Investigation and analysis of the current status of clinical research nurses / 中国临床药理学与治疗学

AIM: To investigate and analyze the current situation and needs of clinical research nurses in China, in order to provide scientific basis for constructing a training system for research nurses, promoting standardized training, and achieving standardized management for them. METHODS:A self-made questionnaire was used to investigate 102 research nurses from nearly 70 well-known clinical trial institutions in China. The contents of the questionnaire mainly included the general information, professional experience and work content of the research nurses, the sense of accomplishment and training needs of clinical trial work. RESULTS: Among the 102 research nurses surveyed, 92.15% have a bachelor's degree or above; 53.92% of those have intermediate or higher professional titles; 74.51% of them are part-time research nurse. Among professional experiences, 19.61% have more than 10 years of clinical trial experience; 47.06%, 40.20%, and 21.17% of surveyed research nurses were authorized to participate in clinical trial drug management, sample management, and quality control; 70.59% of research nurses have a high sense of achievement in their daily work. In terms of education and training needs, clinical trial related laws and regulations, standardized training for clinical trial protocol implementation, and good clinical practice (GCP) are the three most important aspects. CONCLUSION: Clinical research nurses in China have a relatively high level of education and nursing experience, but there is still a large gap in the amount of professional full-time clinical research nurses in China. Due to the rapid development of innovative drugs and devices, as well as the urgent need to improve the clinical research system, it is necessary to establish a training, assessment, and evaluation system for research nurses that is in line with China's national conditions in order to improve the professional level of research nurses, and improve the quantity and quality of clinical trial research on innovative drugs and devices in China.

Effect of Linggui Zhugantang on Mitochondrial Fusion-fission and Sirt3/ AMPK Signaling Pathway in Chronic Heart Failure Rats After Myocardial Infarction / 中国实验方剂学杂志

ObjectiveTo investigate the effects of Linggui Zhugantang on mitochondrial fission and fusion and silencing information regulator 3（Sirt3）/adenosine monophosphate dependent protein kinase （AMPK） signaling pathway in chronic heart failure （CHF） rats after myocardial infarction （MI）. MethodSD rats randomly divide into sham operation group （normal saline ，thread only without ligature）， model group （normal saline， ligation of the left anterior descending coronary artery proximal to the heart）， Linggui Zhugantang group （4.8 g·kg-1） and Captopril group （0.002 57 g·kg-1）， with 10 rats in each group. Administere drug continuously for 28 days. Echocardiography detected cardiac function parameters. Hematoxylin eosin （HE） staining observed the pathological changes of the heart. Immunofluorescence detected the levels of reactive oxygen species （ROS）. JC-1 detect mitochondrial membrane potential. Colorimetry measure adenosine triphosphate （ATP）， superoxide dismutase （SOD）， malondialdehyde （MDA）， mitochondrial respiratory chain complex activity （Ⅰ-Ⅳ）. TdT-mediated dUTP nick end labeling （TUNEL） staining detected the apoptosis rate of myocardial tissue. Western blot detected protein expression levels of Sirt3， phosphorylated AMPK （p-AMPK）， phosphorylated dynamic-related protein 1（p-Drp1）， mitochondrial fission protein 1（Fis1）， mitochondrial fission factor （MFF）， optic atrophy protein 1（OPA1）. ResultCompared to the sham group， the left ventricular end diastolic diameter （LVIDd） and left ventricular end systolic diameter （LVIDs） were significantly increased in model group （P<0.01）， while the left ventricular short axis shortening rate （LVFS） and left ventricular ejection fraction （LVEF） were significantly decreased （P<0.01）. There were inflammatory cell infiltration and obvious pathological injury in myocardial tissue. ROS， MDA levels and myocardial cell apoptosis rate were significantly increased （P<0.01）， SOD level， ATP content， and membrane potential were significantly decreased （P<0.01）. The activity of mitochondrial respiratory chain complexes （Ⅰ-Ⅳ） was significantly decreased （P<0.01）. Levels of p-Drp1， Fis1， MFF proteins were significantly up-regulated （P<0.01）， while Sirt3， p-AMPK， OPA1 proteins level were significantly down-regulated （P<0.01）. Compared with model group， LVIDd and LVIDs were significantly decreased （P<0.01）， LVEF and LVFS were significantly increased （P<0.01）. Inflammatory cell infiltration and pathological damage of myocardial tissue were significantly relieved. ROS， MDA levels and myocardial cell apoptosis rate were significantly decreased in Linggui Zhugantang group and Captopril group （P<0.01）， SOD level， ATP content， and membrane potential significantly increased （P<0.01）. The activity of mitochondrial respiratory chain complexes （Ⅰ-Ⅳ） increased significantly （P<0.01），and p-Drp1， Fis1， MFF protein levels were significantly down-regulated （P<0.01）， Sirt3， p-AMPK， OPA1 protein were significantly up-regulated （P<0.01）. ConclusionLinggui Zhugantang can alleviate oxidative stress and apoptosis damage of myocardial cells， maintain mitochondrial function stability， and its effect may be related to mitochondrial mitosis fusion and Sirt3/AMPK signaling pathway.

Estimation model for the exposure of mycophenolic acid in early renal transplant recipients / 中国药房

OBJECTIVE To establish the estimation model for the exposure of mycophenolic acid （MPA） in early renal transplant recipients [calculated by the area under the plasma concentration-time curve with 12 h （AUC0－12 h）]. METHODS Twenty kidney transplant recipients， who received triple immunosuppressive therapy of mycophenolate mofetil （MMF）+tacrolimus+ methylprednisolone， were selected and given MMF dispersible tablets （750 mg， q12 h） on the 15th day after the operation； the blood samples were collected from the patients before and 0.5， 1.0， 1.5， 2.0， 3.0， 4.0， 6.0， 8.0， 12.0 hours after the administration， respectively. The blood concentration of MPA was determined， and the pharmacokinetic parameters of MPA were calculated. The multivariate linear stepwise regression analysis method was used to fit an estimation formula for the finite sampling method suitable for MPA-AUC0－12 h of the recipients. Bland-Altman analysis was used to evaluate the agreement between the estimation formula and the classical pharmacokinetic method. RESULTS The main pharmacokinetic parameters of MPA in 20 renal transplant recipients： c0 was （1.53±0.84） μg/mL， cmax was （12.07±5.97） μg/mL， t1/2 was （5.41±3.67） h， tmax was （1.58±0.75） h， and the average AUC0－12 h calculated by the classical pharmacokinetic method was （33.95±13.40） μg·h/mL. MPA-AUC0－12 h was estimated with sampling points of “4.0， 8.0， 12.0 h”； the simplified calculation formula was AUC0－12 h＝12.058+2.819c4.0+7.045c8.0+ 3.879c12.0 （R 2＝0.934）. The predicted value had a good correlation and consistency with the measured value， and 95.0% of predicted values did not exceed the x±1.96SD （standard deviation） range. CONCLUSIONS The estimation model is established successfully for the exposure of MPA in early renal transplant recipients； the model has better prediction accuracy and fewer sampling points.

Association between monocyte to lymphocyte ratio and mortality in patients with continuous ambulatory peritoneal dialysis / 中华肾脏病杂志

Objective:To investigate the association of monocyte to lymphocyte ratio (MLR) with all-cause mortality and cardiovascular disease (CVD) mortality in patients with continuous ambulatory peritoneal dialysis (CAPD).Methods:It was a retrospective cohort study. The clinical data of 495 incident CAPD patients in the First Affiliated Hospital of Zhengzhou University from January 1, 2013 to December 31, 2019 were retrospectively analyzed. The optimal cut-off value of baseline MLR was determined by the receiver operating characteristic (ROC) curve for predicting all-cause death in the first year of CAPD, and then the patients were divided into high MLR group and low MLR group. The differences of clinical data and laboratory tests were compared between the two groups. The endpoint events were death (all-cause death and CVD death), conversion to hemodialysis, conversion to kidney transplantation, or follow-up until March 31, 2020. The survival curve was drawn by the Kaplan-Meier method, and the Log-rank test was used to compare the survival difference between the two groups. A Cox regression model was established to analyze the relevant factors of all-cause mortality and CVD mortality in CAPD patients.Results:The study included 495 patients, with age of (43.79±12.16) years and 308 (62.22%) males. The median age of dialysis was 17(10, 30) months. By the end of follow-up, 61(12.32%) of 495 patients had died, 51(10.51%) had been converted to hemodialysis, and 28(5.66%) had been converted to kidney transplantation. Of the 61 patients who died, 36(59.02%) died of cardiovascular events. ROC curve analysis results showed that the optimal cut-off value was 38.24%, so there were 246 cases in the high MLR group (MLR>38.24%) and 249 cases in the low MLR group (MLR≤38.24%). The all-cause mortality rates were 6.83% in the low MLR group and 17.89% in the high MLR group, and the CVD mortality rates were 3.21% in the low MLR group and 11.38% in the high MLR group, respectively. The Kaplan-Meier survival curve showed that the survival rate of the low MLR group was significantly higher than that of the high MLR group (all-cause mortality, Log-rank χ2=18.369, P<0.001; CVD mortality, Log-rank χ2=16.142, P<0.001). Using all-cause death as the end event, the 1-year, 3-year and 5-year cumulative survival rates were 99.5%, 89.4% and 79.9%, respectively, with a median survival time of 64 months in the low MLR group. The 1-year, 3-year and 5-year cumulative survival rates were 95.0%, 68.3% and 49.6%, respectively, with a median survival time of 54 months in the high MLR group. Using CVD death as the end event, the 1-year, 3-year and 5-year cumulative survival rates were 99.5%, 95.2% and 91.2%, respectively, with a median survival time of 69 months in the low MLR group. The 1-year, 3-year, and 5-year cumulative survival rates were 97.8%, 78.6%, and 60.8%, respectively, with a median survival time of 60 months in the high MLR group. Multivariate Cox regression analysis showed that MLR was independently associated with all-cause mortality ( HR=2.744, 95% CI 1.484-5.075, P=0.001) and CVD death ( HR=3.249, 95% CI 1.418- 7.443, P=0.005) in CAPD patients. According to the competing risk model analysis, MLR was still independently associated with all-cause mortality and CVD mortality in CAPD patients. Conclusion:MLR is associated with all-cause mortality and CVD mortality in CAPD patients, and can be used as a valuable indicator for judging the prognosis of CAPD patients.

Influencing factors of textbook outcomes in liver surgery after radical resection of gallbladder carcinoma: a national multicenter study / 中华消化外科杂志

Objective:To investigate the influencing factors of textbook outcomes in liver surgery (TOLS) after radical resection of gallbladder carcinoma.Methods:The retrospective case-control study was conducted. The clinicopathological data of 530 patients who underwent radical resection of gallbladder carcinoma in 15 medical centers, including the First Affiliated Hospital of Army Medical University et al, from January 2014 to January 2020 were collected. There were 209 males and 321 females, aged (61±10)years. Patients underwent radical resection of gallbladder carcinoma, including cholecystectomy, hepatectomy, invasive bile duct resection, and lymph node dissection. Observation indicators: (1) situations of TOLS; (2) influencing factors of TOLS. Measure-ment data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data between groups was conducted using the Mann-Whitney U test. The univariate analysis was conducted using the corresponding statistical methods based on data type, and variables with P<0.10 were included in multivariate analysis. Multivariate analysis was conducted using the Logistic stepwise regression model. Results:(1) Situations of TOLS. All 530 patients underwent radical resection of gallbladder carcinoma, and there were 498 cases achieving R 0 resection, 508 cases without ≥grade 2 intra-operative adverse events, 456 cases without postoperative grade B and grade C biliary leakage, 513 cases without postoperative grade B and grade C liver failure, 395 cases without severe com-plications within postoperative 90 days, 501 cases did not being re-admission caused by severe com-plications within postoperative 90 days. Of the 530 patients, 54.53%(289/530) of patients achieved postoperative TOLS, while 45.47%(241/530) of patients did not achieve postoperative TOLS. (2) Influencing factors of TOLS. Results of multivariate analysis showed that American Society of Anesthesiologists classification >grade Ⅱ, preoperative jaundice, T staging as T3?T4 stage, N staging as N2 stage, liver resection as right hemi-hepatectomy, and neoadjuvant therapy were independent factors influencing TOLS in patients undergoing radical resection of gallbladder carcinoma ( odds ratio=2.65, 1.87, 5.67, 5.65, 2.55, 3.34, 95% confidence interval as 1.22?5.72, 1.18?2.95, 2.51?12.82, 2.83?11.27, 1.41?4.63, 1.88?5.92, P<0.05). Conclusion:American Society of Anesthesiologists classification >grade Ⅱ, preoperative jaundice, T staging as T3?T4 stage, N staging as N2 stage, liver resection as right hemi-hepatectomy, and neoadjuvant therapy are independent factors influencing TOLS in patients undergoing radical resection of gallbladder carcinoma.

Role of NLRP3 inflammasome in diabetic neuropathy and prevention and treatment with traditional Chinese medicine / 中国中药杂志

As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid β(Aβ)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.

Research progress of targeting miRNAs in prevention and treatment of ventricular remodeling after myocardial infarction / 中国药理学通报

Myocardial infarction is one of the leading causes of death worldwide, appearing at the last point of atherosclerotic plaque progression and unstable rupture. Impaired cellular signals after myocardial infarction leads to maladaptive changes, leading to ventricular remodeling and heart failure. MicroRNAs (miRNAs/miRs) are a kind of non-coding small RNAs that negatively regulate gene expression and regulate protein synthesis rate by changing the stability of targeted mRNA. This article reviews the latest research progress on the involvement of miRNAs in the progression of atherosclerotic plaques, the molecular mechanism of cardiac injury and subsequent remodeling during infarction, as well as the results of clinical studies, and puts forward the problems and limitations of targeted miRNAs in the treatment of cardiovascular diseases such as myocardial infarction and ventricular remodeling.

Causative Microorganisms Isolated from Patients with Intra-Abdominal Infections and Their Drug Resistance Profiles: An 11-Year (2011-2021) Single-Center Retrospective Study / 生物医学与环境科学（英文）

OBJECTIVE@#To investigate the distribution and antimicrobial susceptibility of causative microorganisms recovered from patients with intra-abdominal infections (IAIs).@*METHODS@#A total of 2,926 bacterial and fungal strains were identified in samples collected from 1,679 patients with IAIs at the Peking Union Medical College Hospital between 2011 and 2021. Pathogenic bacteria and fungi were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Antimicrobial susceptibility testing (AST) was performed using the VITEK 2 compact system and the Kirby-Bauer method. AST results were interpreted based on the M100-Ed31 clinical breakpoints of the Clinical and Laboratory Standards Institute.@*RESULTS@#Of the 2,926 strains identified, 49.2%, 40.8%, and 9.5% were gram-negative bacteria, gram-positive bacteria, and fungi, respectively. Escherichia coli was the most prevalent pathogen in intensive care unit (ICU) and non-ICU patients; however, a significant decrease was observed in the isolation of E. coli between 2011 and 2021. Specifically, significant decreases were observed between 2011 and 2021 in the levels of extended-spectrum β-lactamase (ESBL)-producing E. coli (from 76.9% to 14.3%) and Klebsiella pneumoniae (from 45.8% to 4.8%). Polymicrobial infections, particularly those involving co-infection with gram-positive and gram-negative bacteria, were commonly observed in IAI patients. Moreover, Candida albicans was more commonly isolated from hospital-associated IAI samples, while Staphylococcus epidermidis had a higher ratio in community-associated IAIs. Additionally, AST results revealed that most antimicrobial agents performed better in non-ESBL-producers than in ESBL-producers, while the overall resistance rates (56.9%-76.8%) of Acinetobacter baumanmii were higher against all antimicrobial agents than those of other common gram-negative bacteria. Indeed, Enterococcus faecium, Enterococcus faecalis, S. epidermidis, and S. aureus were consistently found to be susceptible to vancomycin, teicoplanin, and linezolid. Similarly, C. albicans exhibited high susceptibility to all the tested antifungal drugs.@*CONCLUSION@#The distribution and antimicrobial susceptibility of the causative microorganisms from patients with IAIs were altered between 2011 and 2021. This finding is valuable for the implementation of evidence-based antimicrobial therapy and provides guidance for the control of hospital infections.

Association of endemic arsenic poisoning and abnormal electrocardiogram: Meta-analysis / 中华地方病学杂志

Objective:To evaluate the correlation between endemic arsenic poisoning and abnormal electrocardiogram (ECG).Methods:PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Wanfang data, VIP and other databases were used for literature retrieval, and epidemiological literatures related to abnormal ECG of endemic arsenic poisoning published in domestic and abroad were included in the study. The time limit was from the establishment of the database to December 1, 2020. RevMan 5.3 was used for Meta-analysis of binary variables. Random effect model was selected according to the results of heterogeneity, and odds ratio ( OR) was used as the effect index. Characteristic changes were found by subgroup analysis. Bias was published by funnel plot. Results:Nine articles were included in this Meta-analysis, with 6 articles in Chinese and 3 articles in English, respectively. The abnormal ECG changes included QTc prolongation, ST-T segment change, left axis deviation and arrhythmia. Finally, 1 975 cases were included in the exposure group, including 575 cases of abnormal ECG; 750 cases of control group, including 145 cases of abnormal ECG. Meta-analysis showed that the combined OR value [95% confidence interval ( CI)] of abnormal ECG changes was 4.41 (2.83 - 6.87), with statistical significance between the two groups ( Z = 6.56, P < 0.05); the results of subgroup analysis showed that the combined OR values (95% CI) of QTc prolongation, ST-T segment change, left axis deviation and arrhythmia were 12.30 (5.91 - 25.59), 2.74 (1.39 - 5.41), 2.93 (0.89 - 9.62) and 4.13 (2.38 - 7.17), respectively. Conclusions:Endemic arsenic poisoning may cause abnormal ECG. Prolongation of QTc caused by arsenic exposure may be the characteristic change of abnormal ECG.

Rules of acupoint selection in treatment of erectile dysfunction with acupuncture and moxibustion based on data mining technology / 中国针灸

Data mining technology was adopted to analyze the rules of acupoint selection in treatment of erectile dysfunction with acupuncture and moxibustion. All of the articles for acupuncture and moxibustion in treatment of erectile dysfunction were searched from the databases, i.e. Chinese national knowledge infrastructure (CNKI), Wanfang database, VIP, Chinese biomedical literature database (SinoMed) and PubMed, and the clinical trials on erectile dysfunction treated with acupuncture and moxibustion were screened. The database was set up by using Excel 2019 and input into R 4.0.3, and then, the therapeutic method, use frequency of acupoint, meridian tropism, collection visualization analysis, cluster analysis and association rule analysis were summarized. A total of 240 articles were included, with 516 prescriptions and 145 acupoints involved. The methods for treatment of erectile dysfunction included acupuncture and moxibustion therapy, acupuncture, acupoint injection, electroacupuncture, etc. The acupoints with high use frequency were Guanyuan (CV 4), Shenshu (BL 23), Sanyinjiao (SP 6), Mingmen (GV 4), Zusanli (ST 36), Zhongji (CV 3), Ciliao (BL 32), Qihai (CV 6), Taixi (KI 3) and Taichong (LR 3). The meridians involved with high frequency were the bladder meridian of foot-taiyang, the conception vessel, the spleen meridian of foot-taiyin, etc. The common acupoint combination was Shangliao (BL 31), Zhongliao (BL 33), Ciliao (BL 32), Xialiao (BL 34) and Sanyinjiao (SP 6), Shenshu (BL 23), Guanyuan (CV 4). In association rule analysis (confidence ≥ 90%, support ≥ 20%), there were 27 association rules in total. The acupoint combination with the highest support referred to "Shenshu (BL 23), Sanyinjiao (SP 6)→Guanyuan (CV 4)" (support 46.7%) and the acupoint combination with the highest confidence was "Sanyinjiao (SP 6), Qihai (CV 6)→Guanyuan (CV 4)" (confidence 98.0%). The acupoints could be divided into 5 effective clusters. Acupuncture and moxibustion therapy has a certain of rules of acupoint selection in treatment of erectile dysfunction, which provides the evidences for modern clinical trial and treatment.

Liuwei Dihuangwan Regulate Brain Microvessels in SAMP8 Mice Through RAGE/LRP1 Receptors / 中国实验方剂学杂志

ObjectiveTo investigate the protective effect of Liuwei Dihuangwan on neurovascular injury in SAMP8 mice. MethodThe Alzheimer's disease （AD） model with insufficiency of kidney essence was induced in 75 SAMP8 mice aging 6 months. The model mice were divided into model group， positive control group （donepezil hydrochloride， 0.747 mg·kg-1·d-1）， and high-， medium-， and low-dose Liuwei Dihuangwan groups （2.700， 1.350， 0.675 g·kg-1·d-1）， with 15 mice in each group. Fifteen SAMR1 mice were assigned to a normal control group. All mice were administered continuously for 2 months. The spatial memory of mice was tested by the Morris water maze. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the hippocampus and cortex of brain tissues. The immunohistochemical method （IHC） was used to detect the deposition of amyloid β-protein （Aβ） and the expression of von Willebrand factor （vWF） and CD34 in the hippocampus and cortex of brain tissues. Electron microscopy was used to observe the ultrastructural changes in cerebral microvessels. Western blot was used to detect the protein expression levels of the receptor of advanced glycation endproduct （RAGE）， low-density lipoprotein receptor-related protein 1 （LRP1）， vascular endothelial growth factor A （VEGF-A）， and P-selection in the hippocampus and cortex of brain tissues. ResultCompared with the normal control group， the model group showed prolonged escape latency and swimming distance （P<0.01）， increased number of glial cells， decreased number of nerve cells， blurred tight junctions or enlarged gap of the brain microvascular endothelial cells， severely injured membrane structure， swollen mitochondria of endothelial cells， ruptured membrane， massive dissolution in cristae， increased protein expression of Aβ and vWF in the hippocampus and cortex （P<0.01）， reduced protein expression of CD34 （P<0.05）， elevated protein expression of RAGE and P-selection in the cortex （P<0.01）， and decreased protein expression level of LRP1 and VEGF-A （P<0.01）. Compared with the model group， the Liuwei Dihuangwan groups showed shortened escape latency and swimming distance （P<0.05）， reduced number of glial cells in the cortex and hippocampus， increased number of microvessels in the cortex， clear double-layer membrane structure in tight junctions between the microvascular endothelial cells， increased number of mitochondria with intact membrane and recovered mitochondrial cristae， decreased protein expression of Aβ， vWF， RAGE， and P-selection in the hippocampus and cortex （P<0.05）， and increased protein expression of CD34， LRP1， and VEGF-A （P<0.05）. ConclusionLiuwei Dihuangwan can regulate Aβ metabolism through the RAGE/LRP1 receptor system and promote cerebral microvascular angiogenesis by inhibiting vWF expression and increasing VEGF-A and CD34， thereby improving cerebral microvascular injury in SAMP8 mice.

Effect of Liuwei Dihuangwan on Cognitive Ability of SAMP8 Mice by Regulating Autophagy Through PI3K/Akt/FoxO3a Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Liuwei Dihuangwan on memory function of senescence-accelerated mouse prone 8 （SAMP8） mice by regulating autophagy through the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/forkhead box O3a （FoxO3a） pathway. MethodSix male senescence-accelerated mouse resistant 1 （SAMR1） mice of SPF grade aging 6 months were assigned to a normal group， and 24 male SAMP8 mice of SPF grade aging 6 months were randomly divided into a model group， a donepezil group （0.747 mg·kg-1）， and high- and low-dose Liuwei Dihuangwan groups （2.700 and 1.350 g·kg-1）， with 6 mice in each group. The mice were treated with drugs by gavage for 2 months. Morris water maze was used to detect the learning and memory abilities of mice in each group. Nissl staining was used to observe the neurons in the cortex and hippocampus. The positive expression of microtubule-associated protein 1 light chain 3B （LC3B） in the cortex and hippocampus was detected by immunohistochemistry （IHC）. Western blot was used to detect the protein expression of the mammalian ortholog of yeast ATG6 （Beclin-1）， B cell lymphoma-2 （Bcl-2）， autophagy-related gene 5 （ATG5）， cysteinyl aspartate-specific protease 3 （Caspase-3）， Caspase-9， Akt， p-Akt， FoxO3a， and p-FoxO3a. ResultCompared with the normal group， the model group showed prolonged escape latency （P<0.05，P<0.01）， reduced number of platform crossings and the residence time in the target quadrant （P<0.01）， decreased neurons with reduced volume and dispersed distribution in the cortex and hippocampus， increased positive expression of LC3B （P<0.01）， elevated expression of Beclin-1 and ATG5 in the cortex （P<0.01）， declined Bcl-2 expression （P<0.01）， up-regulated Caspase-3 and Caspase-9 expression （P<0.01）， and decreased expression levels of p-Akt/Akt and p-FoxO3a/FoxO3a （P<0.01）. Compared with the model group， the donepezil group and the Liuwei Dihuangwan groups showed shortened 3 d escape latency （P<0.05，P<0.01）， increased number of platform crossings （P<0.01）， and prolonged residence time in the target quadrant （P<0.01）. In the donepezil group， the number of neurons in the cortex and hippocampus was increased. In the Liuwei Dihuangwan groups， the number of neurons and Nissl bodies increased with denser distribution and lower degree of cell damage. The positive expression of LC3B in the cortex and hippocampus was decreased in the donepezil group and Liuwei Dihuangwan groups （P<0.01）. The expression of Beclin-1 was decreased in the Liuwei Dihuangwan groups （P<0.01）. The expression of ATG5 was decreased in the donepezil group and the low-dose Liuwei Dihuangwan group （P<0.01）. The donepezil group and the Liuwei Dihuangwan groups showed the increased expression level of Bcl-2 in the cortex （P<0.01）， decreased expression level of Caspase-3 （P<0.01）， reduced expression level of Caspase-9 （P<0.05，P<0.01）， and elevated expression levels of p-Akt/Akt and p-FoxO3a/FoxO3a （P<0.01）. ConclusionLiuwei Dihuangwan can effectively improve the learning and memory abilities of the SAMP8 mice and protect neurons. Its mechanism may be related to the regulation of the PI3K/Akt/FoxO3a signaling pathway， down-regulation of the expression of ATG5， Beclin-1， and LC3B， and the inhibition of apoptosis.

Xiao Xianxiongtang Regulates Ca2+ Load and Inhibits Epithelial-mesenchymal Transition， Invasion， and Migration of MGC-803 Cells： Based on Wnt5a/ Ca2+/NFAT Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo explore the effect of Xiao Xianxiongtang （XXXT） on the transforming growth factor （TGF）-β1-induced invasion， metastasis， and epithelial-mesenchymal transition （EMT） of gastric cancer MGC-803 cells and the underlying mechanism. MethodThe molecular docking between XXXT and nuclear factor of activated T cells （NFAT） was performed by CB-DOCK （http：//clab.labshare.cn/cb-dock/）. The invasion and metastasis model of MGC-803 cells was established with 10 μg·L-1 TGF-β1. MGC-803 cells were classified into blank group， model group， 0.1 g·L-1 XXXT group， 0.2 g·L-1 XXXT group， and 0.4 g·L-1 XXXT group. For further clarifying the key role of Wnt5a/Ca2+/NFAT signaling pathway in the inhibition of XXXT on gastric cancer， MGC-803 cells were transfected with Wnt5a overexpression plasmid， and then the cells were classified into blank plasmid group， Wnt5a-OE group， blank plasmid + XXXT （0.4 g·L-1） group， and Wnt5a-OE + XXXT （0.4 g·L-1） group. Cell viability was determined by cell counting kit-8 （CCK-8） assay， cell invasion and migration ability by Transwell invasion assay and wound healing assay， expression of EMT-related proteins （E-cadherin， N-cadherin， Vimentin， Snail） and Wnt5a/Ca2+/NFAT signaling pathway-related key proteins ［Wnt5a， calcineurin （CaN）， NFAT1， and p-NFAT1］ by Western blot， and changes in intracellular Ca2+ concentration by immunofluorescence assay. ResultMolecular docking suggested that XXXT acted on Wnt5a/Ca2+/NFAT signaling pathway. XXXT （0.1， 0.2， 0.4 g·L-1） significantly promoted the loss of MGC-803 cell viability （P<0.05，P<0.01）. It inhibited cells from invading the transwell lower chamber and slowed down the healing of cell wounds in a dose-dependent manner （P<0.05， P<0.01）. Moreover， it promoted the expression of E-cadherin while suppressed the expression of N-cadherin， Vimentin， and Snail （P<0.05， P<0.01）. Further experiments showed that XXXT could inhibit the expression of Wnt5a， CaN， NFAT1， and p-NFAT1， and reduce the nuclear expression of NFAT1 and the transcription activity mediated by NFAT1， so as to reduce the cellular Ca2+ concentration （P<0.05， P<0.01）. XXXT can reverse the effect of Wnt5a （P<0.05， P<0.01）. ConclusionXXXT can attenuate the invasion， metastasis， and EMT of MGC-803 cells via the Wnt5a/Ca2+/NFAT pathway， thereby weakening the tumor-promoting effect of TGF-β1. In summary， XXXT may exert therapeutic effect on gastric cancer by regulating the invasion， metastasis， and EMT of gastric cancer cells.

Systematic Review and Meta-Analysis of Efficacy and Safety of Linggui Zhugantang Combined with Conventional Drugs in Delaying Course of Heart Failure / 中国实验方剂学杂志

ObjectiveTo evaluate the efficacy and safety of Linggui Zhugantang in the treatment of heart failure. MethodCNKI，Wanfang Data，VIP，CBM，PubMed，ClinicalKey，Cochrane Library ，Web of Science ，Medline and Embase were systematically searched to screen randomized controlled trials（RCT）of Linggui Zhugantang in the treatment of heart failure. Meta-analysis was performed on the included studies using RevMan 5.3 ResultTwenty-seven studies were included with a total sample size of 3 569 cases，including 1 816 in experimental group and 1 753 in control group. Meta-analysis showed that compared with conventional drugs alone，combination of Linggui Zhugantang and conventional drugs improved the marked effective rate [relative risk（RR）=1.41，95% confidence interval（CI）[1.29，1.54]，P<0.000 01] and the total effective rate（RR=1.21，95%CI[1.17，1.25]，P<0.000 01），decreased the levels of serum B-type brain natriuretic peptide （BNP）[mean difference（MD）=-390.08，95%CI[-538.84，-241.52]，P<0.000 01] and serum N-terminal pro-brain natriuretic peptide（NT-proBNP）（MD=-713.83，95%CI[-828.41, -599.25]，P<0.000 01）， left ventricular end-diastolic diameter（LVDD）（MD=-5.23，95%CI[-7.18, -3.29]，P<0.000 01）, left ventricular end-systolic diameter（LVSD）（MD=-4.54，95%CI[-6.75，-2.33]，P<0.000 01）, tumor necrosis factor-α（TNF-α）（MD=-37.53，95%CI [-50.72，-24.34]，P<0.000 01）and interleukin-6（IL-6）（MD=-23.64，95%CI [-47.40，0.11]，P=0.05）, increased left ventricular ejection fraction（LVEF）（MD=5.73，95%CI [3.33，8.14]，P<0.000 01），and cardiac output [stroke volume (SV) ]（MD=5.90，95%CI[4.56，7.25]，P<0.000 01）. In addition, the combination prolonged the 6 minute walking test distance（MD=51.08，95%CI [33.01，69.16]，P<0.000 01），reduced the traditional Chinese medicine (TCM) syndrome score（MD=-3.50，95%CI [-4.92，-2.07]，P<0.000 01），and improved quality of life（MD=-7.26，95%CI [-10.43，-4.09]，P<0.000 01），with higher safety（RR=0.36，95%CI [0.17，0.79]，P=0.01）. ConclusionLinggui Zhugantang combined with conventional drug therapy could improve cardiac function，reduce cardiac fibrosis，and improve prognosis, with high safety.

Progress of radiotherapy combined with immunotherapy for head and neck cancer / 肿瘤研究与临床

As immunotherapy has become the latest treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC), radiotherapy combined with immunotherapy has become the focus of this field. It has been reported that radiotherapy combined with immunotherapy can produce synergistic effect, but the mechanism of synergistic effect has not been determined yet. Basic researches involve immune cells and immunoregulation of microenvironment, and clinical researches include timing of combination therapy, radiotherapy site, treatment mode and dose, and selection of beneficiary population. This paper reviews the progress of combined application of radiotherapy and immunotherapy in the field of basic and clinical treatment of head and neck cancer.

Extract from Modified Xiao Xianxiongtang Inhibits Epithelial-mesenchymal Transition and Invasion and Migration Mediated by TGF-β1 of Human Gastric Cancer MGC-803 Cells via Wnt5a/Ca2+/NFAT Signaling Pathway / 中国实验方剂学杂志

Objective:This studu aims to investigate the effect of aqueous extract of modified Xiao Xianxiongtang on the epithelial mesenchymal transition（EMT） and the change of its invasion and migration ability of human gastric cancer MGC-803 cells mediated by transforming growth factor-<italic>β</italic>₁（TGF-<italic>β</italic>₁），and to explore the mechanism of regulating Wnt5a/Ca²⁺/ activated T-cell nuclear factor（NFAT） signaling pathway to inhibit EMT and invasion and metastasis of MGC-803 cells. Method:TGF-<italic>β</italic>₁（10 μg·L^-1）was used to induce EMT and the invasion and metastasis model of human gastric cancer MGC-803 cells. Transwell chamber experiment， scratchhealing experiment， Western blot and immunofluorescence assay were used to detect cell invasion and migration ability， expression of EMT marker protein and key protein expression of Wnt5a/Ca²⁺/NFAT signaling pathway， and intracellular Ca²⁺ concentration. Result:Compared with the blank group， TGF-<italic>β</italic>₁ could significantly enhance the invasion and migration ability of MGC-803 cells（<italic>P</italic><0.01）， down-regulate the level of E-cadherin（<italic>P</italic><0.01）， up-regulate protein expressions of N-cadherin， Snail and Vimentin（<italic>P</italic><0.01）， and induce cell Wnt5a， calcineurin （CaN）， total protein of activated T-cell nuclear factor 1（NFAT1）， up-regulation of phosphorylated proteins p-NFAT1 and NFAT1 nucleoprotein and intracellular accumulation of Ca²⁺（<italic>P</italic><0.01）. Compared with the TGF-<italic>β</italic>₁ group， modified Xiao Xianxiongtang （10， 20， 40 mg·L^-1） could significantly inhibit this phenomenon，and 40 mg·L^-1 had the best effect（<italic>P</italic><0.05，<italic>P</italic><0.01）.The specific inhibitors of Wnt5a/Ca²⁺/NFAT signaling pathway （<italic>R</italic>）-（+）-Bay-K-8644 and modified Xiao Xianxiongtang （40 mg·L^-1） could significantly inhibit theinvasion and migration of MGC-803 cells mediated by TGF-<italic>β</italic>₁， up-regulate the level of E-cadherin， and down-regulate expressions of N-cadherin， Snail， Vimentin， Wnt5a， CaN and NFAT1 proteins and reduce the intracellular accumulation of Ca²⁺（<italic>P</italic><0.05，<italic>P</italic><0.01）.Moreover， （<italic>R</italic>）-（+）-Bay-K-8644 combined with modified Xiao Xianxiongtang （40 mg·L^-1） had stronger inhibitory effect（<italic>P</italic><0.05，<italic>P</italic><0.01）. Conclusion:These results suggest that modified Xiao Xianxiongtang can inhibit the EMT mediated by TGF-<italic>β</italic>₁ via Wnt5a/Ca²⁺/NFAT signaling pathway，thereby reducing the invasion and migration ability of MGC-803 cells.

Evaluation of clinical efficacy of microwave ablation in situ for thoracic, lumbar and sacral spinal metastases / 中华放射肿瘤学杂志

Objective:To evaluate the clinical outcomes of patients with single spinal metastasis of thoracic, lumbar or sacral vertebra treated with microwave ablation in situ.Methods:For 28 patients with single spinal metastasis of thoracic, lumbar or sacral vertebra, detailed and personal surgical plans were carried out. Instead of en bloc resection, hyperthermia ablation in situ was performed followed by strengthening procedures under the guidance of G-arm fluoroscopy machine. Intraoperatively, spinal cord and nerve root were properly protected. The bone defects were reconstructed by bone cement after the diseased lesions were revomed. All patients were followed up for almost 1 year postoperatively. During follow-up, X-ray and MRI images were obtained, and the level of pain and neurologic outcomes were also examined.Results:All 28 patients successfully received microwave ablation in situ. The average ablation time was approximately 8 minutes and the average amount of bone cement implanted was approximately 10.5 ml. The pain scores of digital pain classification before and 3 months after operation were 7.86±1.58 and 3.07±1.89( P<0.05). The postoperative neurological function of 22 patients was improved than that before operation. No significant changes were observed in 5 patients. The neurological function of the affected limb was relieved, whereas the symptoms of the healthy limb were slightly worse in the remaining case. Conclusions:Microwave ablation in situ is a feasible and effective surgical method for single spinal metastasis of thoracic, lumbar or sacral vertebra. It might possess many advantages, such as clear surgical field, smaller incisions, less bleeding, and safe margins during the operations. Further more, it could significantly relieve pain, restrict tumor growth, and improve the quality of life of patients. It is an innovative and distinctive therapeutic alternative for single spinal metastasis, which deserves widespread application.

Research Progress on Antitumor Active Components and Mechanism of Xiao Xianxiongtang / 中国实验方剂学杂志

Tumor is one of the diseases that seriously endanger human health， and how to treat tumor effectively is still one of the important problems in the field of medicine. At present， most of the radiotherapies and chemical drugs for cancer have serious side effect despite of an obvious efficacy. With a unique syndrome differentiation treatment system and overall concept， traditional Chinese medicine has become the key research and development object of antitumor drugs due to many advantages， such as multiple channels， multiple levels， multiple links， multiple targets and less toxicity， and could can fully mobilize the immune and epidemic prevention mechanism of the body. A large number of studies have shown that Xiao Xianxiongtang and its effective ingredients have obvious antitumor effect. Many doctors have applied Xiao Xianxiongtang and modified formulas in clinical treatment of tumors， and relevant pharmacological studies have also confirmed the effectiveness of this formula， but with a lack of systematic summary of its effective ingredients and its mechanism of action. Now， with alkaloids， ketones， sterols and phenols in Xiao Xianxiongtang as the starting point， this study mainly focuses on inhibition of tumor cell proliferation， invasion and migration， induction of tumor cell apoptosis and autophagy， inhibition of tumor cell cycle， enhancement of tumor cell sensitivity， inhibition of tumor angiogenesis and regulation of immunosuppressive tumor microenvironment from two ways to sort out composition， function and mechanism of drugs. In this paper， effective components， main targets and mechanism of intervention in the tumor development of Xiao Xianxiongtang were reviewed， in order to provide a new idea for subsequent antitumor research and development of this prescription.

Diagnostic value of heart-type fatty acid-binding protein combined with echocardiography in sepsis with cardiac insufficiency / 中华危重病急救医学

Objective:To observe the value of heart-type fatty acid-binding protein (H-FABP) and echocardiographic indexes in the diagnosis of cardiac insufficiency in sepsis.Methods:A prospective observational study was conducted. Eighty patients with sepsis admitted to the department of critical care medicine of the First Affiliated Hospital of Medical College of Shihezi University from October 2016 to January 2018 were enrolled. General clinical data such as gender, age, acute physiology and chronic health evaluationⅡ(APACHEⅡ), sequential organ failure assessment (SOFA) score, hospitalization time and 28-day mortality were recorded. Echocardiographic indexes at 1, 3, 7, 10 days after diagnosis, and white blood cell (WBC), neutrophilic granulocyte percentage (N%), N-terminal pro-brain natriuretic peptide (NT-proBNP), serum H-FABP level were recorded. Sepsis patients were divided into normal cardiac function group ( n = 30) and cardiac insufficiency group ( n = 50) according to cardiac function, the differences of echocardiographic indexes and cardiac markers between the two groups at different time points were compared. Logistic regression was used to screen out cardiac ultrasound indexes and cardiac markers that affect the occurrence of cardiac dysfunction in sepsis patients, and then receiver operating characteristic (ROC) curve analysis was performed. Results:Comparing the general data of the two groups, only the SOFA score of the cardiac insufficiency group was significantly higher than that of the normal cardiac function group (6.12±4.09 vs. 4.57±2.45, P < 0.05). N% and H-FABP in cardiac insufficiency group were higher than those in normal cardiac function group at the same time (N%: F = 6.973, P = 0.010; H-FABP: F = 17.303, P = 0.000). Without considering the time factor, there were significant differences in left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), stroke volume (SV), cardiac output (CO), left ventricular fractional shortening (LVFS), E-point of septal separation (EPSS), isovolumic relaxation time (IVRT), E peak deceleration time (EDT), A peak duration (Ad), left ventricular systolic pulmonary vein velocity (S), blood flow velocity of pulmonary vein in early left ventricular diastolic period (D), tricuspid orifice early diastolic blood flow velocity (E'), tricuspid orifice late diastolic blood flow velocity (A'), systolic velocities of the right ventricular free wall tricuspid annulus (Sm), and pulmonary valve annulus blood flow velocity (PVBV) between the two groups. ROC curve analysis of cardiac ultrasound indicators and cardiac markers screened by Logistic regression showed that the area under ROC curve (AUC) and the positive and negative predictive values were: LVEDV was 0.636, 77.30%, 56.03%; SV was 0.779, 88.82%, 71.19%; LVEF was 0.753, 92.12%, 55.21%; CO was 0.754, 88.82%, 77.19%; LVFS was 0.728, 81.25%, 66.99%; EPSS was 0.663, 96.99%, 51.56%; IVRT was 0.775, 86.97%, 73.55%; A' was 0.908, 96.58%, 89.60%; Sm was 0.738, 93.37%, 56.77%; H-FABP was 0.673, 80.26%, 57.25%, respectively. H-FABP was tested in parallel with LVEDV, SV, LVEF, CO, LVFS, EPSS, IVRT, A', Sm, and the positive predictive values were higher than the single diagnostic test (85.45%, 93.91%, 96.72%, 94.74%, 89.43%, 98.00%, 92.00%, 99.42%, 93.60%, respectively), the negative predictive values were lower than the single diagnostic test (50.89%, 57.93%, 49.15%, 58.18%, 57.05%, 45.74%, 57.92%, 64.13%, 47.78%, respectively). Conclusion:Cardiac ultrasound indicators LVEDV, SV, LVEF, CO, LVFS, EPSS, IVRT, A', and Sm combined with H-FABP are of certain value in the diagnosis of sepsis-associated heart dysfunction.

Prevention and treatment of gastric leakage after laparoscopic sleeve gastrectomy / 中华消化外科杂志

It is proven that laparoscopic sleeve gastrectomy (LSG) is effective for obesity, type 2 diabetes mellitus and other obesity-related complications. The surgical procedure of LSG is relatively simple, with few short-term or long-term complications, which has increasing be applicated in recent years. As more hospitals in China carry out LSG, the related reports of its complications have gradually increased. The most common complications of LSG include gastric leakage, bleeding, and gastric cavity stenosis. Among them, gastric leakage is a more difficult problem, and untreated or improper treatment can bring serious consequences to patients. Based on the current progress in clinical treatment of gastric leakage after LSG and practical experience, the authors summarize and discusse the clinical experience of the prevention and treatment of such patients.