Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance...Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.展开更多
This paper investigated the use of magnesium phosphate cement (MPC) for solidifying sludge with different humic acid (HA) content (ranging from 0 to 4.5%) and explored the solidification mechanism. Fluidity, setting t...This paper investigated the use of magnesium phosphate cement (MPC) for solidifying sludge with different humic acid (HA) content (ranging from 0 to 4.5%) and explored the solidification mechanism. Fluidity, setting time, unconfined compressive strength (UCS), the strength formation mechanism, and the spontaneous imbibition process of solidified sludge (SS) were studied. The results indicate that MPC can be used as a low-alkalinity curing agent. As the HA content increases, fluidity and setting time also increase, while hydration temperature and strength decrease. Additionally, the failure mode of SS transitions from brittleness to ductility. The strength of SS is composed of the cementation strength provided by MPC hydration products, matric suction, osmotic suction, and the structural strength of the sludge. MPC reduces the structural strength caused by the shrinkage of pure sludge under the action of matric suction, but the incorporation of MPC significantly improved the strength when the sludge is eroded by water. X-ray diffraction (XRD) and scanning electron microscopy (SEM) show that the sludge and MPC can form a dense solid body, forming various hydration products, and synergistically improve the mechanical properties of the sludge.展开更多
基金supported by the Academic Leader Training Programof Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13)Shanghai Municipal Health Commission(Grant No.202340094).
文摘Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
基金This research work was financially supported by the National Natural Science Foundation of China(Grant No.51972209).
文摘This paper investigated the use of magnesium phosphate cement (MPC) for solidifying sludge with different humic acid (HA) content (ranging from 0 to 4.5%) and explored the solidification mechanism. Fluidity, setting time, unconfined compressive strength (UCS), the strength formation mechanism, and the spontaneous imbibition process of solidified sludge (SS) were studied. The results indicate that MPC can be used as a low-alkalinity curing agent. As the HA content increases, fluidity and setting time also increase, while hydration temperature and strength decrease. Additionally, the failure mode of SS transitions from brittleness to ductility. The strength of SS is composed of the cementation strength provided by MPC hydration products, matric suction, osmotic suction, and the structural strength of the sludge. MPC reduces the structural strength caused by the shrinkage of pure sludge under the action of matric suction, but the incorporation of MPC significantly improved the strength when the sludge is eroded by water. X-ray diffraction (XRD) and scanning electron microscopy (SEM) show that the sludge and MPC can form a dense solid body, forming various hydration products, and synergistically improve the mechanical properties of the sludge.
