Objective To investigate the role of interleukin 17 in the differentiation of macrophages from monocyte in vivo and its applicability in Obliterative bronchiolitis (OB).Methods Pathogen-free male C57BL/6 (n =20),IL-17-defcient C57BL/6 (n =10) and BALB/c (n =10) weighing 20-25 g.Weight-matched mice were assigned to three experimental groups.Experimental group A:BALB/c (n =5) →C57 BL/6 (n =10).Experimental group B:BALB/c (n =5) →IL-17-defcient C57BL/6(n =10).Normal control group:C57BL/6(n =10).The CD80 expression in macrophages in spleens were analysed by flowcytometry 7 days after operation.Native and transplanted lungs were harvested after 14 days and 28 days,stained with HE,and examined under light microscopy.Results Compared to experimental group A,CD80 expression of macrophages reveales a significant decrease in spleen of experimental group B.Furthermore,airway obliteration and destruction of the epithelium in experimental group A were significantly better compared with that of experimental group B on day 14 and 28 after transplantation.Conclusion IL-17 deficiency decreased the polarization of monocytes to macrophages and attenuate the pathology of obliteral bronchiolitis in murine model after trachea transplantaion.

Objective To summary the application of computer aided three-dimensional visualization technique in different kinds of mandibular detects reconstruction with vascularized free fibular flap.Methods Five patients diagnosed of recurrent mandibular ameloblastoma underwent the virtually operation by software with a thin-slice CT scan,which determined shape and position of the free flap,and preoperative resin model and modules were designed and prefabricated.Then the titanium plates were bent precisely,and the surgical reconstruction proceeded exactly as expected from the modeling process.Results All operations were achieved successfully.The extent of the lesion was coincident with the preoperative CT results,and the vascularized free fibular flaps were harvested and implanted into the defect regions accurately.The mean distance was (0.23 ±2.10) mm compared with the virtual fibula.The mean time of operation was 4.4 hours.Following up the mean 12.8 months,all patients obtained the excellent functional and cosmetic outcomes.Conclusion The procedure of operation was simplified and the time was shortened with reconstruction exactly using computer aided three-dimensional visualization technique,and the clinical therapeutic efficacy of reconstruction of mandibular defect with vascularized free fibular flaps was improved notably.

Objective To investigate the effects of toll-like receptor 9 (TLR9) agonist CpG ODN2216 on the sensitivity of pancreatic cancer cell line PANC1's to gemcitabine.Methods The immunofluorescence staining method and Western blot method were used to examine the expression of TLR9 protein in PANC1 cells.The changes of sensitivity to gemcitabine after CpG ODN2216 treatment were examined by MTT assay.Results The TLR9 protein was highly expressed in PANC1 cells and the median inhibition concentration of gemcitabine against PANC1 cells was reduced from (1.23 ± 0.14) mg/L to (0.28 ± 0.13) mg/L after CpG ODN2216 treatment,and the difference between the two groups was statistically significant (P ＜0.01).After 0.01,0.10,1.00,10.00 mg/L gemcitabine treatment with CpG 0DN2216,the inhibition rates of PANC1 were (34.4 ±1.3)％,(43.5 ± 2.7)％,(76.3 ± 2.5)％,(95.3 ± 2.2)％ ; and without CpG ODN2216,the inhibition rates of PANC1 were (14.5 ± 0.9) ％,(23.5 ± 1.1) ％,(44.8 ± 1.4) ％,(63.6 ± 1.8) ％,and the difference between the two groups was statistically significant (P ＜ 0.01).Conclusions The sensitivity of PANC1 cells to gemcitabine can be enhanced by CpG ODN2216.

Objective:To discuss the scientificity and feasibility of risk-based monitoring strategies in Investigator initiated Trials.Methods:" Guideline for Good Clinical Practice" promulgated by NMPA, " Oversight of Clinical Investigations-a Risk-based Approach to Monitoring" and " A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers Guidance for Industry DRAFT GUIDANCE" promulgated by the US FDA and other documents were analyzed, the practical experience of Investigator initiated Trials was also summarized.Results:It was recommended that clinical investigators use risk-based monitoring strategies in Investigator initiated Trials. The main idea of risk-based monitoring is to determine the key process and key data of the study, carry out risk rating on the project, and adopt corresponding monitoring methods according to the risk level when formulating the monitoring plan. At the same time, during the clinical trial development process, the risk and data quality of the research center should be regularly evaluated to grasp the risk changes of different centers. In accordance with trends, adjust the method, content and frequency of monitoring.Conclusions:To apply risk-based monitoring strategies in Investigator initiated Trials is scientificity and feasibility. Risk based monitoring can meet the data quality requirements of clinical trials, without affecting the analysis results of the main outcomes, and can further improve the efficiency and effectiveness of monitoring.

Objective:Discuss the problems of multi-center pharmaceutical clinical trial which initiated by investigator (IIT), providing references for developing study management strategies.Methods:By analyzing the site recruitment, academic and ethical review, study contract, study training, quality control, influencing factors of subject enrollment, proposed management strategies of multi-center pharmaceutical clinical study which initiated by investigator.Results:While conducting multi-center pharmaceutical clinical study initiated by investigator, the study experiences, study team, hospital equipment, and the internal process of hospitals are the factors which ensure the progress and quality of clinical study. Most of the sites have no clear statement of scientific review, but most of the high-level hospitals do not use the ethical review results of the head hospitals, the ethics must be reviewed repeatedly; Contract also has different requirements due to different management departments. During the preparation and implement of IIT, the investigators should undergo a rigorous training which is a key element to ensure the quality of the study. Research quality and progress restrict each other and are affected by many factors, detailed quality control measures should be developed, training and inspection, and the cooperation of project management and data management, also with discover the data problems of sites and communicate with investigators timely to ensure the improvement measures are implemented.Conclusions:There are many factors have impact on study progress and quality of multi-center pharmaceutical clinical trial of IIT. Before conducting research, protocols should be developed scientifically, and fully assessing its feasibility, screening study sites strictly, shorten the time of ethical review and contract preparation. Study training, inspection, data management, risk management and document management should be implement strictly, and make full use of information platforms and means, improve management efficiency and IIT progress and quality.

Animals ; Monkeypox/drug therapy* ; Antiviral Agents/therapeutic use* ; Phosphoric Monoester Hydrolases/therapeutic use* ; Macaca fascicularis

Antiviral Agents/pharmacology* ; COVID-19 ; Coronavirus 3C Proteases ; Humans ; Lactams ; Leucine ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Nitriles ; Proline ; Protease Inhibitors/pharmacology* ; SARS-CoV-2

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Antiviral Agents/therapeutic use* ; Binding Sites ; COVID-19/virology* ; Coronavirus Papain-Like Proteases/metabolism* ; Crystallography, X-Ray ; Drug Evaluation, Preclinical ; Drug Repositioning ; High-Throughput Screening Assays/methods* ; Humans ; Imidazoles/therapeutic use* ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Naphthoquinones/therapeutic use* ; Protease Inhibitors/therapeutic use* ; Protein Structure, Tertiary ; Recombinant Proteins/isolation & purification* ; SARS-CoV-2/isolation & purification*