The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Objective    To evaluate the clinical effects of segmentectomy versus lobectomy under single utility port video-assisted thoracic surgery on inflammatory factors and immune cells in peripheral blood of non-small cell lung cancer patients, and to analyze the effect of changes of postoperative inflammatory factors and immune cells on the prognosis of the patients. Methods    The clinical data of 256 patients who underwent segmentectomy or lobectomy under single utility port video-assisted thoracic surgery for non-small cell lung cancer in the First Affiliated Hospital of Hebei North University from January 2016 to October 2020 were retrospectively collected. According to the operation method, they were divided into a segmentectomy group (126 patients with 79 males and 47 females at an age of 63.4±6.2 years) and a lobectomy group (130 patients with 91 males and 39 females at an age of 62.9±5.6 years). The change of inflammatory factors (C reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-α) and immune cells (CD4+T cells, CD8+T cells and natural killer cells) were recorded and analyzed before operation (T0) and 1 day (T1), 3 days (T2), 7 days (T3), 1 month (T4) after the operation between the two groups. According to postoperative recurrence situations, they were divided into a recurrence group and a non-recurrence group, multivariate logistic regression analysis was used to analyze the relationship between the change of postoperative inflammatory factors, immune cells, and the prognosis of patients with non-small cell lung cancer. Results    (1) There was no statistical difference in sex ratio, underlying diseases, body mass index, levels of preoperative inflammatory factors or immune cells between the two groups (all P>0.05). (2) The changes of postoperative inflammatory factors in the segmentectomy group were significantly less than those in the lobectomy group at T1-T3 (all P<0.05), and the changes of postoperative immune cells in the segmentectomy group were significantly less than those in the lobectomy group at T1-T4 (all P<0.05). (3) The changes of postoperative inflammatory factors and immune cells on postoperative day 3 in the recurrence group were significantly more than those in the non-recurrence group (all P<0.05). (4) Multivariate logistic regression analysis showed that the changes of postoperative inflammatory factors and immune cells on postoperative day 3 may be the risk factors for postoperative recurrence and metastasis in patients with non-small cell lung cancer (all P<0.05). Conclusion    Single utility port video-assisted thoracic surgery segmentectomy for the treatment of non-small cell lung cancer can reduce the inflammatory response and protect body's immune function, and the change of postoperative inflammatory factors and immune cells in postoperative day 3 may be the risk factors for postoperative recurrence and metastasis in patients with non-small cell lung cancer.

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound

OBJECTIVETo investigate the clinical efficacy and learning curve of thoracoscopic and laparoscopic esophagectomy(TLE) in the treatment of esophageal carcinoma.

METHODSClinical data of 350 consecutive patients with esophageal carcinoma undergoing TLE in the West China Hospital between February 2008 and October 2013 were retrospectively analyzed. Patients in the early stage(n=150) were chronologically and evenly divided into three groups, and perioperative outcomes were compared between the three groups in order to evaluate the learning curve.

RESULTSThere were no intraoperative deaths. Intraoperative complications occurred in 29(8.3%) patients. Thirteen(3.7%) cases were converted to open operation including 9 thoracotomy and 4 laparotomy. The mean operative time was 332.5(range 230-780) min and the mean blood loss was 160.8(range 15-4000) ml. The tumor free resection margins (R0) were completely in 333(95.1%) cases. The mean lymph nodes harvested was 21.6(range 6-42). The average length of postoperative hospital stay was 11.6(range 7-93) d. Postoperative complications occurred in 75(21.4%) patients, and 3(0.8%) patients died within 30 days after surgery. Compared with TLE 1 group, TLE 2 group presented shorter operative time, less blood loss, shorter postoperative hospital stay, lower postoperative complication rate, and more lymph nodes harvested(all P<0.05). Only blood loss was less in TLE 3 group as compared to TLE 2 group, and other perioperative results were found to be of no statistical differences between the two groups. There was no significant difference in 30-day mortality between the three groups.

CONCLUSIONSTLE is a technically feasible and safe procedure and provides comparable oncological outcomes with open esophagectomy, thus suggesting that TLE is an alternative approach in the treatment of esophageal carcinoma. A plateau of TLE skill can be reached after 50 surgical procedures.

China ; Esophageal Neoplasms ; Esophagectomy ; Humans ; Laparoscopy ; Length of Stay ; Lymph Node Excision ; Lymph Nodes ; Operative Time ; Postoperative Complications ; Retrospective Studies

Liver cancer is a malignant tumor. The current operation or chemoradiotherapy cannot achieve a satisfactory effect, and relapse and metastasis are always big problems in the treatment of liver cancer. According to the recent theory of liver cancer stem cells, the genesis, development, relapse, metastasis, and prognosis of liver cancer are all related to liver cancer stem cells. If the liver cancer stem cells are treated by targeted therapy, which would reduce the number of or destroy the stem cells, the relapse, metastasis, and drug resistance after tumor resection may be reduced or eliminated. The progress in targeted therapy for liver cancer stem cells is reviewed here. Although there are many types of targeted therapies for liver cancer stem cells, it is still a key problem that the targeting is not strong enough, which needs to be solved urgently. Whether the dual- or multi-targeting would solve this problem still needs to be confirmed by further experimental studies.

Objective To investigate the clinical efficacy and learning curve of thoracoscopic and laparoscopic esophagectomy (TLE) in the treatment of esophageal carcinoma. Methods Clinical data of 350 consecutive patients with esophageal carcinoma undergoing TLE in the West China Hospital between February 2008 and October 2013 were retrospectively analyzed. Patients in the early stage (n=150) were chronologically and evenly divided into three groups, and perioperative outcomes were compared between the three groups in order to evaluate the learning curve. Results There were no intraoperative deaths. Intraoperative complications occurred in 29 (8.3%) patients. Thirteen (3.7%) cases were converted to open operation including 9 thoracotomy and 4 laparotomy. The mean operative time was 332.5 (range 230-780) min and the mean blood loss was 160.8 (range 15-4000) ml. The tumor free resection margins (R0) were completely in 333 (95.1%) cases. The mean lymph nodes harvested was 21.6(range 6-42). The average length of postoperative hospital stay was 11.6(range 7-93) d. Postoperative complications occurred in 75(21.4%) patients, and 3(0.8%) patients died within 30 days after surgery. Compared with TLE 1 group, TLE 2 group presented shorter operative time, less blood loss, shorter postoperative hospital stay, lower postoperative complication rate, and more lymph nodes harvested (all P<0.05). Only blood loss was less in TLE 3 group as compared to TLE 2 group, and other perioperative results were found to be of no statistical differences between the two groups. There was no significant difference in 30-day mortality between the three groups. Conclusions TLE is a technically feasible and safe procedure and provides comparable oncological outcomes with open esophagectomy, thus suggesting that TLE is an alternative approach in the treatment of esophageal carcinoma. A plateau of TLE skill can be reached after 50 surgical procedures.

Objective To investigate the clinical efficacy and learning curve of thoracoscopic and laparoscopic esophagectomy (TLE) in the treatment of esophageal carcinoma. Methods Clinical data of 350 consecutive patients with esophageal carcinoma undergoing TLE in the West China Hospital between February 2008 and October 2013 were retrospectively analyzed. Patients in the early stage (n=150) were chronologically and evenly divided into three groups, and perioperative outcomes were compared between the three groups in order to evaluate the learning curve. Results There were no intraoperative deaths. Intraoperative complications occurred in 29 (8.3%) patients. Thirteen (3.7%) cases were converted to open operation including 9 thoracotomy and 4 laparotomy. The mean operative time was 332.5 (range 230-780) min and the mean blood loss was 160.8 (range 15-4000) ml. The tumor free resection margins (R0) were completely in 333 (95.1%) cases. The mean lymph nodes harvested was 21.6(range 6-42). The average length of postoperative hospital stay was 11.6(range 7-93) d. Postoperative complications occurred in 75(21.4%) patients, and 3(0.8%) patients died within 30 days after surgery. Compared with TLE 1 group, TLE 2 group presented shorter operative time, less blood loss, shorter postoperative hospital stay, lower postoperative complication rate, and more lymph nodes harvested (all P<0.05). Only blood loss was less in TLE 3 group as compared to TLE 2 group, and other perioperative results were found to be of no statistical differences between the two groups. There was no significant difference in 30-day mortality between the three groups. Conclusions TLE is a technically feasible and safe procedure and provides comparable oncological outcomes with open esophagectomy, thus suggesting that TLE is an alternative approach in the treatment of esophageal carcinoma. A plateau of TLE skill can be reached after 50 surgical procedures.

OBJECTIVETo explore the safety and feasibility of extensive mediastinal lymphadenectomy during thoracoscopic esophagectomy in the treatment of esophageal carcinoma.

METHODSClinical data of 125 patients with esophageal carcinoma undergoing thoracoscopic and laparoscopic esophagectomy(TLE) in West China Hospital of Sichuan University between May 2009 and December 2011 were retrospectively analyzed. Patients were divided into 2 groups: non-extensive mediastinal lymphadenectomy group(non-extensive group, n=53) and extensive mediastinal lymphadenectomy group(extensive group, n=72). Perioperative outcomes of these two groups were compared.

RESULTSNo significant differences were found in the time of thoracic operation, length of intensive care unit stay and postoperative hospital stay, postoperative complication and the overall mortality between the two groups. Compared with non-extensive group, extensive group showed less blood loss during thoracic operation [(140.6±62.1) ml vs. (167.7±69.2) ml, P=0.023], more thoracic lymph nodes harvested (12.2±4.2 vs. 9.0±4.1, P<0.01). Seventeen patients (23.6%) in extensive group were found to have positive recurrent laryngeal nerve lymph nodes, which resulted in upstaging of TNM in 7 patients(9.7%). The incidence of recurrent laryngeal nerve palsy was higher in extensive group as compared to non-extensive group, but the difference was not statistically significant (6.9% vs. 1.9%, P=0.240).

CONCLUSIONExtensive mediastinal lymphadenectomy during thoracoscopic esophagectomy is a feasible and safe procedure for esophageal carcinoma patients, which can increase the number of harvested lymph node and the accuracy of tumor staging.

Carcinoma ; pathology ; surgery ; China ; Esophageal Neoplasms ; pathology ; surgery ; Esophagectomy ; methods ; Humans ; Laparoscopy ; Length of Stay ; Lymph Node Excision ; methods ; Lymph Nodes ; pathology ; Neoplasm Staging ; Postoperative Complications ; Retrospective Studies

Hepatic myelopathy is one of special category changes of nervous system,which was secondary to the end-stage hepatic diseases and is a syndrome of myeleterosis.It usually occurred after portosystemic shunt surgery or collateral circulation of portosystemic vein.The prognosis of hepatic myelopathy is poor,and the progression of this disease is slow.Surgical approaches such as dissociation of colon and anastomosis of ileum and rectum aimed at reducing the absorption of toxic substance and thus to breakdown the blood ammonia and improve the symptoms of nervous system,but the effects are not satisfactory.The clinical data of 1 patient with hepatic myelopathy who received liver transplantation at the Second Affiliated Hospital of Dalian Medical University in April 2012 were retrospectively analyzed.The clinical symptoms and physical signs were improved,and muscle strength was effectively recovered in the patient.Liver transplantation might be an effective method for the treatment of hepatic myelopathy.