Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations are influenced by random and uncontrollable factors, and the risk of the next widespread epidemic remains. Dual-target drugs that synergistically act on two targets exhibit strong therapeutic effects and advantages against mutations. In this study, a novel computational workflow was developed to design dual-target SARS-CoV-2 candidate inhibitors with the Envelope protein and Main protease selected as the two target proteins. The drug-like molecules of our self-constructed 3D scaffold database were used as high-throughput molecular docking probes for feature extraction of two target protein pockets. A multi-layer perceptron (MLP) was employed to embed the binding affinities into a latent space as conditional vectors to control conditional distribution. Utilizing a conditional generative neural network, cG-SchNet, with 3D Euclidean group (E3) symmetries, the conditional probability distributions of molecular 3D structures were acquired and a set of novel SARS-CoV-2 dual-target candidate inhibitors were generated. The 1D probability, 2D joint probability, and 2D cumulative probability distribution results indicate that the generated sets are significantly enhanced compared to the training set in the high binding affinity area. Among the 201 generated molecules, 42 molecules exhibited a sum binding affinity exceeding 17.0 kcal/mol while 9 of them having a sum binding affinity exceeding 19.0 kcal/mol, demonstrating structure diversity along with strong dual-target affinities, good absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and ease of synthesis. Dual-target drugs are rare and difficult to find, and our "high-throughput docking-multi-conditional generation" workflow offers a wide range of options for designing or optimizing potent dual-target SARS-CoV-2 inhibitors.

Objective:To summarize our experience in 13 cases of intestinal autotransplantation (IATx) after resection of lesions involving the roots of mesenteric vessels.Methods:The clinical data of 13 patients undergoing IATx in Xijing hospital were retrospectively analyzed. The etiology, surgical procedure and complications were analyzed. The patients were followed up by telephone and regular evaluations.Results:All 13 cases of IATx were successfully completed. For 12 patients who were diagnosed with tumors involving the mesenteric roots, the tumors were removed for cure intent avoiding massive intestinal resection. Pancreaticoduodenectomy was carried out simultaneously in 11 cases. The postoperative complication rate was 85% (11/13). The autograft was resected in 1 patient on the 1st postoperative day due to necrosis from mesenteric thrombosis, leading to short bowel syndrome. One-year survival was 69% (9/13). Among 4 deaths, 1 patient died of liver metastasis, and another died of liver and lung metastases. Five patients were alive 2 years postoperatively.Conclusion:IATx while-technically challenging, avoiding short small bowel syndrome in properly selected patients after resection of lesions especially benign ones involving the roots of mesenteric vessels that were traditionally considered to be "unresectable".

OBJECTIVETo assess the efficacy of sacral neuromodulation (SNM) in patients with intractable constipation.

METHODSA total of 7 patients with intractable constipation were treated with pereutaneous test stimulation of the S3 nerve root and were assessed by sacral never stimulation system in our department from January 2013 to January 2014. Four of these 7 patients received operation for constipation before. The efficacy was assessed by bowel habit diary, clinic constipation scores, subjective questionnaire and clinical signs.

RESULTSThe constipation symptoms were improved significantly in all the 7 patients. The frequency and volume of defecation per week were increased obviously, and the average urine was increased. Six patients underwent permanent implantation of the SNS system. After a median 4 months follow-up, the defecation frequency increased from 0.6 ± 0.5 to 8.0 ± 2.5 per week (P<0.01), and the defecation time decreased from (22.9 ± 11.5) to (3.7 ± 0.8) min (P<0.01). The Cleveland clinic constipation score decreased from 24.6 ± 4.2 to 9.0 ± 0.9 (P<0.01), and the visual analogue scale(VAS) score increased from 8.1 ± 0.9 to 82.5 ± 5.2 (P<0.01).

CONCLUSIONSNM is a clinically efficacious, minimally invasive and safe new technique, which offers an alternative treatment for the patients with intractable constipation resistant to conservative treatment, especially for the patients refractory to traditional operations.

Objective To assess the efficacy of sacral neuromodulation (SNM) in patients with intractable constipation. Methods A total of 7 patients with intractable constipation were treated with pereutaneous test stimulation of the S3 nerve root and were assessed by sacral never stimulation system in our department from January 2013 to January 2014. Four of these 7 patients received operation for constipation before. The efficacy was assessed by bowel habit diary, clinic constipation scores, subjective questionnaire and clinical signs. Results The constipation symptoms were improved significantly in all the 7 patients. The frequency and volume of defecation per week were increased obviously, and the average urine was increased. Six patients underwent permanent implantation of the SNS system. After a median 4 months follow-up, the defecation frequency increased from 0.6 ±0.5 to 8.0 ±2.5 per week (P<0.01), and the defecation time decreased from (22.9 ±11.5) to (3.7 ±0.8) min (P<0.01). The Cleveland clinic constipation score decreased from 24.6±4.2 to 9.0±0.9 (P<0.01), and the visual analogue scale(VAS) score increased from 8.1±0.9 to 82.5±5.2(P<0.01). Conclusion SNM is a clinically efficacious, minimally invasive and safe new technique, which offers an alternative treatment for the patients with intractable constipation resistant to conservative treatment , especially for the patients refractory to traditional operations.

Objective To assess the efficacy of sacral neuromodulation (SNM) in patients with intractable constipation. Methods A total of 7 patients with intractable constipation were treated with pereutaneous test stimulation of the S3 nerve root and were assessed by sacral never stimulation system in our department from January 2013 to January 2014. Four of these 7 patients received operation for constipation before. The efficacy was assessed by bowel habit diary, clinic constipation scores, subjective questionnaire and clinical signs. Results The constipation symptoms were improved significantly in all the 7 patients. The frequency and volume of defecation per week were increased obviously, and the average urine was increased. Six patients underwent permanent implantation of the SNS system. After a median 4 months follow-up, the defecation frequency increased from 0.6 ±0.5 to 8.0 ±2.5 per week (P<0.01), and the defecation time decreased from (22.9 ±11.5) to (3.7 ±0.8) min (P<0.01). The Cleveland clinic constipation score decreased from 24.6±4.2 to 9.0±0.9 (P<0.01), and the visual analogue scale(VAS) score increased from 8.1±0.9 to 82.5±5.2(P<0.01). Conclusion SNM is a clinically efficacious, minimally invasive and safe new technique, which offers an alternative treatment for the patients with intractable constipation resistant to conservative treatment , especially for the patients refractory to traditional operations.

Objective To explore the associations between coagulation factor Ⅶ (FⅦ)polymorphisms and its haplotype with risk of ischemic cerebrovascular diseases (ICVD) in Henan Han population. Methods Five hundred and twelve cases with ICVD as patient group and 560 healthy subjects as control were recruited in the study. The polymorphisms of R353Q, 5'F7 and IVS7 were detected by PCR-RFLP. The genotype frequency and allele gene frequency were compared between ICVD group and control group. The haplotype was analyzed by SHEsis software. Results The RQ genotype frequencies and Q allele frequencies of ICVD group were significantly lower than those of control group. The distribution of H7 allele frequencies and H6H7 genotype frequencies of FⅦ/IVS7 polymorphisms had significant difference between ICVD group and control group. Finally, the prevalence of R-P0-H6 haplotype in ICVD group(53. 3% )was higher than that in control group (47.5%, OR = 1. 219, 95% CI 1. 028-1. 446,P =0.023). Conclusions In Henan Han population, the Q allele of F Ⅶ/R353Q polymorphisms and the H7 allele of F Ⅶ/IVS7 polymorphisms may be protective genetic factors against ischemic cerebrovascular disease, and the R-P0-H6 haplotype may be a risk factor of ischemic cerebrovascular disease.

Objectives To compare total laparoscopic gastrectomy with intracorporeal hand-sewn Gl reconstruction and laparoscopy-assisted gastrectomy for gastric cancer. Methods Between July 2009 and July 2010, 21 patients of gastric cancer underwent total laparoscopic D2 radical gastrectomy with intracorporeal hand-sewn reconstruction and 28 did laparoscopy-assisted D2 radical gastrectomy in Xijing Hospital of Digestive Diseases. All patients were operated on by an experienced surgeon. Patient demographics, TNM stage, location of tumor, the intraoperative and postoperative details of the two groups were compared. Results In the 21 patients undergoing total laparoscopic gastrectomy, there were 15 of distal gastrectomy and 6 of total gastrectomy, compared with 21 and 7 in laparoscopy-assisted group. In total laparoscopic group, intracorporeal hand-sewn technique was used for gastro-jejunal and jejuno-jejunal (J-J)anastomosis, and 25 mm circular stapler was used for esophago-jejunal anastomosis. The operation time was significant longer in total laparoscopic group than in laparoscopy-assisted group of (279 ± 65 ) min vs.(232 ±40) min (P ＜ 0.05 ). No significant difference was observed between the two groups in proximal margin [(5.7 ± 1.5 )cm vs. (5.1 ± 1.4) cm, P ＞ 0.05] and distal margin [( 3.1 ± 0.9 )cm vs. ( 2.9 ±0.9) cm,P ＞0.05]. The iv narcotic use in laparoscopy-assisted group was 1.8 d but it was not used in total laparoscopic group. The first passing flatus was on day 3 in total laparoscopic group compared with 4.8 d in laparoscopy-assisted group. Both groups had 2 postoperative early complications, one intra-abdominal infection and one lung infection in total laparoscopic group compared with one wound infection and one lung infection in laparoscopy-assisted group. There was no anastomosis-related complications after 4 months of follow-up. Conclusions The operation time and postoperative early complication was acceptable for selected patients treated by total laparoscopic D2 radical gastrectomy with intracorporeal hand-sewn GI tract reconstruction in hands of experienced laparoscopic surgeon.

Objective To investigate the role and the mechanism of Apr-1 gene on cholangiocarcinoma QBC939 cell lines proliferation and cell cycle regulation. Methods Apr-1 gene was transfected into QBC939 cells by using liposomes to establish a QBC939 cell model ( QBC939-Apr-1 ) stably expressing Apr-1 gene. Apr-1 mRNA expression and the changes in cell cycle and cell growth of QBC939 cells were analyzed by RT-PCR, flow cytometry ( FCM ) and growth curve before and after transfection. The regulatory effect of Apr-1 gene on the expression of cell cycle-related genes was investigated in QBC939 cells before and after Apr-1 transfection using cell cycle gene microarrays. Results Significant suppression of cell growth was observed with the cell model stably expressing Apr-1 gene. Apr-1 over-expression caused cell arrest from 9% to 13% (P ＜0. 01 ) increase in G2 population. Cell cycle gene microarrays demonstrated that the expression of Skp2 、UBE1 was up-regulated, while the expression of MRE11A 、CKS2 、CDK8 、CDC45 was down-regulated by more than 3 folds. Conclusions Apr-1 gene suppresses QBC939 cell proliferation in vitro, QBC939 cells presented with differences in the expression of cell cycle-related genes after Apr-1 gene transfection.