RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma

Dysregulation of mTORC1/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types; however, the mechanism of mTORC2 in tumorigenesis is still obscure. Here, we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to mTOR inhibitors. We demonstrated that RICTOR, the key factor of mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis (TNM) phase of ESCC patients. Furthermore, we found that mTORC1/ mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of RAD001 and PP242 both and . Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.

Discovery of 1,2,3triazolo4,5-pyrimidine derivatives as highly potent, selective, and cellularly active USP28 inhibitors

Ubiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investigating the roles of deubiquitinase. In this current study, we reported the synthesis and biological evaluation of new [1,2,3]triazolo[4,5-]pyrimidine derivatives as potent USP28 inhibitors. Especially, compound potently inhibited USP28 (IC = 1.10 ± 0.02 μmol/L,  = 40 nmol/L), showing selectivity over USP7 and LSD1 (IC > 100 μmol/L). Compound was cellularly engaged to USP28 in gastric cancer cells. Compound reversibly bound to USP28 and directly affected its protein levels, thus inhibiting the proliferation, cell cycle at S phase, and epithelial-mesenchymal transition (EMT) progression in gastric cancer cell lines. Docking studies were performed to rationalize the potency of compound . Collectively, compound could serve as a new tool compound for the development of new USP28 inhibitors for exploring the roles of deubiquitinase in cancers.

Discovery of WS-157 as a highly potent, selective and orally active EGFR inhibitor

EGFR tyrosine kinase inhibitor (EGFR-TKI) has been used successfully in clinic for the treatment of solid tumors. In the present study, we reported the discovery of from our in-house diverse compound library, which was validated to be a potent and selective EGFR-TKI. showed excellent inhibitory activities against EGFR (IC = 0.81 nmol/L), EGFR (IC = 1.2 nmol/L) and EGFR (IC = 1.1 nmol/L), but was less effective or even inactive against other nine kinases. also displayed excellent antiproliferative activities against a panel of human cancer cell lines, and exhibited the ability to reduce colony formation and wound healing the same as gefitinib. We found that upon oral administration showed better anti-tumor activity in A431 bearing xenograft mouse models compared to gefitinib. In addition, showed better intestinal absorption than gefitinib and had favorable pharmacokinetic properties and microsomal metabolic stability in different species. These studies indicate that has strong antitumor activity and , and could be used for the development of anti-lung cancer agent targeting EGFR.

Computing thinking-based teaching reform of computer network course / 中华医学图书情报杂志

Computing thinking is one of the hotspots in computer education field,computer network is the core course of computer,and social information process is increasing the need of computer network professionals.The characteristics of computer network course,teaching of computer network course and problems related with teaching of computer network course were analyzed in aspects of its teaching contents,teaching methods and examination methods in order to train more excellent applied professionals of computer network and improve the computing thinking of undergraduates.The ways or methods for training the computing thinking of undergraduates were put forward,which can thus provide new ideas for the teaching reform of computer network course in colleges and universities.

Assessment of the value of academic libraries / 中华医学图书情报杂志

Assessment of the value of academic libraries is an effective means to describe the value of academic libraries themselves. The dimension and factors for the assessment of the value of domestic and foreign academic li-braries were analyzed according to the assessment of the value of Shanxi Medical University Library, and the frame-work for the assessment of the value of academic libraries was proposed in terms of the impact of academic libraries on higher education.

The application reserch of ultrasonography for screening of developmental dysplasia of the hip in infants / 重庆医学

Objective To evaluate the value of ultrasonic Graf methods in screening developmental dysplasia of the hip (DDH)in infants .Methods 1 580 cases of 0-6 monthes old infants without severe limb anomalies were examined .Bilateral hip joints were examined mcluded analyzed according to Graf method .Results A total of 1 580 cases included 3 160 hip joints were analyzed ,827 were male (52 .34% ) and 753 were female (52 .34% ) among them .104 cases (6 .58% ) were diagnosed with abnormalities of the hip joints .Among the 104 cases ,88 cases (5 .57% ) were type Ⅱa hip joints ,9 cases (0 .57% ) were type Ⅱ b ,5 cases (0 .32% ) were type Ⅱc ,1 case (0 .06% ) and 1 case (0 .06% ) were type Ⅲ and type Ⅳ respectively .In each month of age abnormalities of the hip joints were diagnosed as followed :79 cases(9 .69% ) were one month old ,13 cases (3 .98% ) were two month old ,2 cases (2 .15% ) were three month old ,6 cases (2 .26% ) were four month old ,1 cases (2 .44% ) was five month old and 3 cases (7 .69% ) were six month old .Conclusion Ultrasonic Graf method can provide the basic data for incidence of developmental dysplasia of hip in infants in local region and may be helpful to offer the related standards for early screening the abnormalities of the hip joints .

Efficiency analysis of the first time platelet transfusion in patients with blood diseases / 白血病·淋巴瘤

Objective To study the efficiency of the first time platelet transfusion in patients with blood diseases.Methods Investigate the effect of platelet transfusion in 87 patients with blood diseases.All the patients were transfused 10U platelet (platelet≥2.5×1011 ).Observe CCI after platelet transfusion and analyse the influence factors to the efficiency of the first time platelet transfusion such as the kind of diseases,splenomegaly,fever,age and sex.Results After platelet transfusion,66 patients (75.9 ％) were effective.The efficancy rates were 80.0 ％,78.1％,65.2 ％,82.3 ％ in AA,ITP,AL,MDS (x2=2.88,P＞0.05).In 31 patients with a fever and infaction the efficancy rate was 58.1％,but it was 85.7％ in 56 patients without a fever and infaction (x2=8.3308,P＜0.01).The efficancy rate in 59 patients with non-splenomegaly was 86.4 ％.It was higher than that in 28 patients with splenomegaly which was 53.6％(x2=11.2033,P＜0.01).The efficancy rate was 76.0％ in male patients and it was 75.7 ％ in female patients (x2=- 0.0012,P＞0.05).The efficancy rate was 74.5 ％ in young group (＜60 years old)and 77.8 ％ in old group (≥60 years old)(x2=0.1231,P＞0.05).Conclusion Fever and splenomegaly are the influence factors to the efficiency of the first time platelet transfusion.