Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor.

The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate β-catenin/TCF signaling is poorly understood. In the present study, using CRISPR/Cas9 genome-editing technology, we show that Izb reverses β-catenin-mediated PTHR signaling switch and enhances PTH-induced cAMP generation and cAMP response element-luciferase activity in osteoblasts. Izb increases active forms of β-catenin and promotes β-catenin translocation, thereby dissociating β-catenin from the PTHR at the plasma membrane. Furthermore, Izb facilitates PTH-stimulated GSK3β phosphorylation and β-catenin phosphorylation. Thus Izb enhances PTH stimulation of β-catenin/TCF signaling via cAMP-dependent activation, and this effect is due to its separating β-catenin from the PTHR. These findings provide evidence that Izb may be used to improve the therapeutic efficacy of PTH for the treatment of osteoporosis and other resorptive bone diseases

手术室风险管理

Objective: To study the risk management of operating room and to improve operating room efficiency. Methods: Firstly, make clear   the internal risk management and external regulatory frameworks, organizational principles and their respective functions on the basis of the risk management of operating room. Results: The checklist approach was employed for extensive identification and potential risk in operating room, even if the risk could be controlled. Conclusion: This study designs risk management plans and establishes a risk register, to strengthen the emergency response capacity and improve operating room efficiency.目的  研究手术室风险管理，提高手术室工作效率。方法  基于手术室风险管理首先要明确内部和外部的管理框架，组织原则及各自的职能。结果  采用检查列表的方式，广泛识别手术室目前存在的和可能发生的风险，即使出现风险可控。结论  研究设计手术室风险管理计划，建立风险登记簿，加强突发事件应对能力，提高了手术室工作效率