Bone marrow mesenchymal stem cell (BMSC)-derived exosomes have been found to enhance fracture healing. In addition, microRNAs contributing to the healing of various bone fractures have attracted widespread attention in recent years, but knowledge of the mechanisms by which they act is still very limited. In this study, we clarified the function of altered microRNA-19b (miR-19b) expression in BMSCs in fracture healing. We modulated miR-19b expression via mimics/inhibitors in BMSCs and via agomirs in mice to explore the effects of these changes on osteogenic factors, bone cell mineralization and the healing status of modeled fractures. Through gain- and loss-of function assays, the binding affinity between miR-19b and WWP1/Smurf2 was identified and characterized to explain the underlying mechanism involving the KLF5/β-catenin signaling pathway. miR-19b promoted the differentiation of human BMSCs into osteoblasts by targeting WWP1 and Smurf2. Overexpression of WWP1 or Smurf2 degraded the target protein KLF5 in BMSCs through ubiquitination to inhibit fracture healing. KLF5 knockdown delayed fracture healing by modulating the Wnt/β-catenin signaling pathway. Furthermore, miR-19b enhanced fracture healing via the KLF5/β-catenin signaling pathway by targeting WWP1 or Smurf2. Moreover, miR-19b was found to be enriched in BMSC-derived exosomes, and treatment with exosomes promoted fracture healing in vivo. Collectively, these results indicate that mesenchymal stem cell-derived exosomal miR-19b represses the expression of WWP1 or Smurf2 and elevates KLF5 expression through the Wnt/β-catenin signaling pathway, thereby facilitating fracture healing.
This study aimed to establish a nomogram for the prognostic prediction of patients with early-onset cervical cancer (EOCC) in both overall survival (OS) and cancer-specific survival (CSS). The 10,079 patients diagnosed with EOCC between 2004 and 2015 were captured within the Surveillance, Epidemiology, and End Results (SEER) database and further were divided into training and validation sets randomly. The independent prognostic factors were identified in a retrospective study of 7,055 patients training sets randomly. Besides, the prognostic nomogram was developed using R software according to multivariable Cox regression analysis. Furthermore, the model was externally validated using the data of 3,024 patients diagnosed at different times enrolled in the SEER database. In training set, the C-indexes for OS and CSS prediction were 0.831 (95% confidence interval [CI]: 0.815-0.847) and 0.855(95%CI:0.839-0.871). The results of ROC indicated that nomograms possessed better predict performance compared with TNM-stage and SEER-stage. And the areas under the curve (AUC) of the nomogram for OS and CSS prediction in ROC analysis were 0.855(95%CI:0.847-0.864) and 0.782(95%CI:0.760-0.804), respectively. In addition, calibration curves presented perfect agreements between the nomogram-predicted and actual 1-, 3-, and 5-year in the validation cohort, in OS rate and CSS rate. This study established and validated a prognostic nomogram that provided an accurate prediction of 3-, 5-, and 10-year OS and CSS of EOCC patients, which contributed to clinicians to be useful for patients’ counseling and clinical trial designing.
Background:Scholars in developed and emerging economies have widely tested the interactions between foreign direct investment, financial development, economic growth and environmental degradation. Despite a number of empirical and review studies, it is not yet wrap up either the associations are negative, positive, direct or indirect. Additionally, minor attention is given to the indirect role of foreign direct investment in environmental degradation; perhaps no study has yet demonstrated the mediating role of financial development and economic growth between foreign direct investment and environmental degradation in Asian economies. Referring to the fragmented outputs and consequences as well as lacking the indirect role, the present study examines the influence of foreign direct investment on environmental degradation with the mediating role of financial development and economic growth. Results:Secondary data of 21 Asian countries from 1980-2018 were gathered from World Bank Indicators and then performed STATA to test the paths. Our findings are slightly different from the studies conducted in developed economies. The results indicate that foreign direct investment significantly improves environmental quality by deteriorating environmental pollution. It also significantly improves economic growth in the selected regions. Surprisingly, our study shows that foreign direct investment has a significant negative influence on financial development in the Asian regions. Both financial development and economic growth significantly negatively influence environmental degradation in Asian regions. However, financial development partially mediates while economic growth does not play any mediating role between foreign direct investment and environmental degradation in the Asian countries. Trade openness and population growth as control factors do not show any significant role in the model. Conclusions:This research recommends policymakers to focus on the inflow of foreign direct investment in order to enhance economic growth and environmental quality. It is strongly suggested for policymakers to attenuate the political intervention (e.g. ensure the political stability) in the inflow of foreign direct investment, so financial resources can be impartially distributed in the industrial sector and thus the nations will have an effective financial development system. Other implications have described.
Background:Scholars in developed and emerging economies have widely tested the interactions between foreign direct investment, financial development, economic growth and environmental degradation. Despite a number of empirical and review studies, it is not yet wrap up either the associations are negative, positive, direct or indirect. Additionally, minor attention is given to the indirect role of foreign direct investment in environmental degradation; perhaps no study has yet demonstrated the mediating role of financial development and economic growth between foreign direct investment and environmental degradation in Asian economies. Referring to the fragmented outputs and consequences as well as lacking the indirect role, the present study examines the influence of foreign direct investment on environmental degradation with the mediating role of financial development and economic growth. Results:Secondary data of 21 Asian countries from 1980-2018 were gathered from World Bank Indicators and then performed STATA to test the paths. Our findings are slightly different from the studies conducted in developed economies. The results indicate that foreign direct investment significantly improves environmental quality by deteriorating environmental pollution. It also significantly improves economic growth in the selected regions. Surprisingly, our study shows that foreign direct investment has a significant negative influence on financial development in the Asian regions. Both financial development and economic growth significantly negatively influence environmental degradation in Asian regions. However, financial development partially mediates while economic growth does not play any mediating role between foreign direct investment and environmental degradation in the Asian countries. Trade openness and population growth as control factors do not show any significant role in the model. Conclusions:This research recommends policymakers to focus on the inflow of foreign direct investment in order to enhance economic growth and environmental quality. It is strongly suggested for policymakers to attenuate the political intervention (e.g. ensure the political stability) in the inflow of foreign direct investment, so financial resources can be impartially distributed in the industrial sector and thus the nations will have an effective financial development system. Other implications have described.
Background: Metastasis is the leading cause of the high morality of esophageal squamous cell carcinoma (ESCC), so early monitoring metastasis of esophageal cancer is the key to improve the survival rate of ESCC patients. However, there have not been effective biomarkers for predicting metastasis of ESCC patients,it is an urgent need to identify ESCC metastasis-related proteins. Methods: iTRAQ-based proteomic method was performed in highly metastatic 30M cell established in our previous study and the corresponding parental cells KYSE30.The expression of IFI16 was verified using western blotting and immunohistochemistry (IHC). Then, cck8, transwell assay,mouse metastasis experiments were performed to determine the functional role of IFI16 in esophageal cancer. Finally, RAN-Seq, qpcr, transwell assay were used to investigate the underlying mechanism of IFI16 in esophageal cancer metastasis. Results: The data showed that IFI16 was upregulated in 30M cell compared with KYSE30 cell. IFI16 also increased in ESCC tumor compared with non-tumor tissue. Kaplan-Meier survival curve analysis showed that the relapse-free survival (RFS) of patients with high IFI16 level was worse than that of patients with low IFI16 level (P=0.0449). In addition, IFI16 knockdown did not affect the cell growth, but inhibited ESCC cell migration and invasion in ESCC cells. Moreover, IFI16 knockdown suppressed the lung metastasis of 30M cells in mouse models. Finally, we performed an RNA-Seq assay in IFI16-knocking down 30M cells and identified that knocking down IFI16 downregulated the expression of fibroblast growth factor proteins (FGF1, FGF2 etc.). Furthermore, overexpressing FGF1 and FGF2 rescued the lost of migration and invasion ability of 30M mediated by IFI16 knockdown. Conclusion: Our results demonstrated that IFI16 was a key ESCC metastasis-related protein and played a role in ESCC metastasis through promoting the FGF proteins expression.
Testing engineers in the third-party software testing center are often puzzled with some non-technical problems, such as, how to deal with the developers' reactance, and how to meet the end users' satisfaction, during the software testing process. Unfortunately, little attention has been paid to solve such kind of problems. In this paper, we argue that the high quality and high productivity pursued by software testing require us not only to emphasize the hard skills of testing engineers but also to enhance their soft skills in an appropriate and systematic way, which should deserve more attention. We furthermore argue that attention should be paid to obtain qualitative insight and feedback from testing engineers and to explore in what way to acquire the useful information. We conduct a qualitative study to explore and understand testing engineers' soft skills from five different test teams based on multidimensional perspective levels under the analysis of grounded theory. The on-going research work's agenda is given, several research challenges are analyzed and at last future work is proposed.
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