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Yanan Yang,1,* Shuoye Yang,1,2,* Beibei Zhang,1 Jinpeng Wang,1 Di Meng,1 Lan Cui,1,2 Lu Zhang1,2 1School of Biological Engineering, Henan University of Technology, Zhengzhou, People’s Republic of China; 2Key Laboratory of Functional Molecules for Biomedical Research, Zhengzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuoye Yang, School of Biological Engineering, Henan University of Technology, Lianhua Street, Gaoxin District, Zhengzhou, 450001, People’s Republic of China, Tel/Fax: +86-371-67756513, Email yangshuoyehaut@163.comIntroduction: RNA interference (RNAi) stands as a widely employed gene interference technology, with small interfering RNA (siRNA) emerging as a promising tool for cancer treatment. However, the inherent limitations of siRNA, such as easy degradation and low bioavailability, hamper its efficacy in cancer therapy. To address these challenges, this study focused on the development of a nanocarrier system (HLM-N@DOX/R) capable of delivering both siRNA and doxorubicin for the treatment of breast cancer.Methods: The study involved a comprehensive investigation into various characteristics of the nanocarrier, including shape, diameter, Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), encapsulation efficiency, and drug loading. Subsequently, in vitro and in vivo studies were conducted on cytotoxicity, cellular uptake, cellular immunofluorescence, lysosome escape, and mouse tumor models to evaluate the efficacy of the nanocarrier in reversing tumor multidrug resistance and anti-tumor effects.Results: The results showed that HLM-N@DOX/R had a high encapsulation efficiency and drug loading capacity, and exhibited pH/redox dual responsive drug release characteristics. In vitro and in vivo studies showed that HLM-N@DOX/R inhibited the expression of P-gp by 80%, inhibited MDR tumor growth by 71% and eliminated P protein mediated multidrug resistance.Conclusion: In summary, HLM-N holds tremendous potential as an effective and targeted co-delivery system for DOX and P-gp siRNA, offering a promising strategy for overcoming MDR in breast cancer.Keywords: mesoporous silica nanoparticles, multidrug resistance, small interfering RNA, doxorubicin, hybrid nanoparticles

Dongdong Li,1 Lijun Bian,1 Lili Cui,2 Jingying Zhou,1 Gaotian Li,1 Xiaoyan Zhao,1 Liao Xing,1 Jiaxing Cui,1 Bo Sun,1 Chunlai Jiang,1,3,4 Wei Kong,1,3,4 Yong Zhang,1,3,4 Yan Chen1,3,4 1National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, People’s Republic of China; 2Beijing Institute of Drug Metabolism, Beijing, People’s Republic of China; 3Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, People’s Republic of China; 4NMPA Key Laboratory of Humanized Animal Models for Evaluation of Vaccines and Cell Therapy Products, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Yan Chen; Yong Zhang, National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, People’s Republic of China, Tel +86-431-85167751, Fax +86-431-85167674, Email chen_yan0417@126.com; zhypharm@jlu.edu.cnPurpose: Heterologous immunization using different vaccine platforms has been demonstrated as an efficient strategy to enhance antigen-specific immune responses. In this study, we performed a head-to-head comparison of both humoral and cellular immune response induced by different prime-boost immunization regimens of mRNA vaccine and adjuvanted protein subunit vaccine against varicella-zoster virus (VZV) in middle-aged mice, aiming to get a better understanding of the influence of vaccination schedule on immune response.Methods: VZV glycoprotein (gE) mRNA was synthesized and encapsulated into SM-102-based lipid nanoparticles (LNPs). VZV-primed middle-aged C57BL/6 mice were then subjected to homologous and heterologous prime-boost immunization strategies using VZV gE mRNA vaccine (RNA-gE) and protein subunit vaccine (PS-gE). The antigen-specific antibodies were evaluated using enzyme-linked immunosorbent assay (ELISA) analysis. Additionally, cell-mediated immunity (CMI) was detected using ELISPOT assay and flow cytometry. Besides, in vivo safety profiles were also evaluated and compared.Results: The mRNA-loaded lipid nanoparticles had a hydrodynamic diameter of approximately 130 nm and a polydispersity index of 0.156. Total IgG antibody levels exhibited no significant differences among different immunization strategies. However, mice received 2×RNA-gE or RNA-gE>PS-gE showed a lower IgG1/IgG2c ratio than those received 2×PS-gE and PS-gE> RNA-gE. The CMI response induced by 2×RNA-gE or RNA-gE>PS-gE was significantly stronger than that induced by 2×PS-gE and PS-gE> RNA-gE. The safety evaluation indicated that both mRNA vaccine and protein vaccine induced a transient body weight loss in mice. Furthermore, the protein vaccine produced a notable inflammatory response at the injection sites, while the mRNA vaccine showed no observable inflammation.Conclusion: The heterologous prime-boost strategy has demonstrated that an mRNA-primed immunization regimen can induce a better cell-mediated immune response than a protein subunit-primed regimen in middle-aged mice. These findings provide valuable insights into the design and optimization of VZV vaccines with the potentials to broaden varicella vaccination strategies in the future.Keywords: varicella-zoster Virus, mRNA vaccine, glycoprotein E, lipid nanoparticles, heterologous prime-boost, cell-mediated immunity

Na Li,1 Liufu Cui,1 Gary Tse,2,3 Panagiotis Korantzopoulos,4 Konstantinos P Letsas,5 George Bazoukis,6,7 Shuohua Chen,8 Nan Zhang,2 Xuemei Yang,9 Peipei Liu,10 Lili Wu,11 Gan-Xin Yan,12,13 Gregory Yoke Hong Lip,14,15 Shouling Wu,8 Tong Liu2 1Department of Rheumatology and Immunology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 2Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, People’s Republic of China; 4First Department of Cardiology, University of Ioannina Medical School, Ioannina, Greece; 5Arrhythmia Unit, Laboratory of Cardiac Pacing and Electrophysiology, Onassis Cardiac Surgery Center, Athens, Greece; 6Department of Cardiology, Larnaca General Hospital, Larnaca, Cyprus; 7European University Cyprus, Medical School, Nicosia, Cyprus; 8Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 9School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 10School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 11Department of Cardiology, Shanghai Songjiang District Central Hospital, Shanghai, People’s Republic of China; 12Lankenau Medical Center and Lankenau Institute for Medical Research, Wynnewood, PA, USA; 13Department of Cardiology, Fuwai Huazhong Hospital, Zhengzhou, Henan Province, People’s Republic of China; 14Liverpool Centre for Cardiovascular Sciences, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK; 15Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Tong Liu, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China, Email liutong@tmu.edu.cn; liutongdoc@126.com Shouling Wu, Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China, Email drwusl@163.comObjective: This study aimed to explore the impact of a combination of hyperuricemia (HUA) and excessive high-sensitivity C-reactive protein (hs-CRP) levels on the likelihood of developing cardiac conduction block (CCB). Additionally, it sought to assess whether the influence of uric acid (UA) on CCB is mediated by hs-CRP.Methods: A prospective study was executed utilizing data from the Kailuan cohort, including 81,896 individuals initially free from CCB. The participants were categorized into four groups depending on the existence of HUA and low-grade inflammation (hs-CRP> 3 mg/L). Cox regression analysis was employed to ascertain hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident CCB. A mediation analysis was performed to determine if hs-CRP functioned as a mediator in the connection between UA levels and the incidence of CCB.Results: During a median observation period of 11.8 years, we identified 3160 cases of newly occurring CCB. Compared with the low UA/low CRP group, the combination of HUA and low-grade inflammation elevated the CCB risks (HR:1.56, 95% CI:1.22– 1.99), atrioventricular block (AVB) (HR:1.88, 95% CI:1.27– 2.77), and right bundle branch block (HR:1.47, 95% CI:1.02– 2.12), respectively. Mediation analysis revealed that in the HUA group, compared with the non-HUA group, the risk of CCB elevated by 14.0%, with 10.3% of the increase mediated through hs-CRP.Conclusion: HUA combined with elevated hs-CRP increased the risk of CCB, especially AVB. The connection between UA and the CCB risk was partly mediated by hs-CRP. Keywords: hyperuricemia, inflammation, cardiac conduction block, combined exposure, risk factors, mediation

Wenyan Sun,1,&ast; Xuetong Zhao,2– 4,&ast; Nicola Dalbeth,5,&ast; Robert Terkeltaub,6 Lingling Cui,1 Zhen Liu,1 Lin Han,1 Can Wang,1 Hui Zhang,1,7 Yiming Bao,2– 4 Changgui Li,1,7 Jie Lu1,7 1Shandong Provincial Key Laboratory of Metabolic Diseases, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, People’s Republic of China; 3CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Science and China National Center for Bioinformation, Beijing, People’s Republic of China; 4University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China; 5Department of Medicine, University of Auckland, Auckland, New Zealand; 6VA San Diego VA Healthcare Center, University of California San Diego, San Diego, CA, USA; 7Institute of Metabolic Diseases, Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Lu, Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China, Email 13127006046@163.com Changgui Li, Shandong Provincial Key Laboratory of Metabolic Diseases, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China, Email changguili@vip.163.comObjective: This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables.Methods: We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA< 6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set.Results: Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR.Conclusion: Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.Keywords: gout, febuxostat, urate-lowering therapy, machine learning model

Liuping Cui,1,2 Ran Liu,1 Fubo Zhou,1 Yumei Liu,1 Bing Tian,1 Ying Chen,2,&ast; Yingqi Xing1,3,4,&ast; 1Department of Vascular Ultrasound, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Beijing Diagnostic Center of Vascular Ultrasound, Beijing, People’s Republic of China; 4Center of Vascular Ultrasound, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingqi Xing, Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, 45 Changchun Road, Beijing, Xicheng District, 100053, People’s Republic of China, Tel +86-18610047846, Email xingyq2009@sina.comPurpose: Intraplaque neovascularization, assessed using contrast-enhanced ultrasound (CEUS), is associated with ischemic stroke. It remains unclear whether detection of intraplaque neovascularization combined with color Doppler ultrasound (CDUS) provides additional value compared with CDUS alone in assessing ischemic stroke risk. Therefore, we investigated the clinical value of combined CEUS, CDUS, and clinical features for ischemic stroke risk stratification.Patients and Methods: We recruited 360 patients with ≥ 50% carotid stenosis between January 2019 and September 2022. Patients were examined using CDUS and CEUS. Covariates associated with ischemic stroke were identified using multivariate logistic regression analysis. The discrimination and calibration were verified using the C-statistic and Hosmer–Lemeshow test. The incremental value of intraplaque neovascularization in the assessment of ischemic stroke was analyzed using the Delong test.Results: We analyzed the data of 162 symptomatic and 159 asymptomatic patients who satisfied the inclusion and exclusion criteria, respectively. Based on multivariate logistic regression analysis, we constructed a nomogram using intraplaque neovascularization, degree of carotid stenosis, plaque hypoechoicity, and smoking status, with a C-statistic of 0.719 (95% confidence interval [CI]: 0.666– 0.768) and a Hosmer–Lemeshow test p value of 0.261. The net reclassification index of the nomogram was 0.249 (95% CI: 0.138– 0.359), and the integrated discrimination improvement was 0.053 (95% CI: 0.029– 0.079). Adding intraplaque neovascularization to the combination of CDUS and clinical features (0.672; 95% CI: 0.617– 0.723) increased the C-statistics (p=0.028).Conclusion: Further assessment of intraplaque neovascularization after CDUS may help more accurately identify patients at risk of ischemic stroke. Combining multiparametric carotid ultrasound and clinical features may help improve the risk stratification of patients with ischemic stroke with ≥ 50% carotid stenosis.Plain Language Summary: We studied whether using contrast-enhanced ultrasound (CEUS) to detect intraplaque neovascularization could help better determine the risk of ischemic stroke. We compared the combined use of color Doppler ultrasound (CDUS) and CEUS with CDUS alone in patients with more than 50% carotid narrowing. Our findings showed that combining clinical details, CDUS, and CEUS was more effective (0.719 vs 0.672). This means that CEUS provides extra insight when gauging ischemic stroke risk compared with CDUS alone. This could help in accurately identifying patients at high risk of stroke. However, more extensive studies are needed to fully understand the role of these tests in the evaluation of stroke risk. Keywords: atherosclerosis, contrast-enhanced ultrasound, vulnerable plaque, carotid ultrasound

Liqin Yuan, Lin Cui, Jie Wang, Li Gong Department of Gynecology, Rizhao People’s Hospital, Rizhao, Shandong Province, 276800, People’s Republic of ChinaCorrespondence: Li Gong, Rizhao People’s Hospital, Rizhao, Shandong Province, 276800, People’s Republic of China, Tel +86-18663351821, Email gongli0768@163.comPurpose: Meigs’ syndrome is a rare gynecological disease characterized by the triad of benign ovarian tumor, ascites, and pleural effusion. Ovarian malignancies should be highly suspected in a postmenopausal woman with a pelvic mass, ascites, hydrothorax, and an elevated carbohydrate antigen 125 (CA125) level. It can be challenging to make a preoperative diagnosis of Meigs’ syndrome. In this report, we present a case of Meigs’ syndrome caused by an ovarian fibrothecoma and review the relevant literature to raise awareness and avoid misdiagnosis.Case Presentation: An 82-year-old woman with a 2-week history of abdominal distension was admitted to the Department of Gynecology. Ultrasound and thoracoabdominal computed tomography scans showed a left-sided hypoechoic mass in the pelvic cavity with bilateral pleural effusion and massive ascites. The CA125 concentration was 1040 U/mL (normal, 0– 35 U/mL). With a working diagnosis of ovarian malignancy, the patient underwent ultrasound-guided fine-needle puncture of the pelvic mass and paracentesis to drain the ascites. The fine-needle puncture and paracentesis fluid analysis results revealed that the ascites did not contain any tumor cells, and the pelvic mass was identified as a spindle cell tumor. Immunohistochemistry confirmed that it was a sex-cord stromal tumor. Total abdominal hysterectomy and bilateral adnexectomy were performed under general anesthesia. The pathology results confirmed the mass to have been an ovarian fibrothecoma. At the 2-month postoperative follow-up, the ascites and hydrothorax had resolved and not recurred, and the CA125 level was normal.Conclusion: Despite the high suspicion of ovarian carcinoma in postmenopausal women presenting with pelvic mass, ascites, pleural effusion, and elevated CA125, Meigs’ syndrome should be considered.Keywords: Meigs’ syndrome, ascites, pleural effusion, CA125, ovarian fibrothecoma, ovarian cancer

Kunjing Han,1,&ast; Yiping Chen,2,&ast; Min Li,2 Liping Cui1 1Department of Nursing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People’s Republic of China; 2School of Nursing, Shanxi Medical University, Jinzhong, Shanxi Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liping Cui, Department of Nursing, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, No. 99, Longcheng Street, Taiyuan, 030032, People’s Republic of China, Tel +86 0351-8368114, Email cuiliiping@163.comBackground: Stroke is a critical public health issue in China that necessitates a closer examination of family resilience (defined here as the collective capacity of individuals, families and communities to effectively navigate challenges, recover from adverse events and foster positive adaptation). Amid rising stroke incidence, this study addresses the dearth of research on family resilience among stroke survivors in China, aiming to assess its level, identify influencing factors and establish coping strategies for family caregivers.Methods: This mixed-methods research employed a sequential explanatory design. Questionnaires were distributed to 258 stroke survivors and their family members at outpatient follow-up visits. In the first stage (ie the quantitative research stage), the research tools for data collection included a general demographic sociological data questionnaire, the Family Resilience Assessment Scale (FRAS), the Self-Efficacy for Managing Chronic Disease 6-Item Scale, the Caregiver Burden Scale, the Family Functioning Scale and the Social Support Rating Scale. Quantitative data were analysed using IBM SPSS 26.0 software, utilising descriptive statistics for summarising sociodemographic characteristics and conducting analyses, such as independent-sample t-tests, one-way analysis of variance and Spearman correlation analysis. The second stage (ie the qualitative research stage) involved complementing and validating the data, developing a quantitative–qualitative interview framework and selecting participants for interviews. Colaizzi’s seven-step analysis was applied to analyse interview data. In the third stage, the quantitative and qualitative research results were integrated, and a comprehensive analysis was performed to obtain an accurate conclusion.Results: A total of 242 families responded to the questionnaire (response rate: 93.8%). In total, the mean age of stroke survivors was 61.86 ± 8.76 years old, and 69.8% were male. The quantitative results showed that the FRAS mean score was (185.33 ± 24.78), which was above the medium level. The multiple linear regression analysis confirmed that family function was the strongest influencing factor on family resilience (β = 0.948, p

Zhipeng Wang,1,&ast; You Yin,2,&ast; Yuhui Mu,1,3,&ast; Lili Cui,1 Xinhua Song,1 Jianhua Zhuang,2 Shouhong Gao,1 Xia Tao,1 Wansheng Chen1 1Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 2Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 3College of Traditional Chinese Medicine, Yunnan University of Traditional Chinese Medicine, Kunming, Yunnan, 650500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianhua Zhuang, Department of Neurology, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Email jianhuazh11@126.com Xia Tao, Department of Pharmacy, Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), No. 415, Fengyang Road, Shanghai, 200003, People’s Republic of China, Tel/Fax +86– 21– 81886191, Email taoxia@smmu.edu.cnObjective: This study aims to explore the mechanism underlying the induction of phlebitis by aescinate and create an early-warning model of phlebitis based on metabolomics.Methods: Patients with cerebral infarction enrolled had been treated with aescinate. Plasma samples were collected either before administration of aescinate, upon the occurrence of phlebitis, or at the end of treatment. Non-targeted metabolomics and targeted amino acid metabolomics were carried out to analyze metabolic profiles and quantify the metabolites.Results: Untargeted metabolomics revealed six differential metabolites in baseline samples versus post-treatment samples and four differential metabolites in baseline samples from patients with or without phlebitis. Pathways of these differential metabolites were mainly enriched in amino acid metabolism. Ten differential amino acids with a VIP value of > 1 were identified in the baseline samples, enabling us to distinguish between patients with or without phlebitis. A logistic regression model was constructed (AUC 0.825) for early warning of phlebitis of grade 2 or higher.Conclusion: The occurrence of aescinate-induced phlebitis, which can be predicted early during onset, may be associated with perturbations of the endogenous metabolic profile, especially the metabolism of amino acids. Keywords: aescinate, diagnostic model, mechanism, metabolomics, phlebitis

Dang SC, Qian XB, Jin W, Cui L, Chen JX, Gu M. Onco Targets Ther. 2019;12:785–794. We, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication of the article, concerns were raised about the duplication of images from Figure 5 with images from an unrelated article. Specifically, The image for Figure 5A, Blank, has been duplicated with images from Figure 2C, Migration, Blank and Invasion, PLL3.7, from Chen B, Zhu A, Tian L, et al. [Corrigendum] miR‑23a suppresses pancreatic cancer cell progression by inhibiting PLK‑1 expression. Molecular Medicine Reports. 2022;26:222. https://doi.org/10.3892/mmr.2022.12738. The corresponding author did respond to our queries and explained that some experiments were carried out by a third party. However, they were unable to provide details of the third party or provide a satisfactory explanation for how the images came to be duplicated or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author was notified of this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Yan Wang,1– 4,&ast; Limei Cui,2– 4,&ast; He Zhao,1– 4,&ast; Huhuifen He,1– 4 Liang Chen,2– 4 Xicheng Song,2– 4 Dawei Liu,2– 4 Jingjing Qiu,2– 4 Yan Sun2– 4 1The Second Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 2Department of Otolaryngology and Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Sun, Department of Otorhinolaryngology & Head and Neck Surgery, Yuhuangding Hospital Affiliated to Qingdao University, No. 20 East, Yuhuangding Road, Yantai, Shandong, 264000, People’s Republic of China, Email entsunyan@126.comAbstract: Degenerative diseases affect people’s life and health and cause a severe social burden. Relevant mechanisms of microglia have been studied, aiming to control and reduce degenerative disease occurrence effectively. This review discussed the specific mechanisms underlying microglia in neurodegenerative diseases, age-related hearing loss, Alzheimer’s disease, Parkinson’s disease, and peripheral nervous system (PNS) degenerative diseases. It also reviewed the studies of microglia inhibitors (PLX3397/PLX5622) and activators (lipopolysaccharide), and suggested that reducing microglia can effectively curb the genesis and progression of degenerative diseases. Finally, microglial cells’ anti-inflammatory and pro-inflammatory dual role was considered the critical communication point in central and peripheral degenerative diseases. Although it is difficult to describe the complex morphological structure of microglia in a unified manner, this does not prevent them from being a target for future treatment of neurodegenerative diseases.Keywords: microglia, neurodegenerative diseases, neuroinflammation

Ping Lu,1 Lingyun Cui,1 Xinghu Zhang2 1Center for Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of China; 2Department of Neuroinfection and Neuroimmunology, Center for Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, People’s Republic of ChinaCorrespondence: Xinghu Zhang, Department of Neuroinfection and Neuroimmunology, Center for Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring Road West, Beijing, 100070, People’s Republic of China, Tel + 86 10 5997 6585, Email xhzhtiantan@hotmail.comPurpose: Primary angiitis of the adult central nervous system (PACNS) is an increasingly recognized but limited disease. Using previous case reports, we sought to summarize the clinical symptoms, imaging manifestations, treatment, and prognosis of patients with biopsy-confirmed PACNS to guide clinical diagnosis and management.Methods: We searched the Web of Science database for studies published from January 2000 to April 2023, with the language set to English and the document type limited to [Article or Review or Letter or Editorial Material]. A systematic review of all case reports met the inclusion and exclusion criteria was performed. These patients’ clinical, pathological, and imaging characteristics were analyzed, and treatment and prognostic data were summarized.Results: We analyzed 69 articles, including 76 patients with biopsy-confirmed PACNS. And 57.9% of the patients were male, the median age at presentation was 47.0 years, and focal neurological deficits were the most common symptom in patients (78.9%), followed by headache (52.6%). The median duration of biopsy was 1.1 months, of which 49 (64.5%) patients were lymphocytic, 13 (17.1%) were granulomatous, 11 (14.5%) were amyloidotic, and 3 (3.9%) were necrotizing PACNS. Relapse events occurred in 41 (53.9%) patients, including 34 (44.2%) relapses and 8 (10.5%) deaths. Univariate logistic regression analysis revealed that symptomatic epilepsy, prolonged biopsy time window, and CD20 expression in pathological tissues might be independent risk factors for recurrent events in patients (HR=4.69, 95% CI: 1.51– 14.54, p=0.007; HR=1.11, 95% CI: 1.00– 1.22, p=0.043; HR=5.33, 95% CI: 1.07– 26.61, p=0.041).Conclusion: Adult PACNS is associated with frequent relapses and high mortality. Symptomatic epilepsy, prolonged biopsy time window, and CD20 expression in pathological tissue may be associated with recurrent events.Keywords: PACNS, biopsy, recurrence, CD20, comprehensive review

Weimin Wang,1,&ast; Shaohong Zhang,1,&ast; Lei Cui,2 Yu Chen,2 Xingxing Xu,2 Longchuan Wu2 1Department of Gerontology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian, People’s Republic of China; 2Department of Respiratory Medicine, Huaian Hospital of Traditional Chinese Medicine, Affiliated to Nanjing University of Traditional Chinese Medicine, Huaian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longchuan Wu; Xingxing Xu, Email wlc020711@163.com; blxxxbhl@163.comBackground: Bufei Yishen formula (BYF) is an effective prescription for the clinical treatment of chronic obstructive pulmonary disease (COPD). However, the molecular mechanism by which it exerts its pharmacological effects remains to be explored.Methods: The human bronchial cell line BEAS-2B was treated with cigarette smoke extract (CSE). Cellular senescence markers were detected by Western blot and ELISA. Potential transcription factor of klotho was predicted using JASPAR and USCS databases.Results: CSE induced cellular senescence with intracellular accumulation of cellular senescence biomarkers (p16, p21 and p27) and increased secretion of senescence-related secretory phenotypic (SASP) factors (IL-6, IL-8, and CCL3). In contrast, BYF treatment inhibited CSE-induced cellular senescence. CSE suppressed the transcription, expression and secretion of klotho, whereas BYF treatment rescued its transcription, expression and secretion. CSE downregulated the protein level of ZNF263, whereas BYF treatment rescued the expression of ZNF263. Furthermore, ZNF263-overexpressing BEAS-2B cells could inhibit CSE-induced cellular senescence and SASP factor secretion by upregulating the expression of klotho.Conclusion: This study revealed a novel pharmacological mechanism by which BYF alleviates clinical symptoms of COPD patients, and regulating ZNF263 and klotho expression may be beneficial to the treatment and prevention of COPD.Keywords: Bufei Yishen formula, cell senescence, ZNF263, klotho, senescence-related secretory phenotypic

Changhao Dong,1,2 Rui Xian,1,2 Guangxiang Wang,2,3 Lihong Cui1,2 1Department of Gastroenterology, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China; 2Department of Gastroenterology, The Sixth Medical Center of PLA General Hospital of Beijing, Beijing, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Lihong Cui, Department of Gastroenterology, the Sixth Medical Center of PLA General Hospital of Beijing, No. 6 Fucheng Road, Haidian Distract, Beijing, 100048, People’s Republic of China, Tel +86-10-66957541, Email cuilhkeyan@163.comPurpose: There is probably a high prevalence of small intestinal bacterial overgrowth (SIBO) in patients with gallbladder polyps (GBPs). To date, no study has evaluated the occurrence of SIBO in patients with GBPs. The aim of this study was to investigate the prevalence of SIBO in patients with GBPs and explore the possible association between these two conditions.Patients and Methods: The hydrogen-methane breath test was used to diagnose SIBO, and patients were divided into GBPs and control groups based on whether GBPs were found under ultrasound. Clinical and paraclinical factors were compared between the two groups.Results: A total of 297 subjects were included in this study. The prevalence of SIBO was significantly higher in the GBPs group than in the control group (50.0% vs.30.8%, p< 0.01). Multivariate logistic regression analysis showed that male (OR=2.26, 95% CI=1.12– 4.57, p=0.023), SIBO (OR=3.21, 95% CI=1.69– 6.11, p< 0.001), fatty liver (OR=2.91, 95% CI= 1.50– 5.64, p=0.002) and BMI (OR=1.13, 95% CI=1.01– 1.26, p=0.035) were independently associated with GBPs. And by subgroup analysis, we found that the association between SIBO and GBPs was stronger in females than in males (p for interaction< 0.001). In addition, SIBO (OR=5.11, 95% CI=1.42– 18.36, p=0.012) and fasting glucose (OR=3.04, 95% CI=1.27– 7.28, p=0.013) were found to be associated with solitary polyps.Conclusion: SIBO was highly prevalent in patients with GBPs, and this association seemed to be stronger among females.Keywords: gut microbiota, bacterial overgrowth, breath test, gallbladder polyps

Lijuan Xiong,1,&ast; Xu Long,1,&ast; Lijun Ni,2,&ast; Lili Wang,2 Yang Zhang,1 Lili Cui,1 Jian Guo,2 Chunying Yang1 1Department of Laboratory Medicine, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guizhou, People’s Republic of China; 2Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Guo, Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 1800 Yuntai Road, Pudong New Area, Shanghai, People’s Republic of China, Tel +86-17701810639, Email guojian1110@126.com Chunying Yang, Department of Laboratory Medicine, the Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 83 Feishan Street, Yunyan District, Guiyang City, Guizhou Province, People’s Republic of China, Tel +86-13658504875, Email 2590470591@qq.comPurpose: Matrix-assisted laser desorption-ionization-time of flight mass spectrometry (MALDI-TOF) has recently been widely used in clinical microbiology laboratories, with the advantages of being reliable, rapid, and cost-effective. Here, we reported the performance of two MALDI-TOF MS instruments, EXS3000 (Zybio, China) and Autof ms1000 (Autobio, China), which are commonly used in clinical microbiology field.Methods: A total of 209 common clinical common isolates, including 70 gram-negative bacteria strains, 58 gram-positive bacteria strains, 33 yeast strains, 15 anaerobic bacteria strains, and 33 mold strains, and 19 mycobacterial strains were tested. All strains were identified by EXS3000 (Zybio, China) and Autof ms1000 (Autobio, China). Sequence analysis of 16S rRNA or ITS regions was used to verify all strains.Results: Current study found that species-level discrimination was found to be 191 (91.39%) and 190 (90.91%) by EXS3000 and Autof ms1000, respectively. Genus-level discrimination was 205 (98.09%) by the EXS3000 and 205 (98.09%) by the Autof ms1000, respectively. The correct results at species level of the EXS3000 were 91.43% (64/70) for gram-negative bacteria, 93.1% (54/58) for gram-positive cocci, 93.94% (31/33) for yeast, 100% (15/15) for anaerobes and 81.82% (27/33) for filamentous fungi. The correct results at species level of the Autof ms1000 were 92.86% (65/70) for gram-negative bacteria, 91.38% (53/58) for gram-positive cocci, 93.94% (31/33) for yeast, 100% (15/15) for anaerobes and 78.79% (26/33) for filamentous fungi.Conclusion: Although the results show that the EXS3000 and Autof ms1000 systems are equally good choices in terms of analytical efficiency for routine procedures, the test result of EXS3000 is slightly better than Autof ms1000. It’s worth mentioning that the target plate of the EXS 3000 instrument is reusable, but the target plate of the Autof ms1000 is disposable, making the EXS3000 more effective in reducing costs.Keywords: evaluation, MALDI-TOF mass spectrometry, EXS3000, Autof ms1000, clinical isolates, identification, gram-negative bacteria, gram-positive bacteria, mycobacteria, yeast, anaerobic bacteria

Bai Yi Song1 &ast;, Chen Chen2 &ast;, Wen Hu Xu,1 Bai Lin Cong,3 Zheng Yi Guo,1 Zai Hao Zhao,4 Lan Cui,1 Yin Hua Zhang1,4,5 1Cardiovascular Medicine Department, Yanbian University Hospital, Yanji, 133000, People’s Republic of China; 2Department of Emergency Medicine, Yanbian University Hospital, Yanji, 133000, People’s Republic of China; 3Cardiovascular Medicine Department, Jilin City Central Hospital, Jilin, 132011, People’s Republic of China; 4Research Center, Yanbian University Hospital, Yanji, 133000, People’s Republic of China; 5Department of Physiology & Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, Seoul, 03080, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Yin Hua Zhang; Lan Cui, Yanbian University Hospital, Yanji, 133000, People’s Republic of China, Tel +86 433 2660129, Email yinzhang87@gmail.com; lancui@ybu.edu.cnBackground: There are clear gender differences in the pathological process and outcome in acute myocardial infarction (AMI) patients but inflammatory responses remain clarified. Here, we aimed to analyse the correlations between inflammatory cells and organ injury parameters in AMI patients and compared between male and female groups.Methods: A total of 603 AMI patients who underwent percutaneous coronary intervention (PCI) within 24 hours of the onset were analysed retrospectively. Basic information and hematological parameters detected 6 hours before the PCI were collected, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) were calculated. Renal, liver function indicators, and myocardial enzymes were measured. Left ventricular ejection fraction (EF) and fractional shortening (FS) on days 5– 7 after PCI were obtained. Western blot was performed to detect iNOS, eNOS and nNOS expression in H9C2 rat cardiomyocytes treated with IL-6 with and without estrogen and testosterone.Results: WBC, NEU, MON, MLR, CK, ALT and CREA of male patients were significantly higher than females, but FS was lower in females. NEU, MON and MLR were positively correlated with CK, CK-MB, AST, and ALT in males, whereas LYM were correlated with these parameters in female. NEU and NLR were inversely correlated with EF or FS only in female. Estrogen and testosterone reduced IL-6-induced iNOS protein expression in H9C2 cardiomyocytes, estrogen enhanced IL-6-induced nNOS protein expression.Conclusion: NEU, MON, MLR in male AMI patients, and LYM in female patients were associated with organ injury parameters. Estrogen regulation of nitric oxide pathway may mediate the protective effects in female.Keywords: acute myocardial infarction, gender differences, immune cells, renal function indicators, liver function indicators, nitric oxide synthases

Ping Yang,1,2 Chao Liu,3 Zhenchao Wu,2 Jiajia Zheng,4 Juan Yi,1 Nan Wu,2 Zhangli Wu,1,2 Ming Lu,2,3 Liyan Cui,4,&ast; Ning Shen1– 3,&ast; 1Institute of Medical Technology, Peking University Health Science Center, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Infectious Diseases, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Laboratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liyan Cui; Ning Shen, Email cliyan@163.com; shenningputh@163.comPurpose: This study aimed to identify the clinical outcomes, microbiological features and risk factors for difficult-to-treat resistance (DTR) Klebsiella pneumoniae (Kp) infection.Materials and Methods: A retrospective study was conducted at Peking University Third Hospital from January 2020 to March 2021. DTR was defined as resistance to ≥ 1 carbapenem, ≥ 1 extended-spectrum cephalosporin, and ≥ 1 fluoroquinolone. Hypervirulent Kp (HvKp) was defined as peg-344-, iroB-, iucA-, rmpA-, or rmpA2-positive. Clinical data were collected. Antimicrobial susceptibility testing and string tests were performed to determine resistance and hypermucoviscosity phenotype. Whole genome sequencing was performed to analyze the sequence type (ST), capsular serotypes, resistance and virulence genes. Risk factors for 30-day mortality were analyzed.Results: Fifty DTR-Kp (50.0%) strains were identified among 100 patients. Compared to non-DTR-Kp group, a significant number of patients with DTR-Kp infection experienced ICU admission (44.0% versus 10.0%, P< 0.001) and mechanical ventilation after Kp detection (26.0% versus 10.0%, P=0.037). Notably, the percentage of hvKp among the DTR-Kp isolates increased consistently over the 15 months evaluated. Most DTR-Kp strains belonged to ST11 (82.0%), followed by ST15 (12.0%), ST86 (2.0%), ST996 (2.0%), and ST3157 (2.0%). DTR-Kp isolates possessed various resistance genes, such as blaKPC-2, blaTEM-1D and fosA3 (90.0%, 80.0% and 72.0%, respectively). Importantly, the yersiniabactin genes were significantly clustered in DTR group (48/50, 96.0%). The 30-day mortality was significantly higher in patients with DTR-Kp infection than non-DTR-Kp group (38.0% versus 8.2%, P=0.001). DTR-Kp infection (odds ratio [OR] = 4.196) was an independent risk factor for the 30-day mortality of Kp-infected patients. Additionally, cerebrovascular disease (OR = 2.780) and Charlson comorbidity index (OR= 1.584) were independent risk factors for DTR-Kp infections.Conclusion: DTR-hvKp is rapidly emerging. The DTR-Kp strains harbored various resistance genes and high rates of yersiniabactin siderophore genes. DTR-Kp infection was an independent risk factor for mortality, suggesting that enhanced awareness essential.Keywords: Klebsiella pneumoniae, difficult-to-treat resistance, mortality, risk factor

Yanqin Li,1,&ast; Xiaoqian Sun,1,&ast; Xiangning Liu,1,&ast; Junjun Li,2 Xuan Li,1 Gang Wang,1 Yizhou Liu,1 Xiangyu Lu,2 Lingwen Cui,2 Mingyan Shao,3 Yong Wang,1,3,4 Wei Wang,1,4,5 Chun Li2,4 1College of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Modern Research Center for Traditional Chinese Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 4Beijing Key Laboratory of TCM Syndrome and Formula, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 5Guangzhou University of Chinese Medicine, Guangdong, 510006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wang, Guangzhou University of Chinese Medicine, Guangdong, 510006, People’s Republic of China, Tel +86 13910026960, Email wangwei26960@126.com Chun Li, Modern Research Center for Traditional Chinese Medicine, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China, Tel +86 15810068615, Email lichun19850204@163.comBackground: Acute myocardial ischemia (AMI) is a common heart disease with increasing morbidity and mortality year by year. Persistent and sterile inflammatory infiltration of myocardial tissue is an important factor triggering of acute myocardial ischemia secondary to acute myocardial infarction, and NLRP3 inflammasome activation is an important part of sterile inflammatory response after acute myocardial ischemia. Previous studies have shown that Qishen granule (QSG) can significantly inhibit the inflammatory injury of myocardial tissue caused by ischemia, but its effect and specific mechanism of inhibiting the activation of NLRP3 inflammasome have not been reported. This study was to investigate the specific mechanism of QSG inhibiting inflammation after AMI, and to validate the possible targets.Methods: The myocardial ischemia model in mice was established by ligation of the left anterior descending coronary artery. Echocardiography was used to evaluate the cardiac function of the mice. Plasma CK-MB and cTnl were detected by ELISA to evaluate the degree of myocardial injury. The extent of myocardial tissue inflammation in mice was assessed by HE staining and immunohistochemistry of IL-18, IL-1β. The expressions of NLRP3, ASC, Caspase-1, and CD86 were detected by immunofluorescence; detection of key pathway proteins P2X7R, NEK7, NLRP3, ASC, Caspase-1, and effector proteins IL-18, IL-1β by Western blot. In vitro experiments, ATP+LPS was used to construct a RAW264.7 macrophage NLRP3 inflammasome activation model. Immunofluorescence and Western blot analysis were performed to detect the expression of NLRP3 pathway activator and effector proteins. Plasmid-transfected P2X7R overexpression and immunoprecipitation assays were used to evaluate the QSG-regulated NLRP3 inflammasome activation pathway.Results: QSG rescued cardiac function and further reduced inflammatory effects in mice by inhibiting NLRP3 inflammasome activation. In vitro, QSG inhibited LPS combined with ATP-induced NLRP3 inflammasome activation in RAW264.7 macrophages by downregulating the expression of NLRP3 inflammasome key pathway proteins. In addition, inhibition or overexpression of P2X7R in RAW264.7 macrophages and immunoprecipitated protein interactions further confirmed that QSG reduces macrophages inflammasome activation via the P2X7R-NEK7-NLRP3 pathway.Conclusion: P2X7R-NEK7-NLRP3 inflammasome activation is a novel therapeutic mechanism of QSG in the treatment of acute myocardial ischemia.Keywords: acute myocardial ischemia, inflammation, macrophages, P2X7R-NEK7, NLRP3 inflammasome, Qishen granule

Qian Wang,1 Chen Yong,1 Min Wang,1 Lei Cui,1 Si-Ming Yuan1,2 1Department of Plastic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, People’s Republic of China; 2Department of Plastic Surgery, Jinling Hospital, Nanjing School of Clinical Medicine, Southern Medical University, Nanjing, 210002, People’s Republic of ChinaCorrespondence: Si-Ming Yuan, Department of Plastic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, People’s Republic of China, Email yuansm@163.comObjective: Refractory port-wine stain (PWS) usually contains hypertrophic, nodular lesions or severe scars due to improper treatment, making surgical treatment a necessity. This study aims to introduce our experiences in surgical management of refractory PWSs in the scalp and face.Methods: From January of 2013 to September of 2018, 25 patients with refractory PWSs in the scalp and face received surgeries in our department. Clinical manifestation of the disease, the surgical procedures and postoperative complications were reviewed. A Visual Analog Scale (VAS) was applied to evaluate the outcomes.Results: In this study, surgical procedures included serial resection (4 cases), complete resection followed by local flap transplantation (6 cases) or skin grafting (7 cases), and two-staged surgeries using expanded flaps (5 cases) or expanded prefabricated flap (3 cases). All the skin grafts and flaps survived well. Follow-up evaluation with VAS showed that most patients were satisfied with the surgery.Conclusion: The surgical procedures should depend on the site, area and type of the lesions and patients’ personal requirement. Individualized surgical treatment of refractory PWSs achieved satisfactory results in re-establishing symmetric facial contour and improving the overall appearance.Keywords: port-wine stain, surgery strategy, scalp and face

Luoyang Ma,1,2 Xiaoyan Zheng,1,3 Rui Lin,1 Antonia RuJia Sun,4 Jintong Song,1 Zhiqiang Ye,1 Dahong Liang,1 Min Zhang,1 Jia Tian,1 Xin Zhou,2 Liao Cui,1 Yuyu Liu,1 Yanzhi Liu1,3,5 1Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 2Marine Medical Research Institute of Zhanjiang, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 3Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang city, Guangdong province, 524045, People’s Republic of China; 4Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen City, Guangdong Province, 518055, People’s Republic of China; 5Shenzhen Osteomore Biotechnology Co., Ltd., Shenzhen city, Guangdong Province, 518118, People’s Republic of ChinaCorrespondence: Yanzhi Liu; Yuyu Liu, Tel +86-759-2388405 ; +86-759-2388588, Email liuyanzhi02@163.com; liuyuyu77@163.comAbstract: Drug delivery for osteoarthritis (OA) treatment is a continuous challenge because of their poor bioavailability and rapid clearance in joints. Intra-articular (IA) drug delivery is a common strategy and its therapeutic effects depend mainly on the efficacy of the drug-delivery system used for OA therapy. Different types of IA drug-delivery systems, such as microspheres, nanoparticles, and hydrogels, have been rapidly developed over the past decade to improve their therapeutic effects. With the continuous advancement in OA mechanism research, new drugs targeting specific cell/signaling pathways in OA are rapidly evolving and effective drug delivery is critical for treating OA. In this review, recent advances in various IA drug-delivery systems for OA treatment, OA targeted strategies, and related signaling pathways in OA treatment are summarized and analyzed based on current publications.Keywords: osteoarthritis, knee, drug delivery, intra-articular

Dandan Zhao,1,2 Xiaoxiao Zhang,1,2 Yuhui Tang,1,2 Peilin Guo,1,2 Rong Ai,1,2 Mengmeng Hou,1,2 Yiqi Wang,1,2 Xiwei Yuan,1,2 Luyao Cui,1,2 Yuguo Zhang,1,2 Suxian Zhao,1,2 Wencong Li,1,2 Yang Wang,1,2 Xiaoye Sun,1,2 Lingdi Liu,1,2 Shiming Dong,1,2 Lu Li,1,2 Wen Zhao,1,2 Yuemin Nan1,2 1Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei Province, 050051, People’s Republic of China, Tel +86 311-66781227, Fax +86 311-66781289, Email nanyuemin@163.comPurpose: The aim of this study was to identify and validate novel biomarkers for distinguishing among hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), liver fibrosis/liver cirrhosis (LF/LC) and chronic hepatitis B (CHB).Patients and Methods: Transcriptomic sequencing was conducted on the liver tissues of 5 patients with HCC, 5 patients with LF/LC, 5 patients with CHB, and 4 healthy controls. The expression levels of selected mRNAs and proteins were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining, and were verified in validation set (n=200) and testing set (n=400) via enzyme-linked immunosorbent assay (ELISA).Results: A total of 9 hub mRNAs were identified by short time-series expression miner and weighted gene co-expression network analysis. Of note, the results of qRT-PCR and IHC staining demonstrated that SHC adaptor protein 1 (SHC1), SLAM family member 8 (SLAMF8), and interleukin-32 (IL-32) exhibited gradually increasing trends in the four groups. Subsequent ELISA tests on the validation cohort indicated that the plasma levels of SHC1, SLAMF8 and IL-32 also gradually increased. Furthermore, a diagnostic model APFSSI (age, PLT, ferritin, SHC1, SLAMF8 and IL-32) was established to distinguish among CHB, LF/LC and HCC. The performance of APFSSI model for discriminating CHB from healthy subjects (AUC=0.966) was much greater compared to SHC1 (AUC=0.900), SLAMF8 (AUC=0.744) and IL-32 (AUC=0.821). When distinguishing LF/LC from CHB, APFSSI was the most outstanding diagnostic parameter (AUC=0.924), which was superior to SHC1, SLAMF8 and IL-32 (AUC=0.812, 0.684 and 0.741, respectively). Likewise, APFSSI model with the greatest AUC value displayed an excellent performance for differentiating between HCC and LF/LC than other variables (SHC1, SLAMF8 and IL-32) via ROC analysis. Finally, the results in the test set were consistent with those in the validation set.Conclusion: SHC1, SLAMF8 and IL-32 can differentiate among patients with HCC, LF/LC, CHB and healthy controls. More importantly, the APFSSI model greatly improves the diagnostic accuracy of HBV-associated liver diseases.Keywords: HBV-associated liver diseases, transcriptome sequencing technology, SHC adaptor protein 1, SLAM family member 8, interleukin-32

Yu Zhang,1– 3,&ast; Li Cui,2,&ast; Yizeng Lu,4 Jixiang He,5 Hidayat Hussain,6 Lei Xie,4 Xuan Sun,2 Zhaoqing Meng,7 Guiyun Cao,7 Dawei Qin,1 Daijie Wang2,3 1School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, People’s Republic of China; 2School of Pharmaceutical Sciences and Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250014, People’s Republic of China; 3Biological Engineering Technology Innovation Center of Shandong Province, Heze Branch of Qilu University of Technology (Shandong Academy of Sciences), Heze, 274000, People’s Republic of China; 4Shandong Provincial Center of Forest and Grass Germplasm Resources, Jinan, 250102, People’s Republic of China; 5School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250353, People’s Republic of China; 6Department of Bioorganic Chemistry, Leibniz Institute of Plant BioChemistry, Halle, D-06120, Germany; 7Shandong Hongjitang Pharmaceutical Group Co., Ltd., Jinan, 250103, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dawei Qin, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, People’s Republic of China, Tel/Fax +86 53189631208, Email qdw@qlu.edu.cn Daijie Wang, Biological Engineering Technology Innovation Center of Shandong Province, Heze Branch of Qilu University of Technology (Shandong Academy of Sciences), Heze, 274000, People’s Republic of China, Tel +86 53182605319, Fax +86 53182964889, Email wangdaijie@qlu.edu.cnBackground: The leaves of L. japonica (LLJ) are widely used as medicine in China. It is rich in caffeoylquinic acids, flavonoids and iridoid glycosides and has strong reducing capacities. Therefore, it can be used as a green material to synthesize silver nanoparticles.Methods: LLJ was used as a reducing agent to produce the LLJ-mediated silver nanoparticles (LLJ-AgNPs). The structure and physicochemical properties of LLJ-AgNPs were characterized by ultraviolet spectroscopy (UV-Vis), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and x-ray powder diffraction (XRD). Antioxidant activity of LLJ-AgNPs was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging. Antibacterial activity was determined by 96 well plates (AGAR) gradient dilution, while the anticancer potential was determined by MTT assay.Results: The results showed LLJ-AgNPs had a spherical structure with the maximum UV-Vis absorption at 400 nm. In addition, LLJ-AgNPs exhibited excellent antioxidant properties, where the free radical scavenging rate of LLJ-AgNPs was increased from 39% to 92% at concentrations from 0.25 to 1.0 mg/mL. Moreover, LLJ-AgNPs displayed excellent antibacterial properties against E. coli and Salmonella at room temperature, with minimum inhibitory values of 10− 6 and 10− 5 g/L, respectively. In addition, the synthetic LLJ-AgNPs exhibited a better inhibition effect in the proliferation of cancer cells (HepG2, MDA-MB − 231, and Hela cells).Conclusion: The present study provides a green approach to synthesize LLJ-AgNPs. All those findings illustrated that the produced LLJ-AgNPs can be used as an economical and efficient functional material for further applications in food and pharmaceutical fields.Keywords: leaves of Lonicera japonica Thunb, LLJ-AgNO3-NPs, green approach, antioxidant, antibacterial, anticancer

Wanbing Feng,1– 6 Di Zhang,1– 6 Linlin Fu,1– 6 Jingmei Hu,1– 6 Shanshan Gao,1– 6 Xiaocui Song,1 Linlin Cui1– 6 1Center for Reproductive Medicine, Department of Reproductive Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 3Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, People’s Republic of China; 4Shandong Key Laboratory of Reproductive Medicine, Jinan, Shandong, People’s Republic of China; 5Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, People’s Republic of China; 6National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Linlin Cui; Xiaocui Song, Center for Reproductive Medicine, Department of Reproductive Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 157, Jingliu Road, Shizhong District, Jinan, Shandong, People’s Republic of China, 250001, Tel +86 531 85651598, Fax +86 531 87068226, Email fdclear3@126.com; babyjuncong@163.comObjective: To investigate the effect of maternal estradiol (E2) elevation on long-term metabolic manifestations in the offspring.Study Design and Setting: This was a retrospective cohort study. Overall, 3690 children conceived by in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) between July 2014 and December 2017 were recruited and divided into four groups categorized by maternal E2 quartiles (Q1, < 2420; Q2, 2420– 3839; Q3, 3839– 5599; and Q4, ≥ 5599 pg/mL). The metabolic profiles were measured during childhood. Linear mixed models were used to evaluate the association between maternal E2 elevation and metabolic phenotypes of the offspring.Results: Lipoprotein cholesterol (LDL-C) was significantly higher in the highest quartile group than in the lowest quartile group during infancy (adjusted mean difference [95% confidence interval, CI]): 0.11 [0.02, 0.20], P = 0.005), but the difference disappeared in the later childhood phase. In children born after fresh embryo transfer, LDL-C showed an increasing trend with the increase in maternal E2 level (adjusted mean difference [95% CI]: Q2 vs Q1, − 0.01 [− 0.11, 0.08], Q3 vs Q1, 0.06 [− 0.04, 0.15], Q4 vs Q1, 0.10 [0, 0.20]). Other metabolic variables were comparable across increasing quartiles of maternal E2 levels.Conclusion: This study demonstrates a temporary increase in LDL-C levels in infants with higher levels of maternal preconception E2 levels. However, the long-term safety of hyperestrogens after ovarian stimulation in the next generation is favorable. The mechanism underlying the transiently increased metabolic dysfunction risk in infants conceived by IVF/ICSI requires investigation in future studies.Keywords: offspring, supraphysiologic estradiol, controlled ovarian hyperstimulation, assisted reproductive technology

Xi Zhang,1,&ast; Hongyan Wang,1,&ast; Chenzhen Du,1 Xiaoyun Fan,2 Long Cui,3 Heming Chen,4 Fang Deng,5 Qiang Tong,6 Min He,7 Mei Yang,8 Xingrong Tan,9 Lin Li,10 Zerong Liang,11 Yaqin Chen,12 Deqing Chen,13 David G Armstrong,14 Wuquan Deng1 1Department of Endocrinology, Chongqing University Central Hospital, Chongqing University, Chongqing, People’s Republic of China; 2Department of Endocrinology, Hospital for Occupational Diseases of Chongqing, Chongqing, People’s Republic of China; 3Department of Endocrinology, Armed Police Hospital of Chongqing, Chongqing, People’s Republic of China; 4Department of Endocrinology, Ankang Central Hospital, Ankang, Shaanxi, People’s Republic of China; 5Department of Endocrinology, Chongqing Southwest Hospital, Chongqing, People’s Republic of China; 6Department of Endocrinology, Chongqing Xinqiao Hospital, Chongqing, People’s Republic of China; 7Department of Endocrinology, The People’s Hospital of Shapingba District, Chongqing, People’s Republic of China; 8Department of Endocrinology, The First People’s Hospital of Chongqing Liangjiang New Area, Chongqing, People’s Republic of China; 9Department of Endocrinology, The 9th People’s Hospital of Chongqing, Chongqing, People’s Republic of China; 10Department of Endocrinology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, People’s Republic of China; 11Department of Endocrinology, Chongqing Red Cross Hospital, People’s Hospital of Jiangbei District, Chongqing, 400020, People’s Republic of China; 12Department of Endocrinology, The People’s Hospital of Shizhu, Chongqing, People’s Republic of China; 13Department of Endocrinology, The People’s Hospital of Rongchang, Chongqing, People’s Republic of China; 14Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA&ast;These authors contributed equally to this workCorrespondence: Wuquan Deng Email wuquandeng@cqu.edu.cnBackground: Recurrence of high-risk diabetic feet, after wound, healing is a common challenge among diabetic patients. Continuous use of an offloading device significantly prevents recurrence of high-risk diabetic feet, although patient adherence is imperative to ensuring this therapy’s clinical efficacy. In this study, we explored clinical outcomes of patients with a high-risk diabetic foot who had been prescribed with custom-molded offloading footwear under different adherence conditions.Methods: A total of 48 patients (17 females and 31 males) with high-risk diabetic feet, who had been with prescribed offloading footwear in 13 medical centers across 4 cities, were enrolled in the current study. The patients were assigned into either continuous offloading therapy (COT, n = 31) or interrupted offloading therapy (IOT, n = 17) groups, according to their adherence to the therapy. All patients were followed up monthly, and differences in recurrence, amputation, and deaths between the groups were analyzed at 4 months after therapy.Results: Forty-eight patients met our inclusion criteria and were therefore included in the final analysis. Among them, 31 were stratified into the COT group and adhered to offloading therapy throughout the study period, whereas 17 were grouped as IOT and exhibited interrupted adherence to offloading therapy. We found statistically significant differences in recurrence rates (0 vs 38.46%, p < 0.01), amputation (0 vs 11.76%, p < 0.01), and deaths (0% vs 5.88%, p < 0.01) between the groups during follow-up.Conclusion: Patients’ adherence is imperative to efficacy of custom-molded offloading footwear during treatment of high-risk diabetic foot. Further studies are needed to elucidate the role of improved design of the offloading device and the need for enhanced patient education for improved adherence.Keywords: custom-molded offloading footwear, high-risk diabetic foot, patient adherence

Formation damage caused by organic contaminates is one of the most important issues that undermine well injectivity and productivity. Anionic surfactants are commonly used to mobilize the organic contaminates trapped by capillary forces. The electrostatic repulsion between anionic surfactant heads reduces the surfactant density at the oil-water interface, consequently reducing the interfacial efficiency. In this paper, a novel surfactant blend of anionic-cationic surfactants (Sa/c) was designed and showed much higher efficiency than traditional ones because of the strong electrostatic attraction between anionic and cationic surfactants. The oil-water interfacial tension (IFT) was reduced to 3 × 10−4 mN/m, and the viscosity of crude oil was reduced by 92%. In addition, the freezing point of the residual oil was decreased by 20.9%. Moreover, Sa/c altered the wettability and inhibited the clay swelling. Field applications were conducted in sandstone reservoirs at temperatures of about 120 °C and permeabilities below 10 mD. The average injection pressure drops were greater than 30%. The findings of this study can help for better understanding the advantages of Sa/c with high interfacial activity and revealed that formation damage caused by the organic contaminates in high temperature and low permeability sandstone reservoirs can be effectively remediated by this novel surfactant blend. [ABSTRACT FROM AUTHOR]

To prepare a high quality Fe-based ceramic composite coating, 17-4ph+30% WC alloy powder was clad onto a 17-4ph stainless steel substrate by high speed laser cladding (HSLC) and a metal matrix composite (MMC) clad without cracks and pores was achieved. The WC particle distribution, microstructure formation and evolution mechanism of the MMC laser clad were studied in detail. The results show that the phase composition of the MMC laser clad mainly includes γ-Fe, W2C, WC, Ni3Fe, Cr23C6, etc. The WC particles in the MMC laser clad show a good metallurgical bonding with the 17-4ph substrate, the dilution rate of the clad is low and the higher heat input causes more WC particles to melt and decompose, generating more hard strengthening phases. The grain refinement strengthening, solid solution strengthening and second phase strengthening are more prominent, which provides a scientific basis for optimizing the preparation of high quality Fe-based ceramic composite coatings. [ABSTRACT FROM AUTHOR]