Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a, a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC₅₀ = 0.24 μmol/L). Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies.

Objective: To analyze density of stromal tumor-infiltrating lymphocytes (sTIL) and expression of lymphocyte-activation gene-3 (LAG-3) protein in advanced gastric adenocarcinomas, and to investigate the correlation of sTIL and LAG-3 with the prognosis in patients with advanced gastric adenocarcinoma. Methods: The clinicopathological characteristics and follow-up data of 260 patients with advanced gastric adenocarcinoma were collected at Fujian Cancer Hospital, from January 2011 to December 2014. The percentage of sTILs was reported semi-quantitatively using histological section evaluation, the LAG-3 protein was detected using immunohistochemistry, and the expression was correlated with the clinicopathological features and patient outcomes. Results: Among the 260 cases, high density of sTIL was detected in 173 cases (66.5%) while LAG-3 high expression was observed in 160 cases (61.5%). These cases were divided into four groups. Group Ⅰ: 48 cases (18.5%) were sTIL low/LAG-3 low; group Ⅱ: 52 cases (20.0%) were sTIL high/LAG-3 low; group Ⅲ: 39 cases (15.0%) were sTIL low/LAG-3 high; group Ⅳ: 121 cases (46.5%) were sTIL high/LAG-3 high. Kaplan-Meier survival analyses showed that patient prognoses were related to age, tumor size, tumor location, Lauren classification, perineural invasion, vascular invasion, TNM staging, postoperative adjuvant chemotherapy and molecular classification (P<0.05). Meanwhile, higher densities of sTIL and higher expression of LAG-3 were associated with better prognosis. Multivariate survival analysis showed age, tumor size, Lauren classification and postoperative adjuvant chemotherapy were independent prognostic factors for patient survival. The results showed a poor prognosis in low-sTIL/low-LAG-3 patients. Conclusions: Compared with low density of sTIL and low expression of LAG-3, high density of sTIL and high expression of LAG-3 are associated with better outcomes in patients with advanced gastric adenocarcinoma, respectively. Combined detecton of sTIL and LAG-3 may be more useful in gastric cancer than using either alone. Age, tumor size, Lauren classification and postoperative adjuvant chemotherapy are independent prognostic factors for patients with advanced gastric adenocarcinoma.
Adenocarcinoma/pathology* ; Humans ; Immunohistochemistry ; Lymphocytes, Tumor-Infiltrating/metabolism* ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/pathology*

Objective To discuss the types, characteristics, and the evaluation of disability of knee injuries. Methods The data of 133 cases of knee injury from 2017 to 2019 were collected and statistically analyzed according to the region of injury, the degree of disability, etc. Results One hundred and twenty-five cases of injury were compound, and 8 cases were simple. The incidences of ligament injury, meniscus injury and fracture were 88.72%, 75.19% and 57.89%, respectively. Of the cruciate ligament injuries, 12 cases were posterior cruciate ligament injury while 51 cases were anterior cruciate ligament injury, and the differences between the two kinds of injury had statistical significance （P<0.05）; 32 cases were secondary traumatic arthritis. The rates of disability of knee injuries were 38.35% （Grade Ⅸ and Ⅹ）. Conclusion Compound knee injuries are common, and traumatic arthritis has a relatively high rate. Multiple injuries can affect the stability and weight-bearing of the knee joint. It is suggested that in addition to evaluating the range of motion of knee joint, multiple factors should be considered to assess disability.
Anterior Cruciate Ligament ; Anterior Cruciate Ligament Injuries/epidemiology* ; Humans ; Knee Injuries/epidemiology* ; Knee Joint ; Posterior Cruciate Ligament

The pediatric population is different from adults in their physi-ological function and tissues structure, and therefore they should not be assumed simply as the small adults.The drug development for pediatric population is helpful to improve the health of children in the whole coun-try.However, the clinical investigation of medicinal products for adults can not apply for children and there has not available guidance for chil-dren for a while.Accordingly, Chinese Food and Drug Administration ( CFDA) issues the guidance for clinical investigation of medicinal prod-ucts in the pediatric population, which ensure the clinical trials are more scientific and ethic. This paper means to interpret the guidance and therefore to help the development of clinical trials in pediatric population.

The pediatric population is different from adults in their dis-ease types and medication use in clinics.The drug clinic trial in pediatric population provides reliable clinic data for new drug development and medication use, and is helpful to promote the health of children.Howev-er, considering the specificity of children, it is changeable to conduct the drug clinic trials, especially for the study protocol design.Accordingly, CFDA issues the guidance for clinical investigation of medicinal products in the pediatric population, which ensure the clinical trials are more sci-entific and ethic.This paper means to interpret the guidance and there-fore to help the development of clinical trials in pediatric population.

Nitric oxide (NO), which is involved in the regulation of the cardiovascular system, nervous system, immune system, reproductive system, digestive system and other physiological activities, is an important biological substance with activity. Under normal physiological conditions, neuronal nitric oxide synthase (nNOS) can precisely regulate the nervous system NO production, release, diffusion and inactivation processes. But an excess of NO associates with the development of cerebral ischemia, Alzheimer's and Parkinson's psychosis nervous system diseases, while inhibition of nNOS activity can regulate the content of NO in vivo, and produce a therapeutic effect on some of the nervous system diseases. This review mainly describes the structure and regulation of nNOS and recent developments of small molecule inhibitors of nNOS.
Alzheimer Disease ; physiopathology ; Brain Ischemia ; physiopathology ; Humans ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type I ; antagonists & inhibitors ; metabolism ; Parkinson Disease ; physiopathology

OBJECTIVETo explore the effect of half circle external fixation for the treatment of open tibial fractures.

METHODSFrom March 2005 to March 2011, 94 patients with open tibiofibula fractures were treated by closed manipulative or Kirschner-wire poking reduction with half circle groove external fixation including 63 males and 31 females with an average age of 39 years old ranging from 17 to 65 years old. Among these patients, 5 cases were cross shaped fractures, 19 were oblique form and spiral fractures, 70 cases were comminuted fractures. According to the fracture Gustilo classification, 49 cases were type IIIA, 45 were type IIIB. The incidence of wound infection, fracture healing time were observed. The function was evaluated according to the Johner-Wruhs standard.

RESULTSAll patients were followed up for 14 to 63 months (averaged 29 months). The wound healing time was from 16 to 39 weeks (means 21.4 weeks). No fracture nonunion, osteomyelitis and calf compartment syndrome occurred. The wounds of 81 cases were healed at the first period,deep wound infection occurred in 2 cases. According to the function Johner-Wruhs evaluation criteria:the result was excellent in 52 cases, good in 37 cases, fair in 5 cases.

CONCLUSIONClosed manipulative or Kirschner-wire poking reduction and half circle groove external fixation can reduce the infection rate of open tibiofibula fractures. For open tibiofibula comminuted fractures, after the half circle groove external fixation for 3 to 6 weeks, a middle Kirschner-wire was removed according to fracture end healing situation to make fixation dynamic and promote fracture healing.

Adolescent ; Adult ; Aged ; Bone Wires ; External Fixators ; Female ; Fracture Fixation ; instrumentation ; Fractures, Comminuted ; surgery ; Fractures, Open ; surgery ; Fractures, Ununited ; surgery ; Humans ; Male ; Middle Aged ; Tibial Fractures ; surgery ; Young Adult

Objective:To explore the effect of half circle external fixation for the treatment of open tibial fractures. Meth-ods: From March 2005 to March 2011,94 patients with open tibiofibula fractures were treated by closed manipulative or Kirschner wire poking reduction with half circle groove external fixation including 63 males and 31 females with an average age of 39 years old ranging from 17 to 65 years old. Among these patients ,5 cases were cross shaped fractures ,19 were oblique form and spiral fractures,70 cases were comminuted fractures. According to the fracture Gustilo classification,49 cases were typeⅢA,45 were typeⅢB. The incidence of wound infection,fracture healing time were observed. The function was evaluated according to the Johner Wruhs standard. Results:All patients were followed up for 14 to 63 months (averaged 29 months). The wound healing time was from 16 to 39 weeks (means 21.4 weeks). No fracture nonunion,osteomyelitis and calf compart-ment syndrome occurred. The wounds of 81 cases were healed at the first period ,deep wound infection occurred in 2 cases. According to the function Johner-Wruhs evaluation criteria:the result was excellent in 52 cases,good in 37 cases,fair in 5 cases. Conclusion:Closed manipulative or Kirschner wire poking reduction and half circle groove external fixation can reduce the infection rate of open tibiofibula fractures. For open tibiofibula comminuted fractures ,after the half circle groove external fixation for 3 to 6 weeks,a middle Kirschner wire was removed according to fracture end healing situation to make fixation dy-namic and promote fracture healing.

BACKGROUNDSeveral studies have evaluated the association between polymorphisms of encoding excision repair cross complementation group 1 (ERCC1) enzyme and lung cancer risk in diverse populations but with conflicting results. By pooling the relatively small samples in each study, it is possible to perform a meta-analysis of the evidence by rigorous methods.

METHODSEmbase, Ovid, Medline and Chinese National Knowledge Infrastructure were searched. Additional studies were identified from references in original studies or review articles. Articles meeting the inclusion criteria were reviewed systematically, and the reported data were aggregated using the statistical techniques of meta-analysis.

RESULTSWe found 3810 cases with lung cancer and 4332 controls from seven eligible studies. T19007C polymorphism showed no significant effect on lung cancer risk (C allele vs. T allele: odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.80 - 1.04; CC vs. TT: OR = 0.76, 95%CI = 0.56 - 1.02; CC vs. (CT + TT): OR = 0.96, 95%CI = 0.84 - 1.10). Similarly, there was no significant main effects for T19007C polymorphism on lung cancer risk when stratified analyses by ethnicity (Chinese or Caucasian). No significant association was found between C8092A polymorphism (3060 patients and 2729 controls) and the risk of lung cancer (A allele vs. C allele: OR = 1.03, 95%CI = 0.95 - 1.11; AA vs. CC: OR = 1.08, 95%CI = 0.88 - 1.33; AA vs. (AC + CC): OR = 1.08, 95%CI = 0.88 - 1.31).

CONCLUSIONWe found little evidence of an association between the T1900C or C8092A polymorphisms of ERCC 1 and the risk of lung cancer in Caucasian or Han Chinese people.

Asian Continental Ancestry Group ; genetics ; DNA-Binding Proteins ; genetics ; Endonucleases ; genetics ; Genetic Predisposition to Disease ; genetics ; Humans ; Lung Neoplasms ; genetics ; Polymorphism, Genetic ; genetics

OBJECTIVETo investigate the oxidative damage to lung tissue and peripherial blood in PM2.5-treated rats.

METHODSPM2.5 samples were collected using an auto-sampling instrument in summer and winter. Treated samples were endotracheally instilled into rats. Activity of reduced glutathione peroxidase (GSH-Px) and concentration of malondialdehyde (MDA) were used as oxidative damage biomarkers of lung tissue and peripheral blood detected with the biochemical method. DNA migration length (microm) and rate of tail were used as DNA damage biomarkers of lung tissue and peripheral blood detected with the biochemical method.

RESULTSThe activity of GSH-Px and the concentration of MDA in lung tissue significantly decreased after exposure to PM2.5 for 7-14 days. In peripheral blood, the concentration of MDA decreased, but the activity of GSH-Px increased 7 and 14 days after experiments. The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood. The DNA migration length (microm) and rate of tail in lung tissue and peripheral blood significantly increased 7 and 14 days after exposure to PM2.5. The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood.

CONCLUSIONPM2.5 has a definite oxidative effect on lung tissue and peripheral blood. The activity of GSH-Px and the concentration of MDA are valuable biomarkers of oxidative lung tissue damage induced by PM2.5. The DNA migration length (microm) and rate of tail are simple and valuable biomarkers of PM2.5-induced DNA damage in lung tissues and peripheral blood. The degree of DNA damage in peripheral blood can predict the degree of DNA damage in lung tissue.

Animals ; DNA Damage ; drug effects ; Drug Administration Routes ; Drug Administration Schedule ; Lung ; drug effects ; pathology ; Lung Diseases ; blood ; chemically induced ; pathology ; Male ; Oxidative Stress ; Particle Size ; Particulate Matter ; administration & dosage ; toxicity ; Rats ; Rats, Wistar ; Seasons