Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma / 医学前沿

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson's correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial-to-mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.

Relationship between hepatic venous pressure gradient and parameters of Doppler ultrasound in 68 patients with pyrroidine alkaloid-related hepatic sinusoidal obstruction syndrome / 中华消化杂志

Objective:To investigate the relationship between hepatic venous pressure gradient (HVPG) and parameters of Doppler ultrasound in patients with pyrroidine alkaloid-related hepatic sinusoidal obstruction syndrome (PA-HSOS).Methods:From February 17, 2017 to April 22, 2020, the clinical data of 68 patients with PA-HSOS who underwent HVPG manometry and Doppler ultrasound examination at Drum Tower Hospital, the Affiliated Medical College of Nanjing University were retrospectively analyzed, which included HVPG, Drum Tower severity scoring (DTSS), time from PA-HSOS related symptoms appeared to diagnosis after taking pyrroidine alkaloid (hereinafter referred to as diagnosis time), and parameters of Doppler ultrasound induding portal vein trunk diameter (PD), peak portal vein velocity (PPV), splenic vein trunk diameter (SD) and peak splenic vein velocity (PSV). Receiver operating characteristic curve (ROC) was used to determine the optimal cut-off value of HVPG for predicting non-response to anticoagulation therapy. Binary logistic regression was used to analyze the independent risk factors for non-response to anticoagulation therapy, and Kaplan-Meier survival curve was used to analyze the prognostic survival rate of patients with different HVPG levels. Unitary linear regression was applied to analyze the correlation of HVPG with PD, PPV, SD and PSV in patients with different HVPG levels, patients with mild, moderate and severe DTSS, and patients with diagnosis time >1 month or ≤ 1 month. Chi-square test was used for statistical analysis.Results:The results of ROC analysis showed that the optimal cut-off value of HVPG for predicting non-response to anticoagulant therapy was 20.165 mmHg(1 mmHg=0.133 kPa). The result of multivariate analysis indicated that high HVPG (HVPG>20.165 mmHg) was an independent risk factor for predicting non-response to anticoagulant therapy ( OR (95% confidence interval)=6.039(1.466 to 24.869), P=0.013). Kaplan-Meier survival curve demonstrated that prognostic survival rate of patients with high HVPG was lower than that of patients with low HVPG (HVPG≤20.165 mmHg) (78.4% vs.96.8%), and the difference was statistically significant( χ2=4.74, P=0.030). The results of unitary linear regression analysis showed that there was a negative correlation between HVPG and PPV in 68 patients with PA-HSOS( r=-0.330, P=0.006); HVPG was positively correlated with PD and SD in patients with high HVPG ( r=0.540 and 0.341, P=0.001 and 0.039); there was a negative correlation between HVPG and PSV in patients with mild DTSS ( r=-0.519, P=0.019), HVPG was negatively correlated with PPV in patients with moderate DTSS ( r=-0.400, P=0.014). In patients with diagnosis time ≤1 month, there was a negative correlation between HVPG and PPV ( r=-0.391, P=0.010). Conclusions:HVPG can assist in judging the response to anticoagulation therapy and the prognosis of patients with PA-HSOS. Parameters of Doppler ultrasound can help to assess the degree of HVPG elevation in patients with PA-HSOS under certain conditions.