Objective To evaluate the pharmacokinetic characteristics and safety of single and multiple oral azvudine tablets in healthy young and elderly Chinese subjects.Methods This was a open-label and parallel-group study.The trial consisted of two groups:healthy young subjects group and healthy elderly subjects group,with 12 subjects in each group.Enrolled subjects were first given a single dose,fasting oral azvudine tablet 5 mg,after a 3-day cleansing period entered the multiple dose phase,fasting oral azvudine tablet 5 mg·d-1 for 7 days.Results After a single dose of azvudine 5 mg,Cmax and AUC0-∞ were(4.76±2.12)ng·mL-1,(6.53±2.20)ng·mL-1·h,and Tmax,t1/2 were 0.75,1.87 h in young subjects;Cmax and AUC0-∞ were(6.40±3.25)ng·mL-1,(9.50±3.70)ng·mL-1·h,and Tmax,t1/2 were 0.63,2.66 h in elderly subjects.After a multiple dose of azvudine 5 mg·d-1 for 7 d,Cmax and AUC0-∞ were(3.26±1.61)ng·mL-1,(5.38±2.19)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.88,2.13 h in young subjects;Cmax,ss and AUC0-∞,ss were(3.97±2.09)ng·mL-1,(6.71±3.26)ng·mL-1·h,and Tmax,ss,t1/2,ss were 0.75,2.56 h in elderly subjects.Elderly/young geometric mean ratios and 90％CIs were 128.37％(88.23％-186.76％),139.93％(105.42％-185.72％),140.03％(106.33％-184.41％)for azvudine Cmax,AUC0-t,AUC0-∞ after a single dose,and were 118.66％(80.83％-174.20％),118.41％(83.60％-167.69％),118.95％(84.78％-166.89％)for azvudine Cmax,AUC0-t,AUC0_∞ after a multiple dose of azvudine 5 mg·d-1 for 7 d.Conclusion After single and multiple oral administration of azvudine tablets,systemic exposure to azvudine was higher in healthy elderly subjects compared with healthy young subjects.After taking azvudine tablets,the types,severity and incidence of adverse events and adverse drug reactions in healthy elderly people were not significantly different from those in healthy young subjects.Azvudine was found to be safe and well tolerated in healthy elderly subjects.

Objective To explore the causal relationship between social stress and tinnitus onset using a two-sample Mendelian randomization approach. Methods Genetic data pertaining to social stress and tinnitus were extracted from genome-wide association studies (GWAS) databases. Single nucleotide polymorphisms (SNP) that were independent and strongly correlated with social stress were selected as instrumental variables, with tinnitus serving as the outcome variable. Mendelian randomization analyses were performed using inverse-variance weighted (IVW) method, weighted median method, and Mendelian randomization-Egger regression. The intercept term from Mendelian randomization-Egger regression was utilized to assess horizontal pleiotropy, Cochran's Q statistic was employed to evaluate heterogeneity, and leave-one-out analysis was conducted for sensitivity assessment. Results The social stress dataset encompassed 459, 742 samples, while the tinnitus dataset comprised 117, 882 samples. A total of 10 SNPs tightly associated with social stress were identified as instrumental variables. The analysis results of random-effects inverse variance weighting (IVW), weighted median method, and Mendelian randomization-Egger regression were similar (OR=1.251, 1.274, 1.438), indicating that social stress was a risk factor for tinnitus, and there was a positive causal effect between them, with no heterogeneity or pleiotropy in the results. Conclusion There is a causal relationship between social stress and tinnitus onset, which may offer novel perspectives for the clinical prevention and treatment of tinnitus in the future.

The peeled stems of Syringa pinnatifolia(SP) is a representative Mongolian folk medicine with the effects of anti-depression, heat clearance, pain relief, and respiration improvement. It has been clinically used for the treatment of coronary heart disease, insomnia, asthma, and other cardiopulmonary diseases. As part of the systematic study on pharmacological substances of SP, 11 new sesquiterpenoids were isolated from the terpene-containing fractions of the ethanol extract of SP by liquid chromatography-mass spectrometry(LC-MS) and proton nuclear magnetic resonance(~1H-NMR) guided isolation methods. The planar structures of the sesquiterpenoids were identified by MS, 1D NMR, and 2D NMR data analysis, and were named pinnatanoids C and D(1 and 2), and alashanoids T-ZI(3-11), respectively. The structure types of the sesquiterpenoids included pinnatane, humulane, seco-humulane, guaiane, carryophyllane, seco-erimolphane, isodaucane, and other types. However, limited to the low content of compounds, the existence of multiple chiral centers, the flexibility of the structure, or lack of ultraviolet absorption, the stereoscopic configuration remained unresolved. The discovery of various sesquiterpenoids enriches the understanding of the chemical composition of the genus and species and provides references for further analysis of pharmacological substances of SP.
Syringa ; Sesquiterpenes ; Terpenes ; Asthma ; Chromatography, Liquid

OBJECTIVE: To explore the effect of dichloromethane extraction phase of ethanol extract from stem of Patrinia scabiosaefolia Fisch.(DPSS) on proliferation and differentiation of K562 cells and its related mechanism. METHODS: MTT assay was used to detect the effects of DPSS at 0, 25, 50, 100 and 200 μg/ml on the proliferation of K562 cells at 24, 48 and 72 hours. Flow cytometry was used to analyze the changes of cell cycle and apoptosis at 24 and 48 hours. Wright-Giemsa staining was used to observe the morphological changes of K562 cells. The cell surface antigens CD33 and CD11b were detected by flow cytometry. RESULTS: The proliferation of K562 cells treated with different concentrations of DPSS was inhibited in a time-dose dependent manner (r=-0.96). Cell cycle analysis showed that with the increase of DPSS concentration, cells in G₂/M phase increased (r=0.88), and cells were blocked in G₂/M phase. Flow cytometry results showed that with the apoptosis rate of K562 cells was the highest when treated with 200 μg/ml DPSS for 48 h. Morphological observation showed that the K562 cell body increased, the amount of cytoplasm increased, the ratio of nucleus to cytoplasm decreased, and the nuclear chromatin was rough after DPSS treatment. Cell differentiation antigen, CD33 and CD11b, were positively expressed after treated with DPSS. CONCLUSION DPSS can induce apoptosis through cell cycle arrest, inhibit the proliferation of K562 cells, and induce K562 cells to differentiate into monocytes, which has a potential anti-leukemia effect.
Humans ; K562 Cells ; Patrinia ; Methylene Chloride/pharmacology* ; Apoptosis ; Cell Proliferation ; Cell Differentiation

Objective:To investigate the risk factors of central lymph node metastasis (CLNM) in cN0 paillary thyroicl microcarcinoma (PTMC) and to establish a nomogram model for predicting the probability of cN0 PTMC CLNM.Methods:The clinicopathological data of 192 patients with cN0 PTMC admitted to the Department of General Surgery of the Second Hospital of Lanzhou University from Aug. 2016 to Aug. 2020 were retrospectively analyzed. There were 41 males and 151 females, 50 with CLNM and 142 without CLNM. The patients were divided into 2 groups according to the presence or absence of pathologically confirmed CLNM. Patient’s age, gender, tumor diameter, multiple, with Hashimoto’s disease, with nodular goiter, with or without near the posterior dorsal membrane, aspect ratio >1, with or without extratumoral infiltration, with or without lymphadenopathy, TSH levels, and TG levels were statistically analyzed. Pearson chi-square test was used to analyze the count data of hypothesis test, and the R language software package was used for Logistic multivariate analysis. The entry conditions were screened by stepwise regression to establish a nomogram prediction model, and the Bootstrap method was used for model verification. P<0.05 was considered statistically significant. Results:Multivariate logistic analysis showed that extratumoral invasion ( P=0.032) , presence of lymphadenopathy ( P=0.010) , and TG>68 μg/L ( P=0.007) were risk factors for central lymph node metastasis. The optimal model was established by stepwise regression. The factors included tumor diameter ≥0.5 cm, nodular goiter, extratumoral invasion, lymphadenopathy and TG>68 μg/L (AIC: 212.27) . The nomogram model was established according to the above risk factors. The consistency index (c-index) was 0.711. The results of calibration graph drawing and internal and external validation demonstrated its good consistency and applicability. Conclusion:Extratumoral invasion, lymphadenopathy, and TG>68 μg/L are risk factors for cN0 PTMC CLNM, and the nomogram established in the study can effectively predict the CLNM rate in patients with cN0PTMC and contribute to clinicians’ diagnosis and treatment decisions.

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.
Chemotherapy, Adjuvant ; Female ; Gastrectomy ; Humans ; Male ; Neoadjuvant Therapy ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/surgery*

Objective:To explore whether peripheral blood CD8 +T lymphocyte dysfunction is correlated with the programmed death receptor-1 (PD-1) expression in patients with acute-on-chronic liver failure (HBV-ACLF). Methods:Peripheral blood mononuclear cells (PBMC) were collected from patients with HBV-ACLF and healthy controls. CD8 +T lymphocytes number and PD-1 expression condition in CD8 +T lymphocytes were detected by flow cytometry. CD8 +T lymphocytes isolated from peripheral blood of HBV-ACLF patients were further cultured in vitro. One group was added with PD-L1-IgG fusion protein (ACLF+PD-1 group), and the other group was added with IgG fusion protein (ACLF group). Proliferation ability (ki67), cell viability (CD69), and secretion ability of effector cytokines (IL-2, IFN-γ, TNF-α) were analyzed. Results:30 cases with HBV-ACLF and healthy controls were enrolled. CD8 +T lymphocytes absolute number was significantly lower in the peripheral blood of patients with ACLF group (333.88 ± 147.74)/μl than healthy controls (872.50 ± 206.64)/μl ( P < 0.001). PD-1 expression in peripheral blood CD8 +T lymphocytes were significantly increased in ACLF group (13.33% ± 2.52%), ( P = 0.027) than healthy controls (7.02% ± 2.12%). In in vitro culture, compared with healthy controls, the peripheral blood CD8 +T lymphocytes cell viability (CD69), proliferation ability (ki67) (all P ??< 0.001), and the level of cytokine production (IL-2, IFN-γ, TNF-α) (all P < 0.05) were equally weakened in patients with ACLF group. Compared with ACLF group, CD8 +T cell viability (CD69), proliferation ability (KI67) (all P < 0.05), and the level of cytokine production were weakened in ACLF+PD-1 group (all P < 0.05). Conclusion:HBV-ACLF patients have CD8 +T lymphocyte dysfunction. Therefore, PD-1 may have correlation in the regulation of CD8 +T lymphocyte dysfunction in ACLF patients.

Objective: To evaluate the effects of incretin-based therapies on body weight as the primary outcome, as well as on body mass index (BMI) and waist circumference (WC) as secondary outcomes. Methods: Databases including Medline, Embase, the Cochrane Library, and clinicaltrials.gov (www.clinicaltrials.gov) were searched for randomized controlled trials (RCTs). Standard pairwise meta-analysis and network meta-analysis (NMA) were both carried out. The risk of bias (ROB) tool recommended by the Cochrane handbook was used to assess the quality of studies. Subgroup analysis, sensitivity analysis, meta-regression, and quality evaluation based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) were also performed. Results: A total of 292 trials were included in this study. Compared with placebo, dipeptidyl-peptidase IV inhibitors (DPP-4Is) increased weight slightly by 0.31 kg [95% confidence interval ( ): 0.05, 0.58] and had negligible effects on BMI and WC. Compared with placebo, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lowered weight, BMI, and WC by -1.34 kg (95% : -1.60, -1.09), -1.10 kg/m (95% : -1.42, -0.78), and -1.28 cm (95% : -1.69, -0.86), respectively. Conclusion GLP-1 RAs were more effective than DPP-4Is in lowering the three indicators. Overall, the effects of GLP-1 RAs on weight, BMI, and WC were favorable.

BACKGROUND: Previous studies found that treatment with awn needles can improve the inflammatory response after spinal cord injury, reduce the expression of high-mobility group protein 1 (HMGB-1) and pro-inflammatory factors, and inhibit the activity of nuclear transcription factors and the occurrence of neuronal apoptosis. OBJECTIVE: To analyze the relationship between the mechanism of inflammatory response and the HMGB-1/Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway after spinal cord injury. METHODS: The T9-10 spinal cord injury model was made according to the internationally recognized modified Allen’s modeling method. The blood samples of the spinal cord and tail artery were obtained for Basso, Beattie and Bresnahan scoring at 6, 24 hours, 3 and 7 days after modeling. The HMGB-1 content in the spinal cord and tail artery serum was measured by ELISA to determine the highest point of HMGB-1 in the spinal cord and the change rule of HMGB-1 content in serum and spinal cord. Taking the highest HMGB-1 content as the research point and using glycyrrhizic acid as the HMGB-1 inhibitor, the rats were divided into four groups: model group, glycyrrhizic acid group (intragastric administration of glycyrrhizic acid, 200 mg/kg), blank group and sham operation group. The highest HMGB-1 expression was determined by ELISA. The spinal cord was obtained at the highest point of HMGB1 expression. The correlation between HMGB-1/TLR4/NF-κB signaling pathway and inflammation after spinal cord injury was explored by immunoblotting and RT-PCR detection, and the pathological changes of spinal cord in rats were observed. Approval for this study was obtained by the Animal Experimental Ethics Committee of Zhejiang Chinese Medical University. RESULTS AND CONCLUSION: The expression of HMGB-1 in the spinal cord and blood at 3 days after spinal cord injury was significantly higher than that at 6 hours, 24 hours, and 7 days (P < 0.05). At 3 days after spinal cord injury, the expressions of HMGB-1, TLR4, NF-κB, interleukin-6, and tumor necrosis factor-α in the glycyrrhizic acid group were lower than those in the model group, but higher than those in the blank group and sham operation group (P < 0.05). The expressions of HMGB-1, TLR4 and NF-κB at gene and protein levels in the glycyrrhizic acid group were lower than those in the model group, but higher than those in the blank group and the sham operation group (P < 0.05). To conclude, after spinal cord injury, HMGB-1 in blood and spinal cord increased significantly and reached the highest value at 3 days. After inhibiting HMGB-1, it was found that the HMGB-1/TLR4/NF-κB pathway is one of the important pathways to induce inflammation after spinal cord injury.

OBJECTIVE: To choose the disease-causing gene in a Chinese pedigree with ankylosing spondylitis (AS) by whole-exome sequencing (WES), and provide theory basis for mechanism of disease. METHODS: Clinical data of AS pedigree were collected, including 2 males, the age were 48 and 18 years old, the course of disease were 23 and 4 years. Whole blood genomic DNA of AS was extracted to perform whole exome sequencing, the results were compared with human databases, common variations which had been reported were wiped out, then non synonymous single nucleotide variants(SNVs) from the family members were combined, and candidate genes was selected initially. RESULTS: Totally 80 G data was obtained from AS family with high quality.By comparing results between patient and normal subject, and filtering with number of biological database, the result showed heterozygous mutation of JAK2 gene 12 exon c.1709 A>G (p.Tyr570Cys) may be the potential disease-causing gene. The variant c.1151T>C of MUC3A gene may be one of the causes of intestinal symptoms in the family members. CONCLUSION It is feasible to find t candidate gene mutations of AS by Exon sequencing. The mutation c.1709 A>G in gene JAK2 identified by whole exome sequencing might be the pathogenic mutation in this AS pedigree.
Exome ; Humans ; Male ; Mucin-3 ; Mutation ; Pedigree ; Spondylitis, Ankylosing ; Whole Exome Sequencing