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FLT3 inhibitors (FLT3i) are widely used for the treatment of acute myeloid leukemia (AML), but adaptive and acquired resistance remains a primary challenge. Inhibitors simultaneously blocking adaptive and acquired resistance are highly demanded. Here, we observed the potential of CHK1 inhibitors to synergistically improve the therapeutic effect of FLT3i in FLT3-mutated AML cells. Notably, the combination overcame adaptive resistance. The simultaneous targeting of FLT3 and CHK1 kinases may overcome acquired and adaptive resistance. A dual FLT3/CHK1 inhibitor 30 with a good oral PK profile was identified. Mechanistic studies indicated that 30 inhibited FLT3 and CHK1, downregulated the c-Myc pathway and further activated the p53 pathway. Functional studies showed that 30 was more selective against cells with various FLT3 mutants, overcame adaptive resistance in vitro, and effectively inhibited resistant FLT3-ITD AML in vivo. Moreover, 30 showed favorable druggability without significant blood toxicity or myelosuppression and exhibited a good oral PK profile with a T

A series of novel non-covalent peptidomimetic proteasome inhibitors possessing bulky group at the C-terminus and N-alkylation at the N-terminus were designed with the aim to increase metabolic stabilities in vivo. All the target compounds were screened for their inhibitory activities against human 20S proteasome, and most analogs exhibited notable potency compared with the positive control bortezomib with IC

To investigate the cognitive ability and coping strategy to mental disorders among medical workers in ear-nose-throat departments and its impact on doctor-patient relationship. Methods: A total of 78 medical workers (including doctors, nurses, and technicians) in ear-nose-throat departments from 10 general hospitals in Hunan Province were investigated by self-compiled questionnaire on the perspective and coping strategy to mental disorders among medical workers. Results: Mental disorders except depression and schizophrenia were poorly understood in respondents, and many of their coping strategies were inappropriate. Furthermore, subjects tend to avoid too much contact with psychiatric patients for being afraid of the mental disorders. The poorer understanding of mental disorders, the more inappropriate coping strategies in dealing with mental disorders (P0.001). Moreover, there was a significant difference in inappropriate coping strategies to mental disorders between patients being abused and patients not being abused (P=0.017). Factors such as education background (P=0.031) and the hospital level (P=0.038) also impacted the coping strategies to mental disorders. Conclusion: Among all mental disorders, only depression and schizophrenia are coped with the right way in medical workers of ear-nose-throat departments. In addition, obviously negative attitude and avoidance are found in dealing with mental disorders by medical workers. Importantly, poor cognitive ability to mental disorders is the main reason for hurting doctor-patient relationship in the ear-nose-throat departments.目的：调查耳鼻喉科医务人员对精神疾病的认知辨识程度、处理方式及其对医患关系的影响。方法：采取多阶段抽样方法选取10所医院耳鼻喉科医务人员78人作为研究对象，用自编《医务人员对精神疾病的认知辨识程度现状与处理方式调查问卷》收集医务人员基本情况、对精神疾病的认知辨识程度及医患关系体验等信息。结果：受访医务人员对除抑郁症、精神分裂症之外的其他精神疾病关注度较低，对精神疾病患者态度消极，存在害怕心理，并避免与其过多接触。医务人员对精神疾病认知辨识程度越低，对精神疾病患者正确处理的可能性越低(P0.001)。医务人员认知误区与其遭受患者或家属辱骂之间比较差异有统计学意义(P=0.017)。医务人员的学历(P=0.031)、所在医院级别(P=0.038)是其对精神疾病认知辨识程度的影响因素。结论：耳鼻喉科医务人员对除抑郁症、精神分裂症之外的其他精神疾病关注度较低，且存在处理精神疾病态度消极，处理方法以回避为主等问题。耳鼻喉科医务人员对精神疾病认知辨识程度低下可能是导致耳鼻喉科医患矛盾较多的重要原因。.