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Background/Aim: Ethyl β-carboline-3-carboxylate (β-CCE) is one of the effective ingredients of Picrasma quassioides (P. quassioides). As a β-carboline alkaloid, it can antagonize the pharmacological effects of benzodiazepines by regulating neurotransmitter secretion through receptors, thus affecting anxiety and physiology. However, its efficacy in cancer treatment is still unclear. Materials and Methods: We explored the effect of b-CCE on SiHa cells using MTT assay, western blot, flow cytometry, LDH release, T-AOC, SOD, and MDA assays. Results: We investigated the cytotoxicity of β-CCE in SiHa cells and verified that β-CCE could induce cell apoptosis in a time- and concentration-dependent manner. In this process, treatment with β-CCE significantly increased the levels of cytoplasmic and mitochondrial reactive oxygen species (ROS), which disturb the oxidation homeostasis by regulating the total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and malondialdehyde (MDA) production. Notably, the addition of N-acetylcysteine (NAC) (ROS scavenger) effectively alleviated β-CCE-induced apoptosis in SiHa cells. In addition, β-CCE might activate the p38/MAPK signaling pathway, as the pre-treatment with SB203580 (p38 inhibitor) significantly reduced β-CCE-induced apoptosis in SiHa cells. Conclusion: β-CCE has an anti-tumor activity. It activates the p38/MAPK signaling pathway by increasing intracellular ROS levels, which subsequently induce SiHa cell apoptosis. Our results provide a novel therapeutic target for treatment of cervical cancer.

This study aims to systematically assess the effectiveness and safety of Huazhi Rougan granule in the treatment of non-alcoholic fatty liver.The PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), WanFang databases, VIP databases, Chinese Biomedical Literature Database (SinoMed) were searched to identify the relevant randomized controlled trials, from the establishment of the database to June 7, 2020. The Cochrane risk of bias tool for assessing risk of bias was employed to evaluate the quality of the literatures included. Meta-analyses were performed using RevMan 5.3 software.A total of 23 related literature were retrieved, 9 studies with 1,142 participants were included in the meta-analysis. The overall quality of evidence for this study is low. Meta-analysis results suggest that, Huazhi Rougan granule combined with conventional treatment was significantly superior to the silybin control group in the improvement of liver B-ultrasound, reduction of serological indexes, increase of high-density lipoprotein and total clinical effective rate, which was statistically significant. The improvement of serum lipid parameters included alanine aminotransferase (ALT): [mean deviation (MD) =-10.49, 95% confidence interval (CI): -17.09, -3.90, P0.05], aspartate transaminase (AST): (MD =-9.44, 95% CI: -14.62, -4.26, P0.05), total cholesterol (TC): (MD =-0.77, 95% CI: -0.94, -0.60, P0.05), triglyceride (TG): (MD =-0.40, 95% CI: -0.56, -0.24, P0.05). Reduce low-density lipoprotein cholesterol: (MD =-0.40, 95% CI: -0.56, -0.24, P0.05). Clinical effective rate: [risk ratio (RR) =1.25, 95% CI: 1.16, 1.36, P0.05]. Occurrence of adverse reactions: Of the 9 studies included, 5 reported adverse reactions, of which 3 reported no drug-related adverse reactions. Adverse reactions were reported in 2 cases, all of which were mild adverse reactions.The clinical efficacy of Huazhi Rougan granule combined with conventional basic therapy in the treatment of non-alcoholic fatty liver may be better than that of conventional basic therapy combined with silybin, which may improve the B-ultrasonic grading effect of the liver and reduce the serum lipid parameters of the patients. it may improve the clinical symptoms of non-alcoholic fatty liver, and the incidence of adverse reactions is low, but the number of existing clinical studies is small and the quality is low, in order to further verify the above conclusions. More high-quality clinical RCT trials need to be carried out, and internationally recognized outcome indicators should be selected and uniformly included in the scoring criteria.

Background As the use of Chinese herbal medicine (CHM) in the international market increases, the number of clinical studies including randomized controlled trials (RCTs) of CHM which published in international journals has also increased. Using bibliometrics, we systematically and comprehensively analyzed the research status of CHM RCTs published in English during the period of 2010 to 2019. Methods Electronic searches in MEDLINE, EMBASE, and Cochrane Library databases were undertaken. CHM RCTs published in English between January 2010 and December 2019 were included. We randomly selected 20% from the eligible articles. Descriptive statistical analysis was carried out by extracting information on general information, characteristics of the study participants, interventions, outcomes, and risk of bias assessment of included RCTs. Results Two hundred and twenty-seven CHM RCTs published in English were included in our study. Chinese Journal of Integrative Medicine was the journal which published most of the relevant papers (22.0%). A total of 45,774 participants were included, sample size ranged from 12 to 3,143 (median: 115). The most common disease was the circulatory diseases (n=36, 15.9%). Decoction was the most common dosage form (28.2%), and "CHM vs. placebo" was the most common type of control (36.1%). The median of the total number of outcomes was 4 (range: 1-14), 92 (40.5%) did not clearly specify any primary outcome, 56 (24.7%) did not report any adverse event, 41 (18.1%) and 68 (30.0%) reported traditional Chinese medicine (TCM)- specific outcomes and quality of life, respectively. Eighty-five (37.4%) did not report sufficient information about the random sequence generation process, 100 (44.1%) used the adequate allocation concealment, 92 (40.5%) blinded participants and key study personnel, and 24 (10.6%) blinded outcome assessors. Conclusions Our results provided insight into the research status regarding CHM RCTs published in English during the past decade, this study may be helpful in understanding research trends in this field.

It has been established that obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. Chronic intermittent hypoxia (CIH) activates sympathoadrenal system and upregulates β3 adrenergic receptor (β3 AR). However, the effect of selective β3 AR agonist mirabegron in CIH-induced atherosclerosis remains unknown. We generated a CIH-induced atherosclerosis model through exposing ApoE−/− mice to CIH (8 h per day, cyclic inspiratory oxygen fraction 5–21%, 60-s cycle) for 6 weeks after 4-week high-fat dieting and investigated the effects of mirabegron, a selective β3 AR agonist, on CIH-induced atherosclerosis. The coronary endarterectomy (CE) specimens from coronary artery disease patients with OSA and without OSA were collected. The expression of β3 AR was significantly elevated in CIH-induced atherosclerosis model. Furthermore, treatment with mirabegron (10mg/kg per day by oral administration for 6 weeks) ameliorated atherosclerosis in ApoE−/− mice in CIH but not in normoxia. Mechanistically, mirabegron activated β3 AR and ameliorated intraplaque oxidative stress by suppressing p22phox expression and reactive oxygen species (ROS) level. In addition, in human CE specimens, β3 AR was also upregulated associated with increased p22phox expression and ROS level both in the lumen and in the plaque of coronary artery in OSA subjects. This study first demonstrated that mirabegron impeded the progression of CIH-induced atherosclerosis, at least in part, via β3 AR–mediated oxidative stress, suggesting a promising therapeutic strategy for protecting against atherosclerosis induced by CIH.

The paper introduces the placebo acupuncture simulation devices commonly used in clinical trial of acupuncture therapy. These devices are composed of Streitberger, Park, Takakura, Foam and Phantom acupuncture. Because acupuncture therapy is a kind of complex intervention, there are the controversies in methodology for the acupuncture placebo control of clinical trial. Placebo acupuncture may be an effective control, with a certain of specific therapeutic effect. The blinding effect of placebo acupuncture is highly questioned, specially, the sensation of介绍针刺临床试验中常用的安慰针刺模拟装置，包括Streitberger装置、Park装置、Takakura装置、Foam装置以及幻影针刺。针刺是一类复杂干预，围绕针刺临床试验安慰剂对照的方法学争论主要包括：安慰针刺可能是一类有效对照，也具有一定的特异性疗效；安慰针刺的设盲效果备受质疑，尤其是很难模仿针刺过程中的得气感。本研究据此对针灸临床试验中安慰剂对照的选择和使用情境给出建议。.

Thequot;triple combinationquot; review system provides an opportunity for the transformation of human use experience into new Chinese drugs. However, there are some methodological and technical limitations in the assessment of human experience. Hence, the efficacy and safety evaluation methods should be established in accordance with the characteristics of Chinese herbs. This study summarized some evidence-based methodology to promote the transformation of human use experience to new Chinese drugs, mainly including the individualized pragmatic randomized controlled trial(RCT), cluster RCT, single-case RCT, single arm RCT with objective performance criteria, and partially nested RCT. As the real world data can be used to support the transformation of human experience, attention should be paid to convenient and efficient collection of data, prudent selection of design types, and adoption of appropriate ana-lysis methods to deal with confounding bias, including multi-factor regression model and propensity score. The newly proposed mixed research method can also be utilized to assess the human use experience, which is suitable for mining the theory of traditional Chinese medicine(TCM) and expert experience from different aspects. Meanwhile, considering the study design requirements and TCM cha-racteristics, this study put forward the common problems and solutions in the development of new Chinese drugs based on human use experience, including how to select the feasible outcome indicators, how to collect prescription data in the case of herb and dosage adjustment, and how to evaluate the comprehensive effectiveness of TCM from the perspective ofquot;combination of disease and syndromequot;.

The appropriate sample size estimation is very important in the design of clinical trials. However, insufficient or inappropriate sample size estimation is still a prominent problem in the currently published acupuncture and moxibustion clinical trials. At present, the superiority test, non-inferiority test and equivalence test have been widely used in acupuncture and moxibustion clinical trials. This article focuses on the application, calculation methods and PASS11 software using of these three hypothesis test types. In view of the problems in the estimation of sample size in acupuncture and moxibustion clinical trials, the particularity of sample size estimation in acupuncture and moxibustion is summarized from the aspects of parameter setting, ratio of intervention group and control group, and multi-group comparison, in order to guide acupuncture clinical researchers to correctly estimate sample size when conducting clinical trials.确定合适的样本量是临床试验研究设计的关键步骤，而未报告样本量估计或估计不合理在目前发表的针灸临床试验中仍是一个比较突出的问题。目前临床试验假设检验类型的优效性试验、非劣效性试验和等效性试验已普遍应用于针灸临床试验中，本文针对这3种类型的适用情况、计算方法和PASS11软件的操作进行介绍。并针对针灸临床试验样本量估计时存在的问题，从参数设定、组间比例确定、多个比较组方面，对针灸领域样本量估计的特殊性进行总结，以期指导针灸临床研究者在进行临床试验时正确估计样本量。.

In order to analyze the incidence of adverse events(AE) and evaluate the related influencing factors in randomized controlled trials(RCTs) of oral Chinese medicine which published in English, Medline, EMbase, and the Cochrane Central Register of Controlled Trials(CENTRAL) database were searched. Oral Chinese medicine RCTs published in English from January 2009 to July 2018 were collected to extract the basic characteristics, subjects, intervention characteristics and AE information. The AE incidence of each study was merged by using Meta analysis. Finally, 218 RCTs were included, of which 28.4% did not report any AE. A total of 1 634 AE occurred in 103 oral Chinese medicine groups, and the total incidence of AE was 11.2%(95%CI[10.7%, 11.7%]). The highest incidence of AE came to blood routine laboratory abnormalities, 8.0%(95%CI[6.6%, 9.7%]), followed by neurological and psychiatric systems 7.9%(95%CI[6.6%, 9.5%]), digestive system 7.8%(95%CI[6.8%, 8.9%]) and liver function abnormalities 7.6%(95%CI[6.4%, 8.9%]). Among the oral dosage forms, tablets and granules had the highest incidence of AEs, while decoction and oral liquids had the lowest incidence. The combination of oral Chinese medicine and Western medicine had the highest incidence of AE. As the medication course increased, the incidence of AE increased accordingly. The incidence of AE in children was higher than that in adults. Based on the analysis results, the higher AE incidence of oral Chinese medicine was in the neuropsychiatric system, gastrointestinal system and liver function abnormalities. The incidence of AE was related to the dosage form, drug combination, medication duration, and patient age. We should pay attention to the AE in children due to modern dosage forms of traditional Chinese medicine, combination of Chinese and Western medicine, and long course of medication.

Purpose To determine the ability of nonperfusion, vessel density, and morphologic measurements using projection-resolved optical coherence tomography angiography to detect early retinal microvasculature impairments in diabetes mellitus. Methods A retrospective review was performed on Type 2 diabetes mellitus patients with no diabetic retinopathy (DR) or mild nonproliferative DR and age-matched controls imaged with optical coherence tomography angiography. Foveal avascular zone-related metrics and extrafoveal avascular area were measured in optical coherence tomography angiography images. Vessel density and fractal dimension were calculated with and without a skeletonization process. The vessel diameter index and vessel tortuosity were computed. The area under the receiver operating characteristic curve (AUC) estimated diagnostic performances. Results Dilated capillary diameter was observed in the deep capillary plexus in the diabetic groups. Vessel density and fractal dimension of skeletonized deep capillary plexus significantly and progressively decreased in the no DR and mild nonproliferative DR groups compared with controls. Superficial extrafoveal avascular area, vessel density, and fractal dimension of the skeletonized deep capillary plexus had the highest diagnostic performance to differentiate mild nonproliferative DR from control eyes, with AUCs of 0.885, 0.876, and 0.876, respectively. Conclusion Vessel density and fractal dimension from the skeletonized deep capillary network may be the most sensitive for detecting early retinal capillary loss in diabetes mellitus.

It has been recognized that patients with hypothyroidism have higher risks of atherosclerosis and coronary heart disease, however, the mechanisms are largely unknown. Considering that macrophage dysfunction plays an important role in the formation and development of atherosclerosis plaques, this study aimed to investigate the direct effects of thyroid hormone on macrophage functions and to provide new insight for the mechanism of hypothyroid atherosclerosis. RAW264.7 cells (mouse leukaemic monocyte macrophage cell line) were incubated with oxidized low-density lipoprotein (oxLDL) to establish macrophage foam cells model in vitro, and the protective effects of different concentration of thyroxine (T4) on the macrophage foam cells function were explored. The proliferation, migration and cell aging of macrophages were detected by MTT method, scratch test and β-galactosidase staining respectively. The ELISA method was used to detect the secretion of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin-1β (IL-1β). Western blot analysis was applied to measure the phosphorylation of focal adhesion kinase (FAK), which was required for the process of proliferation and migration of macrophages. The results showed that oxLDL significantly inhibited the macrophage proliferation and migration, induced cell senescence, and promoted the secretion of TNF-α, MCP-1, and IL-1β; while T4 reversed those effects of oxLDL on macrophage in a concentration-dependent manner. Moreover, oxLDL increased the phosphorylation of FAK in macrophage, while T4 concentration-dependently reversed the effect. These results suggest that T4 modulates macrophage proliferation, migration, senescence, and secretion of inflammation factors in a concentration-dependent way.

This article is the series of methodology of clinical prediction model construction (total 16 sections of this methodology series). The first section mainly introduces the concept, current application status, construction methods and processes, classification of clinical prediction models, and the necessary conditions for conducting such researches and the problems currently faced. The second episode of these series mainly concentrates on the screening method in multivariate regression analysis. The third section mainly introduces the construction method of prediction models based on Logistic regression and Nomogram drawing. The fourth episode mainly concentrates on Cox proportional hazards regression model and Nomogram drawing. The fifth Section of the series mainly introduces the calculation method of C-Statistics in the logistic regression model. The sixth section mainly introduces two common calculation methods for C-Index in Cox regression based on R. The seventh section focuses on the principle and calculation methods of Net Reclassification Index (NRI) using R. The eighth section focuses on the principle and calculation methods of IDI (Integrated Discrimination Index) using R. The ninth section continues to explore the evaluation method of clinical utility after predictive model construction: Decision Curve Analysis. The tenth section is a supplement to the previous section and mainly introduces the Decision Curve Analysis of survival outcome data. The eleventh section mainly discusses the external validation method of Logistic regression model. The twelfth mainly discusses the in-depth evaluation of Cox regression model based on R, including calculating the concordance index of discrimination (C-index) in the validation data set and drawing the calibration curve. The thirteenth section mainly introduces how to deal with the survival data outcome using competitive risk model with R. The fourteenth section mainly introduces how to draw the nomogram of the competitive risk model with R. The fifteenth section of the series mainly discusses the identification of outliers and the interpolation of missing values. The sixteenth section of the series mainly introduced the advanced variable selection methods in linear model, such as Ridge regression and LASSO regression.

Taking the construction of STKOS (Science and Technology Knowledge Organization System) Service System in Intelligence 3.0 as the mainline, this paper first analyzes various functions that the system shall have, and designs the overall architecture of the system. Second, it introduces the implementation of the system from the perspectives of STKOS registration, triple retrieval, visual presentation and Web services. At last, it presents the key points in the future study.

Development of skeletal muscle is a complicated biological process regulated by various regulation factors and signal pathways. MicroRNAs (miRNAs) are novel gene regulators that control muscle cell development. microRNA-143 (miR-143) is highly expressed in skeletal muscle, and we found that miR-143 level is significantly increased during bovine skeletal muscle satellite cells (MSCs) differentiation process through microarray analysis and qRT-PCR detection. However, the function of miR-143 in bovine muscle development remained unclear. In our work, the functions of miR-143 in bovine MSCs myogenic differentiation were investigated. We discovered that IGFBP5 is directly regulated by miR-143 using a dual-luciferase reporter assay. Overexpression of miR-143 led to decreased level of IGFBP5 protein and restrained cell proliferation and differentiation, while downregulation of miR-143 resulted in increased levels of IGFBP5 protein and restrained cell proliferation but improved differentiation. IGFBP5, an important component of IGF signaling pathway, contributes greatly to bovine muscle cell development. A mechanism that miR-143 can regulate the proliferation and differentiation of bovine MSCs through changing expression of IGFBP5 was elucidated by our study.

The development of a scientific evaluation tool is a prerequisite to reflect the efficacy of traditional Chinese medicine (TCM). At present, separate analysis of each outcome is the most commonly used method in randomized controlled trials (RCTs) of TCM, while this method has been reported to have some limitations. Combination evaluation of multiple primary outcomes including diseases and symptoms can reflect the efficacy of TCM comprehensively and objectively. Now, several multivariate statistical methods have been proposed to analyze RCTs with multiple clinical outcomes. In this article, we highlighted the two commonly used methods, global statistical test (GST) methodology and alpha-adjustment procedures, and introduced an evaluation mode. First, we used one stage adaptive adjustment strategy to estimate the correlation among multiple primary outcomes in blindness, which can resolve the inappropriate correlation estimation among multiple primary outcomes, then we introduced an adaptation of the Bonferroni procedure which can account for correlated data to calculate the alpha of individual outcome. GST using O’Brien ranking procedure and the corresponding global treatment effect (GTE) measure were used to assess the treatment’s global impact. We will conduct a randomized, double-blind, controlled trial with compound Danshen dripping pills for stable angina to explore establishing the evaluation mode. We hope that the introduction of this approach can provide methodological aid for the assessment of therapeutic effect of TCM.