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Na Cui,1 Xue Li,1 Xin Wen,1 JingJing Xu,2 Li Chen1 1Department of Obstetrics and Gynecology, Baoding No.1 Central Hospital, Baoding City, Hebei Province, 071000, People’s Republic of China; 2Department of Ultrasound, Baoding No.1 Central Hospital, Baoding City, Hebei Province, 071000, People’s Republic of ChinaCorrespondence: Li Chen, Department of Obstetrics and Gynecology, Baoding No.1 Central Hospital, No. 320 Changcheng North Street, Baoding City, Hebei Province, 071000, People’s Republic of China, Email chenliphd1407@outlook.comObjective: Analyze women treated with underwent cold knife conization (CKC) to remove advanced squamous intraepithelial lesions (CIN) of the cervix. The histopathological upgrading of the lesions previously detected on vaginal biopsy and postoperative pregnancy outcomes of were investigated, to identify high-risk subgroups in women.Methods: A retrospective study was conducted at the First Central Hospital of Baoding City from June 2019 to December 2022 to analyze confirmed cases of Cervical Intraepithelial Neoplasia CIN-II and CIN-III. Investigation of pathological changes in postoperative pathological tissues, and to perform binary logistic analysis to identify risk factors for histopathological escalation in postoperative lesions. We analyze the effects of CKC surgery on pregnancy outcomes in patients by comparing against a control group of healthy pregnant women.Results: Out of the 176 patients diagnosed with CIN-II who underwent cervical biopsy, 39 (22.16%) were found to have a final specimen diagnosis of CIN-III, while 7 (3.98%) were downgraded to CIN-I. Among the 108 patients diagnosed with CIN-III who underwent cervical biopsy, 7 cases (6.48%) were ultimately confirmed to have CIN-III. Ki67-positive, p16-positive (OR = 1.13, 95% CI 1.01– 1.15), and colposcopy biopsy for CIN-II (OR = 1.59, 95% CI 1.33– 3.6) were independent risk factors for pathological upgrade after CKC. Compared with healthy pregnant women, CIN patients had higher rates of premature birth (14.4%), premature rupture of the fetal membrane (13.6%), and cesarean section (37.5%) (P < 0.05). The mode of conception, abortion rate, ectopic pregnancy rate, and postpartum hemorrhage were not different between healthy pregnant women and CIN patients (P > 0.05).Conclusion: Following cervical multi-point biopsy or CKC, along with pathological examination, the accurate diagnosis of cervical lesions is crucial as it allows for more precise identification of such lesions. Additionally, CKC increases the risk of premature birth, premature rupture of membranes, and the need for cesarean section.Keywords: cervical intraepithelial neoplasia, cold knife conization, pregnant women, colposcopy biopsy

Xiang Wen,1,&ast; Xiaohui Wu,1,&ast; Zhishan Deng,1,&ast; Fan Wu,1,2 Huajing Yang,1 Shan Xiao,1 Cuiqiong Dai,1 Changli Yang,3 Shuqing Yu,4 Ruiting Sun,1 Pixin Ran,1,2 Yumin Zhou1 1State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease & National Center for Respiratory Medicine & Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Guangzhou National Laboratory, Guangzhou, Guangdong, People’s Republic of China; 3Wengyuan County People’s Hospital, Shaoguan, People’s Republic of China; 4Lianping County People’s Hospital, Heyuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yumin Zhou; Pixin Ran, Email zhouyumin410@126.com; pxran@gzhmu.edu.cnBackground: The previous findings on the correlation between spirometry and high-density lipoprotein (HDL) cholesterol are intriguing yet conflicting. The aim of this research is to evaluate the relationship between HDL levels and spirometry as well as imaging parameters in patients with chronic obstructive pulmonary disease (COPD) in China.Methods: This study encompasses a total of 907 COPD patients. Participants with complete data from questionnaire interviews, lipid profile examinations, spirometry testing, and computed tomography (CT) scans were included in the analysis. A generalized additive model was employed to identify the non-linear relationship between HDL levels and both spirometry and imaging parameters. In the presence of non-linear correlations, segmented linear regression model was applied to ascertain threshold effects.Results: After adjusting for various factors, we found a non-linear correlation between HDL levels and spirometry/imaging parameters, with an inflection point at 4.2 (66 mg/dL). When Ln (HDL) was below 4.2, each unit increase correlated significantly with reduced post-bronchodilator FEV1 (0.32L, 95% CI: 0.09– 0.55), decreased predicted FEV1% (11.0%, 95% CI: 2.7– 19.3), and lowered FEV1/FVC (8.0%, 95% CI: 4.0– 12.0), along with notable increases in Ln (LAA− 950) by 1.20 (95% CI: 0.60– 1.79) and Ln (LAA− 856) by 0.77 (95% CI: 0.37– 1.17). However, no significant associations were observed when Ln (HDL) was greater than or equal to 4.2.Conclusion: A non-linear correlation existed between HDL levels with lung function and CT imaging in COPD patients. Prior to reaching 66 mg/dL, an elevation in HDL was significantly associated with impaired lung function, more severe gas trapping and emphysema.Keywords: COPD, high-density lipoprotein, lung function, computed tomography imaging

Yuanping Chen,1 Chao Liu,1 Xinglin Wen,2 Chen Wang,1 Jing He1 1Department of Oncology, Ganzhou People’s Hospital, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of China; 2Department of Medical Image, Ganzhou People’s Hospital, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, People’s Republic of ChinaCorrespondence: Jing He, Department of Oncology, Ganzhou People’s Hospital, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, 341000, People’s Republic of China, Tel +86_15297720705, Email 382505721@qq.comAbstract: Breast cancer with brain metastasis accounts for the second largest number of brain metastases among solid malignancies. Despite advances in HER2-targeted therapy, 50% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer develop brain metastases and are associated with poor outcomes. In this article, we report the case of a patient with HER2+ metastatic breast cancer who developed brain metastases, despite experiencing a durable effect on extracranial metastases after treatment with trastuzumab and pertuzumab. The patient exhibited intracranial progression while receiving treatment with trastuzumab deruxtecan monotherapy after secondary brain radiotherapy and multiple lines of therapy with anti-HER2 agents, such as pyrotinib, lapatinib, tucatinib, and ado-trastuzumab emtansine. However, the administration of anlotinib (an antiangiogenesis medication) and trastuzumab deruxtecan resulted in intracranial and extracranial partial response and was linked to manageable side effects. The present case indicates that the combination of anlotinib and trastuzumab deruxtecan may be a promising treatment option for patients with HER2+ breast cancer with brain metastasis. Nevertheless, further studies are warranted to verify the present findings.Keywords: HER2 positive, breast cancer, brain metastases, anlotinib, trastuzumab deruxtecan

Xuan Wang,1,&ast; Hanjie Yu,2,&ast; Yunheng Zhang,3,&ast; Xin Chang,1 Chengyi Liu,1 Xiaodong Wen,1 Feng Tian,1 Yi Li1 1Department of Foot and Ankle Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi’an, Shaanxi, People’s Republic of China; 3The Second Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Li, Email liyidoctor@163.comObjective: Osteoarthritis (OA) is a common degenerative disease worldwide. While curcumin has shown therapeutic effects on OA, its mechanism remains unknown. This study aimed to investigate the molecular mechanism of curcumin in treating OA through network pharmacology and both in vivo and in vitro experiments.Methods: Curcumin-related targets were obtained using the HERB and DrugBank databases. GeneCards and DisGeNET were used to build a target database for OA. The STRING database was employed to construct protein-protein interaction networks and analyze related protein interactions. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology enrichment analyses of core targets were performed using Metascape. In addition, Autodock software was utilized for molecular docking validation of curcumin and disease targets. Further validation of the main findings was conducted through in vitro and in vivo experiments. In the in vitro experiments, an inflammation model was constructed through nitric oxide donor (SNP) stimulation of chondrocytes. Subsequently, the regulatory effects of curcumin on core targets and signaling pathways were validated using Western blotting and immunofluorescence staining techniques. In the in vivo experiments, an OA model was established by performing medial meniscectomy on male Sprague–Dawley rats. The therapeutic effects were evaluated using enzyme-linked immunosorbent assays, histologic staining, and micro-computed tomography (micro-CT) techniques.Results: Core targets of curcumin relevant to OA therapy included tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, matrix metalloproteinase 9 (MMP-9), B-cell lymphoma 2 (BCL-2), and caspase-3. The major biological processes involved oxidative stress and apoptotic processes, among others. The p38 mitogen-activated protein kinase (p38/MAPK) pathway was identified as the most likely pathway involved. In vitro experiments showed that curcumin significantly reduced oxidative stress levels, inhibited the expression of inflammatory factors IL-6 and Cyclooxygenase-2 (COX-2) and downregulated the expression of MMP-9 and MMP-1. In addition, curcumin was found to regulate the expression of BCL-2 and caspase-3 through the p38/MAPK pathway, inhibiting chondrocyte apoptosis. In vivo animal experiments demonstrated that curcumin significantly reduced the expression of OA-related factors (IL-1, IL-6, and TNF-α). Histological analysis and micro-CT results revealed that curcumin treatment significantly increased cartilage thickness, improved cartilage morphology, structure, and function, inhibited cartilage degradation, and enhanced the resorption of subchondral bone in the knee joints of rats with OA.Conclusion: Curcumin regulates oxidative stress and maintains mitochondrial function, thereby protecting chondrocyte guard. In addition, curcumin attenuates the inflammatory response of chondrocytes by inhibiting the phosphorylation of P38MAPK, slowing down the breakdown of the extrachondral matrix while preventing apoptosis of chondrocytes. Additionally curcumin attenuated cartilage degradation and bone damage while helping to boost bone density.Keywords: osteoarthritis, curcumin, molecular mechanism, network pharmacology, p38/MAPK

Xiaoli Wen, Gaosi Xu Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of ChinaCorrespondence: Gaosi Xu, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, 330006, People’s Republic of China, Tel/Fax +860791 86312770, Email gaosixu@163.comAbstract: Recently, bispecific antibodies (BsAbs) are evolving the landscape of cancer treatment and have significantly improved the outcomes of relapsed or refractory cancer patients. As increasing BsAbs entered clinical practice, specific toxicities have emerged, and renal side-effects have been described. However, there are a lack of studies analyzing the nephrotoxicity in the anti-cancer BsAbs recipients systematically. In this review, we demonstrate the etiologies, mechanisms, other risk factors and treatment options of kidney injury in the BsAbs recipients to provide a more comprehensive insight into the nephrotoxicity post-BsAbs therapy. Significantly, due to the limited clinical trial data on each subject, we mainly conclude the related etiologies, mechanisms, and risk factors of nephrotoxicity that occur in T-cell-engaging BsAbs recipients. Nephrotoxicity associated with non-T-cell BsAbs may be associated with adverse nephrotoxicity of related monoclonal antibodies to two specific antigens. The aim of this paper is to provide nephrologists and oncologists with theoretical knowledge to provide better medical management for recipients who receive BsAbs, especially T-cell-engaging BsAbs treatment.Keywords: bispecific antibodies, nephrotoxicity, acute kidney injury, cytokine release syndrome, tumor lysis syndrome, cancer

Xiaochen Wen,1,&ast; Yaping Zhou,1,&ast; Yinan Li,2 Xiahan Li,1 Pengfei Qu1 1School of Philosophy and Sociology, Lanzhou University, Lanzhou, People’s Republic of China; 2School of Management, Lanzhou University, Lanzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yaping Zhou, School Philosophy & Sociology, Lanzhou University, Lanzhou, Gansu, 730000, People’s Republic of China, Tel/Fax +86 0931-8913710, Email ypzhou@lzu.edu.cn Yinan Li, School of Management, Lanzhou University, Lanzhou, 730000, People’s Republic of China, Email li8man@outlook.comBackground: In the post-epidemic era, the problem of short-video app addiction among older adults has become increasingly prominent, and people have begun to pay attention to the negative emotional and psychological consequences of Perceived Overload of short-video apps. Given the growing mental health concerns of older adults, it is critical to understand the potential relationship between the Perceived Overload of short video apps for older adults and older adults’ mental health.Methods: This study applied the stress-strain-outcome (SSO) framework to explore the relationship between perceived overload of a short-video application and loneliness, mental health, and Confucianism tenets in 1300 Chinese older adults. The relationship between perceived overload and loneliness, mental health, and Confucianism tenet moderated mediation models of perceived overload and mental health were created using SPSS 26.0 and PROCESS 4.1 for SPSS.Results: The perceived overload of a short video application for older adults directly predicted loneliness and mental health in older adults, and the Confucianism tenet moderated the mediation process between perceived overload and mental health. Perceived overload affects mental health through loneliness in older adults.Discussion: The results of this study are of practical significance for understanding the current problem of short-video addiction among older adults. Understanding the effects of perceived overload on older adults’ loneliness and mental health can help prevent loneliness and mental health problems caused by short-video addiction among older adults on the one hand, and on the other hand, it can also help to develop targeted coping strategies and create psychological intervention programs based on the Confucianism tenet of intervention ethics to improve mental health in a changing technological stress environment.Keywords: perceived overload, loneliness, mental health, Confucianism tenet

Liqun Luo,1 Xiulin Wen,1 Jingrong Wang,2 Qian Xiao,3 Liuju Su,3 Min Zhou3 1Department of Nursing, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Surgical, The Second Affiliated Hospital of the Air Force Military Medical University, Xi’an, People’s Republic of China; 3School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of ChinaCorrespondence: Xiulin Wen, Tel +86 13991893501, Email 332919997@qq.comBackground: Pressure injuries are present in all healthcare environments and not only pose a significant health risk to individuals but also impose a heavy economic burden on society and families. Nurses, as the primary caregivers responsible for the prevention and management of pressure injuries, have knowledge that directly determines the incidence of pressure injuries.Aim: To understand the current status of nurses’ knowledge of pressure injuries in Shaanxi Province and the factors influencing it.Design: A cross-sectional survey.Methods: In April - May 2022, 16,599 nurses from hospitals at all levels in Shaanxi Province were selected as survey subjects by convenience sampling method. They were surveyed using the general information questionnaire and the Pieper-Zulkowski pressure injury Knowledge Questionnaire through the Questionnaire Star platform.Results: 16,599 nurses had a pressure injury knowledge score of (44.32± 10.11). Wound description and pressure ulcer staging dimensions were less than 60% correct. Comparison of pressure injury knowledge scores of nursing staff with different genders, hospital levels, titles, education, whether they were specialized nurses in wound stoma when they last attended a lecture on pressure ulcers, when they last read literature or books on pressure ulcers, and whether they ever looked for information about pressure ulcers on the Internet showed that the differences were statistically significant (P < 0.05), which were the influencing factors of the knowledge scores of the nursing staff in Shaanxi Province.Conclusion: Clinical nurses’ awareness of stress-related injuries still needs to be improved, and nursing administrators can improve the quality of pressure-related injury care by increasing nursing staff’s awareness through continuing education, tiered training, and other measures.Keywords: pressure injury, knowledge, prevention, management, influencing factor

Yunpeng Feng,1 Shifeng Qiao,1 Jie Chen,1 Xin Wen,2 Yanlei Chen,3 Xiaoyu Song,1 Jiaxin Xu,1 Xiucheng Qiao,1 Jing Yang,2 Shenshen Zhang,1 Yang Feng,1 Yu Gao4 1The Second Ward of Colorectal Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of China; 3The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 4School of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning, 12100, People’s Republic of ChinaCorrespondence: Yu Gao, School of Basic Medical Sciences, Jinzhou Medical University, No. 40, Section 3 Songpo Road, Jinzhou, Liaoning, 121000, People’s Republic of China, Tel +86 15904161717, Email jzykdxgy@163.comPurpose: This research explored the association between CD163-labeled M2-type macrophages and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) of 38 colorectal cancer (CRC) liver metastases. In addition, we investigated the correlation differences between M2-type macrophages and CAFs in the tumor microenvironments of 38 primary colorectal cancer patients with confirmed liver metastases and 946 colorectal cancer patients, as well as possible mechanisms of action between the two cells.Methods: The Immunohistochemistry (IHC) method was applied to detect the expression levels of M2-type macrophages and CAFs in the tissues of 984 cases of CRC and to analyze the correlation between M2-type macrophages and CAFs in colorectal cancer tissues. The IHC method was also applied to detect the expression levels of M2-type macrophages and CAFs in the liver metastases of 38 cases of CRC in the experimental group and to analyze the correlation between the two cells in liver metastases.Results: 1. M2-type macrophages and CAFs expression were significantly higher in 38 primary colorectal cancer patients compared to 946 controls, and the expression of M2-type macrophages was significantly positively correlated with CAFs. 2. In 984 CRC cases, M2-type macrophages and CAFs expression levels were significantly higher in the cancer tissues than in the paired paracancerous tissues. 3. The expression levels of M2-type macrophages and CAFs in primary colorectal cancer were significantly higher in the experimental group than in colorectal cancer tissues without distant metastasis.Conclusion: M2-type macrophages and CAFs are involved in the development of the colorectal cancer tumor microenvironment, and their interaction influences the initiation and progression of liver metastasis in colorectal cancer. It may provide new clinical ideas for early diagnosis of CRC liver metastases and searching for immune targets.Keywords: M2-type macrophages, cancer-associated fibroblasts, colorectal cancer, liver metastasis

Xili Wen,1 Yujun Cai,1 Kai Li,1 Zisu Wang,1 Weiyi Zhang,1 Man Qin2 1School of Physical Education, Shanghai University of Sport, Shanghai, People’s Republic of China; 2Shanghai Lixin University of Accounting and Finance, Shanghai, People’s Republic of ChinaCorrespondence: Man Qin, Shanghai Lixin University of Accounting and Finance, Shanghai, People’s Republic of China, Email hnqinman@126.comPurpose: The study aims to explore the relationship and potential mechanisms between screen time and anxiety and have a clear understanding of the role of negative emotions and emotion regulation, thus providing guidance for Chinese college students to improve mental health.Methods: We conducted a questionnaire survey by selecting 1721 academic college students from 6 colleges and universities in 5 provinces in China, and the data were analyzed through the Process program of SPSS for mediating effect and moderating effect.Results: There is a significant positive relationship between screen time and anxiety, negative emotions play a mediating role between the two (indirect effect = 0.32, p < 0.001), mediating effect accounts for 59.88% of the total effect, and emotion regulation regulates the direct relationship between screen time and anxiety (interaction effect = 0.027, p < 0.001).Conclusion: This study sheds light on the potential mechanisms by which screen time affects anxiety in academic college students, providing a fresh perspective on anxiety reduction. Screen time positively affects anxiety levels, where negative emotions have a mediating role and emotion regulation has a moderating role. In the future, we can control screen ++time, increase physical activities, reduce negative emotions, and improve the emotional regulation ability to relieve anxiety, so as to improve the mental health of academic college students, and expect to have a positive impact on future learning, life, and planning.Keywords: college students, sedentary behavior, anxiety, negative emotions, emotion regulation

Zisu Wang,1 Kai Li,1 Shuangshuang Guo,2 Xili Wen,1 Ziyi He,1 Yujun Cai1 1School of Physical Education, Shanghai University of Sport, Shanghai, People’s Republic of China; 2Physical education Group, High school Attached to Shanghai Normal University Minhang Campus, Shanghai, People’s Republic of ChinaCorrespondence: Yujun Cai, School of Physical Education, Shanghai University of Sport, Shanghai, People’s Republic of China, Email caiyujun@sus.edu.cnPurpose: The purpose of this study was to examine the relationships between academic engagement and moderate-to-vigorous physical activity (MVPA), muscle-strengthening exercise (MSE) and sedentary behavior (SB) among adolescents, so as to provide evidence from the perspective of exercising for students to learn efficiently, teachers to improve classroom teaching, and schools to improve educational quality.Methods: A questionnaire survey was conducted in 12 junior high schools in Shanghai, China, which were selected by a multi-stage stratified cluster sampling method. Then, with the valid data of 2078 students collected from the survey. A data analysis was performed using SPSS Statistics 26.0. Multiple linear regression models were adopted to analyze the factors affecting adolescent academic engagement and to determine whether MVPA, MSE, and SB play roles in it.Results: (1) The differences in academic engagement depended on the exercise adherence to the recommended amount of MVPA, MSE, and screen-based SB. (2) In terms of the three independent variables of total time, MSE (β = 0.206) and MVPA (β = 0.175) showed a significant positive correlation with academic engagement, while SB (β = − 0.155) was negatively correlated with academic engagement. (3) From the linear regression model of eight combination groups divided by the exercise adherence to the recommended amount of MVPA, MSE and SB, the group that met none of the recommendations (β = − 0.235) showed a significant negative effect on academic engagement, while the groups that met any two or all three of the recommendations demonstrated strong positive correlations with academic engagement (P < 0.001).Conclusion: Increasing adolescents’ muscle-strengthening exercise and moderate-to-vigorous physical activity and reducing sedentary behavior can effectively promote academic engagement. Therefore, adolescents are suggested to reach the recommended amounts of physical activity, muscle-strengthening exercise, and sedentary behavior so as to improve academic engagement more effectively.Keywords: moderate-to-vigorous physical activity, muscle-strengthening exercise, academic engagement, sedentary behaviors

SuWen Yang,1– 3,&ast; Bing Wang,2,4,5,&ast; Jing Li,6 Xue Zhao,7 Yan Zhu,8 Qian Sun,9 HongMei Liu,2,4,5 XiaoJun Wen1 1School of Basic Medical Sciences, Basic Medical School, Guizhou Medical University, Guiyang, 550025, People’s Republic of China; 2Engineering Research Centre of Medical Biotechnology, Guizhou Medical University, Guiyang, Guizhou, 550025, People’s Republic of China; 3People’s Hospital of Kaiyang, Guiyang, 550300, People’s Republic of China; 4Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, Guizhou, 550025, People’s Republic of China; 5School of Biology and Engineering, Guizhou Medical University, Guiyang, Guizhou, 550025, People’s Republic of China; 6Department of Microbial Immunology, The First Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 7Department of Clinical Laboratory, The First People’s Hospital of Guiyang, Guiyang, 550002, People’s Republic of China; 8Department of Clinical Laboratory, The Fourth People’s Hospital of Guiyang, Guiyang, 550002, People’s Republic of China; 9Department of Emergency Medicine, The First People’s Hospital of Guiyang, Guiyang, 550002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: XiaoJun Wen; HongMei Liu, Guizhou Medical University, Guiyang, 550025, People’s Republic of China, Email 2547285543@qq.com; hmliu@gmc.edu.cnPurpose: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common pathogens of community- and hospital-acquired infections, and its prevalence is increasing globally. Guiyang is the capital city of Guizhou Province, Southwest China; as the transport and tourism centre of Southwest China, Guizhou Province is bordered by Yunnan, Sichuan, Chongqing, and Guangxi Provinces. Although MRSA prevalence is increasing, little is known about its aspects in the area. The purpose of this study was to analyse MRSA molecular characteristics, antimicrobial resistance, and virulence genes in Guiyang.Methods: In total, 209 MRSA isolates from four hospitals (2019– 2020) were collected and analysed by antimicrobial susceptibility testing and molecular classification by the MLST, spa, and SCCmec typing methods. Isolate antibiotic resistance rates were detected by a drug susceptibility assays. PCR amplification was used to detect the virulence gene-carrying status.Results: Twenty-four STs, including 4 new STs (ST7346, ST7347, ST7348, and ST7247) and 3 new allelic mutations, were identified based on MLST. The major prevalent ST type and clone complex were ST59 (49.8%) and CC59 (62.7%), respectively. Spa type t437 (42.1%) and SCCmec IV (55.5%) were identified by spa and SCCmec typing methods as the most important types. Drug sensitivity data showed that the multidrug resistance rate was 79.0%. There were significant differences in multidrug resistance rates and virulence gene-carrying rates for seb, hla, hlb, cna and bap between ST59 and non-ST59 types.Conclusion: ST59-SCCmecIV-t437 is a major epidemic clone in Guiyang that should be monitored by local medical and health institutions. The situation differs from other adjacent or middle provinces of China, which may be due to the special geographical location of the region and the trend in antibiotic use or lifestyle. This study provides empirical evidence for local medical and health departments to prevent and control the spread of MRSA.Keywords: methicillin-resistant Staphylococcus aureus, MRSA, multilocus sequence type, MLST, Staphylococcal protein A type, SPA, Staphylococcal chromosomal cassette mec type, SCCmec, multidrug-resistant organism, virulence gene

Luxinyi Xu,1,2 Xiaotong Wen,1,2 Ying Yang,1,2 Dan Cui1,2 1School of Public Health, Wuhan University, Wuhan, 430071, People’s Republic of China; 2Global Health Institute, Wuhan University, Wuhan, 430071, People’s Republic of ChinaCorrespondence: Dan Cui, School of Public Health, Wuhan University, 115&num; Donghu Road, Wuhan, 430071, People’s Republic of China, Tel +86 133 1715 0755, Email 00008766@whu.edu.cnBackground: Patients with both diabetes and hypertension could face more health risks than those with either condition alone, and less attention has been paid to their management outcomes, so this study may be the first to specifically address this problem. We aimed to examine the management outcomes of blood pressure (BP) in hypertensive patients with/without diabetes and fasting plasma glucose (FPG) in diabetic patients with/without hypertension.Methods: Follow-up data were obtained from the National Basic Public Health Service Project in Sanming (2017– 2021). A total of 25,795 adults with hypertension only, 4111 adults with diabetes only, and 5729 comorbid adults (namely, hypertensive patients with diabetes) were included. Generalized estimating equations were applied.Results: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with hypertension only both dropped significantly (Coef. = − 0.00088, P < 0.001; Coef. = − 0.00081, P < 0.001). DBP in comorbid patients decreased considerably (Coef. = − 0.00033, P < 0.001). Pulse pressure in comorbid patients grew rapidly (Coef. = 0.00044, P < 0.001). BP control rate in patients with hypertension only increased significantly (OR = 1.00039, P < 0.001). FPG control rates in diabetic patients with/without hypertension grew markedly (OR = 1.00013, P < 0.001; OR = 1.00020, P < 0.001). Comorbid patients had lower baseline SBP and DBP but higher latest SBP than patients with hypertension only (Coef. = − 1.18872, P < 0.001; Coef. = − 1.16049, P < 0.001; Coef. = 1.0634, P < 0.001). Comorbid patients had lower baseline BP and FPG control rates than those with either condition alone, and differences were greater at the latest follow-up (OR = 0.28086, P < 0.001; OR = 0.91012, P = 0.049; OR = 0.04020, P < 0.001; OR = 0.69465, P < 0.001).Conclusion: BP and FPG management outcomes have achieved progress. Comorbid patients have poorer performance than patients with either disease alone in BP levels especially the SBP level and control rates of SBP, DBP, and FPG. Future studies should be conducted using national data and include more confounding factors.Keywords: hypertension, diabetes mellitus, comorbidity, blood pressure, fasting plasma glucose, longitudinal studies

Jiamin Li,1 Chen Zhu,1 Ying Liu,1 Baoyun Song,2 Jingfen Jin,3 Yilan Liu,4 Xianxiu Wen,5 Shouzhen Cheng,6 Xinjuan Wu1 1Department of Nursing, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Nursing, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China; 3Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, People’s Republic of China; 4Department of Nursing, Wuhan Union Hospital, Jianghan District, Wuhan, People’s Republic of China; 5Department of Nursing, Sichuan Academy of Medical Sciences and Sichuan People’s Hospital, Chengdu, People’s Republic of China; 6Department of Nursing, Sun Yat-sen University First Affiliated Hospital, Guangzhou, People’s Republic of ChinaCorrespondence: Xinjuan Wu, Email wuxinjuan@sina.comBackground: Pressure injury is a common problem in intensive care units. Critical care nurses play an important role in multidisciplinary teams performing pressure injury treatment. Identifying the clinical status of pressure injury treatment may contribute to improving care quality.Aim: To identify the knowledge, attitudes, and practices regarding pressure injury treatment in critical care nurses.Design: A cross-sectional survey.Methods: Secondary data were extracted from a multicenter clinical trial. Knowledge and attitudes toward pressure injury treatment were assessed through a self-administered eight-item questionnaire. The observed practices were recorded using a case report form. The report was in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement.Results: A total of 950 critical care nurses in 15 hospitals from six provinces/municipalities of China were investigated. The mean knowledge score was 2.89 ± 1.16 (95% confidence interval: 2.82– 2.97) out of a possible total of 5 points. The correct rates of selecting wound dressings and pain management were 34.4% and 45.6%, respectively. The mean attitude score was 9.07 ± 1.09 (95% confidence interval: 9.00– 9.13) out of a possible total of 12 points. A total of 2092 patient days of pressure injury treatment practices were observed and recorded. Repositioning was the most commonly employed treatment measure (98.8%). Foam dressing was the common dressing for stage I (53.6%), stage II (47.5%), and more severe pressure injury (67.9%), including stage III, IV, unstageable, and suspected deep tissue injury.Conclusion: Critical care nurses exhibited a generally low level of knowledge and moderate attitudes regarding pressure injury treatment. Practices of pressure injury treatment were generally acceptable.Keywords: pressure injury, treatment, knowledge, attitude, practice, evidence implementation

Xiaofang Wen,1,&ast; Nan Zeng,1,&ast; Ningbo Zhang,1,2,&ast; Tingting Ou,1 Xiaowei Li,1 Xiaoying Li,1 Wangen Li,1 Kang Xu,3 Tao Du1 1Department of Endocrinology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, People’s Republic of China; 2Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, 518036, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Du; Kang Xu, Email dutao@gzhmu.edu.cn; xukang@mail.sysu.edu.cnBackground: Although flash continuous glucose monitoring systems (FCGM) accuracy has been extensively studied in diabetes, its accuracy is still not fully evaluated in type 2 diabetes (T2D) patients in real-world settings. In the present study, we aim to assess the effects of diabetes complications and related comorbidities on FCGM accuracy in T2D patients with diabetes complications and related comorbidities in the real world.Methods: FCGM data were collected at eight-time points daily (3 AM, 7 AM, 9 AM, 11 AM, 1 PM, 5 PM, 7 PM, and 9 PM) from 742 patients with T2D and compared with simultaneous fingertip capillary blood glucose (reference blood glucose, REF), and the difference was evaluated using Parkes error grid (PEG), surveillance error grid (SEG), and logistic regression analysis.Results: In total, 25,579 FCGM/REF data pairs were included in the study. The FCGM values were lower than the paired REF values in 75% of the pairs. The maximum bias (− 23.0%) and maximum mean absolute relative difference (24.5%) were observed at 3 AM among eight-time points. SEG analysis also demonstrated the highest percentage of paired readings in moderate and great risk zone (C and D) at 3 AM than PEG analysis (7.33% vs 0.43%, P< 0.001). According to the SEG classification, hypoglycemia, infection, diabetic foot, diabetic ketoacidosis, and hypertension were independent risk factors that impaired FCGM accuracy in patients.Conclusion: FCGM commonly underestimates blood glucose levels. Compared with PEG, SEG analysis seems more conducive to the analysis of FCGM performance. The present data highlights the impairment of diabetes complications and related comorbidities on the FCGM accuracy in T2D patients.Keywords: flash continuous glucose monitoring system, type 2 diabetes, surveillance error grid, Parkes error grid, diabetes complications

Yuqi Zhou,1,&ast; Guifang Wang,2,&ast; Tianqi Wang,1 Jiajia Wang,3 Xutao Wen,3 Haishui Sun,1 Lei Yu,1 Xiaoying Liu,4 Juanjuan Zhang,1 Qin Zhou,3 Yan Sun1 1School of Stomatology, Weifang Medical University, Weifang, People’s Republic of China; 2Department of Prosthodontics, Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, People’s Republic of China; 3Department of Oral Surgery, Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, People’s Republic of China; 4School of Bioscience and Technology, Weifang Medical University, Weifang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qin Zhou, Department of Oral Surgery, Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, People’s Republic of China, Tel +86 15900827810, Email qin_zq@163.com Yan Sun, School of Stomatology, Weifang Medical University, Weifang, Shandong Province, 261053, People’s Republic of China, Tel +86 13356797219, Email sunyan@wfmc.edu.cnIntroduction: The nanostructural modification of the oral implant surface can effectively mimic the morphology of natural bone tissue, allowing osteoblasts to achieve both proliferation and differentiation capabilities at the bone interface of the dental implant. To improve the osteoinductive activity on the surface of titanium implants for rapid osseointegration, we prepared a novel composite coating (MAO-PDA-NC) by micro-arc oxidation technique and immersion method and evaluated the proliferation, adhesion, and osteogenic differentiation of osteoblasts on this coating.Methods: The coatings were prepared by micro-arc oxidation (MAO) technique and immersion method, and characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM) for different coatings; the loading of PDA was examined using Fourier transform infrared spectroscopy (FTIR); the ion release capacity of the coatings was determined by inductively coupled plasma emission spectrometry (ICP-OES); the interfacial bonding of the coatings was examined using nanoscratch experiment strength. The cytotoxicity of the coating was examined by live/dead staining kit; cell proliferation viability was examined by CCK-8 kit; adhesion and osteogenic effect of the coating were examined by immunofluorescence staining and RT-PCR; osteogenic differentiation was examined by alkaline phosphatase staining.Results: The surface morphology of titanium implants was modified by micro-arc oxidation technology, and a new MAO-PDA-NC composite coating was successfully prepared. The results showed that the MAO-PDA-NC coating not only optimized the physical and chemical properties of the titanium implant surface but also significantly stimulated the biological properties of osteoblast adhesion, proliferation, and osteogenic differentiation on the coating surface.Conclusion: These results show that MAO-PDA-NC composite coating can significantly improve the surface properties of titanium implants and achieve a stable bond between implant and bone tissue, thus accelerating early osseointegration.Keywords: proliferation, differentiation, micro-arc oxidation, osseointegration

Mu-zi Li,1– 5 Xiao-yang Wen,1– 5 Xiao-qiang Liu,1– 6 Yu-qing Wang,1– 5 Lei Yan1– 5 1Center for Reproductive Medicine, Shandong University, Jinan, People’s Republic of China; 2Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, People’s Republic of China; 3Shandong Key Laboratory of Reproductive Medicine, Jinan, People’s Republic of China; 4Medical Integration and Practice Center, Shandong University, Jinan, People’s Republic of China; 5Reproductive Hospital Affiliated to Shandong University, Jinan, People’s Republic of China; 6Reproductive Medicine Center, Qingdao Women and Children’s Hospital, Qingdao, People’s Republic of ChinaCorrespondence: Lei Yan, Email yanlei@sdu.edu.cnIntroduction: Chronic endometritis is a common disease in women of childbearing age and can cause pelvic inflammatory disease. The cGAS-STING pathway plays an important role in many inflammatory diseases.Purpose: The aim of this study was to investigate the relationship between the cGAS-STING pathway and endometritis.Methods: We collected endometrium samples from patients with endometritis to detect changes in the cGAS-STING pathway. In vitro, human endometrial stromal cells (HESC) were stimulated with lipopolysaccharide (LPS), and a mouse STING gene-knockout model was established by CRISPR/cas9 for STING to further explore the mechanism underlying its effects in endometritis. We used Western blotting (WB) and immunohistochemical staining to detect the variations in protein levels and real-time PCR to study the variations in gene expression.Results: We observed the activation of the cGAS-STING pathway and an increase in the expression of cytokine-encoding genes, including IL-8, IL-6, IL-1β, and IFN-β 1, in endometrial tissues of patients with endometritis. Stimulation of HESCs using LPS demonstrated increase in the expression of proteins involved the cGAS-STING pathway and the gene expression of inflammatory cytokines. STING-knockdown experiments demonstrated a decrease in the gene expression levels of inflammatory cytokines. Moreover, we also identified the translocation of IRF3 and STING after LPS stimulation. Regarding mitochondrial function, LPS led to an increase in reactive oxygen species levels and a reduction in mitochondrial membrane potential. However, we observed that the mitochondrial DNA (mtDNA) leaked into the cytoplasm, upregulating the levels of proteins involved in the cGAS-STING pathway upon LPS stimulation. Furthermore, our results showed that LPS induced hyperemia, inflammatory factor production, and expression of Pho-TBK1 in wild-type mice compared with the levels in control mice, and STING gene-knockdown alleviated these effects.Conclusion: LPS induces mitochondrial dysfunction in endometrial stromal cells, resulting in mtDNA leakage and promoting endometritis by stimulating the cGAS-STING pathway.Keywords: endometritis, cGAS-STING, lipopolysaccharide, mitochondrial dysfunction, mitochondrial DNA, inflammatory factors

Jun Hou,1,&ast; Dezhi Zheng,2,&ast; Xudong Wen,3,&ast; Wenjing Xiao,4 Fei Han,5 Hongmei Lang,6 Shiqiang Xiong,1 Wei Jiang,5 Yonghe Hu,4 Mengshan He,7 Pan Long4,5 1Department of Cardiology, Chengdu Third People’s Hospital/Affiliated Hospital of Southwest Jiaotong University, Chengdu, People’s Republic of China; 2Department of Cardiovascular Surgery, the 960th Hospital of the PLA Joint Logistic Support Force, Jinan, People’s Republic of China; 3Department of Gastroenterology and Hepatology, Chengdu First People’s Hospital, Chengdu, People’s Republic of China; 4School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, People’s Republic of China; 5Department of Ophthalmology, the General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 6The Center of Obesity and Metabolic Diseases, Department of General Surgery, Chengdu Third People’s Hospital & the Affiliated Hospital of Southwest Jiaotong University, Chengdu, People’s Republic of China; 7Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pan Long, Department of Ophthalmology, the General Hospital of Western Theater Command, Rongdu Avenue #270, Chengdu, People’s Republic of China, Tel +86-181-9125-6132, Email longpan1005@qq.com Yonghe Hu, School of Materials Science and Engineering, Southwest Jiaotong University, No. 111, North First Section of the Second Ring Road, Chengdu, People’s Republic of China, Tel +86-138-8059-6789, Email huyonghe789@sina.comPurpose: High-altitude environment mainly with hypobaric hypoxia could induce pathological alterations in ocular tissue. Previous studies have mostly focused on sporadic case reports and simulated high-altitude hypoxia experiments. This aim of this study was to explore the proteomic and morphological changes of ocular tissue in mice at real altitude environment.Methods: In this study, mice were flown from Chengdu (elevation: 500 m) to Lhasa (elevation: 3600 m). After exposure for 1day, 3, 6, 10, 20, 30, and 40days, the mice were euthanatized to obtain blood and ocular tissue. Serological tests, ocular pathological examinations, integral ocular proteomics analysis, and Western blot were conducted.Results: We focused on acute phase (1– 3 days) and chronic phase (> 30 days) during high-altitude acclimatization. Serum interleukin-1 was increased at 3 days, while superoxide dismutase, interleukin-6, and tumor necrosis factor-α showed no statistical changes. H&E staining demonstrated that the cornea was edematous at 3 days and exhibited slower proliferation at 30 days. The choroid showed a consistently significant thickening, while there existed no noticeable changes in retinal thickness. Overall, 4073 proteins were identified, among which 71 and 119 proteins were detected to have significant difference at 3 days and 40 days when compared with the control group. Functional enrichment analysis found the differentiated proteins at 3 days exposure functionally related with response to radiation, dephosphorylation, negative regulation of cell adhesion, and erythrocyte homeostasis. Moreover, the differential profiles of the proteins at 40 days exposure exhibited changes of regulation of complement activation, regulation of protein activation cascade, regulation of humoral immune response, second-messenger-mediated signaling, regulation of leukocyte activation, and cellular iron homeostasis. Interestingly, we found the ocular proteins with lactylation modification were increased along high-altitude adaptation.Conclusion: This is the first work reporting the ocular proteomic and morphological changes at real high-altitude environment. We expect it would deep the understanding of ocular response during altitude acclimatization.Keywords: altitude response, ocular proteomics analysis, cornea edema, choroid thickening, post-translational modification

Cuiqiong Dai,&ast; Zihui Wang,&ast; Zhishan Deng, Fan Wu, Huajing Yang, Shan Xiao, Xiang Wen, Youlan Zheng, Jianwu Xu, Lifei Lu, Ningning Zhao, Peiyu Huang, Yumin Zhou, Pixin Ran State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pixin Ran; Yumin Zhou, The State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, No. 195 Dongfeng Xi Road, Guangzhou, 510000, People’s Republic of China, Tel +86-020 83205187, Fax +86-020 81340482, Email pxran@gzhmu.edu.cn; zhouyumin410@126.comBackground: Serum total bilirubin has been reported to have antioxidant properties against chronic respiratory diseases. The objective of our study is to evaluate the association of total bilirubin (TB) with annual lung function decline in COPD patients with different GOLD stages.Methods: This study used pooled data from two observational and prospective cohorts of 612 COPD patients whose TB levels were measured at baseline. The associations between TB and postbronchodilator FEV1, FEV1pred, FVC, FVCpred, FEV1/FVC, and the rate of their decline were all determined using linear regression models in the total population and strata of GOLD stages.Results: Serum TB was positively related to FEV1 and FVC in the total group (β 0.02, 95% CI 0.001∼ 0.02, P = 0.025 and β 0.02, 95% CI 0.002∼ 0.03, P = 0.022, respectively). Additionally, TB was inversely associated with the annual decline in FEV1 and FEV1pred (β 4.91, 95% CI 1.68∼ 8.14, P = 0.025 and β 0.21, 95% CI 0.06∼ 0.36, P = 0.022, respectively) when adjusted for multivariables. After stratification, the significant associations merely persisted in COPD patients with GOLD 2 and GOLD 3– 4.Conclusion: Increased TB level was related to less annual decline in FEV1 as well as FEV1pred in moderate-to-severe COPD but not mild COPD, which indicated the different status of TB in different COPD severity and the possible role as potential biomarker merely in moderate-to-severe COPD. Future researches to determine whether TB could be served as biomarker for COPD and the mechanisms should be focused on some target patients with a certain disease severity.Keywords: total bilirubin, COPD, lung function, GOLD stage, decline

Huajing Yang,1,&ast; Zihui Wang,1,&ast; Shan Xiao,1 Cuiqiong Dai,1 Xiang Wen,1 Fan Wu,1,2 Jieqi Peng,1 Heshan Tian,1 Yumin Zhou,1,2 Pixin Ran1,2 1National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Laboratory, Bio-Island, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pixin Ran; Yumin Zhou, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Tel +86 2083205187, Fax +86 20-81340482, Email pxran@gzhmu.edu.cn; zhouyumin410@126.comBackground: The effect of serum uric acid (SUA) levels on lung function in chronic obstructive pulmonary disease (COPD) people remained unclear. We aimed to investigate the association between SUA and lung function.Methods: A cross-sectional study was performed to measure the SUA levels and lung function in 2797 consecutive eligible individuals. Of these, individuals in our study were divided into two groups, the COPD group (n=1387) and the non-COPD group (n=1410). The diagnosis of COPD is defined as post-bronchodilator first second of forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio of less than 0.70. Multivariable adjustment linear models were applied to estimate the effect of SUA levels on FEV1% predicted, FVC% predicted, and FEV1/FVC stratified by COPD status.Results: After multivariable adjustment, each 1 mg/dL increase of SUA was significantly associated with a decrease in FEV1% predicted (− 1.63%, 95% confidence interval [CI] − 2.37 to − 0.90), FVC % predicted (− 0.89%, 95% CI − 1.55 to − 0.24), and FEV1/FVC (− 0.70%, 95% CI − 1.10 to − 0.30). In the COPD group, each 1 mg/dL increase of SUA was significantly associated with decreases in FEV1% predicted (− 1.87%, 95% CI − 2.91 to − 0.84), FVC% predicted (− 1.35%, 95% CI − 2.35 to − 0.34), and FEV1/FVC (− 0.63%, 95% CI − 1.18 to − 0.08). However, no significant association between lung function and SUA was found among people without COPD.Conclusion: High SUA levels were associated with lower lung function, especially in COPD patients. However, no statistically significant effect of SUA on lung function was found in people without COPD.Keyword: serum uric acid, lung function, COPD, non-COPD

Cuiqiong Dai,1,&ast; Zihui Wang,1,&ast; Huajing Yang,1,&ast; Shan Xiao,1 Jianwu Xu,1 Zhishan Deng,1 Fan Wu,1,2 Xiang Wen,1 Youlan Zheng,1 Lifei Lu,1 Ningning Zhao,1 Peiyu Huang,1 Yumin Zhou,1,2 Pixin Ran1,2 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Laboratory, Bio-Island, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pixin Ran; Yumin Zhou, Tel +86-20 3710 3616, Fax +86-20 81340482, Email pxran@gzhmu.edu.cn; zhouyumin410@126.comBackground: The potential protective role of serum total bilirubin (TB) for chronic obstructive pulmonary disease (COPD) is controversial. We aimed to investigate whether serum TB could prevent airflow limitation (reduce the risk of COPD) and whether these associations were causal or reversely causal.Methods: We conducted a multi-center and cross-sectional study including 3069 participants. Logistic regression model (LRM) with restricted cubic spline (RCS) and priori defined quintile categories were used to assess the associations of TB with COPD. Besides, ordinary least squares (OLS) regression model with RCS curves were applied to assess the dose-response relationship between serum TB and airflow limitation (FEV1/FVC). To verify the causal direction between TB and COPD, a bidirectional Mendelian randomization analysis was carried out with GWAS data from European ancestry.Results: In the cross-sectional study, the relationship between levels of TB and COPD risk was U shaped (P=0.001), and the low and high concentrations of TB apparently increasing the risk of COPD (OR 1.40, 95% CI 1.07 to 1.82 for less than 9 μmol/L; OR 1.36, 95% CI 1.06 to 1.76 for 9.01– 1 0.88 μmol/L; OR 1.50, 95% CI 1.16 to 1.95 for more than 13 μmol/L). There was a significant non-linear relationship between TB and FEV1/FVC (non-linear p=0.004). Furthermore, results of bidirectional Mendelian randomization analysis (OR 1.000; 95% CI 0.983 to 1.017 for MR and OR 0.998; 95% CI 0.976 to 1.020 for reversal MR) did not support the causal effects between serum TB and FEV1/FVC after controlling the effect of potential confounders and revised causality.Conclusion: Our study reveals that there was non-linear does-response pattern between serum TB and COPD. However, there was little evidence for the linear causal associations of serum TB with airflow limitation. The relationship of TB with COPD needs further study and careful interpretation.Keywords: total bilirubin, COPD, airflow limitation, Mendelian randomization analysis

Zihan Wei, Ying Zhang, Sizhen Yang, Chenhui Cai, Jiawen Ye, Hao Qiu, Xu Hu, Yiyun Qu, Xuan Wen, Tongwei Chu Department of Orthopedics, Xinqiao Hospital of Chongqing, Second Affiliated Hospital of Army Medical University, Chongqing, 400037, People’s Republic of ChinaCorrespondence: Tongwei Chu, Department of Orthopedics, Xinqiao Hospital of Chongqing, Second Affiliated Hospital of Army Medical University, Chongqing, 400037, People’s Republic of China, Tel/Fax +8613708388336, Email chtw@sina.comObjective: To compare the cervical sagittal balance parameters and clinical efficacy of three fusion devices after short-segment anterior cervical discectomy and fusion.Patients and Methods: Retrospectively analyzed 516 patients with cervical spondylosis who underwent surgery at our hospital from May 2013 to May 2019. All patients had complete data and were divided into three groups according to the selected fusion cage. Neck and upper limb pain were assessed by the visual analog scale (VAS) score. Neurological function was evaluated by the modified Japanese Orthopedics Society (mJOA) score. Also, the curvature of the cervical spine and the occurrence of dysphagia were observed.Results: There were no significant differences in the general information, thoracic inlet angle, T1 slope, or surgical data among the groups (p> 0.05). There were significant differences in the scores between pre- and postoperatively in the different groups (p< 0.05). There were no significant differences in the C2-C7 Cobb angle or C2-C7 sagittal vertebral axis before the operation among the groups (p> 0.05). There was a significant difference in the correction and loss of correction among the groups postoperatively and on follow-up (p> 0.05). Dysphagia was less likely in the Zero-P VA fusion group than in the other two groups.Conclusion: Different fusion instruments can relieve the symptoms. In the Prodisc-C Vivo group, no significant improvement in cervical sagittal balance was achieved. A good effect on improving sagittal balance was observed in both the Zero-P VA fusion and Skyline anterior cervical titanium plate groups, but a better effect on preventing dysphagia was observed in the Zero-PVA fusion group.Keywords: retrospective analyze, cervical spondylosis, anterior cervical discectomy and fusion, cervical sagittal balance parameters, fusion devices

Liang Zhang,1,&ast; Zhentao Yang,1,&ast; Shiyu Zhang,1 Ke Zhou,1 Wu Zhang,2 Sunbin Ling,1 Ruiqi Sun,1 Hong Tang,1 Xue Wen,3 Xiaowen Feng,1 Penghong Song,1 Xiao Xu,1 Haiyang Xie,1 Shusen Zheng1,2 1Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Zhejiang, 310003, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, Zhejiang, 310004, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiyang Xie; Shusen ZhengSchool of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, Zhejiang, 310000, People’s Republic of ChinaTel/Fax +86 571 87236570; +86 571 87236466Email xiehy@zju.edu.cn; shusenzheng@zju.edu.cnPurpose: Patients receiving liver transplantation (LT) for hepatocellular carcinoma (HCC) are at high risk of tumor recurrence. Polyploidy is a fascinating characteristic of the liver and correlates with HCC development and progression. This study aims to investigate the association between hepatocyte polyploidy spectrum and HCC recurrence after LT.Patients and Methods: Thirty-two paired HCC, peritumoral, cirrhotic, and normal liver specimens were employed to examine the hepatocyte polyploidization pattern during liver tumorigenesis. Clinicopathological implications of polyploidy spectrum for LT recipients with HCC were investigated in 205 patients from two transplant centers. Immunofluorescence staining was performed on paraffin-embedded tissue sections to determine the ploidy profiles in situ. Expression levels of CD4, CD8, forkhead box protein 3 (Foxp3) and programmed death-ligand 1 (PD-L1) were measured using immunohistochemistry. An array-based multiplex ELISA system was used for the quantitative measurement of 40 unique inflammatory cytokines.Results: The fraction of mononuclear polyploidy increased, whereas that of binuclear polyploidy reduced during hepatocarcinogenesis. Recipients with highly mononuclear polyploid HCC (HMP–HCC) had inferior recurrence-free survival and HCC-specific survival than poorly mononuclear polyploid HCC recipients. These two groups differed in abundance of infiltrative CD8+ cytotoxic T cells and FoxP3+ Treg cells, and PD-L1 expression, as well as circulating granulocyte–macrophage colony-stimulating factor, interferon-γ and interleukin-10 levels. HMP–HCC constituted an independent recurrence predictor and could improve the discriminative efficacy of clinical prediction models (Milan criteria, AFP model, and Metroticket 2.0 criteria). A scoring system incorporating the ploidy signature was developed and validated, allowing for an improved risk prediction relative to the RETREAT score and post-MORAL score.Conclusion: Polyploid spectra are associated with tumor immunophenotype and provide supplementary prognostic information in LT for HCC.Keywords: polyploidy, immunosurveillance, tumor-infiltrating lymphocytes, cytokines, tumor recurrence

Lemeng Zhang, Yongzhong Luo, Tianli Cheng, Jianhua Chen, Hua Yang, Xiaoping Wen, Zhou Jiang, Haitao Li, Changqie Pan Thoracic Medicine Department 1, Hunan Cancer Hospital, Changsha, Hunan Province, 410013, People’s Republic of ChinaCorrespondence: Yongzhong Luo Tel/Fax +86-731-89762220Email luoyongzhong@hnca.org.cnPurpose: The prognostic value of an N6-methyladenosine (m6A) methylation-related immune gene signature for lung adenocarcinoma (LUAD) was investigated.Patients and Methods: Gene expression and clinical phenotype data of LUAD patients were downloaded from The Cancer Genome Atlas database. A list of immune-related genes was retrieved from the InnateDB database. Correlation analysis, survival analysis, and univariate and multivariate Cox regression analyses were performed. After allocating patients into a high-risk or a low-risk group, the corresponding survival rates, immune microenvironment, expression of immune checkpoint genes, and modulation of Kyoto Encyclopedia of Genes and Genomes pathways were examined. Finally, the expression levels of prognostic biomarkers were assessed in the GSE126044 dataset.Results: Seven m6A-related immune prognostic genes were identified. High expression of PSMD10P1, DIDO1, ABCA5, and CIITA was associated with high survival rates, while that of PRC1, ZWILCH, and ANLN was associated with low survival rates. The high- and low-risk groups showed significant differences in terms of the abundance of six tumor-infiltrating immune cell types and expression of 12 immune checkpoint genes. The risk group acted as an independent prognostic factor (hazard ratio = 0.398, 95% confidence interval = 0.217– 0.729, P = 0.003). Finally, the developed nomogram could predict most efficiently the 1-, 2-, and 3-year survival probability of LUAD patients with a C-index of 0.833.Conclusion: A seven-gene risk signature, associated with the immune microenvironment in LUAD, showed independent prognostic value.Keywords: lung adenocarcinoma, N6-methyladenosine methylation, immune-related genes, immune microenvironment, prognostic signature

Rui Zhao, Shan Gao, Haiqi He, Jia Zhang, Guangjian Zhang, Xiaopeng Wen Department of Thoracic Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaCorrespondence: Xiaopeng WenDepartment of Thoracic Surgery, First Affiliated Hospital of Xi’an Jiaotong University, #277 West Yanta Road, Xi’an City, Shaanxi Province, 710061, People’s Republic of ChinaEmail xiaopengwmd@163.comObjective: To evaluate the distribution of high frequency mutant genes and the expression of PDL1 in different types of lung cancer.Methods: This retrospective analysis was conducted on 330 patients who were diagnosed with primary lung cancer and treated in our hospital from October 2018 to October 2020. The patients were listed into non-small cell carcinoma group (101 cases), squamous carcinoma group (28 cases) and adenocarcinoma group (201 cases) according to their pathological results. The gene mutations were detected using EGFR, KRAS, and BRAF gene mutation detection kits, and the expression of PDL1 was detected by immunostaining. The mutation of EGFR, KRAS and BRAF genes and PDL1 expression in patients with different types of lung cancer were compared.Results: The patients in the adenocarcinoma group had the highest incidence of EGFR gene mutation, the mutation rate of the gene whose mutation location was exon 18 was significantly higher, and the difference between each group was statistically significant (P < 0.05). The patients in the adenocarcinoma group had the highest incidence of KRAS gene mutation, the mutation rate of the gene whose mutation location was exon 2 was obviously the highest, exon 15 was the lowest, and the difference between each group was statistically significant (P < 0.05). There was no significant difference in the distribution of BRAF gene mutations among groups, and all mutations occurred on exon 15, with no statistically significant difference between each group (P > 0.05). PD-L1 expression in NSCLC patients was significantly higher than that in other lung cancer patients (P < 0.05).Conclusion: EGFR and KRAS genes showed obvious specific expressions in patients with different types of lung cancer and they were more common in patients with lung adenocarcinoma. Gene mutation and PDL1 expression are high in patients with lung adenocarcinoma.Keywords: lung cancer, typing, gene mutation, PD-L1

Dong-qi Lin,1 Jin-guo Zhu,1 Xiao-hua Xu,1 Ke Xiao,1 Xu-qing Wen,1 Qi-fa Zheng,1 Yu-hua Zhou,2 Xin-ying Cai3 1Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, People’s Republic of China; 2Nursing Department, Shantou Central Hospital, Shantou, Guangdong, People’s Republic of China; 3Clinical Research Center, Shantou Central Hospital, Shantou, Guangdong, People’s Republic of ChinaCorrespondence: Xin-ying CaiClinical Research Center, Shantou Central Hospital, Wai-ma Road 114, Shantou, Guangdong, People’s Republic of ChinaTel +86 754-88903584Fax +86 754-88548117Email cxy305527@yeah.netPurpose: The association between the process of postoperative pneumonia and lung cancer recurrence remains elusive in lung cancer surgery. Herein, the association between postoperative pneumonia and lung cancer recurrence was investigated, emphasizing the warning role of postoperative specific pneumonia in primary lung cancer resection patients.Methods: The occurrence of postoperative pneumonia was assessed in 4– 6 months (PPFS), 7– 12 months (PPST), and lung cancer recurrence within 1 year (LRO) in 332 patients. The primary outcome was the development of PPST and LRO according to PPFS occurrence. The relevant risk factors of PPFS, PPST, and LRO were identified through multivariable regression analysis.Results: During follow-up, 151 (45.48%) participants experienced PPFS. Irrespective of the existing postoperative pneumonia in 1– 3 months (PPOT), PPFS significantly increased the risk of PPST (P < 0.01) and LRO (P < 0.01), and persistent PPST further increased the risk of LRO (P < 0.001). The generalized estimating equation identified chemotherapy as an independent risk factor for PPFS and PPST.Conclusion: PPFS was associated with the increased risk of PPST and LRO. Postoperative pulmonary inflammation assessed 4 months post-surgery also significantly influenced LRO development, indicating a need for close follow-up of lung inflammatory conditions to improve patient outcomes.Keywords: chemotherapy, targeted therapy, inflammatory environment, risk factors

Chenglin Han,1 Shuxiao Chen,2 Haiyang Ma,3 Xiangchuan Wen,4 Zilong Wang,1 Yingkun Xu,1 Xunbo Jin,1,5 Xiao Yu,5 Muwen Wang1,5 1Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 3Department of Thoracic Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 4Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 5Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Xiao YuDepartment of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jingwu Road, Huaiyin District, Jinan City, Shandong Province, People’s Republic of ChinaTel +86-15168889682Email surgeonyuxiao@126.comMuwen WangDepartment of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 9677 Jingshidong Road, Jinan City, Shandong Province, People’s Republic of ChinaTel +86-15168886899Email docwmw1@163.comBackground: Ribophorin II (RPN2) is a highly conserved glycoprotein involved in the N-linked glycosylation of multiple proteins. RPN2 was reported to be associated with malignant phenotype in several tumors. However, the function of RPN2 in bladder cancer (BCa) remains unclear.Methods: Expression of RPN2 in BCa and adjacent tissues was compared by bioinformatics analysis, immunohistochemistry, and Western blotting. qRT-PCR was performed to explore the correlation between RPN2 expression and various clinical features in 38 patients. We assessed the effects of RPN2 on the biological activity of BCa both in vitro and in vivo, and explored its potential mechanisms based on gene set enrichment analysis (GSEA).Results: We found that RPN2 was highly expressed in human BCa compared with normal adjacent tissues. There was a significant positive correlation between higher RPN2 mRNA levels and tumor T stage, lymph node (LN) metastasis and the degree of pathological differentiation in 38 patients with BCa. We further demonstrated that RPN2 silencing inhibited the growth and metastasis of BCa both in vitro and in vivo. Western blotting revealed that RPN2 knockdown suppressed epithelial-mesenchymal transition (EMT) and inhibited the PI3K-Akt pathway.Conclusion: These data suggest that RPN2 functions as an oncogene to promote tumor development and is a promising prognostic factor and therapeutic target in BCa.Keywords: bladder cancer, RPN2, poor prognosis, EMT, PI3K-Akt pathway

Zheng Wang,1,* Xiaoxi Wang,2,* Fei Cheng,2 Xue Wen,2 Shi Feng,2 Fang Yu,2 Hui Tang,2 Zhengjin Liu,3 Xiaodong Teng2 1Department of Neurology, Hangzhou Seventh People’s Hospital, Hangzhou, People’s Republic of China; 2Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhengjin LiuDepartment of Pathology, Zhongshan Hospital, Xiamen University, 201 Hubin South Road, Xiamen, Fujian, 361004, People’s Republic of ChinaEmail liuzhengjin@163.comXiaodong TengDepartment of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310000, People’s Republic of ChinaEmail teng1102069@zju.edu.cnBackground: Glioma is a common intracranial malignant tumor with high rates of invasiveness and mortality. This study aimed to investigate the mechanism of rapamycin in glioma.Methods: U118-MG cells were treated with and without rapamycin in vivo and then collected for RNA sequencing. Differentially expressed miRNAs (DEMs) were screened and verified. MiR-26a-5p was selected for functional verification, and the target gene of miR-26a-5p was identified. The effects of miR-26a-5p on cell proliferation, cell cycle, apoptosis, and autophagy were also investigated.Results: In total, 58 up-regulated and 41 down-regulated DEMs were identified between rapamycin-treated and untreated U118-MG cells. MiR-26-5p levels were up-regulated in U118-MG cells treated with 12.5 μM rapamycin, and death-associated protein kinase 1 (DAPK1) expression, a direct miR-26a-5p target gene, was down-regulated. Rapamycin substantially inhibited cell proliferation and cell percentage in the S phase and promoted cell apoptosis; miR-26a-5p inhibitor increased cell proliferation and cell cycle and decreased cell apoptosis; DAPK1 overexpression further induced cell proliferation, increased the cell number in the S phase, and inhibited apoptosis in glioma cells. Notably, rapamycin increased the autophagy-related Beclin1 protein expression levels and the LC3 II/I ratio.Conclusion: Rapamycin exerts anti-tumor effects by promoting autophagy in glioma cells, which was dependent on the miR-26a-5p/DAPK1 pathway activation by rapamycin.Keywords: rapamycin, autophagy, RNA sequencing, glioma cells, miR-26a-5p, death-associated protein kinase 1

Xiao-Ming Zhang,1,* Jing Jiao,1,* Chen Zhu,1 Na Guo,1 Ying Liu,1 Dongmei Lv,2 Hui Wang,3 Jingfen Jin,4 Xianxiu Wen,5 Shengxiu Zhao,6 Xin-Juan Wu,1 Tao Xu7 1Department of Nursing, Chinese Academy of Medical Sciences - Peking Union Medical College, Peking Union Medical College Hospital (Dongdan Campus), Beijing, 100730, People’s Republic of China; 2Department of Nursing, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 3Department of Nursing, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Nursing, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 5Department of Nursing, Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China; 6Department of Nursing, Qinghai Provincial People’s Hospital, Xining, People’s Republic of China; 7Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin-Juan Wu; Tao Xu Tel/Fax +010 86 6915 6114Email wuxinjuan@sina.com; xutaosd@126.comPurpose: Studies exploring the association of cognitive frailty and mortality have been mainly based on community settings or nursing home settings. The aim of our study was to explore the association between cognitive frailty and 30-day mortality among older Chinese inpatients.Patients and Methods: A national cohort study was performed in different hospitals in China. A baseline survey was conducted from October 2018 and February 2019. Trained investigators collected the 30-day mortality. Cognitive impairment and frailty were defined by the Mini-Cog and FRAIL scale, respectively. Multivariate regression was used to explore the association between cognitive impairment and frailty status with 30-day mortality.Results: Of these participants, there were 3891 (41.91%) women and 5392 (58.09%) men, with an average age of 72.41 (SD=5.72). The prevalence of cognitive frailty was 5.44%. After adjusting for age, gender, education, depression and activities of daily living (ADL), the odds ratios (ORs) for 30-day mortality among inpatients were 3.43 (95% CI: 1.80– 6.55) for cognitive frailty, 1.85 (95% CI: 1.01– 3.41) for frailty only, and 1.43 (95% CI: 0.77– 2.65) for cognitive impairment only compared to the reference group (neither frailty nor cognitive impairment). In addition, the discrimination of 30-day mortality was higher among patients with cognitive frailty (area under the curve =0.676 [95% CI: 0.621– 0.731]) than either frailty (area under the curve =0.644 [95% CI: 0.594– 0.694]) or cognitive impairment (area under the curve = 0.606 [95% CI: 0.556– 0.655]) separately. Stratified analysis showed that these associations still existed when grouped by gender.Conclusion: Our study found that Chinese inpatients with cognitive frailty had a higher risk of 30-day mortality than those without frailty and cognitive impairment, suggesting that clinicians should be encouraged to perform early screening of patients with frailty and cognitive impairment and carry out effective interventions to reverse cognitive frailty syndrome.Keywords: frailty, cognitive impairment, mortality, older adults, Chinese; inpatients

Mengheng Mi,1,2,* Fangcao Wu1 12 2,* Jian Zhu3 3, Fang Liu1 12 2, Guzhen Cui1 14 4, Xueqing Wen1 12 2, Yue Hu5 5, Zhaohui Deng3 3, Xiaojuan Wu1 12 2, Zhengrong Zhang1 14 4, Tingna Qi1 14 4, Zhenghong Chen1 12 2 1Key Laboratory of Microbiology and Parasitology of Education Department of Guizhou, School of Basic Medical Science, Guizhou Medical University/Joint Laboratory of Helicobacter Pylori and Intestinal Microecology of Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 2Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, People’s Republic of China; 3Department of Gastroenterology, Guiyang Hospital of Guizhou Aviation Industry Group, Guiyang, People’s Republic of China; 4Key Laboratory of Endemic and Ethnic Diseases (Guizhou Medical University), Ministry of Education, Guiyang, People’s Republic of China; 5Department of Gastroenterology, Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenghong ChenDepartment of Microbiology, School of Basic Medical Science, Guizhou Medical University, Guiyang, People’s Republic of ChinaTel + 86-13985006815Fax + 86-85188174015Email chenzhenghong@gmc.edu.cnPurpose: Chronic Helicobacter pylori infection causes peptic ulcers in a subpopulation of individuals and is a risk factor for the development of gastric cancer. Multiple infections and heteroresistant H. pylori contribute to poor treatment efficacy. Here, we investigated the extent of genetic diversity among H. pylori strains within a given host and its influence on the results of antibiotic (metronidazole, levofloxacin, clarithromycin, amoxicillin, and tetracycline) susceptibility testing.Materials and Methods: Gastric mucosa biopsy samples were obtained from patients with gastric disorders, including 48 H. pylori positive patients, who were never previously treated for H. pylori infection. Five potential H. pylori colonies isolated from each sample were subcultured for enrichment. Enriched H. pylori colonies were identified through Gram staining and assays for urease, oxidase, and catalase. For each H. pylori monoclonal colony, the antibiotic susceptibility was assessed, genomic DNA was sequenced, and the cytotoxin-associated gene A (cagA) genotype was verified. Co-infection with multiple H. pylori strains was determined using random amplified polymorphic DNA (RAPD)-polymerase chain reaction (PCR).Results: Thirteen gastric mucosa biopsy samples were positive for H. pylori. Five monoclonal strains isolated from each of these 13 patients were identified as H. pylori. RAPD-PCR indicated that intra-patient monoclonal strains of H. pylori in 10 of the 13 samples exhibited heterogeneity. Among the 13 patients, intra-patient monoclonal strains isolated from 4 patients had identical cagA genotype, whereas intra-patient monoclonal strains isolated from the other 9 patients harbored more than one cagA genotype. The antibiotic susceptibility of five intra-patient monoclonal strains from seven patients was inconsistent.Conclusion: The existence of heterogeneous H. pylori strains with resistance to different drugs and virulence were common within the gastric mucosa of an individual patient.Keywords: Helicobacter pylori, heterogeneity, antibiotic resistance, cagA typing

Xiangchuan Wen,1 Baojie Wang,1 Chunjuan Wang,1,2 Chenglin Han,3 Shougang Guo1,2 1Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, People’s Republic of China; 2Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of China; 3Department of Urology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, People’s Republic of ChinaCorrespondence: Shougang GuoDepartment of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jing Wu Road, Huaiyin District, Jinan, 250021 Shandong, People’s Republic of ChinaTel +86-13220585081Email guoshougang1124@163.comPurpose: To explore the effects of immunotherapy and tumour treatment on patients with GABABR encephalitis, evaluate the correlation between immune cell subsets and disease activity, and investigate effective prognostic factors.Patients and Methods: Twenty patients with γ-aminobutyric acid B receptor (GABABR) encephalitis were enrolled from December 2015 to April 2020. The clinical data, modified Rankin Scale (mRS) score, prognosis and percentage of serum lymphocytes were recorded.Results: All patients received first-line immunotherapy. The median mRS scores were 4 and 3 before and after first-line immunotherapy (P< 0.01). Seven patients received second-line immunotherapy and had median mRS scores of 3 and 2 before and after second-line immunotherapy (P=0.015). Small-cell lung cancer was detected in twelve patients. Among the patients who died because of tumours, patients who received tumour treatment lived longer than patients who did not receive tumour treatment (P=0.025). All four surviving patients who received tumour treatment had good outcomes (mRS≤ 2). The median serum CD19+B cell percentage in sixteen patients were 20.00% and 13.42% prior first-line immunotherapy and at the last follow-up (P< 0.01). After a maximum follow-up of 54 months (median: 12; range: 3– 54), eleven patients (55%) had a poor prognosis (mRS> 2). Predictors of a poor prognosis were older age (P=0.031), delayed initial improvement after immunotherapy (> 4 weeks) (P=0.038) and respiratory failure (P=0.038).Conclusion: Aggressive immunotherapy and tumour treatment contribute to improvements in neurological function and a better prognosis of patients with GABABR encephalitis. The serum CD19+B cell percentage may be an indicator of disease activity. Older age, delayed initial improvement after immunotherapy, and respiratory failure may be associated with poor outcomes.Keywords: GABABR encephalitis, immunotherapy, tumour treatment, CD19+B cell percentage, prognosis

Miaoxia Liu,1,2,* Ruihong Wu,1,3,* Xu Liu,1 Hongqin Xu,1 Xiumei Chi,1,3 Xiaomei Wang,1 Mengru Zhan,1 Bao Wang,1 Fei Peng,1 Xiuzhu Gao,1,3 Ying Shi,1 Xiaoyu Wen,1 Yali Ji,2 Qinglong Jin,1 Junqi Niu1 1Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People’s Republic of China; 2Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 3Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, Jilin Province 130021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinglong JinDepartment of Hepatology, First Hospital of Jilin University, 71 Xin Min Street, Changchun 130021, People’s Republic of ChinaTel/Fax +86-431-81875103Email jinql2016@163.comPurpose: GALAD is a statistical model for estimating the likelihood of having hepatocellular carcinoma (HCC) based on gender, age, AFP, AFP-L3, and PIVKA-II. We aimed to assess its performance and build new models in China, where hepatitis B virus (HBV) is the leading etiology of HCC.Patients and Methods: We built the GALAD-C model with the same five variables in GALAD, and the GAAP model with gender, age, AFP, and PIVKA-II, using logistic regression based on 242 patients with HCC and 283 patients with chronic liver disease (CLD). We also collected 50 patients with other malignant liver tumors (OMTs) and 50 healthy controls (HCs). A test dataset (169 patients with HCC and 139 with CLD) was used to test the performance of GAAP.Results: The GALAD-C and GAAP models achieved comparable performance (area under the receiver operating characteristic curve [AUC], 0.922 vs 0.914), and both were superior to GALAD, PIVKA-II, AFP, and AFP-L3% (AUCs, 0.891, 0.869, 0.750, and 0.711) for discrimination of HCC from CLD for the entire dataset. The AUCs of the GALAD, GALAD-C and GAAP models were excellent for the hepatitis C virus (HCV) subgroup (0.939, 0.958 and 0.954), and for discrimination HCC from HCs (0.988, 0.982, and 0.979), but were relatively lower for the HBV subgroup (0.855, 0.904, and 0.894), and for HCC within Milan Criteria (0.810, 0.841, and 0.840). They were not superior to AFP (0.873) for discrimination of HCC from OMT (0.873, 0.809, and 0.823). GAAP achieved an AUC of 0.922 in the test dataset.Conclusion: GALAD was excellent for discrimination of HCC from CLD in the HCV subgroup of a cohort of Chinese patients. The GAAP and GALAD-C models achieved better performance compared with GALAD. These three models exhibited better performance in patients with an HCV etiology than those with HBV.Keywords: hepatocellular carcinoma, alpha-fetoprotein, PIVKA-II, GALAD

Our understanding of interactions among intestinal helminths, gut microbiota and host is still in its infancy in fish. In this study, the effects of Schyzocotyle acheilognathi infection on the intestinal microbiota, growth and immune reactions of grass carp were explored under laboratory conditions. 16S rDNA amplification sequencing results showed that S. acheilognathi infection altered the composition of intestinal microbiota only at the genus level, with a significant increase in the relative abundance of Turicibacter and Ruminococcus (P < 0.05) and a significant decrease in the relative abundance of Gordonia, Mycobacterium and Pseudocanthomonas (P < 0.05). Schyzocotyle acheilognathi infection had no significant effect (P > 0.05) on the alpha diversity indices (including Chao1, ACE, Shannon, Simpson index) of intestinal microbiota in grass carp, but PERMANOVA analysis showed that microbial structure significantly (P < 0.01) differed between hindgut and foregut. PICRUST prediction showed that some metabolism-related pathways were significantly changed after S. acheilognathi infection. The relative abundance of Turicibacter was positively correlated with the fresh weight of tapeworm (foregut: r = 0.48, P = 0.044; hindgut: r = 0.63, P = 0.005). There was no significant difference in the body condition of grass carp between the S. acheilognathi infected group and the uninfected group (P > 0.05). Intestinal tissue section with HE staining showed that S. acheilognathi infection severely damaged the intestinal villi, causing serious degeneration, necrosis and shedding of intestinal epithelial cells. The real-time fluorescent quantitative PCR results showed that S. acheilognathi infection upregulated the mRNA expression of the immune-related genes: Gal1-L2, TGF-β1 and IgM.

Xiaolan Wen,1,2 Yanling Wu,1,2 Annoor Awadasseid,1,3 Yoshimasa Tanaka,4 Wen Zhang1 1Laboratory of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China; 2Laboratory of Molecular Immunology, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou 310051, People’s Republic of China; 3Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, People’s Republic of China; 4Laboratory of Bioinformatics and Molecular Medicine, Center for Medical Innovation, Nagasaki University, Nagasaki, 852-8588, JapanCorrespondence: Yanling WuLaboratory of Molecular Immunology, Zhejiang Provincial Center for Disease Control and Prevention, 3399 Binsheng Road, Binjiang District, Hangzhou, Zhejiang 310051, People’s Republic of ChinaTel +86 138 6715 2930Email ylwu@cdc.zj.cnWen ZhangLaboratory of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, 18 Chaowang Road, Xiacheng District, Hangzhou, Zhejiang 310014, People’s Republic of ChinaTel +86 136 1671 0236Email wzhang63@zjut.edu.cnAbstract: Wnt/β-catenin-mediated signaling is a key pathway regulating tissue growth and development, and tumorigenesis, and has received increasing attention in recent years. In addition to participating in healthy tissue and organ development, ectopic activation of the pathway can cause a variety of tumors and other pathologies. The pathway plays a critical role in many processes such as proliferation, differentiation, apoptosis, migration, invasion, epithelial–mesenchymal transition and cancer cell stemness. The importance of the Wnt signal is self-evident. This review describes the underlying mechanism of Wnt signaling pathway and highlights the latest findings on the relationship between Wnt signaling pathway and tumorigenesis. In addition, the potential relationship between miRNAs and Wnt signaling is presented. Furthermore, we discuss the intrinsic link between Wnt signaling and cancer cell stemness, which shed light on the malignant progression of tumor cells. Finally, cancer treatment strategies based on the canonical Wnt signaling pathway are summarized, hoping to help clinical development.Keywords: Wnt/β-catenin, tumor, miRNAs, cancer stem cell, target, therapeutic strategy

Yiran Li1 *, Qizhi He2 *, Shuangdi Li,1 Xiaoli Wen,3 Lei Ye,1 Kai Wang,3 Xiaoping Wan1 1Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Department of Pathology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 3Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kai Wang Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Shanghai 200040, People’s Republic of ChinaTel +86 (021)-5403-7438Email kaiwangcn@yahoo.comXiaoping Wan Department of Gynecology, Shanghai First Maternity and Infant Hospital, Shanghai 200040, People’s Republic of ChinaTel +86 136-5191-7177Email wanxiaoping62@126.comObjective: To study the characteristics of polymerase epsilon (POLE) exonuclease domain mutations in Chinese patients with endometrial carcinoma (EC).Methods: This study analyzed data from 529 patients with EC in The Cancer Genome Atlas (TCGA) and 467 EC patients evaluated at the Shanghai First Maternity and Infant Hospital (SFMIH). POLE mutation heterogeneity was analyzed in paired curettage and hysterectomy samples from 120 SFMIH patients. Sanger sequencing identified mutations in the POLE exonuclease domain, and correlations between POLE mutation status and various clinicopathological features were determined by chi-squared testing and Cohen’s kappa analysis, with Kaplan–Meier survival curves generated to assess correlations between POLE mutation status and overall survival (OS).Results: Thirty-five mutations were identified in 467 samples (7.5%), and novel mutations were detected in the SFMIH cohort. Compared to the TCGA cohort, the SFMIH cohort had fewer POLE mutations when matched by age (< 60) and histology (endometrioid) (p < 0.001 and p = 0.010, respectively). In our study cohort, POLE mutations were significantly associated with adjuvant treatment (p = 0.029), and patients with POLE mutations who underwent chemoradiotherapy had a poor OS (p < 0.0001). Notably, shorter OS was significantly associated with POLE mutations in hysterectomy samples from patients aged > 60 years or with stage I disease in the paired curettage-hysterectomy group.Conclusion: The significant difference in POLE mutation profiles between the TCGA and SFMIH cohorts, as well as the poor consistency between the curettage and hysterectomy samples, suggests that different parameters need to be applied to determine the prognosis of patients with EC in China.Keywords: endometrial carcinoma, polymerase epsilon mutation, POLE mutation, Chinese cohort, hysterectomy, curettage specimens

Minmin Lin,1,* Yongqiang Yang,2– 4,* Yanxian Yang,2,3,* Guanping Chen,5 Ruowen He,2,3 Yiping Wu,2,3 Lan-Lan Zhong,2,3 Mohamed Abd El-Gawad El-Sayed Ahmed,2,3,6 Siyuan Feng,2,3 Cong Shen,2,3 Xin Wen,2,3 Jin Huang,1 Hongyu Li,7 Xiaobin Zheng,1 Guo-Bao Tian2,3 1Department of Respiratory Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, People’s Republic of China; 2Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China; 3Key Laboratory of Tropical Diseases Control (Sun Yat-sen University), Ministry of Education, Guangzhou 510080, People’s Republic of China; 4School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510006, People’s Republic of China; 5Sun Yat-sen University School of Medicine, Guangzhou 510006, People’s Republic of China; 6Department of Microbiology and Immunology, Faculty of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), Cairo, 6th of October City, Egypt; 7Department of Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guo-Bao Tian; Xiaobin Zheng Email tiangb@mail.sysu.edu.cn; zhxbin@mail.sysu.edu.cnBackground: Bloodstream infection (BSI) caused by carbapenem-resistant Enterobacteriaceae are potentially life-threatening related to poorer outcomes. Colistin is considered one of the last-resort treatments against human infections caused by multidrug-resistant (MDR) Gram-negative bacteria. Therefore, emergence of strains from the blood that co-harboring mcr and carbapenem resistance genes were considered as a serious problem.Purpose: In this study, two mcr-9-harboring MDR Enterobacter cloacae isolates BSI034 and BSI072 recovered from BSI patients were identified, one of which co-harbored mcr-9 and blaNDM-1. The genetic characteristics of the MDR plasmid needed to be clarified.Methods: S1-PFGE and Southern blotting were conducted to determine the location of mcr-9. Whole-genome sequencing was performed to obtain the complete genome and plasmid sequences. The resistome and virulence genes of the strains, accompanied by the genetic characteristics of mcr-9- and blaNDM-1-harboring plasmids, were analyzed.Results: Whole-genome sequencing showed that BSI034 harbored mcr-9-carrying IncHI2-type pBSI034-MCR9 and blaNDM-1-carrying IncX3-type pBSI034-NDM1. The 278,517 bp pBSI034-MCR9 carried mcr-9 along with the other 19 resistance genes. mcr-9 was flanked by IS 903B (1057 bp) and IS 26 (820 bp) in the same orientation. In addition to resistance genes, strain BSI034 also carried a chromosome-located Yersinia high-pathogenicity island, which harbored genes of yersiniabactin biosynthesis operon ybtSXQPAUTE, irp1/2, and fyuA.Conclusion: We described the complete genome and mcr-9/blaNDM-1-co-harboring plasmid of E. cloacae from a BSI patient. Notable differences were observed within mosaic modules between pBSI034-MCR9 and other mcr-9-harboring plasmids due to extensive recombination via horizontal gene transfer.Keywords: MDR, mcr-9, colistin, virulence genes

Yuhang Tian,* Zhao Liu,* Haoyan Tan, Jiahui Hou, Xin Wen, Fan Yang, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin 150080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen ChengDepartment of Ultrasound, Harbin Medical University Cancer Hospital, 150 Haping Road, Nangang District, Harbin 150080, People’s Republic of ChinaTel +86 13313677182Email chengwen69@yahoo.comAbstract: Ultrasound-mediated targeted delivery (UMTD), a novel delivery modality of therapeutic materials based on ultrasound, shows great potential in biomedical applications. By coupling ultrasound contrast agents with therapeutic materials, UMTD combines the advantages of ultrasound imaging and carrier, which benefit deep tissue penetration and high concentration aggregation. In this paper we introduced recent advances in ultrasound contrast agents and applications in tumor therapy. Ultrasound contrast agents were categorized by their functions, mainly including thermosensitive, pH-sensitive and photosensitive ultrasound contrast agents. The various applications of UMTD in tumor treatment were summarized as follows: drug therapy, transfection of anti-oncogene, RNA interference, vaccine immunotherapy, monoclonal antibody immunotherapy, adoptive cellular immunotherapy, cytokine immunotherapy, and so on. In the end, we elaborated on the current challenges and provided perspectives of UMTD for clinical applications.Keywords: ultrasound, targeted delivery, immunotherapy, gene therapy

Abstract Background Species belonging to the genus Lernaea are cosmopolitan parasites that can infect many different freshwater fish hosts. Due to a high degree of morphological intraspecific variability and high levels of interspecific similarities, their classification is extremely difficult and controversial. Although the suitability of the shape of cephalic horns has been questioned decades ago by some experimental infection studies, this character still plays the central role in the identification of Lernaea spp. Methods We used the nominal species Lernaea cyprinacea and Lernaea cruciata to test the hypothesis that the shape of the anchor can exhibit host-induced morphological variability, and that the two taxa may be synonymous. Results We examined 517 wild or farmed specimens of five host fish species (four cyprinids and a mosquitofish), and found that all 16 parasite specimens collected from mosquitofish could be morphologically identified as L. cruciata, whereas the remaining 25 parasite specimens were all identified as L. cyprinacea. We experimentally infected goldfish and mosquitofish specimens with offspring (copepodids) of a single L. cyprinacea specimen: the adult parasites from goldfish were morphologically identified as L. cyprinacea, and those from mosquitofish as L. cruciata. We then used molecular data to corroborate that all these specimens are conspecific. Conclusions Our results suggest that L. cyprinacea and L. cruciata may be synonyms, misidentified as different species as a result of host-induced morphological variation. Given the current shortage of molecular data for the genus Lernaea, in order to resolve the taxonomy of this genus (determine the exact number of species), future studies should aim to sequence as much molecular data as possible, and conduct further experimental infections.

Mei Chen,1 Xin Gao,2 Denggao Huang,1 Shunlan Wang,1 Linlin Zheng,1 Yinyi Chen,3 Xiaohong Wen,1 Yuanhui Gao,1 Hui Cao,1 Shufang Zhang1 1Central Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, Haikou 570208, People’s Republic of China; 2Clinical Laboratory, The First People’s Hospital of Huaihua, Huaihua 418000, People’s Republic of China; 3Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang 421001, People’s Republic of ChinaCorrespondence: Shufang ZhangCentral Laboratory, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No.43 Renmin Avenue, Haikou City, Haikou Province 570208, People’s Republic of ChinaEmail zsf66189665@126.comBackground: Many studies have shown that solute carrier family 35 member F2 (SLC35F2) plays a key role in the biological processes of multiple cancers. However, there have been no reports on the role of SLC35F2 in the occurrence and development of bladder cancer (BC).Methods: SLC35F2 expression data and clinical and prognostic information from BC patients were obtained from databases. SLC35F2 expression in BC was verified by quantitative real-time PCR (qRT-PCR). The influence of SLC35F2 knockdown on the proliferation, apoptosis, migration and invasion in the 5637 and T24 cell lines was studied, and tumor formation experiments were performed in nude mice. Gene set enrichment analysis (GSEA) was used to predict the pathways and functions of SLC35F2 in BC.Results: SLC35F2 was highly expressed in BC tissues and was associated with invasiveness and T stage in BC patients. SLC35F2 knockdown can inhibit the proliferation, migration and invasion of BC cells and can promote apoptosis. SLC35F2 knockdown significantly reduced tumorigenesis in nude mice. GSEA showed that BC, pathways in cancer, apoptosis and the P53 signaling pathway were significantly enriched in SLC35F2 high expression phenotype.Conclusion: SLC35F2 can promote malignant progression and is a potential therapeutic target in BC.Keywords: bladder cancer, SLC35F2, proliferation, migration, invasion

Qi Li,1 Jia Xu,1 Zheng He,2 Xue Wen,1 Fengmei Wang,1 Peng Zhang,1 Jun Li,1 Bei Song,1 Qingyong Wang,1 Ronghai Li,1 Hai Huang3 1Department of Clinical Laboratory of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, People’s Republic of China; 2Department of Clinical Laboratory, The PLA General Hospital, Beijing 100853, People’s Republic of China; 3Department of Urology, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of ChinaCorrespondence: Hai HuangDepartment of Urology, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of ChinaEmail huanghai257@126.comBackground: Matrine (MAT) exhibits higher efficacy of chemotherapy when it is combined with other chemotherapeutic drugs; however, the therapeutic efficacy of matrine in combination with docetaxel (DOC) for prostate cancer, or even androgen-independent prostate cancer, remains poorly understood and the underlying molecular mechanisms have not yet been clearly defined. In the present study, we investigated whether matrine combined with docetaxel can strengthen anti-cancer effect.Methods: In this study, 7 groups were established, including (1) blank control group (cells). (2) 0.1 g/L MAT group, (3) 0.5 g/L MAT group, (4) 0.1 g/L MAT+ 50 μg/L DOC group, (5) 0.5 g/L MAT+ 50 μg/L DOC group, (6) 0.1 g/L MAT+ 100 μg/L DOC group, and (7) 0.5 g/L MAT+ 100 μg/L DOC group. MTS assay was performed to detect the anti-proliferative effects of each group on DU145 and PC-3 cells. At the same time, Transwell assay was performed to detect anti-migrative and anti-invasive effects of each group on DU145 and PC-3 cells. Biochemical colorimetric method and enzyme-linked immunosorbent assay were performed to detect the levels of LDH, IL-1β and IL-18 of each group on DU145 and PC-3 cells. Flow cytometry (FCM) assay was used to do the apoptosis analysis on DU145 and PC-3 cells of each group. At last, Western blot analysis was performed to investigate the expression levels of caspase1 in cells of each group. Statistical analyses were performed with SPSS 17.0 (SPSS Inc, USA) software, and one-way ANOVA and Fisher’s exact test was taken.Results: MTS assay showed that matrine combined with docetaxel could inhibit both DU145 and PC-3 cells’ proliferation in a dose- and time-dependent manner. Transwell assay showed that matrine combined with docetaxel could inhibit both DU145 and PC-3 cells’ migration and invasion in a dose- and time-dependent manner. The levels of LDH, IL-1β and IL-18 of matrine combined with docetaxel-treated DU145 and PC-3 cells were significantly increased, compared with the untreated control cells. Flow cytometry, as well as Annexin-V/PI staining, showed a significant and dose-dependent increase in the number of early, as well as late-stage apoptotic cells in both DU145 and PC-3 cells compared with the untreated control cells. Western blot analysis showed that matrine combined with docetaxel treatment led to the expression of caspase1 in both DU145 and PC-3 cells.Conclusion: It may be more effective to use matrine in combination with docetaxel to treat androgen-resistant prostate cancer because matrine can help to affect proliferation, migration, invasion, apoptosis, metabolism, and have anti-inflammation effect on the tumor cells.Keywords: matrine, docetaxel, androgen-independent prostate cancer, DU145, PC-3

Fei Han,1 Peng Zhang,2 Tianwu Chen,2 Chao Lin,1 Xuejun Wen,1 Peng Zhao1 1Institute for Translational Medicine, Institute for Biomedical Engineering and Nanoscience, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaCorrespondence: Peng Zhao; Peng ZhangInstitute for Translational Medicine, Institute for Biomedical Engineering and Nanoscience, Shanghai East Hospital, Tongji University School of Medicine, Tongji University, Room 222, Shixun Building, Shanghai 200092, People’s Republic of ChinaTel +86 21 65988029Fax +86 21 65983708-0Email zp@tongji.edu.cn; zhangpengym@163.comIntroduction: In anterior cruciate ligament (ACL) reconstruction, hamstring tendon autograft is a well-accepted surgical choice as an alternative ACL graft. But the main disadvantage of autograft is its inefficient healing with host bone-tunnel which will leading to surgery failure.Methods: A biomimetic nanofibrous membrane for tendon-bone integration is fabricated in this work, which is composed of polycaprolactone (PCL) electrospinning membrane and chitosan/hyaluronic acid (CS/HA) multilayers film.Results: By using layer-by-layer (LbL) self-assembly this functional CS/HA multilayer films are deposited on the surface of PCL nanofiber to enable the local delivery of stromal cell-derived factor-1 α (SDF-1α) and bone morphogenetic protein-2 (BMP-2) in tendon-bone interface. This membrane can promote cell proliferation and recruitment, as well as inducing the osteogenic differentiation and recruitment of BMSCs.Conclusion: Further in vivo studies demonstrate that to wrap the tendon autograft using the membrane may afford superior tendon-bone integration and inhibit scar tissue formation in a rabbit ACL reconstruction model. More importantly, the biomechanical properties of the tendon-bone interface have been improved. This study shows that this biomimetic nanofibrous membrane is effective for improving tendon-bone healing after ACL reconstruction surgery.Keywords: anterior cruciate ligament reconstruction, tendon-bone healing, layer-by-layer self-assembly, nanofibrous membrane, stromal derived factor-1α

Jing Zhang,1,* Xiaoxia Wen,1,* Yue Dai,2 Yufeng Xia11Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China; 2Department of Traditional Chinese Medicine and Pharmacology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China *These authors contributed equally to this workCorrespondence: Yufeng XiaDepartment of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, ChinaTel +86 25 83271400Fax +86 25 85301528Email yfxiacpu@126.comYue DaiDepartment of Traditional Chinese Medicine and Pharmacology, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, ChinaEmail yuedaicpu@126.comBackground: Norisoboldine (NOR), the main isoquinoline alkaloid constituent in Radix Linderae, was demonstrated to have an outstanding anti-arthritis activity. However, a poor oral bioavailability of NOR creates a barrier for its development and application.Methods: A new self-nanoemulsifying drug delivery system (SNEDDS) loaded with the phospholipid complex (PC) was designed to improve the oral bioavailability of NOR. NOR-PC was prepared by solvent evaporation method with a mixture of phospholipid and NOR at a mass ratio of 3:1. The property of PC is to improve the liposolubility of NOR, and made PC embedded in the drug delivery system. The physicochemical property of NOR-PC was characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). According to the ability to dissolve NOR-PC, the oil and cosurfactant were chosen. The surfactant was selected based on its emulsification efficiency in SNEDDS. Pseudo-ternary phase diagram was created to select the best formulation of NOR-PC-SNEDDS, and the pharmacokinetic parameters were detected in rats. In addition, intestinal lymphatic transport and liver microsome experiment were studied to gain insight into the mechanism for NOR-PC-SNEDDS increasing the oral bioavailability of NOR.Results: Solubility detection showed that the PC significantly improved the liposolubility of NOR. NOR-PC-SNEDDS was prepared using NOR-PC, Ethyl oleate, Labrasol, Cremophor EL and transcutol HP at a weight ratio of 1:2:3.36:2.24:2.4 (w/w/w/w/w). The particle size and zeta potential of NOR-PC-SNEDDS were 36.72±1.47 nm and −4.91±0.49 mV after dilution with distilled water at a ratio of 1:50 (w/w). The absolute bioavailability of NOR in the NOR-PC-SNEDDS group significantly increased and the value was 372% in relative to NOR group. Further studies indicated that NOR-PC-SNEDDS promoted the oral bioavailability of NOR by enhancing intestinal lymphatic absorption and inhibiting Phase II metabolism of NOR.Conclusion: These findings suggested that NOR-PC-SNEDDS was able to promote the oral bioavailability of NOR, which provided a foundation for the further development and application of NOR.Keywords: norisoboldine, oral bioavailability, self-nanoemulsifying drug delivery system, lymphatic absorption, Phase II metabolism

Xin Gao,1,* Wenwen Zheng,2,* Lili Ye,3 Xiaohong Wen,1 Shunlan Wang,1 Hui Cao,1 Xi Liu,1 Denggao Huang,1 Fei Wang,4 Shufang Zhang11Central Laboratory, Haikou People’s Hospital, Central South University Xiangya School of Medicine Affiliated Haikou Hospital, Haikou 570208, Hainan, People’s Republic of China; 2Department of Clinical Laboratory, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, Guangdong, People’s Republic of China; 3Department of Clinical Laboratory, Jilin Provincial Tumor Hospital, Changchun 130012, People’s Republic of China; 4Department of Urology, People’s Hospital of Hainan Province, Haikou 570311, Hainan, People’s Republic of China*These authors contributed equally to this workBackground: The current study aimed to explore the association between two epigenomic components, miRNA and DNA methylation, in bladder cancer (BC).Methods: Eight paired samples of tumor tissue and matched adjacent normal tissues from BC patients were subjected to methylated DNA immunoprecipitation sequencing and sRNA-Seq for differentially methylated miRNA genes and differential miRNA analysis. The miRNAs regulated by DNA methylation were screened and their functions involved in BC were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) as well as a miRNA–mRNA interaction network.Results: The methylation levels of 212 genes were different between tumors and normal tissues with specific enrichment at transcription initiation and termination sites. Among these genes, 154 were hypermethylated and 58 were hypomethylated. GO and KEGG pathway enrichment analysis indicated that differentially methylated miRNA genes were mainly enriched in tumor-associated GO terms and signaling pathways. Pairwise statistical analysis of MeDIP-Seq and sRNA-Seq data showed that there are 154 and 165 candidate methylation-regulated genes in tumors and normal tissues, respectively. Notably, an interaction network indicated that the miRNAs regulated by methylation regulated a broad range of mRNAs associated with cancer development and progression. In particular, the most differentially expressed miRNAs were validated by qRT-PCR, such that miR-145-5p was downregulated and miR-182-5p was upregulated in patients with bladder cancer.Conclusion: A large number of miRNA genes were modified by methylation in BC. Identification of changes in the expression of these miRNAs provides a great deal of important information for BC diagnosis.Keywords: DNA methylation, 5-methylcytidine, miRNA, bladder cancer

Lin Wang,1,2 Xianzi Wen,1 Fengming Luan,1 Tao Fu,2 Chao Gao,2 Hong Du,1 Ting Guo,1 Jing Han,1 Longtao Huangfu,1 Xiaojing Cheng,1 Jiafu Ji1,21Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 2Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of ChinaCorrespondence: Xiaojing ChengKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaTel +86 108 819 6760Email chengli@bjmu.edu.cnJiafu JiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, People’s Republic of ChinaTel +86 108 819 6048Email jijiafu@hsc.pku.edu.cnPurpose: Eukaryotic translation initiation factor (EIF) plays a vital role in protein synthesis. EIF3B is a core subunit of the EIF3 family, and is overexpressed in many tumors. EIF3B is associated with an unfavorable prognosis, as well as the genesis and development of tumors. However, the potential role of EIF3B in gastric cancer (GC) remains unknown. In the current study, we explored the clinical significance and the possible mechanism of EIF3B in the progression of GC.Methods: EIF3B expression was analyzed in 78 GC tissue samples through quantitative PCR and in 94 GC tissue samples through immunohistochemistry (IHC) staining. The correlation between EIF3B and clinicopathological features was analyzed in GC tissues. The role of EIF3B in GC progression was investigated through in vitro and in vivo assays.Results: EIF3B expression was upregulated in GC tissues (73.4%, IHC). High expression of EIF3B was significantly correlated with the depth of tumor invasion, lymph node metastasis and TNM stage (P=0.000, 0.000 and 0.000, respectively). Multivariate analysis indicated that GC patients with high EIF3B expression suffered a poorer 5-year survival. EIF3B promoted GC cell proliferation and was strongly associated with proliferating cell nuclear antigen (PCNA) expression in GC samples (P=0.009). It also enhanced tumor cell migration and invasion, which were affected through epithelial-mesenchymal transition (EMT) and the Stat3 signaling pathway. Knockdown of EIF3B in GC cells suppressed the growth of xenograft tumors and lung metastatic colonization in vivo. Furthermore, gene set enrichment analysis (GSEA) and Western blot results demonstrated that EIF3B activated the PI3K/AKT/mTOR signaling pathway.Conclusion: Our results suggest that EIF3B plays an oncogenic role in GC progression and serves as an independent prognostic factor for GC patients.Keywords: EIF3B, gastric cancer, prognosis, PI3K/AKT/mTOR pathway

Tianwen Lai,* Xiaoxia Wen,* Dong Wu,* Guomei Su, Yun Gao, Cuifen Chen, Weiquan Wu, Yingying Lv, Zhanghui Chen, Quanchao Lv, Wen Li, Dongming Li, Min Chen, Bin WuDepartment of Respiratory and Critical Care Medicine, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, People’s Republic of China*These authors contributed equally to this workPurpose: Particulate matter (PM) has been implicated as a risk factor for airway injury. However, the molecular mechanisms remain largely unclear. The goal of this study was to determine whether sirtuin1 (SIRT1), an anti-inflammatory and antiaging protein, protects against PM-induced airway inflammation.Methods: The effect of SIRT1 on PM-induced airway inflammation was assessed by using in vivo models of airway inflammation induced by PM and in vitro culture of human bronchial epithelial (HBE) cells exposed to PM, resveratrol (SIRT1 activator), or both.Results: PM-stimulated HBE cells showed a significant decrease in SIRT1 but a notable increase in inflammatory cytokines. SIRT1 gene silencing further enhanced PM-induced expression of inflammatory cytokines. In contrast, resveratrol, a SIRT1 activator, reduced the expression of these cytokines compared with the control cells. In vivo, SIRT1 expression was significantly decreased in lung tissues of PM-exposed mice. Interestingly, resveratrol treatment reversed the enhanced total cells, neutrophils and inflammatory cytokines in PM-induced mice. Moreover, SIRT1 mediated PM-induced inflammatory cytokines expression at least partly through MAPK pathways.Conclusion: These findings suggest that SIRT1 is involved in the pathogenesis of PM-induced airway inflammation and activation of SIRT1 could prevent airway disorders or disease exacerbations induced by airborne particulate pollution.Keywords: particulate matter, SIRT1, resveratrol, airway inflammation

Han Zhang,*,1 Limin Wang,*,2 Yafei Fan,1 Lianhong Yang,1 Xiaojun Wen,3 Yunyun Liu,4 Zhonglin Liu11Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, People’s Republic of China; 2Department of Neurology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Neuroscience Institute, Guangzhou 510080, Guangdong Province, People’s Republic of China; 3Department of Neurology, Guangzhou First Municipal People’s Hospital, Guangzhou Medical University, Guangzhou-Birmingham University Brain and Cognition Center, Guangzhou 510180, People’s Republic of China; 4Department of Neurology, The Sixth Affiliated Hospital Sun Yat-Sen University, Guangzhou 510440, People’s Republic of China*These authors contributed equally to this workPurpose: To assess the present evidence regarding the efficiency, safety, and potential risks of pharmacotherapy used for Parkinson’s disease psychosis (PDPsy) treatment.Patients and methods: We searched the following databases: PubMed, the Cochrane Library, ISI Web of Science, and Embase using the following terms: atypical antipsychotics, pimavanserin, olanzapine, quetiapine, clozapine, Parkinson’s disease and psychosis. We systematically reviewed all randomized placebo-controlled trials comparing an atypical antipsychotic with a placebo.Results: A total of 13 randomized placebo-controlled trials for a total 1142 cases were identified involving pimavanserin (n=4), clozapine (n=2), olanzapine (n=3), and quetiapine (n=4). For each atypical antipsychotic, a descriptive synthesis and meta-analyses was presented. Pimavanserin was associated with a significant improvement in psychotic symptoms compared to a placebo without worsening motor function. Clozapine was efficacious in alleviating psychotic symptoms and did not exacerbate motor function either. Quetiapine and Olanzapine did not demonstrate significant differences in reducing psychotic symptoms but may aggravate motor function.Conclusions: There is strong evidence that pimavanserin is effective for the treatment of PDPsy. Clozapine is also recommended but should be used with caution due to its side effects. In the future, more well-designed randomized controlled trials (RCTs) are needed to confirm and update the findings reported in this meta-analysis.Keywords: clinical trials systematic review/meta-analysis, psychosis, Parkinson’s disease/Parkinsonism

Rui Wang,1 Xiaodan Wen,2 Cheng Huang,1 Yingcong Liang,1 Yujing Mo,1 Ling Xue11Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 2Department of Geriatrics, Guangdong Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of ChinaObjective: Emerging evidence suggests that systemic inflammation is a predictor of poor prognosis in acute myocardial infarction (AMI). In this study, we sought to assess whether inflammation-based prognostic scores are associated with in-hospital outcomes in elderly patients with AMI.Methods: In this retrospective study, patients who were over 75-years-old and met the diagnostic criteria for AMI were consecutively recruited from January 1, 2016, to March 31, 2019. Logistic regression and receiver-operating characteristic (ROC) analyses were performed to evaluate the predictive value of the inflammation-based Glasgow Prognostic Score (GPS), Prognostic Index (PI) and Prognostic Nutritional Index (PNI).Results: A total of 273 patients were enrolled. The incidence of major cardiovascular adverse events (MACEs) and mortality during hospitalization increased significantly with increasing GPS and PI scores. Multiple logistic regression showed that the GPS was independently associated with MACEs (score 1, RR: 6.711, 95% CI: 1.409–31.968; score 2, RR: 14.063, 95% CI: 3.018–65.535) and mortality (score 1, RR: 8.656, 95% CI: 1.068–70.126; score 2, RR: 10.549, 95% CI: 1.317–84.465). The PI was also independently predictive of MACEs (score 2, RR: 5.132, 95% CI: 1.451–18.148). No significant difference was observed in the PNI between patients with different in-hospital outcomes. When in-hospital MACEs were used as an endpoint, the area under the curve (AUC) of the GPS was 0.740 (95% CI 0.678–0.802), and the AUC of the PI was 0.703 (95% CI 0.634–0.773). When mortality was used as an endpoint, the AUC of the GPS was 0.677 (95% CI 0.602–0.753), and the AUC of the PI was 0.667 (95% CI 0.577–0.757).Conclusion: The severity of systemic inflammation is a strong predictor of poor prognosis in elderly patients with AMI. Among these three inflammation-based prognostic scores, the GPS has a better predictive value than the PI and PNI for in-hospital MACEs and mortality.Keywords: inflammation-based prognostic scores, acute myocardial infarction, elderly patients

Abstract Background Parasitic protozoans, helminths, alter the gut microbiota in mammals, yet little is known about the influence of intestinal cestodes on gut microbiota in fish. In the present study, the composition and diversity of the hindgut microbiota were determined in the intestine of common carp (Cyprinus carpio) infected with two tapeworm species, Khawia japonensis and Atractolytocestus tenuicollis. Results The intestine contained a core microbiota composed of Proteobacteria, Fusobacteria and Tenericutes. Infection with the two cestode species had no significant effect on the microbial diversity and richness, but it altered the microbial composition at the genus level. PCoA analysis indicated that microbial communities in the infected and uninfected common carp could not be distinguished from each other. However, a Mantel test indicated that the abundance of K. japonensis was significantly correlated with the microbial composition (P = 0.015), while the abundance of A. tenuicollis was not (P = 0.954). According to Pearsonʼs correlation analysis, the abundance of K. japonensis exhibited an extremely significant (P

Xiaotong Yan,1,* Mingjie Yao,2,* Xiajie Wen,2 Yiwei Zhu,3 Erjiang Zhao,4 Xiangjun Qian,2 Xiangmei Chen,2 Weiquan Lu,4 Quanjun Lv,3 Ling Zhang,5 Fengmin Lu1,2 1Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; 2Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; 3Department of Nutrition and Food Hygiene, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; 4Department of Medical Records, Henan Cancer Hospital, Zhengzhou 450008, China; 5Department of Hepatobiliary Surgery, Henan Cancer Hospital, Zhengzhou 450008, China *These authors contributed equally to this work Aims: To date, curative resection remains to be the most optimal therapeutic choice of hepatocellular carcinoma (HCC), though the overall survival (OS) remains extremely unsatisfactory. To better manage the HCC patients, we evaluated the prognosis predicting values of apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) on the long-time survival of patients who underwent surgical treatment in this study. Methods: A subgroup of 164 patients from our previously described follow-up cohort were enrolled in this study, of whom the pre-surgery ApoB and LDL-C measurements were available. They had been followed until January 2017, with a 19.5 months median survival time. The prognosis predicting values of serum ApoB, LDL-C, and other clinical variables were evaluated through Cox univariate and multivariate analyses, meanwhile, Kaplan–Meier analysis was conducted to obtain the OS curves. Results: Pre-surgery ApoB was an independent prognosis predicting factor with HR as 1.396 (P=0.033), elevated ApoB was associated with worse postsurgery prognosis in HCC patients. Concordantly, Spearman’s correlation analysis revealed that value of pre-surgery ApoB was to some extent correlated with tumor size (r=0.355, P

Jing-Hui Zheng, Gui-Lan Ning, Wen-Hua Xu, Xin-Cheng Wu, Xiao-Cong Ma Department of Cardiology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 530011, China Background: In recent years, there has been substantial research evaluating the relationship between arachidonate 5-lipoxygenase-activating protein (ALOX5AP) polymorphisms and ischemic stroke (IS). The objective of this study was to systematically review and analyze the existing evidence.Methods: A comprehensive search of major electronic databases for studies published between 1990 and 2018 was carried out. Data were synthesized as OR and 95% CI using fixed-effects and random-effects models.Results: A total of 30 studies were available for analysis. The aggregate sample size across all studies was 32,782 (16,294 cases and 16,488 controls). We found no association of the ALOX5AP rs10507391 (OR=1.03 for A allele vs T allele; 95% CI: 0.93–1.14; P=0.557), rs4769874 (OR=1.13 for A allele vs G allele; 95% CI: 1.00–1.28; P=0.050), rs9551963 (OR=1.03 for A allele vs C allele; 95% CI: 0.96–1.11; P=0.372), rs17222814 (OR=1.09 for A allele vs G allele; 95% CI: 0.96–1.24; P=0.195), rs17222919 (OR=0.89 for G allele vs T allele; 95% CI: 0.75–1.06; P=0.175), and rs4073259 (OR=1.20 for A allele vs G allele; 95% CI: 1.00–1.45; P=0.056) polymorphisms with IS risk. Haplotype analysis also did not yield significant findings for the HapA (rs17222814G–rs10507391T–rs4769874G–rs9551963A; OR=1.20; 95% CI: 0.91–1.56; P=0.192) and HapB (rs17216473A–rs10507391A–rs9315050A–rs17222842G; OR=1.11; 95% CI: 0.90–1.38; P=0.339) haplotypes.Conclusion: Current evidence does not support an association of rs10507391, rs4769874, rs9551963, rs17222814, rs17222919, rs4073259, and HapA and HapB with IS risk. Keywords: ischemic stroke, ALOX5AP, genetic polymorphism, haplotype