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.

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

AIM: To assess the effectiveness of endoscopic full-thickness resection (EFR) and laparoscopic surgery in the treatment of gastric stromal tumors arising from the muscularis propria.

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.

Association between social health status and depressive symptoms among community-dwelling elderly adults in Zhejiang Province, China

Objective:Mental disorders of the elderly population in China deserve attention.Social health is significantly associated with depression.This study aimed to evaluate the rate of depressive symptoms and to test the relationships between social health and depressive symptoms among a large sample of community-dwelling elderly adults.Methods:We conducted a cross-sectional study among community-dwelling adults aged 60 years or above in Zhejiang Province,China.Face-to-face interviews were used to complete a structured questionnaire for all participants.We used the Social Health Scale for the Elderly(SHSE)to evaluate social health status and used the short form of the Geriatric Depression Scale to evaluate depressive symptoms.Multivariate logistic regression was used to evaluate the asso?ciation between social health status and depressive symptoms.Results:Of the total of 3757 participants included,1887(50.23%)were female,and the mean±standard deviation(SD)age was(70.0±8.3)years.The rate of depressive symptoms was 25.92%.The social health score was higher in non?depressed participants than in depressed participants(raw score 50.7 vs.48.3,P<0.001).Participants with"moderate”or"good”social health had a significantly lower risk of depressive symptoms than those with“poor"social health(odds ratio(OR)=0.55,95%con fide nee interval(Cl):0.46-0.66 for moderate social health;OR=0.45,95%Cl:0.35-0.60 for good social health).The association between social health and depressive symptoms was con sistent across several subgroups.Con clusi ons:Social health is signify cantly inversely associated with depressive symptoms.The SHSE may serve as an efficient screener to identify those elderly adults with social health deficits,but systematic assessment to guide intervention merits further investigation.