ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans ; Antiviral Agents/therapeutic use* ; Animals ; Male ; Adult ; Mice ; Female ; Endonucleases/antagonists & inhibitors* ; Influenza, Human/drug therapy* ; Young Adult ; Dibenzothiepins/pharmacology* ; Oseltamivir/pharmacology* ; Middle Aged ; Triazines/pharmacology* ; Thiepins/pharmacology* ; Influenza B virus/drug effects* ; Influenza A Virus, H1N1 Subtype/drug effects* ; Pyridines/pharmacology* ; Morpholines ; Pyridones

[摘 要] 目的：研究芳香烃受体（AHR）在乳腺癌中的表达及其对乳腺癌细胞增殖、凋亡和药物敏感性的调控机制。方法：通过GEPIA数据库数据分析乳腺癌组织及癌旁组织中AHR的表达水平，探讨其与患者生存期的关联。利用基因敲低和过表达技术构建AHR表达变化的乳腺癌细胞，采用CCK-8实验、细胞计数和流式细胞分析等方法评估AHR对细胞增殖、凋亡和药物敏感性的影响，通过免疫印迹法验证相关分子机制。此外，利用AHR激动剂6-甲酰基吲哚并[3,2-B]咔唑（FICZ）研究外源性激活AHR对乳腺癌细胞多柔比星（DOX）敏感性的影响。结果：GEPIA数据库数据分析结果显示，乳腺癌组织中AHR呈明显低表达（P < 0.05）；对155例乳腺癌患者的生存期进行统计分析也显示AHR低表达与不良预后呈正相关（P < 0.05）。敲低AHR促进细胞增殖（P < 0.05），过表达则能抑制其增殖（P < 0.05）并促进其凋亡（P < 0.05）。外源激活AHR能增强乳腺癌细胞对DOX的敏感性（P < 0.05）。AHR可与MYC基因启动子结合，抑制MYC表达（P < 0.05），从而影响乳腺癌的进展。结论：AHR在乳腺癌中通过调控MYC表达影响细胞增殖和凋亡，外源激活AHR可能成为提高乳腺癌细胞对DOX敏感性的治疗策略。

Transcranial direct current stimulation (tDCS) is a well-tolerated, safe and noninvasive physical brain stimulation method, which has been widely used in the treatment of some common mental disorders and neurological diseases and has achieved certain clinical effects. It is necessary to develop expert consensus on clinical treatment to improve the use norms in related fields. According to the clinical research published before August 2021 and the method of evidence-based medicine, we published an expert consensus on tDCS in the treatment of depressive disorders, schizophrenia, substance use-related disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder, autism, anxiety disorders, post-traumatic stress disorder, sleep disorders, pain, Parkinson′s disease, stroke, and epilepsy. The consensus also introduced the safety and efficacy of the clinical use of tDCS, and standardized the treatment process and operation technology, aiming to provide guidance for the clinical application of tDCS and promote the standardized development of this treatment technology in the future.

Transcranial direct current stimulation (tDCS) is a well-tolerated, safe and noninvasive physical brain stimulation method, which has been widely used in the treatment of some common mental disorders and neurological diseases and has achieved certain clinical effects. It is necessary to develop expert consensus on clinical treatment to improve the use norms in related fields. According to the clinical research published before August 2021 and the method of evidence-based medicine, we published an expert consensus on tDCS in the treatment of depressive disorders, schizophrenia, substance use-related disorders, obsessive-compulsive disorder, attention deficit hyperactivity disorder, autism, anxiety disorders, post-traumatic stress disorder, sleep disorders, pain, Parkinson′s disease, stroke, and epilepsy. The consensus also introduced the safety and efficacy of the clinical use of tDCS, and standardized the treatment process and operation technology, aiming to provide guidance for the clinical application of tDCS and promote the standardized development of this treatment technology in the future.

【Objective】 To investigate whether 17β-estradiol (βE2) can activate the NF-E2-related factor 2(Nrf2) pathway to resist the downregulation of retinal function induced by light damage. 【Methods】 Two weeks after female SD rats were castrated, they were divided into the following six groups: control group (control), light-damage group (LD), saline group, saline light-damage group (saline-LD), βE2 group, and βE2 light-damage group (βE2-LD). Rats in the light-damage were exposed to 8000-lux fluorescence for 12 h after 18 h of dark adaptation. Then electroretinogram (ERG), immunofluorescence, Real-time PCR and immunohistochemical detection were performed after one day of dark recovery. 【Results】 The results of ERG showed that ERG was lower in LD group than in control group (P<0.05). After light damage, ROS was increased and the mRNA expressions of antioxidant genes, such as Sod1, Sod2, Cat, Glrx1, Glrx2, Txn1, and Txn2 were decreased (all P<0.05). After βE2 administration, compared with those in saline-LD, ROS level was decreased, the levels of Nrf2 protein and antioxidant genes were increased, and ERG was recovered to a certain extent in βE2-LD (P<0.05). 【Conclusion】 βE2 can restore the function of rat retina, and its mechanism might be related to the upregulation of Nrf2 and antioxidant genes.

Objective To investigate the effect of flipped classroom model in the theory teaching of urology,and to provide a reference for promoting teaching methods.Methods The clinical medicine classes 1 and 2 of 2014 in the five-year undergraduate program,with 120 students in each class,were enrolled,with class 1 as teaching reform class and class 2 as traditional teaching class.The flipped classroom model was applied in class 1,and the traditional teaching method was applied in class 2.Tests and questionnaires were used at the end of the class to evaluate teaching effect.All the data were analyzed by Graphpad Prism 6.1,t test and Chi-square test were used for stabistical analysis.Results There were significant differences between the teaching reform class and the traditional teaching class in the mean score of chapter test [(80.78± 9.02) vs.(75.03 ± 7.98),P ＜0.05] and the mean score of comprehensive quality [(82.09 ± 8.89) vs.(76.34 ± 6.45),P＜0.05].The questionnaire survey showed an overall degree of satisfaction of 98.5％ among students;81.67％ of all students actively participated in learning,91.67％ were willing to participate in the teaching with flipped classroom model,75.84％ thought this model improved learning enthusiasm,65％ thought it improved the ability of self-study,73.33％ thought it improved their understanding of the learning content,and 84.17％ thought it strengthened the communication between teachers and students.Conclusion The flipped classroom model has a better effect than the traditional teaching model in the theory teaching of urology and is easily accepted by students.Therefore,it holds promise for clinical application.

Objective To study the correlation between serum lipids and thyroid function after withdrawn of thyroid hormone in the patients with differentiated thyroid cancer .Methods One hundred and thirty cases of differentiated thyroid carcinoma treated by operative therapy in our hospital form August 2014 to August 2015 were selected .Serum FT4 ,TSH ,FT3 ,triglyceride ,total cho-lesterol ,LDL-C ,HDL-C indexes were detected before discontinuation of levothyroxine sodium (L-T4) ,before operation and 3 weeks after drug withdrawn .Thus the correlation between blood lipid levels and thyroid function was analyzed .Results The HDL-C and the TSH level was positively related before operation (P<0 .05) ,other indexes had no obvious correlation with thyroid function (P>0 .05);the blood lipid levels after medication withdrawn had no obvious correlation with thyroid function (P>0 .05);the total cholesterol levels after medication discontinuation had negative correlation with FT 3 and FT4 levels(P<0 .05);HDL-C was nega-tively correlated with FT3 and FT4 levels(P<0 .05) ,and positively correlated with TSH level (P<0 .05);LDL-C was negatively correlated with FT4 (P<0 .05) .Conclusion When the application treatment of thyroid hormone is suspended ,with the TSH level increase ,the HDL-C level has somewhat elevation ;total cholesterol ,HDL-C and LDL-C levels are negatively correlated with FT 3 and FT4 ,after discontinuation of medication withdrawn ,the blood lipids metabolism abnormality is closely related with thyroid function decline .

Objective:To investigate the relationship between VitD 3 concentration and glucose and insulin levels of OGTT in patients with CKD 3-5 stages.Methods: We included the patients with CKD 3 and 4 and 5 stages who fulfill the including standard.All patients were recorded the concentrations of [1,25 (OH):D3]concentration of glucose and insulin at fasting ,postprandial 1 h,2 h during OGTT and concentration of glycosylated hemoglobin level ,C peptide concentration.We performed the correlation analysis about [1,25 (OH):D3],glucose and insulin.Results: We totally included 91 patients with 3-5 stages CKD into our study.The D3 concentration of stage 3 were 160.9-261.3 mmol/L[(218.38±8.67)mmol/L] of stage 3,75.2-166.3 mmol/L[(117.01±4.72) mmol/L] of stage 4 and 11.8-96.5 mmol/L[(41.91±12.83)mmol/L] of stage 5 (P<0.05).The average concentrations of serum glucose at fasting,1 h after the meal and 2 h after the meal was(4.74±0.21)mmol/L,(8.31±0.43)mmol/L and(7.36±0.32)mmol/L in 3 stage and (4.92±0.25) mmol/L,(9.14±0.15) mmol/L and (9.14±0.39)mmol/L at 4 stage and (4.81±0.13)mmol/L, (10.72±0.41)mmol/L and (10.72±0.49)mmol/L at 5 stage (P<0.05).The average concentrations of insulin during OGTT at fasting,1 h after the meal and 2 h after the meal was (6.58±0.32) μU/L,(57.78±5.63)U/L and (42.77±8.45)U/L in 3 stage (6.03±0.53)U/L,(55.69±7.35)U/L and (62.52±5.39)U/L in 4 stage and (6.12±0.65)U/L,(62.82±9.73)U/L and (77.34± 8.62)U/L in 5 stage (P<0.05).Correlation analysis shows that the concentration of 1,25 (OH):D3 of different stages of patients with CKD and vitamin D 3 concentration and glucose tolerance test was found to be inversely associated with the insulin levels ( P<0.05 ) . Conclusion:There are obvious differences of concentration of vitamin D 3 between patients with 3-5 stages of chronic kidney disease (CKD).There also showed a negative correlation relationships between glucose and insulin levels ,and vitamin D3 concentration and glucose and insulin levels at OGTT of patients with 3-5 stages CKD.