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.

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.

Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T cells have been noted in CHARGE syndrome. However, the mechanisms underlying T lymphopenia are largely unexplored. Herein, we observed dramatic decrease of T cells in both chd7knockdown and knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T-cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired. Chd7 might regulate thymus organogenesis through modulating the development of both neural crest cell-derived mesenchyme and pharyngeal endoderm-derived thymic epithelial cells. The expression of foxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region in chd7-deficient embryos. Moreover, the T-cell reduction in chd7-deficient embryos was partially rescued by overexpressing foxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated that chd7 was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T lymphopenia and immunodeficiency in CHARGE syndrome.

Comprehensive analysis of the long noncoding RNA HOXA11-AS gene interaction regulatory network in NSCLC cells.

BACKGROUND: Long noncoding RNAs (lncRNAs) are related to different biological processes in non-small cell lung cancer (NSCLC). However, the possible molecular mechanisms underlying the effects of the long noncoding RNA HOXA11-AS (HOXA11 antisense RNA) in NSCLC are unknown. METHODS: HOXA11-AS was knocked down in the NSCLC A549 cell line and a high throughput microarray assay was applied to detect changes in the gene profiles of the A549 cells. Bioinformatics analyses (gene ontology (GO), pathway, Kyoto Encyclopedia of Genes and Genomes (KEGG), and network analyses) were performed to investigate the potential pathways and networks of the differentially expressed genes. The molecular signatures database (MSigDB) was used to display the expression profiles of these differentially expressed genes. Furthermore, the relationships between the HOXA11-AS, de-regulated genes and clinical NSCLC parameters were verified by using NSCLC patient information from The Cancer Genome Atlas (TCGA) database. In addition, the relationship between HOXA11-AS expression and clinical diagnostic value was analyzed by receiver operating characteristic (ROC) curve. RESULTS: Among the differentially expressed genes, 277 and 80 genes were upregulated and downregulated in NSCLC, respectively (fold change ≥2.0, P < 0.05 and false discovery rate (FDR) < 0.05). According to the degree of the fold change, six upregulated and three downregulated genes were selected for further investigation. Only four genes (RSPO3, ADAMTS8, DMBT1, and DOCK8) were reported to be related with the development or progression of NSCLC based on a PubMed search. Among all possible pathways, three pathways (the PI3K-Akt, TGF-beta and Hippo signaling pathways) were the most likely to be involved in NSCLC development and progression. Furthermore, we found that HOXA11-AS was highly expressed in both lung adenocarcinoma and squamous cell carcinoma based on TCGA database. The ROC curve showed that the area under curve (AUC) of HOXA11-AS was 0.727 (95% CI 0.663-0.790) for lung adenocarcinoma and 0.933 (95% CI 0.906-0.960) for squamous cell carcinoma patients. Additionally, the original data from TCGA verified that ADAMTS8, DMBT1 and DOCK8 were downregulated in both lung adenocarcinoma and squamous cell carcinoma, whereas RSPO3 expression was upregulated in lung adenocarcinoma and downregulated in lung squamous cell carcinoma. For the other five genes (STMN2, SPINK6, TUSC3, LOC100128054, and C8orf22), we found that STMN2, TUSC3 and C8orf22 were upregulated in squamous cell carcinoma and that STMN2 and USC3 were upregulated in lung adenocarcinoma. Furthermore, we compared the correlation between HOXA11-AS and de-regulated genes in NSCLC based on TCGA. The results showed that the HOXA11-AS expression was negatively correlated with DOCK8 in squamous cell carcinoma (r = -0.124, P = 0.048) and lung adenocarcinoma (r = -0.176, P = 0.005). In addition, RSPO3, ADAMTS8 and DOCK8 were related to overall survival and disease-free survival (all P < 0.05) of lung adenocarcinoma patients in TCGA. CONCLUSIONS: Our results showed that the gene profiles were significantly changed after HOXA11-AS knock-down in NSCLC cells. We speculated that HOXA11-AS may play an important role in NSCLC development and progression by regulating the expression of various pathways and genes, especially DOCK8 and TGF-beta pathway. However, the exact mechanism should be verified by functional experiments.

[PI3K-Akt/LKB1-AMPK-mTOR-p70S6K/4EBP1 signaling pathways participate in the regulation of testis development and spermatogenesis: An update].

Male infertility is closely associated with spermatogenesis disorders triggered by aberrant gene expression or abnormal signaling pathways in the testis. The mammalian target of rapamycin (mTOR) is a central regulator of cell metabolism, playing an important role in regulating cell proliferation, differentiation, translation, actin polymerization, cycle progression, energy metabolism, autophagy, and other cellular activities. PI3K-Akt and LKB1-AMPK, the two well-defined classic signal transduction pathways, regulate the expressions of mTOR and its downstream p70S6K/4EBP1 through different molecular pathways. Recent studies show that mTOR-p70S6K/4EBP1 signaling participates in the regulation of the proliferation and differentiation of testicular cells and spermatogenesis. This review focuses on the role of PI3K-Akt/LKB1- AMPK-mTOR signaling cascades in testis development and spermatogenesis, providing some new perspectives for the studies of the molecular mechanism underlying male sterility.

Mesenchymal-epithelial transition factor amplification correlates with adverse pathological features and poor clinical outcome in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related mortality worldwide. Mesenchymal-epithelial transition factor (MET) gene participates in multiple tumor biology and shows clinical potential for pharmacological manipulation in tumor treatment. MET amplification has been reported in CRC, but data are very limited. Investigating pathological values of MET in CRC may provide new therapeutic and genetic screening options in future clinical practice. AIM: To determine the pathological significance of MET amplification in CRC and to propose a feasible screening strategy. METHODS: A number of 205 newly diagnosed CRC patients undergoing surgical resection without any preoperative therapy at Shenzhen Cancer Hospital of Chinese Academy of Medical Sciences were recruited. All patients were without RAS/RAF mutation or microsatellite instability-high. MET amplification and c-MET protein expression were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Correlations between MET aberration and pathological features were detected using the chi-squared test. Progression free survival (PFS) during the two-year follow-up was detected using the Kaplan-Meier method and log rank test. The results of MET FISH and IHC were compared using one-way ANOVA. RESULTS: Polysomy-induced MET amplification was observed in 14.4% of cases, and focal MET amplification was not detected. Polysomy-induced MET amplification was associated with a higher frequency of lymph node metastasis (LNM) (P < 0.001) and higher tumor budding grade (P = 0.02). In the survival analysis, significant difference was detected between patients with amplified- and non-amplified MET in a two-year follow-up after the first diagnosis (P = 0.001). C-MET scores of 0, 1+, 2+, and 3+ were observed in 1.4%, 24.9%, 54.7%, and 19.0% of tumors, respectively. C-MET overexpression correlated with higher frequency of LNM (P = 0.002), but no significant difference of PFS was detected between patients with different protein levels. In terms of concordance between MET FISH and IHC results, MET copy number showed no difference in c-MET IHC 0/1+ (3.35 ± 0.18), 2+ (3.29 ± 0.11) and 3+ (3.58 ± 0.22) cohorts, and the MET-to-CEP7 ratio showed no difference in three groups (1.09 ± 0.02, 1.10 ± 0.01, and 1.09 ± 0.03). CONCLUSION: In CRC, focal MET amplification was a rare event. Polysomy-induced MET amplification correlated with adverse pathological characteristics and poor prognosis. IHC was a poor screening tool for MET amplification.

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.

[Correlation of ¹8F-FDG uptake with tumor-proliferating antigen Ki-67 expression in aggressive lymphoma].

OBJECTIVE: To investigate the correlation between ¹8F-FDG uptake in positron emission tomography/computed tomography imaging and tumor-proliferating antigen Ki-67 expression in aggressive lymphoma. METHODS: Data of ¹8F-FDG PET-CT imaging and immunohistochemical detection of Ki-67 expression of seventy-seven cases with initially diagnosed aggressive lymphoma were retrospectively analyzed. The intensity of ¹8F-FDG accumulation was determined by calculating the maximum standardized uptake value (SUVmax) and average standardized uptake value (SUVave). The average SUV at biopsy site (BxSUVave), SUVmax at biopsy site (BxSUVmax) and SUVmax at the highest tumor activity site of the body (BmSUVmax) were collected. RESULTS: The BmSUVmax, BxSUVmax, and BxSUVave were 13.4 ± 6.8, 11.9 ± 6.8 and 7.3 ± 4.4, respectively,and Ki-67 was (61.2 ± 20.4)% in the 77 aggressive lymphomas. The BmSUVmax was significantly higher than the BxSUVmax or BxSUVave (P < 0.05). The BmSUVmax, BxSUVmax and BxSUVave were positively correlated with the Ki-67 expression in aggressive lymphoma (P < 0.05). A positive correlation was revealed between the BxSUVmax and BmSUVmax (P < 0.05), and between the BxSUVmax and BxSUVave (P < 0.05). No significant correlation was found between the BmSUVmax or BxSUVmax and the Ki-67 in DLBCL (P > 0.05). A positive correlation was observed between the BmSUVmax or BxSUVmax and the Ki-67 expression in NK/T cell lymphoma (P < 0.05). CONCLUSION: The increasing trend of ¹8F-FDG uptake is correlated with the Ki-67 expression in aggressive lymphoma. The results of this study suggest that the metabolic information obtained by using BmSUVmax may help to compensate the limited sampling of histological examination at the biopsy site. Significant correlation in NK/T cell lymphoma suggests that the metabolic information from positron emission tomography-computed tomography may offer a useful parameter in the prognosis and management of this disease.

[Immunophenotypes and gene mutations in colorectal precancerous lesions and adenocarcinoma].

OBJECTIVE: To analyze immunophenotypes and gene mutations of colorectal precancerous lesions and adenocarcinoma, and to compare the difference of carcinogenetic mechanisms between the two precancerous lesions. METHODS: Fifty-three cases of colorectal serrated lesions including 30 hyperplastic polyps, 20 sessile serrated adenomas (SSA) and 3 mixed polyps were collected from January 2006 to June 2012.Forty-five cases of traditional adenomas and 50 cases of colorectal adenocarcinomas were also recruited. Thirty hyperplastic polyps, 20 cases of SSA, 3 mixed polyps and 45 traditional adenomas were investigated by immunohistochemistry for the expression of DNA mismatch repair (MMR) proteins (MLH1, MSH2 and MSH6) and DNA methyltransferase MGMT. Mutations of KRAS, BRAF and PIK3CA genes in 10 cases of SSAs, 10 traditional adenomas, 1 mixed polyps and 50 colorectal adenocarcinomas were analyzed by PCR followed by direct Sanger sequencing. RESULTS: (1) Only 3 cases of hyperplastic polyps lost MLH1 expression, and none of SSAs or traditional adenomas showed loss of MLH1. The negative expression rates of MSH2, MSH6 and MGMT in hyperplastic polyps and SSA were significantly higher than those of traditional adenomas. (2) KRAS mutation was found in 5/10 cases of SSAs, 5/10 traditional adenomas and 1/1 mixed polyps. (3) Colorectal adenocarcinomas harbored the mutations of KRAS (48%, 24/50), BRAF (6%, 3/50) and PIK3CA (4%, 2/50). CONCLUSIONS: Immunophenotypic and gene mutation profiles are different between colorectal serrated lesion and traditional adenoma. Alterations of MMR and MGMT expression play important roles in the pathogenesis of "serrated neoplasm". KRAS mutation is a significant genetic change in the early phase of colorectal carcinogenesis.

[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 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.

[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.

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.

[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.

Carbamates of 4'-demethyl-4-deoxypodophyllotoxin: synthesis, cytotoxicity and cell cycle effects.

In an attempt to generate compounds with superior bioactivity and reduced toxicity, 12 carbamates of 4'-demethyl-4-deoxypodophyllotoxin, N-(1-oxyl-4'-demethyl- 4-deoxypodophyllic)-α-amino acids amides, were synthesized and evaluated for antiproliferative activity and cell cycle effects. These synthesized compounds proved to be more hydrophilic, as well as improved or comparable in vitro cytotoxicities against four cell lines (A-549, HeLa, SiHa, and HL-60) compared with either parent DPT or anti-cancer drug VP-16. Furthermore, flow cytometric analysis exhibited that N-(1-oxyl-4'-demethyl-4-deoxypodophyllic)-d-α-methine amide (15f) induced cell cycle arrest in the G2/M phase in A-549 cells.

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.

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.