With the rapid development of artificial intelligence technology,small molecule generation models have emerged as a significant research direction in the field of drug discovery.These models,including Generative Adversarial Networks(GANs),Variational Autoencoders(VAEs),and diffusion models,have proven to possess remarkable capabilities in optimizing drug properties and generating complex molecular structures.This article comprehensively analyzes the application of the aforementioned advanced technologies in the drug discovery process,demonstrating how they supplement and enhance traditional drug design methods.At the same time,it addresses the challenges facing current methods in terms of data quality,model complexity,computational cost,and generalization ability,with a prospect of future research directions.

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation

Objective To investigate the treatment efficacy,feasibility and safety of laparoscopic resection for gastric gastrointestinal stromal tumors (GISTs) larger than 5 cm.Methods The clinical data of 31 patients who underwent laparoscopic resection of large gastric GISTs between Jan 2010 and Jun 2017 at Sir Run Run Shaw Hospital and People's Hospital of Zhejiang Province were retrospectively analyzed.Results All operations were successful.Two patients were converted to open surgery.The mean tumor size was (7.2 ±0.5) cm.The mean operation time was (127 ± 12) min,intraoperative blood loss was (83 ±25) ml.The first flatus time was (2.2 ±0.8) days,the first diet resumption time was (2.4 ± 1.2) days,and the median postoperative hospital stay was (5.5 ± 1.5) days.The median follow-up time was 25 months.One patient developing liver metastasis 41 months after primary resection received oral mesylate imatinib therapy for 24 months and was still alive at the last follow-up.One patient died of lung cancer 33 months after primary operation without recurrence of gastric GIST.Conclusions Laparoscopic surgery for gastric GIST larger than 5 cm on laparoscopicaly accessible location is feasible and safe.

Objective To analyze the results of assessment of malaria elimination in 9 counties (districts) of Nanchang City, and explore suitable monitoring methods for malaria after elimination of the disease in this region. Methods In 2016, the data from the network reports of malaria epidemic situation, blood examinations of febrile patients, epidemiological questionnaires of local malaria cases, investigation of epidemic focuses and disposal tables were collected and analyzed in Nanchang City from 2010 to 2015. The data of malaria elimination assessment at county ( district ) level of Donghu District , Xihu District , Qingshanhu District and Wanli District in 2013 , Nanchang County and Anyi County in 2014, Jinxian County, Qingyunpu District and Xinjian District in 2015 were collected. At same time, the data of ability of the diagnosis and treatment of malaria in clinicians, the microscopical examinations of Plasmodium in the inspection personnel were collected . Totally 30 negative blood slides and all positive blood slides since 2010 were reviewed. Results From 2010 to 2015, 93 local malaria cases were reported in Nanchang City, the majority of malaria cases were imported except 2 local malaria infection cases in 2010. Totally 64027 febrile patients received blood detections for malaria, of which 101 cases were positive and the positive rate was 0.16％. The positive blood slides review rate was 100.00％ (101/101), the negative blood slides review rate was 9.69％ (6195/63926). 9 counties (districts) all passed the malaria elimination assessment at county ( district ) level . The malaria elimination assessment scores of the 9 counties (districts) were all higher than 90 points. The correct rate of inspection personnel of microscopical examinations of Plasmodium was 91.58％ (174/190), the correct rate of knowledge of the diagnosis and treatment of malaria was 95.00％ (1710/1800), the coincidence rate of blood slides review was 100 . 00％( 304/304 ) in Nanchang , the qualified rate of slides production and dyeing was 88.16％ (268/304). Conclusions All the 9 counties (districts) of Nanchang City have passed the malaria elimination assessment with high scores. After malaria elimination, the monitoring should continue to consolidate the achievements.

Objective: To evaluate the safety and feasibility of laparoscopic radical antegrade modular pancreatosplenectomy(Lap-RAMPS) for left-sided pancreatic adenocarcinoma. Methods: Clinical data of total 12 patients underwent Lap-RAMPS for left-sided pancreatic adenocarcinoma at Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People′s Hospital from March 2016 to August 2017 were reviewed retrospectively.There were 7 male patients and 5 female patients, with median age of 60.5 years old(47-68 years old). Abdominal enhanced CT, pancreatic MRI, PET-CT were performed on all patients to evaluate the lesion and exclude metastasis.Follow-up were done with out-patient clinic or telephone consultancy until October 2017. Results: All patients underwent pure Lap-RAMPS.The medium operative time was 250 minutes(180-445 minutes), and the blood loss was 150 ml(50-500 ml). The medium first flatus time and diet resumption time were 3.0 days(1-5 days) and 3.5 days(1-7 days) respectively.The medium postoperative hospital stay was 9 days(4-18 days). Morbidity occurred in 8 patients with gastric empty delay(n=1), bleeding(n=1), fluid collection(n=3). There was no mortality.The medium overall number of retrived lymph nodes was 15.6 and the positive rate was 41.7%. The R0 rate was 100%.The medium follow-up was 10 months.One patient was diagnosed as liver metastasis after 8 months and accepted chemotherapy.One patient died after 14 months for tumor recurrence and metastasis.Others survived without tumor recurrence or metasitasis. Conclusion Lap-RAMPS is safe and feasible with accepted oncological outcomes for selected left side pancreatic adenocarcinoma under skilled hands.

Objective To evaluate the safety and feasible of adjacent organ resection during laparoscopic pancreaticoduodenectomy(LPD),and summary the surgical strategies.Methods Clinical data of 15 adjacent organ resections combined with LPD from March 2013 to September 2017 were reviewed.There were 10 male and 5 female patients aging from 20 to 86 years,and the body mass index ranged from 19.6 to 34.5 kg/m2.Two patients had previous abdominal surgical history.Two patients underwent preoperative chemotherapy.Results The resected adjacent organs included liver (n =4),stomach (n =3),colon(n =6),right kidney with embolectomy and vasoplastic of inferior vena cava (n =1),and spleen artery aneurysms(n =1).The operative time ranged from 280 to 450 minutes,and the blood loss ranged from 100 to 450 ml.The total complication rate was 5/15 and no one died in 90 days after surgery.The postoperative hospital stay ranged from 10 to 42 days with medium 18 days.The pathology included adenocarcinoma of stomach and duodenum (n =1),gastric cancer invading pancreas or duodenum (n=2),ampullary adenocarcinoma with left hepatolithiasis(n=1),ampullary adenocarcinoma with a benign lesion in left liver (n =1),ampullary adenocarcinoma with single liver metastasis (n =1),ampullary adenocarcinoma(n =1),pancreatic intraductal papillary mucinous neoplasm with splenic artery aneurysms (n=1),pancreatic neuroendocrine neoplasm with colon cancer (n =1),distal common bile duct adenocarcinoma involving righ hepatic duct (n =1),pancreatic neuroendocrine neoplasm invading inferior vena cava and right renal vein(n=1),duodenal adnocarcinoma(n =1),duodenal ewing's sarcoma(n =1),duodenal intesititialoma (n =2).The follow-up was from 3 to 40 months with the medium survival of 17.5 months.Conclusions The oncological outcomes of PD combined with adjacent organ resection is acceptable.Surgical treatment for those patients with periampullary neoplasma and adjacent organ lesions should be aggressive.

Objective To evaluate the safety and feasible of adjacent organ resection during laparoscopic pancreaticoduodenectomy(LPD),and summary the surgical strategies.Methods Clinical data of 15 adjacent organ resections combined with LPD from March 2013 to September 2017 were reviewed.There were 10 male and 5 female patients aging from 20 to 86 years,and the body mass index ranged from 19.6 to 34.5 kg/m2.Two patients had previous abdominal surgical history.Two patients underwent preoperative chemotherapy.Results The resected adjacent organs included liver (n =4),stomach (n =3),colon(n =6),right kidney with embolectomy and vasoplastic of inferior vena cava (n =1),and spleen artery aneurysms(n =1).The operative time ranged from 280 to 450 minutes,and the blood loss ranged from 100 to 450 ml.The total complication rate was 5/15 and no one died in 90 days after surgery.The postoperative hospital stay ranged from 10 to 42 days with medium 18 days.The pathology included adenocarcinoma of stomach and duodenum (n =1),gastric cancer invading pancreas or duodenum (n=2),ampullary adenocarcinoma with left hepatolithiasis(n=1),ampullary adenocarcinoma with a benign lesion in left liver (n =1),ampullary adenocarcinoma with single liver metastasis (n =1),ampullary adenocarcinoma(n =1),pancreatic intraductal papillary mucinous neoplasm with splenic artery aneurysms (n=1),pancreatic neuroendocrine neoplasm with colon cancer (n =1),distal common bile duct adenocarcinoma involving righ hepatic duct (n =1),pancreatic neuroendocrine neoplasm invading inferior vena cava and right renal vein(n=1),duodenal adnocarcinoma(n =1),duodenal ewing's sarcoma(n =1),duodenal intesititialoma (n =2).The follow-up was from 3 to 40 months with the medium survival of 17.5 months.Conclusions The oncological outcomes of PD combined with adjacent organ resection is acceptable.Surgical treatment for those patients with periampullary neoplasma and adjacent organ lesions should be aggressive.

Objective To understand and analyze the infection status of human parasites in Nanchang City, so as to offer a scientific basis for control of parasitic disease. Methods In 2014, a survey was performed according to the scheme of The 3rd National Survey of Principal Human Parasites. Intestinal parasites were surveyed among the residents in Jinxian County and Anyi County, Qingyunpu District and Qingshanhu District in Nanchang City, including the soil-transmitted nematodes (Ascaris lumbricoides, Trichuris trichiura and hookworm), Enterobius vermicularis, tapeworm and intestinal protozoa. Clonorchis sinensis was surveyed among the residents in Qingyunpu District and Qingshanhu District. Toxoplasma gondii was surveyed among the residents in two rural areas (Nanchang County and Xinjian County) and two urban areas (Donghu District and Xihu District). The ovums of the soil-transmitted nematodes, Clonorchis sinensis , tapeworm and other helminths were examined by the Kato-Katz, while Enterobius vermicularis among children was examined by cellophane anal swab, trophozoites and cysts of intestinal protozoa by saline smearing and iodine smearing , and IgG antibodies of Toxoplasma gondii by enzyme-linked immunosorbent assay (ELISA). Results Intestinal parasites were surveyed among 2424 residents in the whole city, in which 2414 residents were tested for the infection of soil-transmitted nematodes and tapeworm;1875 residents were tested for intestinal protozoa infection;74 children were tested for eggs of Enterobius vermicularis; 539 residents were tested for Clonorchis sinensis; and 2400 residents were tested for Toxoplasma gondii. Six kinds of intestinal parasites were found citywide, with a total infection rate of 9.49% (230/2424). The infection rate of soil-transmitted nematodes was 8 . 70% ( 210/2414 ) , in which the infection rate of Ascaris lumbricoides was 0.04% (1/2414), the rate of Trichuris trichiura was 0.91% (22/2414), and of hookworm was 7.83%(189/2414). The infection rate among 3 - 6 years old children of Enterobius vermicularis was 22.97% ( 17/74 ) . Tapeworm and Clonorchis sinensis were not found . The infection rate of intestinal protozoa was 0.21%(4/1875). The positive rate of Toxoplasma gondii's IgG antibody was 5.17% (124/2400). Conclusions In Nanchang City, the infection rate of soil-transmitted nematodes (Ascaris lumbricoides, Trichuris trichiura) and intestinal protozoa was lower. However, the infection rates of hookworm, Toxoplasma gondii and Enterobius vermicularis among 3 - 6 years old children are increasing in local areas. That should be the focus in prevention and control of parasitic disease in the future.

Objective To analyze the epidemiological characteristics of malaria and to discover the regularity of malaria outbreaks in Nanchang City from 1950 to 2015, so as to provide a scientific basis for developing control strategies after the goal of malaria elimination has been achieved. Method Malaria related data, report forms and work summary in Nanchang from 1950 to 2015 were collected and analyzed to indicate malaria distribution characteristics via the descriptive epidemiological methods. Results The total number of malaria cases reported in Nanchang City was 1449878 from 1950 to 2015. The particular years with the three peaks of malaria epidemic from 1950s to 1970s were 1954, 1970 and 1977. The climax of annual mean incidence rate of malaria (6948.75 per 100 thousand) was reached in 1970. Totally 1449739 local recurrence cases were reported between 1950 and 1999. There were 484292 local recurrence cases (accounting for 68.80%, 484292/703911) that were diagnosed in the malaria epidemic seasons, May to August. There were 44931, 25684, 22614 and 5842 cases reported in Nanchang County, Xinjian County, Jinxian County and Qingshanhu District, which ranked the top 4 of epidemic focus areas ( accounting for 90 . 65%, 99071/109293) between 1980 and 1989. The 13245 cases reported between 1972 and 1985 in the three county/districts (Jinxian County, Xihu District and Wanli District), included 8513 cases of male and 4732 cases of female. The 126 cases reported between 2005 and 2015, included 122 imported cases who were mostly returnees after overseas labor output and 57 falciparum malaria cases with a increasing trend year by year. There was no correlation between the seasonal change and the occurrence of malaria. Conclusions The comprehensive prevention and control measures based on eliminating the source of infection can effectively control the epidemic of malaria. It is suggested that the surveillance on imported falciparum malaria cases should be the focus in prevention and control of the disease at the late-stage because the epidemiological characteristics of local malaria cases have died out completely.