Identification of Novel CDK9 Inhibitors with Better Inhibitory Activity and Higher Selectivity for Cancer Treatment by an Effective Two-Stage Virtual Screening Strategy

The aberrant overexpression of cyclin-dependent kinase 9 (CDK9) in cancer cells results in the loss of proliferative control, making it an attractive therapeutic target for various cancers. However, the highly structural similarity between CDK9 and CDK2 makes the development of novel selective CDK9 inhibitors a challenging task and thus limits their clinical applications. Here, an effective two-stage virtual screening strategy was developed to identify novel CDK9 inhibitors with better inhibitory activity and higher selectivity. The first screening stage aims to select potential compounds with better inhibitory activity than Roniciclib, one of the most effective CDK9 inhibitors, through reliable structure-based pharmacophoric virtual screening and accurate molecular docking analyses. The second stage employs a very detailed visual inspection process, in which several structural criteria describing the major difference between the binding pockets of CDK9 and CDK2 are taken into consideration, to identify compounds with higher selectivity than CAN508, one of the CDK9 inhibitors with distinguished selectivity. Finally, three compounds (NCI207113 from NCI database and TCM0004 and TCM3282 from TCM database) with better inhibitory activity and higher selectivity were successfully identified as novel CDK9 inhibitors. These three compounds also display excellent binding stabilities, great pharmacokinetic properties and low toxicity in MD simulations and ADMET predictions. Besides, the results of binding free energy calculations suggest that enhancing van der Waals interaction and nonpolar solvation energy and/or reducing polar solvation energy can significantly improve the binding affinity of these CDK9 inhibitors. Their clinical potentials to serve as anticancer drug candidates can be further evaluated through a series of in vitro/in vivo bioassays in the future. To the best of our knowledge, this is the first attempt to identify novel CDK9 inhibitors with both better inhibitory activity and higher selectivity through an effective two-stage virtual screening strategy.

Endoscopic full-thickness resection for gastric submucosal tumors arising from the muscularis propria layer

AIM:To evaluate the efficacy,safety and feasibility of endoscopic full-thickness resection(EFR) for the treatment of gastric submucosal tumors(SMTs) arising from the muscularis propria.METHODS:A total of 35 gastric SMTs arising from the muscularis propria layer were resected by EFR between January 2010 and September 2013.EFR consists of five major steps:injecting normal saline into the submucosa;pre-cutting the mucosal and submucosal layers around the lesion;making a circumferential incision as deep as the muscularis propria around the lesion using endoscopic submucosal dissection and an incision into the serosal layer around the lesion with a Hook knife;a full-thickness resection of the tumor,including the serosal layer with a Hook or IT knife;and closing the gastric wall with metallic clips.RESULTS:Of the 35 gastric SMTs,14 were located at the fundus,and 21 at the corpus.EFR removed all of the SMTs successfully,and the complete resection rate was 100%.The mean operation time was 90 min(60-155 min),the mean hospitalization time was 6.0 d(4-10 d),and the mean tumor size was 2.8 cm(2.0-4.5cm).Pathological examination confirmed the presence of gastric stromal tumors in 25 patients,leiomyomas in7 and gastric autonomous nerve tumors in 2.No gastric bleeding,peritonitis or abdominal abscess occurred after EFR.Postoperative contrast roentgenography on the third day detected no contrast extravasation into the abdominal cavity.The mean follow-up period was 6mo,with no lesion residue or recurrence noted.CONCLUSION:EFR is efficacious,safe and minimally invasive for patients with gastric SMTs arising from the muscularis propria layer.This technique is able to resect deep gastric lesions while providing precise pathological information about the lesion.With the development of EFR,the indications of endoscopic resection might be extended.

Endoscopic full-thickness resection and laparoscopic surgery for treatment of gastric stromal tumors

AIM: To assess the effectiveness of endoscopic fullthickness resection(EFR) and laparoscopic surgery in the treatment of gastric stromal tumors arising from the muscularis propria.METHODS: Out of 62 gastric stromal tumors arising from the muscularis propria, each > 1.5 cm in diameter, 32 were removed by EFR, and 30 were removed by laparoscopic surgery. The tumor expression of CD34, CD117, Dog-1, S-100, and SMA was assessed immunohistochemically. The operative time, complete resection rate, length of hospital stay, incidence of complications, and recurrence rate were compared between the two groups. Continuous data were compared using in-dependent samples t-tests, and categorical data were compared using χ2 tests.RESULTS: The 32 gastric stromal tumors treated by EFR and the 30 treated by laparoscopic surgery showed similar operative time [20-155 min(mean, 78.5 ± 30.1 min) vs 50-120 min(mean, 80.9 ± 46.7 min), P > 0.05], complete resection rate(100% vs 93.3%, P > 0.05), and length of hospital stay [4-10 d(mean, 5.9 ± 1.4 d) vs 4-19 d(mean, 8.9 ± 3.2 d), P >0.05]. None of the patients treated by EFR experienced complications, whereas two patients treated by laparoscopy required a conversion to laparotomy, and one patient had postoperative gastroparesis. No recurrences were observed in either group. Immunohistochemical staining showed that of the 62 gastric stromal tumors diagnosed by gastroscopy and endoscopic ultrasound, six were leiomyomas(SMA-positive), one was a schwannoglioma(S-100 positive), and the remaining 55 were stromal tumors.CONCLUSION: Some gastric stromal tumors arising from the muscularis propria can be completely removed by EFR. EFR could likely replace surgical or laparoscopic procedures for the removal of gastric stromal tumors.

Small intestinal vascular malformation bleeding:A case report with imaging findings

The small intestine is approximately 5-6 m long and occupies a large area in the abdominal cavity. These factors preclude the use of ordinary endoscopy and X-ray to thoroughly examine the small intestine for bleeding of vascular malformations. Thus,the diagnosis of intestinal bleeding is very difficult. A 47-year-old man presented at the hospital 5 mo ago with dark stool. Several angiomas were detected by oral approach enteroscopy,but no active bleeding was observed. Additionally,no lesions were detected by anal approach enteroscopy;however,gastrointestinal tract bleeding still occurred for an unknown reason. We performed an abdominal vascular enhanced computed tomography examination and detected ileal vascular malformations. Ileum angioma and vascular malformation were detected by a laparoscopic approach,and segmental resection was performed for both lesions,which were confirmed by pathological diagnosis. This report systemically emphasizes the imaging findings of small intestinal vascular malformation bleeding.

中国浙江省社区老年人社会健康状况与抑郁症状的相关性研究（英文）

目的:探究在浙江省老年人群中社会健康状况与抑郁症状的相关性。创新点:釆用专为中国老年人群设计的社会健康量表(SHSE-S),在中国人群中首次揭示了社会健康与老年抑郁症状的相关性,为全面提高老年人的健康状况提供科学依据。方法:采用多阶段分层抽样的方法,纳入3757位浙江省社区常住老年人。釆用包含SHSE-S和老年抑郁量表(GDS)在内的结构式问卷对老年人进行面对面访谈,釆用多因素Logistic回归模型以及亚组分析等方法分析社会健康与老年抑郁症状的关联性。结论:在浙江省老年人群中,SHSE-S得分越高,老年人抑郁症状的患病风险越低。该量表可作为社区筛查老年抑郁症状高危人群的工具,对促进老年人群的健康有重要意义。