, Zoige Plateau, Hengduan Mountains, and southern Tibet Plateau and between climate factors in the Yunan-Guizhou Plateau. The above results indicated that vegetation NPP variation and the influencing factors that dominate its spatial differential in southwest China showed obvious scale effects. Therefore, exploring the dynamic variation in vegetation NPP and its influencing factors at different spatial scales has practical significance for a comprehensive understanding of the vegetation cover situation and formulating regional ecological restoration plans in southwest China.

[Spatio-temporal Variation in Vegetation Cover and Its Driving Mechanism Exploration in Southwest China from 2000 to 2020].

Using the MOD13A3 NDVI time series from 2000 to 2020, climate date from 1999 to 2020, and land use type data in 2000 and 2020, the spatio-temporal variation in vegetation cover and the driving mechanisms of climate change and human activities to vegetation variation were analyzed based on Theil-Sen Median analysis, the Mann-Kendall significance test, the multi-collinearity test, residual analysis, and relative analysis. The results showed that the vegetation cover exhibited a fluctuating and increasing trend with a magnitude of 0.0016 a-1 in southwest China from 2000 to 2020. The increasing trend of vegetation cover was mostly significant in the Guangxi Hills and Yunnan-Guizhou Plateau and slightly significant in the Tibet Plateau. The vegetation cover had increased in the context of climate change and human activities, with an increasing rate of 0.0010 a-1 and 0.0006 a-1, respectively. The vegetation improvement was mostly dominated by the combination effects of climate change and human activities. The vegetation improvement was dominated by climate change, and the relative role of climate change reached 61.86%. What is more, the vegetation degradation was dominated by human activities, and the relative role of human activities reached 58.39%. Vegetation cover was positively related to minimum temperature, precipitation, maximum temperature, potential evapotranspiration rate, and relative humidity and negatively related to mean temperature, atmosphere pressure, sunshine duration, warmth index, and humidity index. As a whole, the minimum temperature, sunshine duration, and precipitation were the dominant climate factors affecting the vegetation variation in southwest China. Furthermore, the land use and land cover change were significantly related to vegetation variation in southwest China. The implementation of ecological afforestation projects could be beneficial to regional vegetation improvement, whereas the vegetation degradation was mostly conducted by the built-up land expansion.

[Dynamic Variation in Vegetation Cover and Its Influencing Factor Detection in the Yangtze River Basin from 2000 to 2020].

Studies on the dynamic variation in vegetation cover and detecting its influencing factors are highly valuable for monitoring regional ecological environment quality and evaluating forestry restoration project effects. In this study, on the basis of the MODIS normalized difference vegetation index (NDVI), in situ climate data, digital elevation model, population density, nighttime lights using Theil-Sen Median analysis, Mann-Kendall significance test, stability analysis, and geographical detector model, the spatiotemporal variation and stability of vegetation cover in the context of multi-spatiotemporal scales were analyzed, and the dominant influencing factors that affect the spatial differentiation of vegetation cover were further detected. The results showed that the vegetation cover showed a fluctuant increasing trend, and the changing trend exhibited obvious spatial heterogeneity with the increasing rate being higher in the middle and lower in the east and west portion of the Yangtze River basin from 2000 to 2020. At the sub-basin scale, except for that in the Taihu Lake basin, the vegetation cover in all sub-basin units exhibited an increasing trend during the study period. The areas with an increasing trend accounted for 84.09% of the study area, in which the areas with extremely significant increases and significant increases accounted for 53.67%, which were mainly distributed in the Wujiang River basin, Yibin-yichang, Jialing River basin, Han River basin, and Dongting Lake basin. The vegetation cover showed lower stability in the upper reaches of the Jinsha-shigu River basin and Taihu Lake basin and higher stability in other sub-basin units of the study area. Elevation was an important factor affecting the vegetation variation in all sub-basin areas. Climatic factors presented the highest impact on vegetation variation in the upper reaches of the Jinsha-shigu River basin, and human activities exhibited the greatest impact on vegetation variation in the Wujiang River basin, lower reaches of Hukou basin, and Taihu Lake basin. The interaction of the two influencing factors on vegetation variation showed mutual and non-linear enhancement, and the interaction between elevation and wind speed presented the highest value, with an explanatory power of 68%. The ecological exploration results showed that human activities combined with topographic factors and climate factors, except for slope and relative humidity, significantly differed in the explanatory power of vegetation variation in the Yangtze River basin. These results can provide a basis for formulating comprehensive vegetation resource management in the Yangtze River basin that takes into account regional climate, topography, and human activities.

[Responding Mechanism of Vegetation Cover to Climate Change and Human Activities in Southwest China from 2000 to 2020].

Studying vegetation cover variation and its responding mechanism to climate change and human activities is of great significance for regional ecological protection and vegetation restoration. In this study, on the basis of MODIS NDVI, in situ climate data, and land use type data using Theil-Sen Median analysis, the Mann-Kendall significance test, residual analysis, partial correlation analysis, and multi-correlation analysis, the spatial and temporal variation in vegetation cover and its response to climate change and the land use/land cover change in each geomorphological unit in southwest China were analyzed. The vegetation cover showed a fluctuant increasing trend, and the changing trend exhibited obvious spatial heterogeneity, with the increasing rate being higher in the southeast and lower in the northwest of southwest China from 2000 to 2020. The vegetation variation was dominated by positive effects of the climate change and human activities in southwest China, and the positive effects were stronger in Guangxi Hill than those in other geomorphological units. Furthermore, from 2000 to 2020 the vegetation cover was positively associated with precipitation and temperature and negatively correlated with relative humidity and sunshine duration in southwest China. Temperature was considered to be the dominate climate factor controlling the vegetation variation in the study area. Urban expansion had decreased the region vegetation cover, but the overall vegetation cover had increased in southwest China due to the suitable regional climate conditions and the implementation of ecological reforestation projection. These results can provide scientific references for ecological protection and economic sustainable development in southwest China.

Association and prognostic significance of alpha-L-fucosidase-1 and matrix metalloproteinase 9 expression in esophageal squamous cell carcinoma.

BACKGROUND: Alpha-L-fucosidase-1 (FUCA1) has been demonstrated to play opposing regulatory roles in adenocarcinoma and non-adenocarcinoma. Moreover, recent studies reported that FUCA1 could decrease the invasion capability by downregulating matrix metalloproteinase 9 (MMP-9) expression. However, the potential role and prognostic significance of FUCA1 in esophageal squamous cell carcinoma (ESCC) have not yet been explored. AIM: To evaluate the status, association, and prognostic value of FUCA1 and MMP-9 expression in ESCC. METHODS: Patients who underwent esophagectomy for ESCC between January 1, 2014, and December 31, 2014 at Sun Yat-Sen University Cancer Center were enrolled. The expression status of FUCA1 and MMP-9 in cancerous tissues was detected using immunohistochemistry. In addition, the expression profiles of the FUCA1 and MMP-9 genes in non-metastatic ESCC were extracted from The Cancer Genome Atlas (TCGA) database. RESULTS: High expression of FUCA1 and MMP-9 was found in 90 patients (75.6%) and 62 patients (52.1%), respectively. In the high FUCA1 expression group, the constituent ratios of patients with stage III disease (61.1% vs 37.9%, P = 0.029), lymphatic invasion (62.2% vs 31.0%, P = 0.003), and high MMP-9 expression (60.0% vs 27.6%, P = 0.002) were significantly higher than those in the low FUCA1 expression group. In Kaplan-Meier univariate analysis, advanced tumor-node-metastasis stage (III, P = 0.001), positive regional lymph node metastasis (N+, P = 0.002), high FUCA1 expression (P = 0.001), and high MMP-9 expression (P = 0.002) were potential predictors of shorter overall survival (OS), which was similar to the results analyzed based on the TCGA database. Further Cox multivariate regression analyses still demonstrated that FUCA1 and MMP-9 expression levels were independent prognostic factors of OS [hazard ratio (HR): 0.484, 95% confidence interval (CI): 0.239-0.979; P = 0.044; and HR: 0.591, 95%CI: 0.359-0.973, P = 0.039, respectively]. CONCLUSION: FUCA1 cooperation with MMP-9 may have a major role in affecting the ESCC invasion and metastatic capability, and serve as a valuable prognostic biomarker in ESCC.

p24G1 Encoded by Grapevine Leafroll-Associated Virus 1 Suppresses RNA Silencing and Elicits Hypersensitive Response-Like Necrosis in Nicotiana Species.

Grapevine leafroll-associated virus 1 (GLRaV-1) is a major pathogen associated with grapevine leafroll disease. However, the molecular mechanisms underlying GLRaV-1 interactions with plant cells are unclear. Using Agrobacterium infiltration-mediated RNA-silencing assays, we demonstrated that GLRaV-1 p24 protein (p24G1) acts as an RNA-silencing suppressor (RSS), inhibiting local and systemic RNA silencing. Electrophoretic mobility shift assays showed that p24G1 binds double-stranded 21-nucleotide small interfering RNA (siRNA), and that siRNA binding is required but not sufficient for its RSS activity. p24G1 localizes in the nucleus and can self-interact through its amino acid 10 to 210 region. Dimerization is needed for p24G1 interaction with importin α1 before moving to the nucleus, but is not required for its siRNA binding and RSS activity. Expression of p24G1 from a binary pGD vector or potato virus X-based vector elicited a strong hypersensitive response in Nicotiana species, indicating that p24G1 may be a factor in pathogenesis. Furthermore, p24G1 function in pathogenesis required its RSS activity, dimerization and nuclear localization. In addition, the region of amino acids 122-139 played a crucial role in the nuclear import, siRNA binding, silencing suppression and pathogenic activity of p24G1. These results contribute to our understanding of the molecular mechanisms underlying GLRaV-1 infection.

Nomogram for predicting overall survival in children with neuroblastoma based on SEER database.

PURPOSE: This study was performed to establish and validate a nomogram for predicting the overall survival in children with neuroblastoma. METHODS: The latest clinical data of neuroblastoma in Surveillance, Epidemiology, and End Results (SEER) database was extracted from 2000 to 2016. The cases included were randomly divided into training and validation cohorts. The survival curves were drawn with a Kaplan-Meier estimator to investigate the influences of certain single factors on overall survival. Also, least absolute shrinkage and selection operator regression was applied to further select the prognostic variables for neuroblastoma. Additionally, receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the accuracy of the nomogram. RESULTS: In total, 1,262 patients were collected and 8 independent prognostic factors were achieved, including patients' age, sex, race, tumor grade, radiotherapy, chemotherapy, tumor site, and tumor size. Then we constructed a nomogram by using the data of the training cohort with 886 cases. Subsequently, the nomogram was validated internally and externally with 886 and 376 cases, respectively. The internal validation revealed that the area under the curves (AUC) of ROC curves of 1-, 3-, and 5-year overall survival were 0.69, 0.78, and 0.81, respectively. Accordingly, the external validation also showed that the AUC of 1-, 3-, and 5-year overall survival were all ≥0.69. Both methods of validation demonstrated that the predictive calibration curves were consistent with standard curves. CONCLUSION: The nomogram possess the potential to be a new tool in predicting the survival rate of neuroblastoma patients.

Investigation of the effect of cochlear implantation on tinnitus, and its associated factors.

Background: Many studies have focused on the suppressive effects of cochlear implants (CIs) on loudness of tinnitus.Aims/objective: This study aimed to examine the effects of CIs and their activation on changes in loudness and tinnitus and explore other factors associated with this effect.Material and methods: We recruited 26 CI recipients according to specific criteria. Participants asked to complete tinnitus questionnaires, while the CI was kept on and at 30 min after the CI was turned off. Tinnitus improvement after CI was tested using Wilcoxon signed rank tests, and correlation was tested using Spearman's rank correlation coefficients and multiple linear regression.Results: After CI, tinnitus reduced from 62% to 46%. Total and partial reduction in tinnitus was seen in 76% subjects with pre-CI tinnitus. However, 6% of the subjects had tinnitus since birth, and none showed worsening tinnitus. The average THI score while the CI on was significantly lower than that CI off.Conclusions: Post-CI tinnitus improvement was seen in 76% of those with pre-CI tinnitus; however, the low risk of new or aggravating tinnitus should be considered, and reasonable expectations for tinnitus reduction should be built into the pre-CI assessment.

Primary colorectal lymphoma: computed tomography and double-contrast barium enema examination findings with histopathological correlation in 19 patients.

BACKGROUND: Primary colorectal lymphoma (PCL) is a rare disorder, the accurate imaging diagnosis of which remains a clinical challenge. This study aimed to characterize the imaging features of PCL by double-contrast barium enema (DCBE) examination and computed tomography (CT) and correlate them with histopathological findings. METHODS: DCBE (n=6) and CT (n=19) findings for 19 pathologically proven PCLs were evaluated and compared with histopathological findings in this retrospective analysis. RESULTS: Non-Hodgkin lymphoma was present in all patients, and the most common histological type was diffuse large B-cell lymphoma (63.2%, 12/19). The most common site was the ileocecum (84.2%, 16/19). CT revealed circumferential infiltrative lesions (68.4%, 13/19), polypoid masses (26.3%, 5/19) and ulcerative lesions (5.3%, 1/19). Most (94.7%, 18/19) lesions appeared as moderate enhancements. Fourteen (73.7%, 14/19) patients had serous membrane infiltration presenting as a poorly defined serous membrane and focal opacities in the pericolonic fat. Regional lymph node involvement was observed in twelve (63.2%, 12/19) patients who presented with aggregated nodules or masses. Frequent findings of the DCBE exam included a filling defect and niche with slight mucosal destruction, mild luminal narrowing and preserved peristalsis. The imaging appearance reflected the gross pathological findings well, although the preoperative diagnostic accuracy was low. CONCLUSIONS: The imaging features of PCL have a relatively characteristic appearance but are still, at times, hardly differentiated from carcinoma. Familiarity with the radiological features of PCL on DCBE and CT can help ensure a correct diagnosis.

Overexpressed BSG related to the progression of lung adenocarcinoma with high-throughput data-mining, immunohistochemistry, in vitro validation and in silico investigation.

PURPOSE: Lung adenocarcinoma (LUAD) of non-small cell lung cancer (NSCLC) is a highly prevalent cancer with high mortality. The gene basigin (BSG) is strongly expressed in certain tumors. This study investigated the expression level of BSG in LUAD and its role in the poor prognosis of LUAD. METHODS: The mRNA expression of BSG in LUAD was from GEO, Oncomine and TCGA database. Prognostic data were provided by SurvExpress. The expression of BSG protein was detected by immunohistochemistry (IHC). Cell function experiments of viability, proliferation and apoptosis assays were performed in A549. Clustering analysis of BSG co-expressed genes was generated by Gene Ontology (GO) Enrichment, KEGG pathway and protein-protein interaction (PPI) network. RESULTS: BSG mRNA level was significantly over-expressed in LUAD (pooled SMD = 0.564, 0.448-0.681, P<0.001). The analysis in SurvExpress revealed that high expression of BSG indicated significantly poor prognosis (pooled HR = 1.20, 1.10-1.30, P<0.0001). IHC assay also showed that BSG protein expression was significantly up-regulated in LUAD (P<0.001), and positive BSG expression was notably associated with higher pathology grade (P = 0.041) and lymphatic metastasis (P = 0.014). Moreover, BSG can enhance the viability and proliferation ability (both P<0.001) and weaken cell apoptosis (P<0.001) in A549. The most enriched GO terms in the co-expressed genes of BSG were translation related enrichment. The KEGG pathway showed that these genes were markedly involved in Ribosome pathways. CONCLUSION: Up-regulated BSG in LUAD is related to advanced progression and poor prognosis by influencing cell viability, proliferation and apoptosis. BSG could be a potential biomarker for the targeted therapy of LUAD.

Determining the prognostic significance of alternative splicing events in soft tissue sarcoma using data from The Cancer Genome Atlas.

BACKGROUND: Surgery, adjuvant chemotherapy, and radiotherapy are the primary treatment options for soft tissue sarcomas (STSs). However, identifying ways to improve the prognosis of patients with STS remains a considerable challenge. Evidence shows that the dysregulation of alternative splicing (AS) events is involved in tumor pathogenesis and progression. The present study objective was to identify survival-associated AS events that could serve as prognostic biomarkers and potentially serve as tumor-selective STS drug targets. METHODS: STS-specific 'percent spliced in' (PSI) values for splicing events in 206 STS samples were downloaded from The Cancer Genome Atlas SpliceSeq® database. Prognostic analyses were performed on seven types of AS events to determine their prognostic value in STS patients, for which prediction models were constructed with the risk score formula [Formula: see text]. Prediction models were also constructed to determine the prognostic value of AS events, and Spearman's rank correlation coefficients were calculated to determine the degree of correlation between splicing factor expression and the PSI values. RESULTS: A total 10,439 events were found to significantly correlate with patient survival rates. The area under the time-dependent receiver operating characteristic curve for the prognostic predictor of STS overall survival was 0.826. Notably, the splicing events of certain STS key genes were significantly associated with STS 2-year overall survival in the present study, including exon skip (ES) events in MDM2 and EWSR1, alternate terminator events in CDKN2A and HMGA2 for dedifferentiated liposarcoma, ES in MDM2 and alternate promoter events in CDKN2A for leiomyosarcoma, and ES in EWSR1 for undifferentiated pleomorphic sarcoma. Moreover, splicing correlation networks between AS events and splicing factors revealed that almost all of the AS events showed negatively correlations with the expression of splicing factors. CONCLUSION: An in-depth analysis of alternative RNA splicing could provide new insights into the mechanisms of STS oncogenesis and the potential for novel approaches to this type of cancer therapy.

miR­146a­5p targets TCSF and influences cell growth and apoptosis to repress NSCLC progression.

Several studies have indicated that microRNAs (miRs) mediate multiple pathways associated with tumorigenesis and progression. Our preliminary study experimentally verified that miR­146a­5p has a role in the biological behavior of non­small cell lung cancer (NSCLC) cells. To perform further investigation of miR­146a­5p, the present study evaluated miR­146a­5p by targeting its downstream gene tumor collagenase stimulatory factor (TCSF) to influence cell viability, proliferation and apoptosis in NSCLC. Online sequence prediction, a thorough search of the open source database The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC) of TCSF in clinical lung cancer tissues, and a dual­luciferase assay, as well as assays to test viability, proliferation and apoptosis in vitro, were conducted to explain the targeted regulation association between miR­146a­5p and TCSF in NSCLC. The miRanda and TargetScanHuman database revealed that TCSF and miR­146a­5p had target binding sites. A luciferase reporter assay demonstrated that miR­146a­5p and TCSF did have complementary sequences (P<0.05). From the TCGA database, TCSF was highly expressed in lung adenocarcinoma and lung squamous cell carcinoma tissues when compared with normal lung tissues (P<0.05). Furthermore, the protein level of TCSF in cancerous lung tissues was determined by IHC, and it was concluded that TCSF protein was also upregulated in NSCLC tissues (P<0.001). A significant difference was identified following in vitro experiments for the NSCLC cell line A549, which revealed that miR­146a­5p and TCSF regulated cell viability, proliferation and apoptosis. In conclusion, the present study verified the target action association between TCSF and miR­146a­5p with high throughput data analysis and experimental results in NSCLC.

Novel drug candidate for the treatment of several soft­tissue sarcoma histologic subtypes: A computational method using survival­associated gene signatures for drug repurposing.

Systemic treatment options for soft tissue sarcomas (STSs) have remained unchanged despite the need for novel drug candidates to improve STS outcomes. Drug repurposing involves the application of clinical drugs to different diseases, reducing development time, and cost. It has also become a fast and effective way to identify drug candidates. The present study used a computational method to screen three drug­gene interaction databases for novel drug candidates for the treatment of several common STS histologic subtypes through drug repurposing. STS survival­associated genes were generated by conducting a univariate cox regression analysis using The Cancer Genome Atlas survival data. These genes were then applied to three databases (the Connectivity Map, the Drug Gene Interaction Database and the L1000 Fireworks Display) to identify drug candidates for STS treatment. Additionally, pathway analysis and molecular docking were conducted to evaluate the molecular mechanisms of the candidate drug. Bepridil was identified as a potential candidate for several STS histologic subtype treatments by overlapping the screening results from three drug­gene interaction databases. The pathway analysis with the Kyoto Encyclopedia of Genes and Genomes predicted that Bepridil may target CRK, fibroblast growth factor receptor 4 (FGFR4), laminin subunit ß1 (LAMB1), phosphoinositide­3­kinase regulatory subunit 2 (PIK3R2), WNT5A, cluster of differentiation 47 (CD47), elastase, neutrophil expressed (ELANE), 15­hydroxyprostaglandin dehydrogenase (HPGD) and protein kinase cß (PRKCB) to suppress STS development. Further molecular docking simulation suggested a relatively stable binding selectivity between Bepridil and eight proteins (CRK, FGFR4, LAMB1, PIK3R2, CD47, ELANE, HPGD, and PRKCB). In conclusion, a computational method was used to identify Bepridil as a potential candidate for the treatment of several common STS histologic subtypes. Experimental validation of these in silico results is necessary before clinical translation can occur.

Expression of miR­542­3p in osteosarcoma with miRNA microarray data, and its potential signaling pathways.

Osteosarcoma (OS) is the most common pediatric primary bone tumor, with high malignancy rates and a poor prognosis following metastasis. At present, the role of microRNA (miR)­542­3p in OS remains to be elucidated. The purpose of the present study was to investigate the expression level of miR­542­3p in OS, and its potential molecular mechanisms, via a bioinformatics analysis. First, the expression of miR­542­3p in OS based on the continuous variables of the Gene Expression Omnibus database and PubMed was studied. Subsequently, the potential target genes of miR­542­3p were predicted using gene expression profiles and bioinformatics software. On the basis of the Database for Annotation, Visualization and Integrated Discovery, version 6.8, a study of gene ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway knowledge base was conducted to explore the biological value of miR­542­3p in OS. Finally, the protein­protein interaction (PPI) network was completed using the STRING database. The expression of miR­542­3p in OS was revealed to be significantly higher compared with that in normal tissue. In total, 1,036 target genes of miR­542­3p were obtained. The results of the GO enrichment analysis revealed that the significant terms were 'bone development', 'cell cycle arrest' and 'intracellular signal transduction'. The results of the KEGG analysis revealed the highlighted pathways that were targeted to miR­542­3p, including the sphingolipid signaling pathway (P=3.91x10­5), the phosphoinositide 3­kinase (PI3K)­AKT serine/threonine kinase (AKT) signaling pathway (P=3.17x10­5) and the insulin signaling pathway (P=1.04x10­5). The PPI network revealed eight hub genes: Ubiquitin­60S ribosomal protein L40, Ras­related C3 botulinum toxin substrate, mitogen­activated protein kinase 1, epidermal growth factor receptor, cystic fibrosis transmembrane conductance regulator, PI3K regulatory subunit 1, AKT1, and actin­related protein 2/3 complex subunit 1A, which may be the key target genes of miR­542­3p in OS. Taken together, these results have demonstrated that miR­542­3p was overexpressed in OS. The potential target genes and biological functions of miR­542­3p may provide novel insights into the differentially expressed genes that are involved in OS.

Exploration and validation of downregulated microRNA-199a-3p, downstream messenger RNA targets and transcriptional regulation in osteosarcoma.

Osteosarcoma (OS) is a primary bone tumor with a high incidence and mortality in children and adolescents. Emerging evidence shows that microRNAs (miRNAs) participate in biological tumor mechanisms by targeting downstream messenger RNAs (mRNAs). This article aimed to investigate the potential regulatory targets of microRNA-199a-3p (miR-199a-3p) in OS and to contribute to the understanding of miR-199a-3p-related OS regulatory mechanisms. MicroRNA-related Gene Expression Omnibus (GEO) chips, ArrayExpress chips and literature data were used to determine the expression of miR-199a-3p in OS and pooled to explore its potential clinical value. To investigate the target genes of miR-199a-3p further, we integrated the results from the following three-part gene study: Twelve online prediction tools were used to predict the target genes of miR-199a-3p; the GEO GSE89370 chip transfected with miRSelect pEP-miR-199a-3p was used to analyze the downregulated differentially expressed genes (DEGs) in OS cells; and highly expressed DEGs were derived from an in-house microarray generated from three pairs of clinical OS and normal tissue samples acquired through our department. Then, we analyzed the target genes using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases and the protein-protein interaction (PPI) network to further identify the primary target genes. In addition, we constructed transcription factor (TF)-miRNA-joint gene feed-forward regulatory loops (FFLs) with Circuits DB using miR-199a-3p as the core. A comprehensive meta-analysis of a hub of miR-199a-3p targeted genes was performed to integrate expression level, summary ROC (sROC) curves and survival analysis results from the GEO data for verification and exploration. Finally, the expression levels of the hub genes were verified in OS tissues and U2OS cells by immunohistochemistry (IHC) and immunocytochemistry (ICC). Data on miR-199a-3p expression were obtained from three data sets (GSE65071, GSE69524, and PMID 21666078), which showed low miR-199a-3p expression levels in OS tissues. The combined data indicated the same tendency, with the SMD of the random effect model, as shown in forest plots, being -2.8 (95% CI: -4.49, -1.11). In addition, we determined that miR-199a-3p may serve as a molecular marker useful for distinguishing OS tissues from normal tissues with high sensitivity and specificity, with the measured outcomes being 0.94 (95% CI: 0.80, 0.99) and 0.96 (95% CI: 0.78, 1.00), respectively. In addition, 391 genes were considered targets of miR-199a-3p in OS, and the enrichment analysis indicated that these targets were mainly enriched in proteoglycans in cancer and in spliceosomes. Four genes, CDKI, CCNB1, AURKA and NEK2, were regarded as hub targets based on the PPI data. Subsequently, TF-miRNA-joint genes FFLs were constructed in Circuits DB and included 17 TFs and 82 joint targets. These joint targets were mainly enriched in spliceosomes. UBE2D1 and RBM25 were regarded as hub joint targets based on the enrichment analysis. All selected target genes were further verified to ensure that they were upregulated in OS and to determine their prognostic significance. At the experimental verification level, the CDK1 protein was confirmed to be positively expressed in the cytoplasm of OS tissues and the U2OS cell line. Our study verified that miR-199a-3p was obviously downregulated in OS. CDK1, CCNB1, NEK2, AURKA, UBE2D1 and RBM25 were identified as potential target genes of miR-199a-3p in OS.