Activation of the γ-secretase/NICD-PXR/Notch pathway induces Taxol resistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is currently the only subtype lacking efficient targeted therapies. Taxol is the primary chemotherapeutic agent for TNBC. However, Taxol resistance often develops in the treatment of TNBC patients, which importantly contributes to high mortality and poor prognosis in TNBC patients. Recent preclinical studies have shown that the inhibition of Notch pathway by γ-secretase inhibitors can slow down the progression of TNBC. Our studies in bioinformatic analysis of breast cancer patients and TNBC/Taxol cells in vitro showed that there was high correlation between the activation of Notch pathway and Taxol resistance in TNBC. Increased γ-secretase activity (by the overexpression of catalytic core PSEN-1) significantly reduced Taxol sensitivity of TNBC cells, and enhanced biological characteristics of malignancy in vitro, and tumour growth in vivo. Mechanistically, increased γ-secretase activity led to the accumulation of NICD in the nucleus, promoting the interaction between NICD and PXR to activate PXR, which triggered the transcription of PXR downstream associated drug resistance genes. Furthermore, we showed that pharmacological inhibition of γ-secretase with γ-secretase inhibitors (Nirogacestat and DAPT) can reverse Taxol resistance in vivo and in vitro. Our results for the first time demonstrate that the activation of γ -secretase/NCD-PXR/Notch pathway is one of important mechanisms to cause Taxol resistance in TNBC, and the blockades of this pathway may represent a new therapeutic strategy for overcoming Taxol resistance in TNBC.

Quantitation of Enterovirus A71 Empty and Full Particles by Sedimentation Velocity Analytical Ultracentrifugation.

The enterovirus A71 (EV71) inactivated vaccine is an effective intervention to control the spread of the virus and prevent EV71-associated hand, foot, and mouth disease (HFMD). It is widely administered to infants and children in China. The empty particles (EPs) and full particles (FPs) generated during production have different antigenic and immunogenic properties. However, the antigen detection methods currently used were established without considering the differences in antigenicity between EPs and FPs. There is also a lack of other effective analytical methods for detecting the different particle forms, which hinders the consistency between batches of products. In this study, we analyzed the application of sedimentation velocity analytical ultracentrifugation (SV-AUC) in characterizing the EPs and FPs of EV71. Our results showed that the proportions of the two forms could be quantified simultaneously by SV-AUC. We also determined the repeatability and accuracy of this method and found that both parameters were satisfactory. We assessed SV-AUC for bulk vaccine quality control, and our findings indicated that SV-AUC can be used effectively to analyze the percentage of EPs and FPs and monitor the consistency of the process to ensure the quality of the vaccine.

Benefits of Beta-Blockade in Sepsis and Septic Shock: A Systematic Review.

BACKGROUND: Sepsis and septic shock are inflammatory disorders associated with high rates of mortality. Patients with sepsis and septic shock frequently become tachycardic as a result of the utilization of vasopressor therapy and cardiac overcompensation owing to hypotension, predisposing patients to an increased risk of atrial fibrillation. Previously, it was thought that beta-blocker therapy in patients with sepsis would exacerbate hypotension; however, recent studies have shown that may not be the case. OBJECTIVE: This review aims to ascertain whether beta-blocker therapy reduces heart rate in patients with sepsis without a corresponding decrease in blood pressure, and if beta-blockade has a beneficial effect on mortality. METHODS: Several databases including Cochrane, EMBASE, PubMed, SCOPUS, and Web of Science were scoured for trials pertaining to the utilization of beta-blockers in sepsis and septic shock, and trials that were either prospective or controlled were included in this review. RESULTS: In the initial search, 1839 articles were found, and those were subsequently reduced to 14 trials (five randomized controlled trials, nine non-randomized trials) that were deemed appropriate for inclusion in this review. All included trials displayed beneficial effects on heart rate without any detriments to blood pressure. Of the six trials that assessed mortality, four showed substantial benefits. CONCLUSION: The majority of the trials assessed in this review displayed beneficial results for beta-blocker use in patients with sepsis. However, owing to the deficit of large-scale randomized controlled trials addressing this topic, further research is needed to ensure the veracity of these results.