Antibody Inhibition of Influenza A Virus Assembly and Release.

Antibodies are frontline defenders against influenza virus infection, providing protection through multiple complementary mechanisms. Although a subset of monoclonal antibodies (mAbs) have been shown to restrict replication at the level of virus assembly and release, it remains unclear how potent and pervasive this mechanism of protection is, due in part to the challenge of separating this effect from other aspects of antibody function. To address this question, we developed imaging-based assays to determine how effectively a broad range of mAbs against the IAV surface proteins can specifically restrict viral egress. We find that classically neutralizing antibodies against hemagglutinin are broadly multifunctional, inhibiting virus assembly and release at concentrations one- to twenty-fold higher than the concentrations at which they inhibit viral entry. These antibodies are also capable of altering the morphological features of shed virions, reducing the proportion of filamentous particles. We find that antibodies against neuraminidase and M2 also restrict viral egress, and that inhibition by anti-neuraminidase mAbs is only partly attributable to a loss in enzymatic activity. In all cases, antigen crosslinking - either on the surface of the infected cell, between the viral and cell membrane, or both - plays a critical role in inhibition, and we are able to distinguish between these modes experimentally and through a structure-based computational model. Together, these results provide a framework for dissecting antibody multifunctionality that could help guide the development of improved therapeutic antibodies or vaccines, and that can be extended to other viral families and antibody isotypes.

SurvMaximin: Robust Federated Approach to Transporting Survival Risk Prediction Models

ObjectiveFor multi-center heterogeneous Real-World Data (RWD) with time-to-event outcomes and high-dimensional features, we propose the SurvMaximin algorithm to estimate Cox model feature coefficients for a target population by borrowing summary information from a set of health care centers without sharing patient-level information. Materials and MethodsFor each of the centers from which we want to borrow information to improve the prediction performance for the target population, a penalized Cox model is fitted to estimate feature coefficients for the center. Using estimated feature coefficients and the covariance matrix of the target population, we then obtain a SurvMaximin estimated set of feature coefficients for the target population. The target population can be an entire cohort comprised of all centers, corresponding to federated learning, or can be a single center, corresponding to transfer learning. ResultsSimulation studies and a real-world international electronic health records application study, with 15 participating health care centers across three countries (France, Germany, and the U.S.), show that the proposed SurvMaximin algorithm achieves comparable or higher accuracy compared with the estimator using only the information of the target site and other existing methods. The SurvMaximin estimator is robust to variations in sample sizes and estimated feature coefficients between centers, which amounts to significantly improved estimates for target sites with fewer observations. ConclusionsThe SurvMaximin method is well suited for both federated and transfer learning in the high-dimensional survival analysis setting. SurvMaximin only requires a one-time summary information exchange from participating centers. Estimated regression vectors can be very heterogeneous. SurvMaximin provides robust Cox feature coefficient estimates without outcome information in the target population and is privacy-preserving.

Modified posterolateral laparoscopic approach for resection of massive splenomegaly / 中华肝胆外科杂志

Objective:To study the feasibility and efficacy of the modified posterolateral laparoscopic approach for resection of massive splenomegaly.Methods:The data of 48 patients who underwent laparoscopic splenectomy for massive splenomegaly at the Affiliated Hospital of Jiangnan University (Wuxi 4th People's Hospital) from January 2016 to July 2019 were retrospectively analyzed. There were 29 males and 19 females, with an average age of 55.8 years. These 48 patients were divided into two groups according to the operative approach, the study group ( n=26) using the modified posterolateral approach which treated the splenic pedicle as the last step; and the control group ( n=22) which used the posterior tunnel of splenic pedicle established by anterior approach to treat the splenic pedicle first. The operation time, gastrointestinal function, recovery time, intraoperative blood loss, rates of conversion to laparotomy and postoperative complications were compared between two groups. The follow-up data were also analyzed. Results:There were no significant differences in operation gastrointestinal function recovery and hospitalization time between the two groups (all P>0.05). The intraoperative blood loss, numbers of patients with convention to open surgery and intraoperative blood transfusion, were (50.2±15.1) ml vs (160.1±40.3) ml, 2 patients (7.7%) vs 7 patients (31.8%), and 1 patients (3.8%) vs 5 patients (22.7%), in study group and control group respectively. The differences between groups were significant (all P<0.05). The complications of the study group and control group were 9 patients (34.6%) vs 13 patients (59.1%), which were significantly in the two groups ( P<0.05). On follow-up which ranged from 1 to 15 months, the numbers of patients with thrombocytosis and portal vein thrombosis in the study group and the control group were 20 patients (76.9%) vs 17 patients (77.3%), and 7 patients (26.9%) vs 6 patients (27.3%), respectively. Conclusion:The modified posterolateral laparoscopic approach for resection of massive splenomegaly was safe and feasible. It should be promoted to treat massive splenomegaly.

Screening of a Novel Upregulated lncRNA, A2M-AS1, That Promotes Invasion and Migration and Signifies Poor Prognosis in Breast Cancer.

Understanding of prognostic factors and therapeutic targets for breast cancer is imperative for guidance of patient care. We studied 1203 tumour samples from the Gene Expression Omnibus (GEO) to evaluate potential genes related to breast cancer. R software was used to analyse differentially expressed long noncoding RNAs (lncRNAs) in the RNA microarray expression profiles GSE45827 and GSE65216 and to identify a series of differentially expressed lncRNAs associated with human breast cancer. Of these lncRNAs, A2M-AS1, a lncRNA that has not been previously reported, was significantly upregulated in human breast cancer tissues compared with adjacent nontumour tissues. Importantly, A2M-AS1 upregulation was significantly associated with ER-negative, HER2-positive, and basal-like breast cancer and with poor recurrence-free survival and metastasis-free survival in breast cancer patients. After validating these results in 96 collected human breast cancer tissues and 64 paired adjacent noncancerous tissues, we further investigated the roles of A2M-AS1 in human ER-negative and basal-like breast cancer cells. The results revealed that A2M-AS1 significantly promotes human breast cancer cell proliferation, invasion, and migration. Additionally, bioinformatics analysis of genes coexpressed with A2M-AS1 in the context of human breast cancer combined with qRT-PCR and Western blot assays revealed that A2M-AS1 exerts regulatory effects on downstream factors in the cell adhesion molecule pathway, including CD2 and SELL. These results imply that A2M-AS1 might be a promising candidate prognostic factor and therapeutic target for breast cancer.

Surgical drainage versus repair in the treatment of distal common bile duct injury / 中华肝胆外科杂志

Objective To compare the efficacy of surgical drainage versus repair in the treatment of iatrogenic injury of the distal common bile duct detected during operation,and to evaluate the effect of gastrobiliary duct drainage.Methods Patients with iatrogenic choledochal injury were divided into two groups:the drainage group (n =17) and the repair group (n =7).Data on the amounts of postoperative biliary and abdominal cavity drainage,gastrointestinal function recovery,the duration of biliary drainage and hospitalization were compared.Results When compared with the repair group,there were no significant differences in the amounts of postoperative biliary drainage [(310.0± 112.0) vs.(264.0± 144.0) ml] and abdominal cavity drainage [(42.0±25.0) ml vs.(125.0± 195.0) ml)] (both P＞0.05).However,gastrointestinal function recovery [(3.0±1.5)d vs.(4.7±2.0)d],durations of biliary drainage [(7.5±1.0)d vs.(12.7±5.4)d] and hospitalization [(9.5±1.5)d vs.(15.1±5.6)d] of the drainage group were significantly shorter than the repair group (P＜ 0.05).No biliary strictures of cholangitis were detected in the two groups.Conclusion When compared with traditional repair,gastrobiliary drainage was a simpler,safer,and more effective therapeutic strategy for patients with iatrogenic distal common bile duct injury,and with a quicker recovery after treatment.

microRNA-18a Promotes Cell Migration and Invasion Through Inhibiting Dicer l Expression in Hepatocellular Carcinoma In Vitro / 中国医学科学杂志(英文版)

Objective To investigate the effects of microRNA-18a (miR-18a) on migration and invasion of hepatocellular carcinoma (HCC) cells, and its possible mechanism associated with Dicer l.Methods HepG2 and HepG2.2.15 cells were transfected with miR-18a inhibitor using Lipofectamine. Cell invasion was evaluated by transwell invasion assay, and cell migration was detected by transwell migration and wound-healing assays. Moreover, luciferase reporter assay was used to identify whether Dicer expression was regulated by miR-18a. Real-time RT-PCR and western blot were performed to analyze Dicer 1 expression. In addition, a functional restoration assay was performed to investigate whether miR-18a promotes HCC cell migration and invasion by directly targeting Dicer 1.Results miR-18a inhibitor can suppress the migration and invasion of HCC cells. Furthermore, suppression of Dicer l expression by small interfering RNA essentially abolished the inhibition of cell migration and invasion induced by miR-18a inhibitor, restorating these activities to levels similar to the parental HCC cells. Interestingly, suppression of miR-18a in HCC cells resulted in enhanced expression of Dicer l. In addition, the results of a luciferase assay demonstrated targeted regulation of Dicer l by miR-18a.Conclusion Our findings suggest that miR-18a promotes migration and invasion of HCC cells by inhibiting Dicer l expression.

Intraoperative gastrobiliary duct drainage for iatrogenic distal common bile duct injury / 中华普通外科杂志

Objective To evaluate gastrobiliary duct drainage in the treatment for iatrogenic distal common bile duct injury found during the operation.Methods We analyzed clinical data of 17 cases with application of gastrobiliary duct drainage in immediate treatment for the injury of distal common bile duct found during the operation from June 2010 to June 2016.Postoperative bile drainage,postoperative gastrointestinal function recovery,time for removal of the gastrobiliary duct and hospitalization time were recorded.Postoperative bile leakage,intestinal fistula and pancreatic leakage were observed.Patients were followed up until June 2016.Results The mean volume of bile drainage on the third postoperative day were (310 ± 112)ml,the mean time of postoperative gastrointestinal function recovery were (3.0 ± 1.5) days,time for removal of the gastrobiliary stent were (7.5 ± 1.0) days and hospitalization time were (9.5 ± 1.5) days.There was no postoperative bile leakage,intestinal fistula and pancreatic leakage.All patients were followed up for a median time of 12 months (range,1-45 months).Meanwhile,we found no significant biliary strictures and cholangitis patients.Conclusion Gastrobiliary duct drainage is a simple,rational and effective treatment for iatrogenic injury of distal common bile duct during common bile duct exploration.

The diagnostic significance of single or combination lung cancer-related serum biomarkers in high risk lung cancer patients / 中华内科杂志

Objective The aim of this study was to assess the clinical value of pro-gastrin releasing peptide (ProGRP) , squamous cell carcinoma antigen (SCC-Ag), cytokeratin 19 fragment antigen 21-1 (Cyfra21-1) and carcino-embryonic antigen (CEA) in the diagnosis and clinical stage of lung cancer in Chinese patients.Methods Patients with lung cancer and benign lesions confirmed by pathology were enrolled in Peking Union Medical College Hospital from January 2013 to October 2014.The serum levels of four tumor markers (ProGRP, SCC-Ag, Cyfra21-1 and CEA) were measured using immunoassays before treatment.The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the areas under the receiver operating characteristic curve (AUCROC) of these four tumor biomarkers were analyzed for the diagnosis of lung cancer.Results A total of 134 patients were finally analyzed, including 73 patients with lung cancer and the other 61 patients with benign lung disease.The diagnostic sensitivity of serum Cyfra21-1 to lung cancer was 67.1％, the specificity 45.1％, the AUCROC 0.658.The diagnostic sensitivity of the panel including ProGPR, Cyfra21-1 and CEA to lung cancer was 75.3％ , the specificity 57.4％ , the AUCROC 0.702.In the lung cancer group, the AUCROC of ProGRP over 65 ng/L to diagnose small cell lung cancer was 0.954;the AUCROC of SCC-Ag over 1.5 μg/L to diagnose squamous cell lung cancer was 0.788;the AUCROC of Cyfra21-1 to diagnose non-squamous-non-small-cell lung cancer was 0.716.In small cell lung cancer patients, the level of ProGRP in limited-disease small cell lung cancer (LD-SCLC) were significantly higher than that in extensive-disease small cell lung cancer (ED-SCLC) (P =0.005).Conclusion This panel of serum tumor markers including ProGRP, Cyfra21-1 and CEA improves the diagnostic specificity and sensitivity in patients with high-risk lung cancer.The serum CEA level of advanced lung cancer patients is significantly increased.The high level of serum ProGRP predicts the ED-SCLC.

Systematic review on management of perioperative iatrogenic injury of distal common bile duct / 中华肝胆外科杂志

Objective To study the effectiveness of different treatment modalities for iatrogenic injury of distal common bile duct during operation.Methods We browsed Chinese Medical Full-text Data-base with the term of “distal common bile duct injury”.All the clinical studies associated with perioperative latrogenic injury of distal common bile duct and adjacent tissue published after 1990 were enrolled,and we collected the clinical data,mortality and reoperation rate with different treatments for analysis.Results Thirty-four case series and case reports with 233 patients were included.14 patients with isolated duodenal injury were excluded.The overall mortality of the remaining 219 patients was 9.6％,and the reoperation rate was 17.4％.A total of 145 patients who were diagnosed with distal common bile duct injury during and after operation from 21 articles were compared.The mortality and reoperation rate were both 1.9％ among 106 patients who were diagnosed during operation.The figures were 43.6％,and 84.6％ among 39 patients who were diagnosed after operation,respectively.In 9 articles with 46 patients,the clinical outcomes of 21 patients who were treated by intraoperative suture was compared with 25 patients who underwent enhanced biliary and retroperitoneal drainage.The mortality and reoperation rates were 0 in both groups.Conclusions Early detection and management are crucial to perioperative common bile duct injury.Furthermore,no significant difference of clinical outcomes observed between bile drainage and perforation suture groups.

Association of vitamin D receptor gene polymorphisms with autoimmune liver diseases risk / 中国医师进修杂志

Objective To investigate the association of vitamin D receptor gene (Apa1,Bsm1,Taq1) polymorphisms with autoimmune liver diseases risk.Metiods Case control test documents were retrieved through Pubmed,Ovid,Medline,and Web of science databases,according to the inclusion and exclusion criteria included in this study.The design of experiments,the characteristics of the object of study,research results was excerpted,STATA version 12.0 software were used.The correlation intensity was demonstrated with odds ratio (OR) and 95％ confidence interval (CI).Results A total of 6 publications containing 9 studies (7 studies about primary biliary cirrhosis,2 studies about autoimmune hepatitis) published from January 2000 to February 2012 were identified and 844 cases and 1 522 controls were included.The combined results based on all studies showed that there was a statistically significant link between Apa 1 and autoimmune liver diseases (OR =0.85,95％ CI 0.74-0.96,P =0.058,for a vs.A; OR =0.75,95％ CI 0.58-0.97,P =0.212,for aa vs.AA;OR =0.78,95％ CI 0.63-0.98,P =0.235,for Aa vs.AA; OR =0.77,95％ CI 0.63-0.94,P =0.231,for Aa/aa vs.AA),while the Bsm 1 and Taq 1 didn' t show the association with autoimmune liver diseases.Conclusion The current meta-analysis shows that Apal may be a low-penetrant risk factor for autoimmune liver diseases.Bsm1 and Taq1 don't show the association with autoimmune liver diseases.

Influence of silencing Med19 on metastasis and invasion of human breast cancer MCF-7 cells / 实用医学杂志

Objective To investigate the influence of silencing Med19 on metastasis and invasion of human breast cancer MCF-7 cells. Methods lentivirus expression vector delivering small hairpin RNA (shRNA) against Med19 gene was constructed, then transfected of human breast cancer MCF-7 cell line. There were three experimental groups: non-infected (CON) group, Lv-NC-infected (NC) group, and Lv-shMed19-infected (KD) group. To determine the lentiviral infection efficiency, expression of GFP was detected with fluorescence microscopy. The mRNA and protein levels of Med19 in three groups MCF-7 cells were detected by real-time PCR and Western blotting. Scratching and transwell tests were employed to determine the ability of metastasis and invasion of cells. Results The highest infection efficiency was obtained, resulting fluorescent expression identified in more than 90%of MCF-7 cells 120 h after infection. The expression of Med19 mRNA in the KD group was dramatically decreased by 72.3%compared with the NC group, and by 72.1% compared with the CON group, respectively (P < 0.05). The Med19 protein expression in the KD group was significantly lower than that of the NC group and the CON group, with a reduction of 85.4%and 85.3%, respectively (P<0.05). No statistical significance was detected between the NC groups and the CON groups. Thus, the constructed Lv-shMed19 was demonstrated to be active and specific in inhibiting the expression of Med19. Moreover, the invasive distances of KD group, NC group and CON group MCF-7 cells were compared at 6 hour, 12 hour and 24 hour. The invasive ability of MCF-7 cells decreased significantly with the extension of time (P<0.05). The cells passed through polycarbonate membrane in KD group, NC group and CON group were 23.8 ± 4.32, 43.4 ± 3.65 and 45.8 ± 5.81 respectively. The metastatic ability of KD group was significant reduced (P<0.05). Conclusion Silencing of Med19 gene significantly decreases the ability of metastasis and invasion of human breast cancer MCF-7 cells, and then suppresses the malignant biological behavior of breast cancer.

Detection of the tumor markers in patients with gastric precancerous lesions / 国际肿瘤学杂志

It is confirmed that chronic atrophic gastritis (CAG) caused by Helicobacter pylori is the main cause of gastric precancerous lesions.CAG is also the key determinant in gastric cancer risk assessment,which affects pepsinogen and gastrin-17 secretion.Most of the gastric cancer patients have poor prognosis,and non-invasive tools for gastric cancer screening and diagnosis are lacking.Therefore,the early detection of gastric cancer in order to reduce the disease mortality is necessary.Pepsinogen and gastrin-17 are biomarkers of gastric mucosa and gastric antra.The serological testing for the stomach-specific biomarkers offers the possibility to know preneoplastic gastric mucosal conditions.

Prognostic impact of GSTA1 polymorphisms on breast cancer patients treated with cyclophosphamide-based adjuvant chemotherapy / 中华检验医学杂志

Objective To investigate the association between the genetic polymorphisms in GSTA1 and the clinical outcome of breast cancer patients treated with cyclophosphamide-based adjuvant chemotherapy. Methods A total of 137 breast cancer patients receiving cyclophosphamide-based adjuvant chemotherapy were recruited ( 124 cases with infiltrative ductal carcinoma, 5 cases with infiltrative lobular carcinoma and 8 cases with other histological types). PCR-LDR method was used to detect the genotypes of GSTA1. Survival curves were generated by the Kaplan-Meier method, and verified by the log-rank test. Cox proportional hazards regression analysis was used to estimate the prognostic factors in multivariate analysis. Results Of the 137 breast cancer patients, the genotypic frequencies of the GSTA1 * A/* A,* A/* B and * B/* B were 67.2% ( 92/137 ), 31.4% ( 43/137 ) and 1.5% ( 2/137 ), respectively. No significant differences were found between the genotypic frequencies and groups categorization according to age, stage, lymph node metastasis, ER or PR status (x2 = 0. 722,1. 967, 3. 303, 0. 226 and 0. 709, all P ＞0. 05 ) ;through Fisher exact test, also no significant differences were found between the genotypic frequencies and group categorization according to tumor size, histological types and grading ( all P ＞ 0. 05 ) . The recurrence rates in patients with GSTA1 * A/* A and * A/* B or * B/* B genotypes were 47. 8% (44/92) and 31.1% ( 14/45 ), respectively, and the mortality rates were 22. 8% ( 21/92 ) and 17. 8% ( 8/45 ),respectively. Patients with GSTA1 * A/* B and * B/* B genotypes were significantly associated with reduced hazard of relapse (x2 =18.723, P＜0. 01)and mortality (x2 =7.352, P＜0.01), compared to cases with the common * A/* A genotypes, according to Kaplan-Meier survival analysis and log-rank test. Moreover,Cox multivariate analysis showed that GSTA1 polymorphisms appeared to be an independent risk factor for recurrence-free survival ( OR =0. 222, 95% CI:0. 108-0. 458, P ＜0. 01 ) and overall survival ( OR =0. 362,95% CI:0. 145-0. 902, P ＜ 0. 05 ). Conclusion These data indicate that GSTA1 polymorphism may be a potential prognostic factor for recurrence-free survival and overall survival in breast cancer patients treated with cyclophosphamide-based adjuvant chemotherapy.

The experimental study on application of gastrobiliary duct drainage in primary suture after exploration of common bile duct / 中华肝胆外科杂志

Objective To establish an animal model with installation of gastrobiliary duct drainage (GBDD) in the primary suture after exploration of common bile duct, to assess the safety and feasibility of GBDD. Methods Thirty dogs were randomly divided into three groups: control group (n=5), primary suture group (n= 10) and GBDD group (n= 15). Serum TBil levels, bile leakage,and complications were observed and compared. Results No increase in serum TBil level was observed in the control group. However, serum TBil levels were significantly increased in the primary suture group compared to the GBDD group (P＜0. 01). GBDD were all successfully withdrawn at mean (7. 0±1.7) days after the operation. No bile leakage was found in the GBDD group, which was significantly different compared to 5/10 bile leakage cases in primary suture group (P＜0. 05). There were 3/10 cases of bile peritonitis, infection of incisional wound and splitted in the primary suture group, while there were no such complications in the GBDD group (all P＞0.05). Conclusions GBDD is safe and feasible. It can shorten biliary drainage time and prevent occurrence of bile leakage.Therefore, it has unique value in clinical application.

Experiences of gastro-bile duct drainage in treating iatrogentic injury in the bile duct / 中国综合临床

Objective To study the effect of applying gastro-bile duct drainage in iatrogentic injury in the bile duct and reasons of iatrogentic injury in the bile duct. Methods Clinical data of 9 cases with iatrogentic injury in the bile duct were studied retrospectively. Results Nine patients with iatrogentic injury in the bile duct were found in time by affnsion examination, choledochoendoscopy or cholangiography intraoperation, including 5 cases in-jured by metal divining rod,2 cases caused by lithotomy, 1 case injured by laparoscopic elastic separating plier and 1 case injured by common hepatic duct transection. The gastro-bile duct was placed into common bile duct through pa-pilla of duodenum, pylorus and the former wall of gastric. All the cases recovered smoothly. The gastro-bile duct was removed in 8 cases in 6 to 10 days later,in 1 cases in 30 days later,who were followed up for 9 months to 5 years, finding no complications such as stricture of bile duct and retroperitoneal infection. Conclusions Intraoperative cho-ledochoendoacopy,affusion examination and cholangiography are helpful to diagnosis. The better results are achieved by appling gastro-bile duct drainage in iatrogentic injury in the bile duct.

A novel animal model of pulmonary allergic inflammation sensitized and challenged with house dust mite Dermatophagoides farinae / 基础医学与临床

Objective To establish a pulmonary allergic inflammation model with C57BL/6 mice.Methods C57BL/6 mice were divided into control group and treatment group.The mice of treatment group were sensitized by intra peritoneal injection of house dust mite extracts at day 1,3,5,7,9 and 11.Then they were exposed to aerosolized allergen at day 13,16,19,20 and 21.Physiological saline instead of house dust mite extracts was used in control group.All mice underwent pulmonary lavage in 24h after the final exposure to aerosolized allergen challenge.Pathological manifestation of the lung,cell counts and classification were studied and IL-4 and IFN-? levels in BALF were detected by ELISA.Cells from spleen were cultured for 3 d with house dust mite extracts,IL-4 and IFN-? in supernatants was measured by ELISA.Results There was pulmonary eosinophilic inflammation in the mice treated with house dust mite extracts.Compared with control group,total cells,lymphocytes,eosinophils and the level of IL-4 in BALF from treated mice increased significantly,while IFN-? in BALF decreased.The level of IL-4 in cultured splenocyte supernatants also significantly increased,while IFN-? in supernatants decreased.Conclusion A pulmonary allergic inflammation model of is established by sensitizing and challenging C57BL/6 mice with house dust mite Der f.