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
API RP 7G-2标准、NS-2标准是钻探设备制造和检验中常用的两个标准,它们各自具有不同的特点和应用范围,了解这些差异对于确保钻探设备的安全性和可靠性至关重要。通过对二者的深入分析,识别其在钻柱常用构件方面的差异,探讨这些不同对...API RP 7G-2标准、NS-2标准是钻探设备制造和检验中常用的两个标准,它们各自具有不同的特点和应用范围,了解这些差异对于确保钻探设备的安全性和可靠性至关重要。通过对二者的深入分析,识别其在钻柱常用构件方面的差异,探讨这些不同对钻具作业整体表现的潜在影响,为同领域的技术进步与创新提供方向。展开更多
Serial-parallel manipulators are of great interest to academic community in recent years,especially those composed of classical parallel mechanisms.There have been many studies around 2(3RPS)and 2(3SPR)S-PMs,but unfor...Serial-parallel manipulators are of great interest to academic community in recent years,especially those composed of classical parallel mechanisms.There have been many studies around 2(3RPS)and 2(3SPR)S-PMs,but unfortunately their inverse kinematics have not yet been resolved.This paper discovers that the unknown kinematic parameters of middle platform are responsible for the unresolvable of inverse kinematics,meanwhile the unknown kinematic parameters of middle platform also have huge coupling relationships.Therefore,to break through this challenges,the huge coupling relationships are decoupled layer by layer,the kinematic parameters of middle platform are solved by combining Sylvester's elimination method,and the inverse displacements of 2(3RPS)and 2(3SPR)S-PMs are obtained subsequently.This paper not only solves the inverse kinematics of classical 2(3RPS)and 2(3SPR)S-PMs,but also reveals the essence of the inverse kinematics of general(3-DOF)+(3-DOF)6-DOF S-PMs and proposes a corresponding solution.展开更多
API code is introduced at first, and then a comparison of seismic character and seismic hazard between Bohai and Southern California is carried out. The analysis indicates both the seismic frequency and intensity and ...API code is introduced at first, and then a comparison of seismic character and seismic hazard between Bohai and Southern California is carried out. The analysis indicates both the seismic frequency and intensity and the seismic hazard of Bohai are much weaker than that of Southern California. API code states the strength level and deformation level of permanent structures in Southern California takes 200 a and several hundred to a few thousand years respectively. But in the reference codes in China, the seismic levels take 500 a and 10000 a for strength design and deformation design, and it seems too conservative. In China, the deformation level of class A structure takes 2%-3% probabilities of exceedance in reference period 100 a, and that of class B and C often takes 2%-3% in 50 a. Now that offshore platforms may cause server subsequent risk, it is safe to take 1% in 30 a as its deformation design level. On the basis of the above analyses and social economic level and the consistency with present codes, the strength design level and deformation design level of Chinese offshore platforms is suggested to take 200 a and 3000 a respectively.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Supported by National Natural Science Foundation of China(Grant No.52275033)National Natural Science Youth Foundation of China(Grant No.52205033)Hebei Provincial Natural Science Foundation of China(Grant No.E2021203019)。
文摘Serial-parallel manipulators are of great interest to academic community in recent years,especially those composed of classical parallel mechanisms.There have been many studies around 2(3RPS)and 2(3SPR)S-PMs,but unfortunately their inverse kinematics have not yet been resolved.This paper discovers that the unknown kinematic parameters of middle platform are responsible for the unresolvable of inverse kinematics,meanwhile the unknown kinematic parameters of middle platform also have huge coupling relationships.Therefore,to break through this challenges,the huge coupling relationships are decoupled layer by layer,the kinematic parameters of middle platform are solved by combining Sylvester's elimination method,and the inverse displacements of 2(3RPS)and 2(3SPR)S-PMs are obtained subsequently.This paper not only solves the inverse kinematics of classical 2(3RPS)and 2(3SPR)S-PMs,but also reveals the essence of the inverse kinematics of general(3-DOF)+(3-DOF)6-DOF S-PMs and proposes a corresponding solution.
基金Important Research of the Tenth Five-year Plan from China Earthquake Administration ″Seismic hazard assessment and structure seismic fortification″ and ″Reliability of seismic fortification level of offshore platforms″.
文摘API code is introduced at first, and then a comparison of seismic character and seismic hazard between Bohai and Southern California is carried out. The analysis indicates both the seismic frequency and intensity and the seismic hazard of Bohai are much weaker than that of Southern California. API code states the strength level and deformation level of permanent structures in Southern California takes 200 a and several hundred to a few thousand years respectively. But in the reference codes in China, the seismic levels take 500 a and 10000 a for strength design and deformation design, and it seems too conservative. In China, the deformation level of class A structure takes 2%-3% probabilities of exceedance in reference period 100 a, and that of class B and C often takes 2%-3% in 50 a. Now that offshore platforms may cause server subsequent risk, it is safe to take 1% in 30 a as its deformation design level. On the basis of the above analyses and social economic level and the consistency with present codes, the strength design level and deformation design level of Chinese offshore platforms is suggested to take 200 a and 3000 a respectively.
