Objective To explore the molecular mechanism of SHMT2 regulating the invasion and migration of breast cancer cells. Methods Bioinformatics analysis was used to verify the role of SHMT2 in breast cancer tissues. Transwell assay was used to detect the changes of invasion and migration abilities of breast cancer cells. Co-immunoprecipitation, knockdown plasmid transfection and Western blot were used to determine the regulatory relationship between different proteins. Results Bioinformatics analysis showed that the expression level of SHMT2 in invasive breast cancer tissues was significantly higher than that in adjacent normal tissues (P < 0.001). The 5-year disease-specific survival and overall survival in the SHMT2 high expression group were significantly lower than those in the SHMT2 low expression group (both P < 0.001). Transwell assay showed that SHMT2 knockdown significantly reduced the invasion ability (t=5.375, P=0.0058) and migration ability (t=6.274, P=0.0033) of MCF7 cells. Western blot showed that SHMT2 could combine to HAX1, and knockdown of SHMT2 reduced the protein level of HAX1. Transwell assay showed that the inhibitory effect of SHMT2 knockdown on the migration of MCF7 cells could be reversed by overexpression of HAX1 (t=6.274, P=0.0033; t=8.041, P=0.0013), while SHMT2 inhibitor (SHIN1, 10 nmol/L) significantly inhibited the migration of MCF7 cells induced by SHMT2 overexpression (t=10.16, P=0.0005; t=8.741, P=0.0009). Conclusion SHMT2 was closely related to the poor prognosis of breast cancer, and was a key factor in the invasion and migration of breast cancer cells. The mechanism was that SHMT2 increased the invasion and migration ability of breast cancer cells by binding to and up-regulating HAX1. It was verified that SHMT2 inhibitor could significantly reduce the migration ability of breast cancer cells. This study explored the therapeutic potential of SHMT2 inhibitor in metastatic breast cancer, and found potential intervention targets for its clinical treatment.

Objective::This network meta-analysis aims to compare the efficacy and safety of different targeted drug combination treatment for pulmonary arterial hypertension (PAH).Methods::Searches were conducted in Cochrane, PubMed, EMBASE, China National Knowledge Infrastructure, China Biomedical Literature Database, Wanfang Database, and VIP Chinese Science and Technology Journal Data to identify both published and unpublished randomized controlled trials from inception until January 1, 2022. The risk of bias in the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. A network meta-analysis was performed using Stata 16.0 software. The efficacy and safety of different targeted drugs combined treatment for PAH were evaluated based on forest plot, funnel plot, and surface under the cumulative ranking.Results::A total of 29 randomized controlled trails with 4,448 patients treated with 10 different types of targeted drug combinations were included in this study. The results of the surface under the cumulative ranking showed that the combination regimen was the best clinical option to improve symptoms and delay progression in patients with pulmonary artery hypertension compared with monotherapy. Sildenafil in combination with ambrisentan significantly improved the 6-minute walk distance and reduced N-terminal pro-brain natriuretic peptide levels. Bosentan in combination with sildenafil significantly reduced mean pulmonary artery pressure, whereas bosentan in combination with epoprostenol was more effective than other combinations in reducing pulmonary vascular resistance. Bosentan in combination with tadalafil significantly improved the Borg dyspnea score, and bosentan in combination with iloprost was the best combination for improving World Health Organization functional class/New York Heart Association functional class. In terms of safety, there was no significant reduction in the incidence of adverse events, hospitalizations, or all-cause mortality for combination therapy compared with monotherapy. Bosentan combined with sildenafil significantly reduced the risk of serious adverse events, but the risk of discontinuation due to an adverse event was higher than monotherapy. Sildenafil combined with epoprostenol reduced the risk of clinical worsening in patients with PAH.Conclusion::Compared with monotherapy, targeted drug combinations for PAH significantly improves exercise tolerance, pulmonary hemodynamic parameters, and reduces the risk of serious adverse events and clinical worsening in patients. Bosentan in combination with sildenafil and bosentan in combination with iloprost are combinations of targeted agents with significant efficacy and better safety profile than monotherapy for the treatment of PAH. Sildenafil in combination with epoprostenol has a low risk of clinical worsening in PAH.

Objective::This network meta-analysis aims to compare the efficacy and safety of different targeted drug combination treatment for pulmonary arterial hypertension (PAH).Methods::Searches were conducted in Cochrane, PubMed, EMBASE, China National Knowledge Infrastructure, China Biomedical Literature Database, Wanfang Database, and VIP Chinese Science and Technology Journal Data to identify both published and unpublished randomized controlled trials from inception until January 1, 2022. The risk of bias in the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. A network meta-analysis was performed using Stata 16.0 software. The efficacy and safety of different targeted drugs combined treatment for PAH were evaluated based on forest plot, funnel plot, and surface under the cumulative ranking.Results::A total of 29 randomized controlled trails with 4,448 patients treated with 10 different types of targeted drug combinations were included in this study. The results of the surface under the cumulative ranking showed that the combination regimen was the best clinical option to improve symptoms and delay progression in patients with pulmonary artery hypertension compared with monotherapy. Sildenafil in combination with ambrisentan significantly improved the 6-minute walk distance and reduced N-terminal pro-brain natriuretic peptide levels. Bosentan in combination with sildenafil significantly reduced mean pulmonary artery pressure, whereas bosentan in combination with epoprostenol was more effective than other combinations in reducing pulmonary vascular resistance. Bosentan in combination with tadalafil significantly improved the Borg dyspnea score, and bosentan in combination with iloprost was the best combination for improving World Health Organization functional class/New York Heart Association functional class. In terms of safety, there was no significant reduction in the incidence of adverse events, hospitalizations, or all-cause mortality for combination therapy compared with monotherapy. Bosentan combined with sildenafil significantly reduced the risk of serious adverse events, but the risk of discontinuation due to an adverse event was higher than monotherapy. Sildenafil combined with epoprostenol reduced the risk of clinical worsening in patients with PAH.Conclusion::Compared with monotherapy, targeted drug combinations for PAH significantly improves exercise tolerance, pulmonary hemodynamic parameters, and reduces the risk of serious adverse events and clinical worsening in patients. Bosentan in combination with sildenafil and bosentan in combination with iloprost are combinations of targeted agents with significant efficacy and better safety profile than monotherapy for the treatment of PAH. Sildenafil in combination with epoprostenol has a low risk of clinical worsening in PAH.