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Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.
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The spread of SARS-CoV-2 confers a serious threat to the public health without effective intervention strategies1-3. Its variant carrying mutated Spike (S) protein D614G (SD614G) has become the most prevalent form in the current global pandemic4,5. We have identified a large panel of potential neutralizing antibodies (NAbs) targeting the receptor-binding domain (RBD) of SARS-CoV-2 S6. Here, we focused on the top 20 potential NAbs for the mechanism study. Of them, the top 4 NAbs could individually neutralize both authentic SARS-CoV-2 and SD614G pseudovirus efficiently. Our epitope mapping revealed that 16/20 potent NAbs overlapped the same steric epitope. Excitingly, we found that one of these potent NAbs (58G6) exclusively bound to a linear epitope on S-RBD (termed as 58G6e), and the interaction of 58G6e and the recombinant ACE2 could be blocked by 58G6. We confirmed that 58G6e represented a key site of vulnerability on S-RBD and it could positively react with COVID-19 convalescent patients plasma. We are the first, as far as we know, to provide direct evidences of a linear epitope that can be recognized by a potent NAb against SARS-CoV-2 S-RBD. This study paves the way for the applications of these NAbs and the potential safe and effective vaccine design.
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Neutralizing antibodies (Abs) have been considered as promising therapeutics for the prevention and treatment of pathogens. After the outbreak of COVID-19, potent neutralizing Abs to SARS-CoV-2 were promptly developed, and a few of those neutralizing Abs are being tested in clinical studies. However, there were few methodologies detailly reported on how to rapidly and efficiently generate neutralizing Abs of interest. Here, we present a strategically optimized method for precisive screening of neutralizing monoclonal antibodies (mAbs), which enabled us to identify SARS-CoV-2 receptor-binding domain (RBD) specific Abs within 4 days, followed by another 2 days for neutralization activity evaluation. By applying the screening system, we obtained 198 Abs against the RBD of SARS-CoV-2. Excitingly, we found that approximately 50% (96/198) of them were candidate neutralizing Abs in a preliminary screening of SARS-CoV-2 pseudovirus and 20 of these 96 neutralizing Abs were confirmed with high potency. Furthermore, 2 mAbs with the highest neutralizing potency were identified to block authentic SARS-CoV-2 with the half-maximal inhibitory concentration (IC50) at concentrations of 9.88 ng/ml and 11.13 ng/ml. In this report, we demonstrated that the optimized neutralizing Abs screening system is useful for the rapid and efficient discovery of potent neutralizing Abs against SARS-CoV-2. Our study provides a methodology for the generation of preventive and therapeutic antibody drugs for emerging infectious diseases.
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Objective Dieulafoy's lesion is a rare cause of upper gastrointestinal bleeding. The purpose of this study was to recognize the clinical characteristics of gastric Dieulafoy and to identify possible predictive factors of rebleeding. Methods Retrospective study of patients with gastrointestinal bleeding secondary to Dieulafoy's lesion from January 2009 to June 2016. We analyzed the clinical data and endoscopic findings and the correlated with rebleeding risk factors with Dieulafoy's lesion. Results 111 patients were included in the study, 97 (87.4%) patients were male; the most common location of the bleeding lesions were Proximal stomach of 53 cases (47.7%); According to the Forrest type, 46.8% of the cases were arterial (spurting), 52.3% of the cases were arterial (oozing), there were 101 (91.0%) patients treated by endoscopic combined drug therapy. The success rate of Endoscopic hemostatic treatment was 84.2%, endoscopic hemostatic treatment success rate was as follows: single endoscopic, 85.0%; two endoscopic, 84.8%; three endoscopic, 75.0%. The hemostatic treatment success rate of 101 patients with endoscopic combined drug was as follows: Proximal stomach, 83.7%; mid-stomach, 82.1%; and distal stomach, 88.9%. Age (P = 0.002) and blood transfusion (P = 0.004) were risk factors for rebleeding in the study. Blood transfusion was associated with a higher recurrence rate for bleeding (P = 0.018, OR=37.77, 95% CI = 1.86~766.47) for 101 patients with endoscopic in combination with drug. Conclusion Endoscopic therapy is effective for treating Dieulafoy's lesion. The blood transfusion was associated with a high rate of bleeding recurrence. There were no significant differences between the rebleeding and non-rebleeding groups with respect to bleeding location or hemostatic methods.
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Objective To investigate the effects of antibiotic prophylaxis on post-operation complications after endoscopic retrograde cholangio-pancreatography (ERCP).Methods From January 1st,2011 to December 31st,2013,1 951 patients undergoing ERCP were enrolled and divided into postoperative antibiotic prophylaxis group (antibiotics group,630 cases) and postoperative non-antibiotic treatment group (non-antibiotics group,1 321 cases).Complications after ERCP were compared between the two groups.Chi square test,single factor analysis and multiple factor analysis were performed for statistical analysis.Results Among the 1 951 patients,277 patients had postoperative complications:101 patients (5.18％) with post-endoscopic retrograde cholangio-pancreatography pancreatitis (PEP),54 patients (2.77％) with hyperamylasemia,134 patients (6.87％) with biliary infection,eight patients (0.41％) with hemorrhage,one patient (0.05％) with intestinal obstruction and one patient (0.05％) with perforation.The incidence of postoperative biliary infection of antibiotics group was 4.44％ (28/630),which was lower than that of non-antibiotics group (8.02％,106/1 321),and the difference was statistically significant (x2 =8.546,P =0.030).The incidences of PEP of antibiotics group and nonantibiotics group were 4.92％ (31/630) and 5.30％ (70/1 321),respectively.The incidences of postoperative hyperamylasemia of antibiotics group and non-antibiotics group were 3.02％oo (19/630) and 2.65％ (35/1 321),respectively.The incidences of upper gastrointestinal hemorrhage were 3.02％ (19/630) and 2.65％ (35/1 321),respectively.The incidences of intestinal obstruction were 0 (0/630) and 0.08％ (1/1 321),respectively,while the incidences of perforation post-operation were 0.16％ (1/630) and 0 (0/1 321),respectively,and the differences were not statistically significant (all P＞0.05).Cholangiocarcinoma (odd ratios (OR)=2.93,95％ confidence interval (CI) 1.88 to 4.56,P＜0.01) and repeated ERCP during hospitalization (OR=2.53,95 ％ CI 1.63 to 3.93,P＜0.01) were the independent risk factors of cholangitis after operation.However,endoscopic sphincterotomy (OR=0.65,95 ％ CI 0.44 to 0.97,P =0.030) and antibiotics prophylaxis (OR =0.64,95％ CI 0.39 to 0.95,P =0.030) were the protective factors.Conclusions Antibiotic prophylaxis after ERCP can reduce the occurrence of postoperative cholangitis.Paitents with cholangiocarcinoma,repeated ERCP procedures during hospitalization or without endoscopic sphincterotomy should be recommended for antibiotic prophylaxis.
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Objective To analyze the diagnostic value of endoscopic ultrasonography(EUS)for staging of early gastric cancer(EGC)and its influential factors. Methods Clinical information of 120 EGC patients admitted from February 2009 to January 2016 was reviewed. Diagnostic accuracy and the influencing factors of EUS for the invasive depth were analyzed by comparing the results of preoperative EUS and the pathology. Results Thirty-six patients were over-staged by EUS,and 10 patients were under-staged among 120 EGC patients. The accuracy, sensitivity, specificity of EUS for the submucosal invasion were 61.67%(74/120),58.33%(14/24),62.50%(60/96)respectively. The accuracy, sensitivity and specificity for protruded EGCs(Type I)diagnosis were 74.36%(29/39), 50.00%(6/12), 85.19%(23/27) respectively;these three variables were 59.02%(36/61),83.33%(5/6),56.36%(31/55)respectively for flat EGCs(Type Ⅱ), and 45.00%(9/20), 50.00%(3/6), 42.86%(6/14)respectively for excavated EGCs(Type Ⅲ). The univariate factor results showed that differentiated degree, location and endoscopic morphology of the tumor were possible influential factors for over-stage. Multivariate factor results showed that flat type(OR=3.667,95%CI:1.086-12.386,P<0.05)and excavated type(OR=6.552,95%CI:1.421-30.218,P<0.05)were independent risk factors. Gender,age and tumor maximum diameter were not factors influencing the diagnostic accuracy of EUS. Conclusion The EUS shows higher clinical value for diagnosing the invasive depth in EGC. Tumor differentiated degree, location and endoscopic morphology may be the influencing factors for diagnostic accuracy of EUS. Flat type and excavated type may lead to over-staging.
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Objective To investigate the risk factors for post-ERCP complications. Methods Data of the patients who underwent ERCP in the First Affiliated Hospital of Nanchang University from 1 January 2011 to 31 December 2013 were retrospectively analyzed. Post-ERCP complications were analyzed by univariate and multivariate analyses. Results A total of 277 patients out of 1 951 developed complications, 101(5.18%)pancreatitis, 54(2.77%)hyperamylasemia(not including pancreatitis), 134(6.87%) biliary infection,8(0.41%)hemorrhage,1(0.05%)obstruction and 1(0.05%)perforation.Multivariate analyses showed cholangiocarcinoma(P=0.002,OR=2.39, 95% CI:1.38-4.14), long operation time(>60 min)(P=0.020,OR=3.77,95%CI:1.23-11.53)and endoscopic sphincterotomy(EST)(P=0.008, OR=2.56,95% CI:1.28-5.14)and entrance of guidewire to pancreatic duct(P=0.012,OR=1.43, 95%CI:1.08-1.87)were independent risk factors for PEP. Cholangiocarcinoma(P<0.01, OR=2.93, 95%CI:1.88-4.56),multiple times of ERCP during the period of hospitalization(P<0.01, OR=2.53, 95%CI:1.63-3.93)were independent risk factors for post-cholangitis. However, EST(P=0.03, OR=0.65,95%CI:0.44-0.97)and antibiotics prophylaxis after ERCP(P=0.03, OR=0.64, 95% CI:0.39-0.95)were protective factors for post-cholangitis. ConclusionCholangiocarcinoma, endoscopic sphincterotomy, long operation time(> 60 min)and entrance of guidewire to pancreatic duct were independent risk factors for PEP. Cholangiocarcinoma and multiple ERCP during the period of hospitalization are independent risk factors for post-cholangitis.EST and antibiotics prophylaxis after ERCP might reduce the occurrence of cholangitis.