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Zihan Yang,1,* Miaomiao Zhang,2,* Yan Guo,3 Rui Wang,4 Fei Xie5 1First Department of Foot and Ankle Surgery, Tianjin Hospital, Tianjin University, Tianjin, People’s Republic of China; 2Emergency Department, Tianjin Haihe Hospital, Tianjin, People’s Republic of China; 3Administration Department, Tianjin Hospital, Tianjin University, Tianjin, People’s Republic of China; 4School of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 5Nursing Department, Tianjin Hospital, Tianjin University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fei Xie, Email 15265827878@163.comObjective: To investigate the current situation, trending subjects, and future directions in the field of burnout among nurses, and to serve as a resource for researchers conducting related research.Methods: The bibliometric analysis was carried out using R package “bibliometrix”, bibliometric online analysis platform (https://bibliometric.com/) and VOSviewer (1.6.18).Results: The leading countries that had a significant impact on this field were the USA and China. University of Pennsylvania was the most influential institution. Journal of Nursing Management was the top productive journal. Critical care, oncology care, acute care, and infectious disease care were more likely to lead to symptoms of burnout among nurses. “Mental health”, “job satisfaction”, “stress”, and “COVID-19” were the current hot topics in this field.Conclusion: Our study not only provides a thorough outline to assist researchers in understanding the leading countries, institutions, journals, and potential collaborators, but it also examines the current and upcoming trends in this field and inspires researchers to select research directions.Keywords: burnout, nurse, mental health, COVID-19, hotspots, trends

Xiaochen Ma, Xiangyang Sun, Fubo Xie, Wencheng Jian, Qingliang Wang, Yang Xie, Caixia Li, Kai Zhang Department of Radiology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Kai Zhang, Department of Radiology, Qilu Hospital of Shandong University, Jinan, Shandong, People’s Republic of China, Email zhangkai@qiluhospital.comAim: This study aims to explore the role of soluble programmed cell death protein 1 (sPD-1) in individuals with hepatocellular carcinoma (HCC) undergoing treatment with drug-eluting beads transarterial chemoembolization (D-TACE). Additionally, we aim to assess the potential utility of sPD-1 for determining the optimal timing for combining D-TACE with immune checkpoint inhibitors (ICIs).Materials and Methods: A total of 44 HCC patients eligible for D-TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood from the patients were collected on the day before D-TACE and 3, 7, and 30 days after D-TACE, respectively, for the assay of sPD-1. The relationships between sPD-1 levels, clinical features, outcomes, and the fluctuation of sPD-1 during treatment were analyzed.Results: The initial sPD-1 levels in patients were found to be significantly higher than those in the control group. Although the initial sPD-1 levels displayed a decreasing trend with an increase in BCLC stage, no significant differences were observed among patients at different BCLC stages. The sPD-1 level on day 3 after D-TACE was similar to that on day 7 after D-TACE and significantly lower than the initial level. The sPD-1 level on day 30 after D-TACE was significantly higher than that on day 3 and day 7 after D-TACE and nearly returned to the initial level before D-TACE.Conclusion: The level of sPD-1 was found to be significantly elevated in patients with HCC. However, further research is deemed necessary to fully understand the role of sPD-1 as a potential biomarker in the initiation, progression, and prognosis of HCC. The decrease in sPD-1 following D-TACE suggests that immune effector cells might potentially be reduced, as well as immune function weakened, highlighting the need to avoid the prompt administration of ICIs after D-TACE.Keywords: hepatocellular carcinoma, immunotherapy, soluble programmed cell death protein 1, drug-eluting beads transarterial chemoembolization

Jing Zhao,&ast; Li Yu,&ast; Kangyun Sun, Yun Wang, Fangfei Xie Physical Examination Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fangfei Xie; Yun Wang, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guangji Road, Suzhou, Jiangsu, 215008, People’s Republic of China, Tel +86 – 13913186601 ; +86 – 18913151605, Email fangfeixie@hotmail.com; 714388761@qq.comBackground: Studies on the associations between Systemic Immune-Inflammation (SII) and hepatic steatosis in China are still lacking. It is necessary to clarify the relationship between SII and hepatic steatosis in the Chinese population.Methods: This study was conducted from January 2022 to December 2022. A total of 37,095 participants were enrolled, among them, with 20,709 (55.83%) being males, and 16,386 (44.17%) being females. Physical and biochemical indicators were measured during a morning health examination after the examinees had fasted overnight. Diagnoses of hepatic steatosis were determined using an ultrasound test in accordance with the Chinese Guideline. Analysis of variance and chi-square tests were used to analyze the association between SII and hepatic steatosis. Stratification analyses were conducted based on age, gender, and obese status. Restricted cubic spline regression was also performed to explore the shapes of associations between SII and hepatic steatosis.Results: The average age of the 37,095 participants was 44.78 years old, with those with hepatic steatosis (11,599 (31.27%)) averaging 47.06 years old and those (25,496 (68.73%)) in the control group averaging 43.73 years old. SII was positively associated with hepatic steatosis. This association remained significant after conducting stratification analysis by age and gender. The inflection points in the inverted U-shaped curve for the relationship between SII and hepatic steatosis were 399.78 for gender (1000 cells /μL)(nonlinear P< 0.01, OR=1.31 (male), 1.00 (female)) and 385.79 for age (1000 cells /μL)(nonlinear P< 0.01, OR=1.35 (18~44 years old), 1.87 (45~59 years old), 1.93 (60~ years old)).Conclusion: SII is an independent risk factor for hepatic steatosis, and this effect appears to be stronger in subjects with BMI < 28 kg/m2. The nonlinear relationship between SII and hepatic steatosis, characterized by an inverted U-shaped distribution, may serve as a reference for diagnosing and evaluating hepatic steatosis.Keywords: hepatic steatosis, systemic immune-inflammation index, inflammation, association

Timothy Beukelman,1 Millie D Long,2 Rennie L Rhee,3 Michael D Kappelman,4 Peter A Merkel,3,5 William Benjamin Nowell,6 Cassie Clinton,7 Sarah Ringold,8 Vincent Del Gaizo,9 Brian Price,10 Dianne G Shaw,11 Shilpa Venkatachalam,6 David Cuthbertson,12 Fenglong Xie,7 Xian Zhang,4 Jeffrey R Curtis7 1Department of Pediatrics, Division of Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3Department of Medicine, Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, USA; 4Department of Pediatrics, Division of Pediatric Gastroenterology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Department of Biostatistics, Epidemiology, and Informatics; Division of Epidemiology, University of Pennsylvania, Philadelphia, PA, USA; 6Global Healthy Living Foundation, Upper Nyack, NY, USA; 7Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA; 8Department of Pediatrics, Division of Rheumatology, Seattle Children’s Hospital, Seattle, WA, USA; 9Childhood Arthritis and Rheumatology Research Alliance (CARRA) and PARTNERS PPRN, Milwaukee, WI, USA; 10Crohn’s and Colitis Foundation and IBD-Partners, New York, NY, USA; 11Vasculitis Patient Powered Research Network, Kansas City, MO, USA; 12Health Informatics Institute, University of South Florida, Tampa, FL, USACorrespondence: Timothy Beukelman, Email timbeukelman@uabmc.eduBackground: The most reliable and meaningful approach for inclusion of patient-reported outcomes (PROs) in the evaluation of real-world clinical effectiveness of biologics in the treatment of autoimmune diseases is u ncertain. This study aimed to assess and compare the proportions of patients who had abnormalities in PROs measuring important general health domains at the initiation of treatment with biologics, as well as the effects of baseline abnormalities on subsequent improvement.Methods: PROs were collected for patient participants with inflammatory arthritis, inflammatory bowel disease, and vasculitis using Patient-Reported Outcomes Measurement Information System instruments. Scores were reported as T-scores normalized to the general population in the United States. Baseline PROs scores were collected near the time of biologic initiation, and follow-up scores were collected 3 to 8 months later. In addition to summary statistics, the proportion of patients with PROs abnormalities (scores ≥ 5 units worse than the population norm) was determined. Baseline and follow-up scores were compared, and an improvement of ≥ 5 units was considered significant.Results: There was wide variation across autoimmune diseases in baseline PROs scores for all domains. For example, the proportion of participants with abnormal baseline pain interference scores ranged from 52% to 93%. When restricted to participants with baseline PROs abnormalities, the proportion of participants experiencing an improvement of ≥ 5 units was substantially higher.Conclusion: As expected, many patients experienced improvement in PROs following initiation of treatment with biologics for autoimmune diseases. Nevertheless, a substantial proportion of participants did not exhibit abnormalities in all PROs domains at baseline, and these participants appear less likely to experience improvement. For PROs to be reliably and meaningfully included in the evaluation of real-world medication effectiveness, more knowledge and careful consideration are needed to select the most appropriate patient populations and subgroups for inclusion and evaluation in studies measuring change in PROs.Keywords: patient-reported outcome measures, patient outcome assessment, biological therapy, autoimmune diseases

Jianlong Zhou,1,2,&ast; Juanmei Mo,2,&ast; Chaohui Tan,1,&ast; Feng Xie,1 Jing Liang,3 Wenhua Huang1 1Xinhui People’s Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Xinhui, People’s Republic of China; 2Department of Oncology, Guangxi International Zhuang Medicine Hospital, Guangxi University of Chinese Medicine, Nanning, People’s Republic of China; 3The School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenhua Huang, School of Basic Medical Science, Southern Medical University, No. 1023 North Shatai Road, Guangzhou, 510515, People’s Republic of China, Email mwmwmw2014@126.com Jing Liang, School of Basic Medical Science, Guangzhou University of Chinese Medicine, No. 232 East Waihuan Road, Guangzhou, 510006, People’s Republic of China, Email webber0755@sohu.comPurpose: Enhancers are genomic regulatory elements located distally from the target gene, which play a critical role in determining cell identity and function. Dysregulation of enhancers has been frequently observed in various types of cancer, including cervical cancer. However, the identity of enhancers and their associated transcriptional regulators that are involved in cervical cancer remains unclear.Methods: With bioinformatics and 3D genomics, we revealed the enhancers in cervical cancer cell line and calculated which transcription factor (TF) is specifically binding on them based on TFs motif database. We knockdowned this TF and studied its function in cervical cancer cell line in vivo and in vitro.Results: We found 14,826 activated enhancers and predicted that JUND (JunD Proto-Oncogene) is relatively enriched in the sequences of these enhancers. Well-known oncogene MYC and JUN were regulated by JUND through enhancers. To further explore the roles of JUND in cervical cancer, we analyzed the gene expression data of clinical cervical cancer samples and knock-downed JUND by CRISPR-Cas9 in Hela cell line. We found JUND is over-expressed in cervical cancer and the expression of JUND increased along with the cervical cancer progresses. Knockdown of JUND decreased the proliferation of Hela cells in vitro and in vivo and blocked cell cycle in G1-phase. Transcriptome sequencing analysis revealed the identification of 2,231 differentially expressed genes in response to the JUND knockdown treatment. This perturbation resulted in the modulation of several biological processes and pathways that have been previously linked to cancer.Conclusion: These findings provide evidence for the significant involvement of JUND in cervical cancer pathogenesis, thereby positioning JUND as a potential therapeutic target for the treatment of this disease.Keywords: cervical cancer, JUND, transcription factor, enhancer

Kaifei Wang, Ye Hu, Zhimei Duan, Han Fu, Xingshuo Hu, Ying Zhao, Ruoxuan Wen, Lina Li, Fei Xie College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Fei Xie, College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, People’s Republic of China, Tel +86-15001028681, Email xielx301@sina.comBackground: Staphylococcus aureus has been well recognized as an important cause of community-acquired pneumonia (CAP), with non-specific characteristics and poor prognosis. In severe CAP (SCAP) guidelines, β-lactam combined with macrolides or fluoroquinolones therapy was recommended, but the efficacy is not satisfactory due to the continued spread of antimicrobial resistance. Contezolid is a new representative of oxazolidinones in clinical development, but no relevant reports have been reported for the treatment of SCAP. This was the first report of a patient with Staphylococcus aureus SCAP who was successfully treated with contezolid combined with other antibiotics and rehabilitation exercise.Case Presentation: A 44-year-old woman with high blood pressure and diabetes was admitted to our hospital owing to cough, sputum, wheezing for 2 weeks, and aggravation for 2 days. The bronchoscopic alveolar lavage and microorganism-Rapid On Site Evaluation (BAL-mROSE) was used to get pathological data, which were positive for Staphylococcus aureus, in line with blood cultures. During hospitalization, the patient received endotracheal intubation for assisted breathing and anti-infective therapy, including meropenem, linezolid, teicoplanin and tazocin successively. Finally, contezolid obtained excellent result, with platelet recovery to normal levels and significant improvement in pulmonary imaging. Meanwhile, the patient’s swallowing disorder improved after continuous rehabilitation exercise. After discharge, she received contezolid consolidation therapy for 1 week and was free of complaints during the 30-day follow-up without any special treatment for SCAP.Discussion: Treatment with contezolid combined with other antibiotics and rehabilitation exercise for SCAP has shown remarkable efficacy and good safety; hence, this regimen is a promising treatment strategy for this fatal disease.Keywords: severe community-acquired pneumonia, methicillin-sensitive Staphylococcus aureus, antibiotic therapy, contezolid, rehabilitation exercise

Zhao Y, Zheng R, Ning D, Xie F. Cancer Manag Res. 2020;12:4171–4180. We, the Editors and Publisher of Cancer Management and Research, have retracted the following article. Following publication of the article, concerns were raised about the duplication of images from Figures 1 and 3 with images from other unrelated articles. Specifically, The images for Figure 1F have been duplicated with images for Figure 1C and 1D from Fang C, Jiang B, Shi X, Fan C. Hes3 Enhances the Malignant Phenotype of Lung Cancer through Upregulating Cyclin D1, Cyclin D3 and MMP7 Expression. International Journal of Medical Sciences. 2019;16(3):470-476. https://doi.org/10.7150/ijms.28139. Images for Figure 3C, A459 and 3G, H226 have been duplicated with images for Figures 2h and 2i, and 5a and 5b from Zhang X, Liu L, Deng X, et al. MicroRNA 483-3p targets Pard3 to potentiate TGF-β1-induced cell migration, invasion, and epithelial–mesenchymal transition in anaplastic thyroid cancer cells. Oncogene. 2019;38:699–715. https://doi.org/10.1038/s41388-018-0447-1. Images for Figure 3D, A549 and 3H, H226 have been duplicated with images for Figure 9A, CNE2 and 9B, 5-8F from Liang TS, Zheng YJ, Wang J, et al. RETRACTED ARTICLE: MicroRNA-506 inhibits tumor growth and metastasis in nasopharyngeal carcinoma through the inactivation of the Wnt/β-catenin signaling pathway by down-regulating LHX2. J Exp Clin Cancer Res. 2019;38:97. https://doi.org/10.1186/s13046-019-1023-4. When approached for an explanation, the authors were cooperative but were unable to provide a sufficient explanation for the image duplication or provide original data for their study. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors have agreed with 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’.

Yunzhu Wu,1 Fei Xie,2 Ruichen Jiang1 1School of Teacher Education, Anqing Normal University, Anqing, 246133, People’s Republic of China; 2School of Foreign Languages, Anqing Normal University, Anqing, 246133, People’s Republic of ChinaCorrespondence: Ruichen Jiang, School of Teacher Education, Anqing Normal University, Anqing, 246133, People’s Republic of China, Email 1811516004@sus.edu.cnPurpose: The novel coronavirus disease 2019 (COVID-19) pandemic has become a challenge for adolescents in China. This study aimed to explore the relationship between academic anxiety and self-esteem in Chinese candidates preparing for the college entrance examination during the COVID-19 pandemic and to examine the mechanism of mediating effect of self-regulated learning ability.Methods: A cross-sectional study was conducted among 293 college entrance examination candidates (including 170 females) from two middle schools in China using a voluntary, web-based, and anonymous questionnaire implemented via the Questionnaire Star app during COVID-19 prevalence in 2020.Results: This study found that 1) students in the high and low academic anxiety groups had different levels of self-regulated learning ability and self-esteem, 2) the academic anxiety, self-regulated learning ability, and self-esteem levels of students were significantly correlated and 3) after controlling the two independent variables of gender and subject type, academic anxiety had a significant negative predictive effect on self-esteem, and self-regulated learning ability played a mediating role between academic anxiety and self-esteem, where the mediating effect was 18.6%.Conclusion: Based on the observations of the present study, self-regulated learning capacity was a mediator between academic anxiety and self-esteem. These findings suggest an underlying process by which low academic anxiety may increase self-esteem in candidates preparing for the college entrance examination by increasing self-regulated learning ability.Keywords: academic anxiety, self-esteem, self-regulated learning ability

Haowei Li,1,&ast; Shimin Chen,1,&ast; Shengshu Wang,1 Shanshan Yang,2 Wenzhe Cao,1 Shaohua Liu,1 Yang Song,1 Xuehang Li,1 Zhiqiang Li,3 Rongrong Li,1 Xiong Liu,3 Changjun Wang,3 Yong Chen,3 Fei Xie,4 Yao He,1 Miao Liu5 1Institute of Geriatrics, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatrics Diseases, State Key Laboratory of Kidney Diseases, Second Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Disease Prevention and Control, The 1st Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Chinese PLA Center for Disease Control and Prevention, Beijing, People’s Republic of China; 4College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, People’s Republic of China; 5Graduate School of Chinese PLA General Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yao He, Institute of Geriatrics, Beijing Key Laboratory of Aging and Geriatrics, National Clinical Research Center for Geriatrics Diseases, State Key Laboratory of Kidney Diseases, Second Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, People’s Republic of China, Tel +86-10-66876411, Email yhe301@sina.com Yong Chen, Chinese PLA Center for Disease Control and Prevention, 20 Dongdajie Road, Fengtai, Beijing, 100071, People’s Republic of China, Tel +86-10-66948344, Email chenyonger@126.comAim: One of the most common laboratory findings in COVID-19 patients has been observed to be hypercoagulability with elevated D-dimer levels. An activation of thrombosis may be generated by hyperglycemia. We aimed to explore the association between D-dimer and in-hospital outcomes, and evaluate the synergistic effect between elevated D-dimer and hyperglycemia on COVID-19 prognosis.Methods: A retrospective cohort study was undertaken with 2467 COVID-19 inpatients. D-dimer and fasting blood glucose (FBG) on admission and adverse in-hospital outcomes (events of death and aggravated severity) were collected. Cox proportional risk model was performed to assess the association of D-dimer and adverse in-hospital outcomes, and the combined effects of D-dimer and FBG.Results: Among these COVID-19 patients, 1100 (44.6%) patients had high D-dimer (≥ 0.50 mg/L). Patients with high D-dimer were older, with higher FBG (≥ 7.00 mmol/L), and had significantly higher adjusted risk of adverse in-hospital outcomes when comparing with those who with D-dimer< 0.50 mg/L (hazard ratio, 2.73; 95% confidence interval, 1.46– 5.11). Moreover, patients with high FBG and D-dimer levels had an increasing risk (hazard ratio, 5.72; 95% confidence interval: 2.65– 12.34) than those with normal FBG and D-dimer.Conclusion: Risk of adverse in-hospital outcomes is higher among patients with high D-dimer levels. Additionally, this study found for the first time that elevated D-dimer and hyperglycemia had a synergistic effect on COVID-19 prognosis, and this risk was independent of diabetes history.Keywords: D-dimer, hyperglycemia, in-hospital outcomes, COVID-19, cohort study

Yinyu Mu,1 Fuyi Xie,1 Dongdong Yang,1 Guodong Xu2 1Department of Clinical Laboratory, Ningbo Medical Centre, Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of China; 2Department of Cardiothoracic Surgery, Ningbo Medical Centre, Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, 315040, People’s Republic of ChinaCorrespondence: Yinyu Mu; Fuyi Xie, Department of Clinical Laboratory, Ningbo Medical Centre Lihuili Hospital, Ningbo University, 57 Xingning Road, Ningbo, Zhejiang, 315040, People’s Republic of China, Email muyu606@sina.com; 528715297@qq.comPurpose: Circular RNA (circRNA) serves an important role in tumour genesis and development. But, little is known about its role in lung adenocarcinoma (LA). This study aimed to investigate circRNA6783 expression in peripheral whole blood (PWB) of LA and controls and explore its effect on proliferation and apoptosis in human lung adenocarcinoma cells (LAC).Patients and Methods: The levels of circRNA6783 in LA cell lines and peripheral whole blood (PWB) of 40 patients and 30 controls were detected by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). In order to explore the effect of circRNA6783 on LA behavior, we overexpressed circRNA6783 in NCI-H1975 cells. The impact on the proliferation of tumor cells was then examined by Cell Counting Kit 8 (CCK8) assay, and the effects on apoptosis in the cell line were detected using flow cytometry.Results: The expression levels of circRNA6783 were significantly higher in LA cell lines and PWB (P < 0.05). The diagnostic value of the area under the receiver operating characteristic curve (AUC) was 0.830, with a sensitivity of 60% and specificity of 96.7%. In addition, functional experiments showed that overexpression of circRNA6783 restrained cell proliferation, significantly increased spontaneous apoptosis.Conclusion: CircRNA6783 was upregulated in LA PWB. In vitro assessment demonstrated that circRNA6783 could act as a potential biomarker for LA diagnosis.Graphical Abstract: Keywords: lung adenocarcinoma, circular RNA6783, proliferation, apoptosis

Sha He, Zeneng Cheng, Feifan Xie Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, People’s Republic of ChinaCorrespondence: Zeneng Cheng; Feifan XieDivision of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo Road 172, Changsha, 410013, People’s Republic of ChinaTel/Fax +86 731 8265 0446Email chengzn@csu.edu.cn; feifan.xie@csu.edu.cnPurpose: Appropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK) model of gentamicin in CRRT patients and to infer the optimal dosing regimen for gentamicin.Methods: Fourteen CRRT patients dosed with gentamicin were included to establish a population PK model to characterize the variabilities and influential covariates of gentamicin. The pharmacokinetic/pharmacodynamic (PK/PD) target attainment and risk of toxicity for different combinations of gentamicin regimens (3– 7 mg/kg q24h) and CRRT effluent doses (30– 50 mL/h/kg) were evaluated by Monte Carlo simulation. The probability of target attainment (PTA) was determined for the PK/PD indices of the ratio of drug peak concentration/minimum inhibitory concentration (Cmax/MIC > 10) and the ratio of area under the drug concentration–time curve/MIC over 24 h (AUC0-24h/MIC > 100), and the risk of toxicity was estimated by drug trough concentration thresholds (1 and 2 mg/L).Results: A one-compartment model adequately described the PK characteristics of gentamicin. Covariates including body weight, age, gender, and CRRT modality did not influence the PK parameters of gentamicin based on our dataset. All studied gentamicin regimens failed to achieve satisfactory PTAs for pathogens with an MIC ≥ 2 mg/L. A good balance of PK/PD target attainment and risk of toxicity (> 2 mg/L) was achieved under 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose for an MIC ≤ 1 mg/L. CRRT dose intensity had a significant impact on the target attainment of AUC0-24h/MIC > 100 and risk of toxicity.Conclusion: A combination of 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose might be considered as a starting treatment option for CRRT patients, and drug monitoring is required to manage toxicity.Keywords: gentamicin, CRRT, population pharmacokinetics, critically ill

Yanyun Li,1,&ast; Ying-Xin Gong,1,&ast; Qing Wang,1 Shujun Gao,1 Hongwei Zhang,1 Feng Xie,1 Qing Cong,1 Limei Chen,1 Qi Zhou,1 Zubei Hong,2 Lihua Qiu,2 Fang Li,3 Yu Xie,1 Long Sui1 1Department of Gynecology and Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Gynecology and Obstetrics, Renji Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Gynecology and Obstetrics, Shanghai Dongfang Hospital of Tongji University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Long Sui; Yu XieObstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai, 200011, People’s Republic of ChinaTel +86-21-33189900Fax +86-21-63450900Email suilong@fudan.edu.cn; yuxie18@fudan.edu.cnPurpose: Early-stage cervical cancer is usually diagnosed by colposcopy-directed biopsy (CDB) and/or endocervical curettage (ECC), but some neglected lesions must be detected by conization because they are occult. This study aimed to explore the optimal method for detecting these “occult” cervical cancers.Patients and Methods: A total of 1299 patients who were high-risk for early-stage cervical cancer from five centres in China were prospectively included. We evaluated the diagnostic performance of cytology, HPV testing, colposcopy and CDB&ECC for detecting “occult” cervical cancer and discussed the diagnostic importance of transformation zone (TZ) type, conization length and the proportion of cervical cone excision.Results: The diagnostic agreement between colposcopy impression and conization was 64.5% and 72.4% between CDB&ECC and conization. Forty-two patients were finally diagnosed with pathologic cancer, and the sensitivities of cytology, colposcopy, CDB&ECC were 4.8%, 7.1%, and 47.4%, respectively. Twenty cases were neglected by CDB&ECC but further diagnosed as cancer by conization, considered to be occult cervical cancer, accounting for 1.6%. Cytologic high-grade squamous intraepithelial lesion (HSIL)+, positive HPV, biopsy HSIL+ and cervical TZ type 3 were considered risk factors for developing HSIL+, while colposcopy impression HSIL+ was not. There was a significant difference between cancerous and HSIL patients in the proportion of cervical cone excision (P< 0.001), which was recognized as a risk factor (P< 0.001) for detecting cancer, while the length of cervical cone excision was not. The average proportion was 0.62, and the minimal effective proportion was 0.56.Conclusion: Since the incidence of occult cervical cancer neglected by CDB&ECC, colposcopy and cytology was far beyond expectations, conization is necessary, especially in patients with TZ type 3, high-grade cytology and biopsy results. As the cervical length varies in patients, the proportion of cervical cone excision might be a better indicator for detecting occult cervical cancer.Keywords: cervical conization, colposcopy-directed biopsy, high-grade intraepithelial lesion, length proportion, occult cervical cancer, transformation zone

Youting Dang,1 Yunping Zhou,2 Xuehai Ou,2 Qiang Wang,2 Dengke Wei,2 Fei Xie2 1Department of Pediatric Orthopedics, Honghui Hospital, Xi’an Jiao Tong University, Xi’an, Shaanxi, 710054, People’s Republic of China; 2Department of Hand Surgery, Honghui Hospital, Xi’an Jiao Tong University, Xi’an, Shaanxi, 710054, People’s Republic of ChinaCorrespondence: Fei XieDepartment of Hand Surgery, Honghui Hospital, Xi’an Jiao Tong University, 555 East Friendship Road, Xi’an, Shaanxi, 710054, People’s Republic of ChinaEmail xfxf225@163.comBackground: Long non-coding RNAs (lncRNAs) have been implicated in initiation and development of numerous cancers. In the present study, we explored the role of lncRNAs AC007207.2 in osteosarcoma (OS).Methods: Gene expression data of OS tissues was downloaded from the TARGET database. All the experiments were repeated at least three times. Data were analyzed using Perl, R, SPSS v12.0 and GraphPad Prism 8 software.Results: We found lncRNA AC007207.2 was over-expressed in OS tissues and cell lines, and this phenomenon was associated with the worse prognosis of OS. Moreover, we found that AC007207.2 promotes proliferation and metastasis of OS cells via the miR-1306-5p/SIRT7 axis. Meanwhile, we found miR-1306-5p remarkably inhibits the malignant behavior of OS cells.Conclusion: lncRNA AC007207.2 promotes progression of OS by upregulating SIRT7 expression through miR-1306-5p sponging. Thus, lncRNA AC007207.2/miR-1306-5p/SIRT7 axis is a promising therapeutic target for OS treatment.Keywords: LncRNA AC007207.2, osteosarcoma, miRNA

Xinze Wu,1,2,&ast; Guozhen Hou,1,2,&ast; Peipei Han,1 Xing Yu,1 Xiaoyu Chen,1 Peiyu Song,3 Yuanyuan Zhang,1 Yinjiao Zhao,3 Fandi Xie,3 Shumeng Niu,3 Hao Hu,3 Chengyi Sun,1 Yuechen Zhao,1 Hongbing Wang,4 Qi Guo1 1Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China; 2College of Exercise and Health Science, Tianjin University of Sport, Tianjin, People’s Republic of China; 3Shanghai Jiangwan Hospital, Shanghai, People’s Republic of China; 4Department of Rehabilitation, Shanghai Fourth Rehabilitation Hospital, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongbing WangDepartment of Rehabilitation, Shanghai Fourth Rehabilitation Hospital, Shanghai, 20040, People’s Republic of ChinaEmail 15301799929@163.comQi GuoCollege of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences, 279 Zhouzhu Highway, Pudong New Area, Shanghai, 201318, People’s Republic of ChinaTel/Fax +86-22-8333-6977Email guoqijp@gmail.comPurpose: We aimed to propose a serial mediational model to further analyze the relationship between poor physical performance, malnutrition, depression and cognitive impairment in Chinese community-dwelling older adults.Patients and Methods: This study consisted of 1386 community-dwelling Chinese older adults aged 65 years and older in Shanghai, China. Mild cognitive impairment (MCI) was assessed by the Mini-Mental State Examination (MMSE) and Instrumental Activities Of Daily Living (IADL). Physical performance was assessed by short physical performance battery (SPPB). Malnutrition was defined with the Mini Nutritional Assessment (MNA). Depressive symptoms were evaluated by the 30-item Geriatric Depression Scale (GDS). Serial multiple mediator models were used.Results: The mean age of the final analysis sample was 73.62± 6.14, and 57.6% (n=809) were females. The prevalence of MCI was 14.35% (n=199). Physical performance (p< 0.001), nutritional status (p=0.025), and depressive symptoms (p=0.002) were correlated with MCI. The serial mediational model revealed that MNA and GDS scores significantly mediated association of SPPB and MMSE scores (c’=0.4728, p< 0.001). Furthermore, depressive symptoms significantly mediated the association of physical performance and cognition (p=0.0311), while malnutrition had no independent mediating effect between these two factors (p=0.794).Conclusion: Our study examined the serial multiple mediation roles of nutritional status and depressive symptoms on the relationship between physical performance and cognitive function in community-dwelling Chinese older adults. Older adults who were in poor physical condition tend to have worse nutritional status, more severe depression, and poorer cognitive function.Keywords: mild cognitive impairment, nutritional status, depressive symptoms, physical function

Qing-E Xie,1– 3,* Xin Du,4,* Mengyao Wang,1,2,5 Fenfen Xie,3 Zuoyang Zhang,6 Yunxia Cao,1,2,5,7,8 Yajing Liu1,2,5,7,8 1Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, Hefei, 230022, People’s Republic of China; 3Department of Histology and Embryology, Anhui Medical University, Hefei, 230032, Anhui, People’s Republic of China; 4 901th Hospital of PLA Joint Logistic Support Force, Heifei, 230031, Anhui, People’s Republic of China; 5Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People’s Republic of China, Hefei, 230032, Anhui, People’s Republic of China; 6Department of Pathology, Anhui Medical University, Hefei, 230032, Anhui, People’s Republic of China; 7Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei, 230032, Anhui, People’s Republic of China; 8Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, 230032, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunxia Cao; Yajing Liu Email caoyunxia6@126.com; 13385690561@163.comPurpose: Cumulative evidence has demonstrated that breast cancer was the most commonly diagnosed cancer in women. Despite growing evidence for a link between serotonin and tumorigenesis, research on the expression of serotoninergic systems in the human breast cancer cell and tissue has only rarely been reported.Methods: First, immunofluorescence staining, ELISA and Western blotting were used to detect serotonin and melatoninergic systems in various breast cancer cell types. Then, serotonin expression was evaluated in the cultures of TPBC cell line BT-474 and TNBC cell line MDA-MB-231 using immunofluorescence assay. To further explore the diagnostic role of serotonin in breast cancer, serotonin expression was conducted in the TPBC and TNBC tumor sections by immunostaining analysis.Results: Our results suggested that both human breast cancer cells and human breast epithelial cell line could synthesize serotonin and melatonin. Unlike melatonin, serotonin levels varied significantly between human breast cancer and breast epithelial cell line (p< 0.01). In addition, serotonin N-acetyltransferase (NAT) and acetylserotonin methyltransferase (ASMT), the key enzymes in the pathway of melatonin synthesis from serotonin, were also detectable. In agreement with these findings of human breast cancer cell and human breast epithelial cell line, serotonin expression was also much higher in triple-negative (PR−, ER−, HER-2−) breast cancer (TNBC) and triple-positive breast cancer (TPBC) compared to para-carcinoma tissues (PCTs).Conclusion: Here, we provided evidence that the human breast cancer cell (MCF-7, Bcap-37) and human breast epithelial cell (MCF-10A) could synthesize intrinsic serotonin and melatonin, and serotonin expression was higher in the breast cancer tissue compared with PCT. The findings suggested that serotonin might be used as a predictive marker for breast cancer patients.Keywords: serotonin, melatonin, breast cancer, serotonin N-acetyltransferase, acetylserotonin methyltransferase

Fei Xie, Xianfeng Lan, Jingui Lin Department of Hand Surgery, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, Fujian, 350004, People’s Republic of ChinaCorrespondence: Jingui LinDepartment of Hand Surgery, Fuzhou Second Hospital Affiliated to Xiamen University, Shangteng Street, Cangshan District, Fuzhou, 350004, People’s Republic of ChinaTel/Fax +86 17720746077Email linjinguishouwaike@163.comBackground: Bone loss at the metacarpophalangeal joint (MCP) after trauma is difficult to treat.Objective: We aimed to investigate the effectiveness of Swanson’s arthroplasty and the reason for implant fracture.Methods: We retrospectively analyzed the data of 175 patients who underwent emergency MCP arthroplasty between 2013 and 2016. Some patients used a orthosis to limit the radioulnar movement of the metacarpal joint for eight weeks after surgery (Group A), while the other patients underwent only hand rehabilitation after surgery (Group B). The basic information and perioperative data of the patients were compared. The patients were followed up clinically for an average of 65± 19 months. Postoperative and follow-up complications and functional parameters were recorded and compared. Stress model of implant fracture had been analyzed in order to mark the frequent area.Results: A total of 162 patients were followed up, 4 of whom were lost to follow-up completely and 9 of whom were followed up by telephone only. There were 11 and 26 implant fractures in groups A and B, respectively (P=0.019), and the degrees of radioulnar movement were 2± 1° and 7± 4°, respectively (P< 0.01). The disabilities of the arm, shoulder, and hand (DASH) score and MCP joint range of motion (ROM) did not significantly differ.Conclusion: The effect of Swanson’s arthroplasty for bone loss at MCP joint is useful. The radioulnar stress may be the reason for implant fracture. Joint orthosis can reduce the incidence of implant fractures.Keywords: metacarpophalangeal joint defects, Swanson’s arthroplasty, stress model, hand surgery

Xiaoning He,1,2 Mengqian Zhang,1,2 Jing Wu,1,2 Song Xu,3 Xiangli Jiang,4 Ziping Wang,5 Shucai Zhang,6 Feng Xie7,8 1School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, People’s Republic of China; 2Center for Social Science Survey and Data, Tianjin University, Tianjin, People’s Republic of China; 3Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 4Tianjin Medical University Cancer Institute & Hospital, Tianjin, People’s Republic of China; 5Department of Medical Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 6Department of Medical Oncology, Beijing Chest Hospital, Beijing, People’s Republic of China; 7Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 8Centre for Health Economics and Policy Analysis, McMaster University, Hamilton, ON, CanadaCorrespondence: Jing WuSchool of Pharmaceutical Science and Technology, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin, 300072, People’s Republic of ChinaTel +862227405176Fax +862287401830Email jingwu@tju.edu.cnBackground: Cancer treatment decision-making often needs to balance benefits, harms, and costs. This study sought to identify the differences in cancer treatment preference among oncologists, patients and their family members in China.Methods: A semi-structured face-to-face qualitative interview was conducted among oncologists, patients and their family members recruited in four tertiary hospitals in China. The interview guide was developed based on literature review and expert consultation. Participants were asked to indicate their preferences when making lung cancer treatment decisions. All interviews were audio-taped, transcribed verbatim, and thematic analyzed. The preferences were compared among three groups of participants.Results: A total of 17 participants (5 oncologists, 6 dyads of patients and family members) were interviewed between June and July 2019. Five themes, namely, survival benefit, adverse effect/symptom, treatment process, treatment cost, and the impact on daily life were identified. The oncologists and family members gave highest priority on survival benefit, while the patients are concerned most about treatment cost and quality of life.Conclusion: This study reveals different preferences for cancer treatment among oncologists, patients and their family members in China. Education is needed to empower patients and family members and promote share decision-making in this country.Keywords: lung cancer, preference, qualitative interview, survival benefit, cost

Weibo Ma,1,* Yuewen Liu,1,* Ning Wu,1 Hui Zhang,1 Peipei Han,1 Feng Wang,1 Jingru Wang,1 Fandi Xie,2 Shumeng Niu,2 Hao Hu,2 Chenyu Zhang,1 Nuo Chen,1 Yichen Zhang,1 Qi Guo,1 Ying Yu1 1Department of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory Center, Shanghai Jiangwan Hospital, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi GuoDepartment of Rehabilitation Medicine, Shanghai University of Medicine and Health Sciences, No. 279 Zhouzhu Road, Pudong New Area, Shanghai, 201318, People’s Republic of ChinaTel +86-21-8333-6977Fax +86-21-8333-6977Email guoqijp@gmail.comYing Yu Email yuying@sumhs.edu.cnObjective: We examined the association between obesity and physical performance under different metabolic status.Methods: The sample included 1395 Chinese community-dwelling participants (mean age, 71.88 ± 5.87 years; 40.9% men). Being metabolically healthy was defined as having the presence of < 3 of 5 components of metabolic syndrome (MetS); obesity was defined as having a BMI > 28 kg/m2. Participants were divided into four groups based on BMI (non-obese/obese) and metabolic health (healthy/unhealthy). Physical performance was measured by grip strength, 4-m walking speed, and the timed up and go test (TUGT).Results: After multiple adjustments, compared with metabolically healthy non-obese group, the metabolically unhealthy obese group showed lower relative grip strength, lower 4-m walking speed, and higher TUGT (P all < 0.05), and only relative grip strength of the metabolically healthy obese group was significantly lower than that of metabolically healthy non-obese (P < 0.01). Relative grip strength was negatively associated with impaired fasting glucose (β = − 0.071), elevated triglycerides (β = − 0.062), abdominal obesity (β = − 0.230) and general obesity (β = − 0.225) (P all < 0.01). Walking speed and TUGT were only associated with general obesity, rather than other metabolic components. The associations of MetS with physical performance were mainly driven by abdominal obesity.Conclusion: Even in those who are metabolically healthy, obesity (especially general obesity) increases the risk of poor physical performance. Elderly people with general obesity and MetS, whether in combination or alone, have an increased risk of muscle dysfunction, and that combination produces a higher risk of impaired mobility.Keywords: metabolic health, obesity, physical performance, grip strength, 4-m walking speed, TUGT

Wu S, Ai H, Zhang K, Yun H, Xie F. Onco Targets Ther. 2019;12:11623‒11635. The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised regarding the alleged duplication of images in Figures 2, 3 and 6. Specifically, Figure 2E, si-RNA-NC appears to have been duplicated with the same image for Figure 6G, EGOT/miR-33a-5p which has been rotated. Figure 2E, siRNA-EGOT-1 appears to have been duplicated with the same image for Figure 3F, EGOT which has been rotated. Figure 2F, si-RNA-NC appears to have been duplicated with the same image for Figure 3E, lncRNA-NC which has been rotated. Figure 2F, si-RNA-NC appears to have been duplicated with the same image for Figure 6G, NC which has been rotated. Figure 2F, siRNA-EGOT-1 appears to have been duplicated with the same image for Figure 3F, lncRNA-NC. Figure 2F, siRNA-EGOT-1 appears to have been duplicated with the same image for Figure 6H, EGOT/miR-33a-5p which has been rotated. Figure 3E, lncRNA-NC appears to have been duplicated with the same image for Figure 6G, NC which has been rotated. Figure 3F, lncRNA-NC appears to have been duplicated with the same image for Figure 6H, EGOT/miR-33a-5p. The authors did not respond to our queries and the Editor requested to retract the article and the authors were notified of this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Yake Zhang,1,2,* Fangyuan Xie,3,* You Yin,4,* Qin Zhang,1,* Hong Jin,5 Yan Wu,6 Liying Pang,7 Jun Li,2 Jie Gao1,2 1Institute of Translational Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China; 2Laboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, People’s Republic of China; 3Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People’s Republic of China; 4Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China; 5Department of Laboratory Medicine, Hongqi Hospital of Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China; 6Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China; 7The First Clinical Medical College of Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie GaoInstitute of Translational Medicine, Shanghai University, Shanghai, 200444, People’s Republic of ChinaTel/Fax + 86-0577-88816381Email gaojiehighclea@163.comJun LiLaboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, People’s Republic of ChinaTel/Fax + 86-0577-88816381Email lijun1982@lcu.edu.cnPurpose: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most current therapeutic strategies primarily include localized treatment, lacking effective systemic strategies. Meanwhile, recent studies have suggested that RNA vaccines can effectively activate antigen-presenting cells (APCs) and lymphocytes to produce a strong systemic immune response and inhibit tumor growth. However, tumor vaccines loaded with a single tumor antigen may induce immunosuppression and immune evasion, while identifying tumor-specific antigens can require expensive and laborious procedures. Therefore, the use of whole tumor cell antigens are currently considered to be promising, potentially effective, methods. Previously, we developed a targeted liposome-polycation-DNA (LPD) complex nanoparticle that possess a small size, high RNA encapsulation efficiency, and superior serum stability. These particles were found to successfully deliver RNA to tumor sites. In the current study, we encapsulated total tumor-derived RNA in lipid nanoparticles (LNPs) to target dendritic cells (DCs) to incite expeditious and robust anti-tumor immunity.Methods: Total tumor-derived RNA was extracted from liver cancer cells (Hepa1-6 cells). LNPs loaded with tumor RNA were then prepared thin-film hydration method. The ability of RNA LNPs to induce DC maturation, cytotoxicity, and anti-tumor activity, was investigated in vitro and in vivo.Results: The average particle size of LNPs and RNA LNPs was 102.22 ± 4.05 nm and 209.68 ± 6.14 nm, respectively, while the zeta potential was 29.97 ± 0.61 mV and 42.03 ± 0.42 mV, respectively. Both LNPs and RNA LNP vaccines exhibited good distribution and stability. In vitro, RNA LNP vaccines were capable of promoting DC maturation and inducing T lymphocytes to kill Hepa1-6 cells. In vivo, RNA LNP vaccines effectively prevent and inhibit HCC growth.Conclusion: RNA LNPs may serve as an effective antigen specific vaccine to induce anti-tumor immunity for HCC.Keywords: RNA lipid nanoparticles, tumor vaccine, dendritic cells, cancer immunotherapy

Xiumei Tian1 ,* Ao Zeng1 ,* Ziying Liu,1 Cunjing Zheng,2 Yuezi Wei,1 Peiheng Yang,1 Minru Zhang,1 Fanwen Yang,1 Fukang Xie1 1School of Basic Medical Sciences, Affiliated Stomatology Hospital, Guangzhou Medical University, Guangzhou 510182, People’s Republic of China; 2Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fukang Xie Tel +86 20 136 4231 6682Email 378141679@qq.comFanwen Yang Tel +86 20 135 0308 0690Fax +86 20 3710 3509Email yangfanwen@163.comBackground: Understanding the biocompatibility and biointeractions of nano-carbon quantum dots (nano-CQDs) in vitro and in vivo is important for assessing their potential risk to human health. In the previous research, the physical properties of CQDs synthesized by the laser ablation in liquid (LAL) method were analyzed in detail; however, possible bioapplications were not considered.Materials and Methods: CQDs were prepared by LAL and characterized by atomic force microscopy, fluorescence lifetime, absorption spectrum, Fourier-transform infrared spectroscopy, and dynamic light scattering. Their biocompatibility was evaluated in vitro using assays for cytotoxicity, apoptosis, and biodistribution and in vivo using immunotoxicity and the relative expression of genes. Cells were measured in vitro using fluorescence-lifetime imaging microscopy to analyze the biointeractions between CQDs and intracellular proteins.Results: There were no significant differences in biocompatibility between the CQDs and the negative control. The intracellular interactions had no impact on the optical imaging of CQDs upon intake by cells. Optical imaging of zebrafish showed the green fluorescence was well dispersed.Conclusion: We have demonstrated that the CQDs have an excellent biocompatibility and can be used as efficient optical nanoprobes for cell tracking and biomedical labeling except for L929 and PC-3M cells.Keywords: nanoprobe, immunotoxicity, biodistribution, biointeraction, optical imaging

Yongsheng Zhao,1,* Renyan Zheng,2,* Dong Ning,1 Fei Xie1 1Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan; 2Department of Integrated Western and Chinese Colorectal and Anal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan*These authors contributed equally to this workCorrespondence: Yongsheng Zhao Tel +86 13551910279Email zhaoyongss321@163.comPurpose: To investigate the role of miR-625 on the invasion, migration, and epithelial–mesenchymal transition (EMT) of non-small cell lung carcinoma (NSCLC) cells, and the related mechanisms.Materials and Methods: The expression levels of miR-625 and Resistin mRNA in 80 pairs of NSCLC and para-cancerous lung tissues were analyzed by RT-PCR. The relationship between miR-625 and Resistin was predicted by bioinformatics and verified by a dual-luciferase gene reporter assay. NSCLC cells were transfected with Resistin plasmids, si-Resistin plasmids, miR-625 mimics, or miR-625 inhibitors, and proliferation, invasion, and migration were determined by CCK-8, Transwell, and wound scratch assays, respectively. EMT-related proteins were determined by Western blot assay. A xenograft model of NSCLC was established in nude mice to validate the in vitro findings.Results: MiR-625 was significantly downregulated in NSCLC tissue compared to paired para-cancerous lung tissues, while Resistin was markedly increased in tumor tissue. The expression levels of miR-625 and Resistin were negatively correlated in NSCLC tissues, and high levels of Resistin correlated with greater tumor differentiation, more advanced clinical staging, and lymph node metastasis. Furthermore, Resistin was a target gene of miR-625, and the latter downregulated Resistin to inhibit the EMT, proliferation, invasion, and migration of NSCLC cells in vitro, likely via the PI3K/AKT/Snail signaling pathway. Finally, miR-625 also inhibited the tumorigenic effect of NSCLC cells in vivo by downregulating Resistin.Conclusion: MiR-625 acts as a tumor suppressor in NSCLC and inhibits tumor cell invasion and metastasis by blocking the Resistin/PI3K/AKT/Snail pathway and by decreasing EMT.Keywords: miR-625, resistin, EMT, invasion, migration, PI3K/AKT/snail

Fujing Xie,1,* Lianhai Zhang,2,* Qing Yao,3 Liyu Shan,3 Jike Liu,2 Nanhai Dong,4 Jun Liang1 1Department of Pediatrics, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, People’s Republic of China; 2Department of Pediatric Surgery, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, People’s Republic of China; 3Medical College of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, People’s Republic of China; 4Department of Clinical Laboratory, Liaocheng People’s Hospital, Liaocheng 252000, Shandong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Liang; Nanhai Dong West Dongchang Road 67, Liaocheng 252000, People’s Republic of ChinaTel +86 13346255358; +86 13563016897Email 251217955@qq.com; dnhjyk@163.comIntroduction: HB presents with the highest frequency of CTNNB1 mutations, resulting in activation of Wnt signaling pathway. A number of studies have demonstrated CTNNB1 mutation contributed to the development of HB. However, limited research explored the function of lncRNAs in HB with CTNNB1 mutation.Methods: We screened lncRNA expression profiles in CTNNB1-mutated HB samples and identified lncRNAs associated with malignant phenotype in HB. The association between lncRNA and immune microenvironment was investigated. The biological function of lncRNA was further explored using in vitro experiments.Results: TUG1 was identified as onco-lncRNA in CTNNB1-mutated HB. TUG1 was shown to be associated with the infiltration of pro-tumor immunocytes via regulating the expression of CXCR4, a chemokine receptor playing a critical role in regulation of immune microenvironment. Inhibiting TUG1 could increase endogenous levels of miR-335-5p and consequently downregulating CXCR4, a direct target of miR-335-5p.Conclusion: Our findings provide evidence for TUG1 mediating infiltration of pro-tumor immunocytes in HB patients carrying CTNNB1 mutation. TUG1-miR-335-5p-CXCR4 axis might be a promising immunological target for the treatment of HB patients.Keywords: hepatoblastoma, TUG1, CXCR4, immunocyte

Xianli Wei,1,* Junzi Ke,2,3,* Haonan Huang,2,3,* Shikun Zhou,2,3 Ao Guo,4 Kun Wang,2,3 Yujuan Zhan,2,3 Cong Mai,5 Weizhen Ao,3 Fuda Xie,6,7 Rongping Luo,8 Jianyong Xiao,2 Hang Wei,4 Bonan Chen2,3 1Department of Medical Instruments, Guangdong Food and Drug Vocational College, Guangzhou 510520, People’s Republic of China; 2Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 3Research Center of Integrative Medicine, School of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 4School of Medical Information Engineering, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5Department of Abdominal Surgery, Cancer Center of Guangzhou Medical University, Guangzhou 510095, People’s Republic of China; 6The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China; 7Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou 510006, People’s Republic of China; 8School of Foreign Language, Guangdong Pharmaceutical University, Guangzhou 510006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bonan Chen; Hang Wei Email 20171104455@stu.gzucm.edu.cn; crwei@gzucm.edu.cnIntroduction: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Up to now, many genes associated with HCC have not yet been identified. In this study, we screened the HCC-related genes through the integrated analysis of the TCGA database, of which the potential biomarkers were also further validated by clinical specimens. The discovery of potential biomarkers for HCC provides more opportunities for diagnostic indicators or gene-targeted therapies.Methods: Cancer-related genes in The Cancer Genome Atlas (TCGA) HCC database were screened by a random forest (RF) classifier based on the RF algorithm. Proteins encoded by the candidate genes and other associated proteins obtained via protein–protein interaction (PPI) analysis were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The newly identified genes were further validated in the HCC cell lines and clinical tissue specimens by Western blotting, immunofluorescence, and immunohistochemistry (IHC). Survival analysis verified the clinical value of genes.Results: Ten genes with the best feature importance in the RF classifier were screened as candidate genes. By comprehensive analysis of PPI, GO and KEGG, these genes were confirmed to be closely related to HCC tumors. Representative NOX4 and FLVCR1 were selected for further validation by biochemical analysis which showed upregulation in both cancer cell lines and clinical tumor tissues. High expression of NOX4 or FLVCR1 in cancer cells predicts low survival.Conclusion: Herein, we report that NOX4 and FLVCR1 are promising biomarkers for HCC that may be used as diagnostic indicators or therapeutic targets.Keywords: hepatocellular carcinoma, biomarkers, TCGA database, NOX4, FLVCR1

Shiqiang Wang,1,2 Chongling Hu,2 Fei Xie,3 Yanhui Liu1 1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, People’s Republic of China; 3Department of Neurosurgery, Ziyang First People’s Hospital, Ziyang 641300, People’s Republic of ChinaCorrespondence: Yanhui LiuDepartment of Neurosurgery, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Wuhou Zone, Chengdu 610041, People’s Republic of ChinaEmail liuyanhuicd@163.comAbstract: The central nervous system (CNS) is regarded as an immune privileged environment; however, changes in the neuroimmunology paradigm have led to an increased interest in systematic immunotherapy in lung cancer therapy. The presence of the lymphatic system in the CNS as well as the physiological and biochemical changes in the blood–brain barrier in the tumor microenvironment suggests that immunocytes are fully capable of entering and exiting the CNS. Emerging clinical data suggest that inhibitors of programmed death receptor-1/programmed death ligand 1 (PD-1/PD-L1) can stimulate surrounding T cells and thus have antitumor effects in the CNS. For example, PD-1 antibody (pembrolizumab) monotherapy has displayed a 20– 30% encephalic response rate in patients with brain metastases from malignant melanoma or non-small cell lung cancer. Combined application of nivolumab and ipilimumab anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 showed an encephalic response rate of 55% in patients with brain metastases of melanoma. Further evidence is required to verify these response rates and identify the mechanisms of curative effects and drug tolerance. While regional treatments such as whole-brain radiosurgery, stereotactic radiosurgery, and brain surgery remain the mainstream, PD-1/PD-L1 inhibitors display potential decreased neurotoxic effects. To date, five drugs have been approved for use in patients with encephalic metastases of lung carcinoma: the anti-PD-1 drugs, pembrolizumab and nivolumab, and the anti-PD-L1 agents, atezolizumab, durvalumab, and avelumab. In recent years, clinical trials of inhibitors in combination with other drugs to treat brain metastasis have also emerged. This review summarizes the biological principles of PD-1/PD-L1 immunotherapy for brain metastasis of lung cancer, as well as ongoing clinical trials to explore unmet needs.Keywords: immunotherapy, blood–brain barrier, brain metastasis, lung cancer, PD-1/PD-L1 inhibitors

Shimin Wu,1 Hongwu Ai,2 Kehui Zhang,3,4 Hao Yun,3,4 Fei Xie3,4 1Center for Clinical Laboratory, General Hospital of the Yangtze River Shipping, Wuhan Brain Hospital, Wuhan 430030, People’s Republic of China; 2Center for Clinical Laboratory, Wuhan Kangjian Maternal and Infant Hospital, Wuhan 430050, People’s Republic of China; 3Wuhan Center for Clinical Laboratory, Wuhan Fourth Hospital, Wuhan 430030, People’s Republic of China; 4Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430032, People’s Republic of ChinaCorrespondence: Shimin WuGeneral Hospital of the Yangtze River Shipping, Building 5, Huiji Road, Jiang’an District, Wuhan 430030, People’s Republic of ChinaTel +86 2783782519Email mintyrain@126.comBackground: Chronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). EGOT is a long non-coding RNA (lncRNA) induced after HCV infection that increases viral replication by antagonizing the antiviral response. Interestingly, EGOT also acts as a crucial regulator in multiple cancers. However, its role in HCC remains unclear.Methods: Real-time PCR (RT-PCR) was used to detect the expression of EGOT in HCC samples and cell lines. CCK-8 assay and colony formation assay were performed to evaluate the effect of EGOT on proliferation. Scratch healing assay and transwell assay were used to detect the changes of migration and invasion. Flow cytometry was used to detect the effect of EGOT on apoptosis. Interaction between EGOT and miR-33a-5p was determined by bioinformatics analysis, RT-PCR, and dual-luciferase reporter assay. Western blot was used to confirm that high mobility group protein A2 (HMGA2) could be modulated by EGOT.Results: Compared with normal liver tissues, the expression level of EGOT in HCC tissues was significantly up-regulated. EGOT markedly regulated viability, migration and invasion of HCC cells. The expression level of EGOT was negatively correlated the expression level of miR-33a-5p. It is also confirmed that EGOT could specifically bind to miR-33a-5p and could reduce its expression, in turn, up-regulate the expression of HMGA2.Conclusion: Our data imply that EGOT may be a novel therapeutic target for HCC, and highlights the key role of EGOT/miR-33a-5p/HMGA2 in the progression of this deadly disease.Keywords: HCV, HCC, EGOT, miR-33a-5p, HMGA2

Jie Gao,1,2,* Junjie Liu,1,3,* Fangyuan Xie,4,* Ying Lu,3 Chuan Yin,5 Xian Shen1 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China; 2Scientific Research Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, People’s Republic of China; 3Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai, People’s Republic of China; 4Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China; 5Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Gao; Xian ShenDepartment of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109 Xueyuan W Road, Lucheng, Wenzhou, Zhejiang 325000, People’s Republic of ChinaTel +86-0577-88816381; 86-0577-88002709Fax +86-0577-88816381Email gaojiehighclea@163.com; shenxian1963@sina.comPurpose: Conventional chemotherapy is hampered by the presence of breast cancer stem cells (BCSCs). It is crucial to eradicating both the bulky breast cancer cells and BCSCs, using a combination of conventional chemotherapy and anti-CSCs drugs. However, the synergistic ratio of drug combinations cannot be easily maintained in vivo. In our previous studies, we demonstrated that the simultaneous delivery of two drugs via nanoliposomes could maintain the synergistic drug ratio for 12 h in vivo. However, nanoliposomes have the disadvantage of quick drug release, which makes it difficult to maintain the synergistic drug ratio for a long time. Herein, we developed a co-delivery system for docetaxel (DTX)—a first-line chemotherapy drug for breast cancer—and salinomycin (SAL)—an anti-BCSCs drug—in rigid nanoparticles constituted of polylactide-co-glycolide/D-alpha-tocopherol polyethylene glycol 1000 succinate (PLGA/TPGS).Methods: Nanoparticles loaded with SAL and DTX at the optimized ratio (NSD) were prepared by the nanoprecipitation method. The characterization, cellular uptake, and cytotoxicity of nanoparticles were investigated in vitro, and the pharmacokinetics, tissue distribution, antitumor and anti-CSCs activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a SAL/DTX molar ratio of 1:1 was synergistic in MCF-7 cells and MCF-7-MS. Moreover, the enhanced internalization of nanoparticles was observed in MCF-7 cells and MCF-7-MS. Furthermore, the cytotoxicity of NSD against both MCF-7 cells and MCF-7-MS was stronger than the cytotoxicity of any single treatment in vitro. Significantly, NSD could prolong the circulation time and maintain the synergistic ratio of SAL to DTX in vivo for 24 h, thus exhibiting superior tumor targeting and anti-tumor activity compared to other treatments.Conclusion: Co-encapsulation of SAL and DTX in PLGA/TPGS nanoparticles could maintain the synergistic ratio of drugs in vivo in a better manner; thus, providing a promising strategy for synergistic inhibition of breast cancer.Keywords: combined therapy, breast cancer stem cells, docetaxel, salinomycin, nanoparticles

Tian X, Zeng A, Liu Z, et al. Int J Nanomedicine. 2020;15:6519–6529. The authors have advised that there was an error in the Funding section on page 6528. Line 4, the text “(grant Q195026028)” should read “(grant 2019A1515011800)”. The authors apologize for this error. Read the original article

Qian Sun, Qian Li, Fangfang XieDepartment of Obstetrics and Gynecology, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, Gansu 730050, People’s Republic of ChinaObjective: Ovarian cancer (OC) is a common female disease with a poor prognosis. But the possible mechanism of OC tumor progression remains an active area of research. This study is intended to explore the effect of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) on proliferation and apoptosis of OC and its mechanism.Materials and methods: MALAT1 and miR-503-5p expressions in human OC cell lines and normal human ovarian epithelial (HOSE) cell line were measured using qRT-PCR. OC cell line SKOV3 is divided into 4 groups: pcDNA3.1 group, pcDNA3.1-MALAT1 group, si-NC group, and si-MALAT1 group. MTT assay and 5-ethynyl-2ʹ-deoxyuridine (EdU) assay were applied for the detection of cell proliferation. Relationship of MALAT1 with miR-503-5p was verified using luciferase assay and RNA pull-down. The luciferase activity in cells was normalized to RNA concentrations determined by Bradford assays.Results: MALAT1 expression in OC cells was elevated compared with HOSE cells. MTT assay and EdU assay supported that si-MALAT1 could inhibit cell proliferation in OC cells. Treatment of si-MALAT1 results in increased cell apoptosis rate in both SKOV3 cells and OVCAR3 cells. The expression of lncRNA-MALAT1 was negatively associated with the expression of miR-503-5p in OC cells, while luciferase assay and RNA pull-down together supported the direct binding of MALAT1 with miR-503-5p. Knockdown of MALAT1 was able to inhibit the activation of JAK2/STAT3 signal pathway, and MALAT1 overexpression was accompanied by activation of these factors.Conclusion: lncRNA-MALAT1 can negatively target miR-503-5p expression to further promote proliferation and depress apoptosis of OC cells through the JAK2-STAT3 pathway.Keywords: lncRNA-MALAT1, miR-503-5p, ovarian cancer, cell proliferation, cell apoptosis, JAK2/STAT3

Mary S Anthony,1 Mary Anne Armstrong,2 Darios Getahun,3 Delia Scholes,4 Jennifer Gatz,5 Renate Schulze-Rath,6 Debbie Postlethwaite,2 Maqdooda Merchant,2 Amy L Alabaster,2 Giulia Chillemi,2 Tina Raine-Bennett,2 Fagen Xie,3 Vicki Y Chiu,3 Theresa M Im,3 Harpreet S Takhar,3 Michael Fassett,3 Jane Grafton,4 David Cronkite,4 Laura Ichikawa,4 Susan D Reed,4,7 Siu Lui Hui,5 Mary E Ritchey,1 Catherine W Saltus,8 Elizabeth B Andrews,1 Kenneth J Rothman,8 Alex Asiimwe,6 Richard Lynen,9 Juliane Schoendorf101RTI Health Solutions, Research Triangle Park, NC, USA; 2Kaiser Permanente Northern California, Oakland, CA, USA; 3Kaiser Permanente Southern California, Pasadena, CA, USA; 4Kaiser Permanente Washington, Seattle, WA, USA; 5Regenstrief Institute, Indianapolis, IN, USA; 6Bayer AG, Berlin, Germany; 7University of Washington, Seattle, WA, USA; 8RTI Health Solutions, Waltham, MA, USA; 9Bayer HealthCare, Whippany, NJ, USA; 10Bayer OY, Espoo, FinlandObjective: To validate algorithms identifying uterine perforations and intrauterine device (IUD) expulsions and to ascertain availability of breastfeeding status at the time of IUD insertion.Study design and setting: Four health care systems with electronic health records (EHRs) participated: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI). The study included women ≤50 years of age with an IUD insertion. Site-specific algorithms using structured and unstructured data were developed and a sample validated by EHR review. Positive predictive values (PPVs) of the algorithms were calculated. Breastfeeding status was assessed in a random sample of 125 women at each research site with IUD placement within 52 weeks postpartum.Results: The study population included 282,028 women with 325,582 IUD insertions. The PPVs for uterine perforation were KPNC 77%, KPSC 81%, KPWA 82%, and RI 47%; PPVs for IUD expulsion were KPNC 77%, KPSC 87%, KPWA 68%, and RI 37%. Across all research sites, breastfeeding status at the time of IUD insertion was determined for 94% of those sampled.Conclusions: Algorithms with a high PPV for uterine perforation and IUD expulsion were developed at 3 of the 4 research sites. Breastfeeding status at the time of IUD insertion could be determined at all research sites. Our findings suggest that a study to evaluate the associations of breastfeeding and postpartum IUD insertions with risk of uterine perforation and IUD expulsion can be successfully conducted retrospectively; however, automated application of algorithms must be supplemented with chart review for some outcomes at one research site due to low PPV.Keywords: electronic health records, intrauterine device, breastfeeding, validation study, algorithm, postpartum

Fei Xie, Lixin Xie Department of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing 100853, China Background: COPD may lead to cognitive impairment or even dementia. However, the current conclusions are inconsistent with little evidence from prospective, large-sample studies. This study was designed to explore the association of COPD with mild cognitive impairment (MCI) and dementia risk based on a cohort study. Patients and methods: All participants were from the Chinese Longitudinal Health Longevity Survey (CLHLS) 2011/2012 waves. The follow-up survey was conducted in 2014 and the incidence of MCI and dementia were recorded. Results: During the 3-year follow-up period, 712 new cases of MCI and 83 new cases of dementia were diagnosed. The incidence of MCI and dementia were higher in those with COPD than those without COPD at baseline. Cox analysis showed that the HRs of COPD for MCI and dementia incidence were 1.486 (95% CI: 1.207–1.855) and 1.896 (95% CI: 1.079–3.330), respectively after adjusting for related covariates. For different baseline smoking status, those who were current smokers had the highest HRs of COPD for MCI and dementia. Conclusion: Baseline COPD was independently associated with increased risk of MCI and dementia incidence among Chinese elderly, and the association was more pronounced among those who were current smokers. Keywords: chronic obstructive pulmonary disease, dementia, cohort

Naghmeh Foroutan,1,2 Jean-Eric Tarride,1–3 Feng Xie,1,3,4 Mitchell Levine1–3 1Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada; 2Programs for Assessment of Technology in Health (PATH), The Research Institute of St. Joe’s, St Joseph’s Healthcare Hamilton, Hamilton, ON, Canada; 3Centre for Health Economics and Policy Analysis (CHEPA), McMaster University, Hamilton, ON, Canada; 4Program for Health Economics and Outcome Measures (PHENOM), Hamilton, ON, Canada Introduction: Budget impact analysis (BIA) in health care, sometimes referred to as resource impact, is the financial change in the use of health resources associated with adding a new drug to a formulary or the adoption of a new health technology. Several national and transnational organizations worldwide have updated their BIA guidelines in the past 4 years. The aim of the present review was to provide a comprehensive list of the key recommendations of BIA guidelines from different countries that may be of interest for those who wish to build or to update BIA guidelines.Methods: National and transnational BIA guidelines were searched in databases including MEDLINE, EMBASE, Cochrane, EconLit, CINAHL, Business Source Premier, HealthSTAR, and the gray literature including regulatory agency websites. Data were reviewed and abstracted based on key elements in a standard BIA model (analytical model structure, input and data sources, and reporting format).Results: Eight national (Australia, UK, Belgium, Ireland, France, Poland, Brazil, and Canada) and one transnational (International Society for Pharmacoeconomics and Outcomes Research) BIA guidelines were included in this review, and a comprehensive list of BIA recommendations was identified. The review showed that certain recommendations such as patient population assessment, drug-related direct costs, discounting, and disaggregated results were common across the various jurisdictions. BIA guidelines differed from each other in terms of the number and scope of recommendations, the terminology used (eg, the definition of comparators or cost offsets) and the direction of the recommendations (ie, to include or not to include with respect to such items as off-label indications, indirect costs, clinical outcomes, and resource utilization).Conclusion: While there was a common purpose for all of the BIA guidelines that were identified, substantial differences did occur in the specific recommendations. The pharmaceutical financing system structure might explain why guidelines from the UK, Australia, and Canada have more country-specific recommendations. The desire to be consistent with adopted economic evaluation assumptions might be another reason for some observed differences between countries. Further research is required to assess the source of the heterogeneity between BIA recommendations are identified in different guidelines. Keywords: budgetary impact, financial impact, resource impact assessment, pharmaceutical reimbursement, new drug submissions, guidelines

Dazhong Chen,1–3,* Xiaoli Pan,4,* Fangyuan Xie,5,* Ying Lu,2 Hao Zou,2 Chuan Yin,6 Yu Zhang,7 Jie Gao1,2 1Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Department of Pharmaceutical Sciences, Second Military Medical University, Shanghai 200433, China; 3Department of Planning, Kunming General Hospital of Chengdu Military Command, Yunnan 650032, China; 4Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China; 6Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China; 7Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei 441000, China *These authors contributed equally to this work Purpose: Liver cancer is the third leading cause of cancer-related deaths worldwide. Liver cancer stem cells (LCSCs) are a subpopulation of cancer cells that are responsible for the initiation, progression, drug resistance, recurrence, and metastasis of liver cancer. Recent studies have suggested that the eradication of both LCSCs and liver cancer cells is necessary because the conversion of cancer stem cells (CSCs) to cancer cells occasionally occurs. As ATP-binding cassette (ABC) transporters are overexpressed in both CSCs and cancer cells, combined therapies using ABC transporter inhibitors and chemotherapy drugs could show superior therapeutic efficacy in liver cancer. In this study, we developed poly(lactide-co-glycolide)/d-alpha-tocopherol polyethylene glycol 1000 succinate nanoparticles to accomplish the simultaneous delivery of an optimized ratio of doxorubicin (DOX) and elacridar (ELC) to target both LCSCs and liver cancer cells.Methods: Median-effect analysis was used for screening of DOX and ELC for synergy in liver cancer cells (HepG2 cells) and LCSCs (HepG2 tumor sphere [HepG2-TS]). Then, nanoparticles loaded with DOX and ELC at the optimized ratio (NDEs) were prepared by nanoprecipitation method. The cytotoxicity and colony and tumor sphere formation ability of nanoparticles were investigated in vitro, and the tissue distribution and antitumor activity of nanoparticles were evaluated in vivo.Results: We demonstrated that a DOX/ELC molar ratio of 1:1 was synergistic in HepG2 cells and HepG2-TS. NDEs were shown to exhibit significantly increased cytotoxic effects against both HepG2 and HepG2-TS compared with DOX-loaded nanoparticles (NDs) or ELC-loaded nanoparticles (NEs) in vitro. In vivo studies demonstrated that the nanoparticles exhibited better tumor targeting, with NDE showing the strongest antitumor activity with lower systemic toxicity.Conclusion: These results suggested that NDE represented a promising combination therapy against liver cancer by targeting both liver cancer cells and CSCs. Keywords: combined therapy, cancer stem cells, liver cancer, doxorubicin, elacridar, nanoparticles

Feihu Hu,1,2 Chenhai Liu,1,2 Fang Xie,1,2 Xiansheng Lin,1,2 Ji Yang,1,2 Chao Wang,1,2 Qiang Huang1,2 1Department of General Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China; 2Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Hospital, Heifei, China Purpose: To investigate the expression and functional role of Musashi2 (MSI2), an RNA-binding protein, in extrahepatic cholangiocarcinoma (eCCA).Patients and methods: We measured MSI2 expression in human specimens and cell lines using Western blot and quantitative real-time polymerase chain reaction, and we analyzed its association with clinicopathologic features in eCCA patients. Univariate and multivariate analyses were performed to identify risk factors correlated with overall survival and disease-free survival. Functional experiments were used to study the mechanisms of MSI2 in regulating eCCA cell growth, migration, and invasion.Results: MSI2 expression was upregulated significantly in both human specimens and cell lines, and high MSI2 expression was associated with lymph node metastasis, advanced TNM stage, and poor prognosis in eCCA patients. Additionally, MSI2 overexpression promoted eCCA cell growth, migration, and invasion, while MSI2 knockdown repressed eCCA cell migration and invasion by inhibiting epithelial–mesenchymal transition.Conclusion: MSI2 is an independent prognostic factor for eCCA patients, and MSI2 downregulation inhibits eCCA cell growth and metastasis. MSI2 may be a potential therapeutic target for eCCA patients. Keywords: Musashi2, cholangiocarcinoma, prognosis, metastasis, EMT

Huiwen Zhao,1,* Zhe Dong,2,* Fei Xie,3,4 Guanxin Wang,2 Zhihua Wen,5 Lixia Zhang,5 Mwidimi Ndosi,6,7 Wen Luo1 1Joint Department, The 2nd Ward of Joint Surgery, Tianjin Hospital, Tianjin, China; 2Medical Examination Center, No 6 Hospital, Beijing, China; 3Nursing Experimental Teaching Center, Tianjin Hospital, Tianjin, China; 4College of Nursing, Tianjin University of Traditional Chinese Medicine, Tianjin, China; 5Joint Department, The 1st Ward of Joint Surgery, Tianjin Hospital, Tianjin, China; 6Department of Nursing, University of the West of England, Bristol, UK; 7Academic Rheumatology Unit, Bristol Teaching Hospitals, Bristol, UK *These authors contributed equally to this work Background: Patient education is an integral part of the management of osteoarthritis. The educational needs assessment tool (ENAT) was developed in the UK to help direct needs-based patient education in rheumatic diseases. Aim: The aim of the study was to adapt and validate the ENAT into Chinese, for use in severe knee osteoarthritis (KOA). Methods: This cross-cultural validation study took two phases: 1) adaptation of the ENAT into Chinese (CENAT) and 2) validation of the CENAT. The Construct validity was determined using factor analysis and criterion-related validity by comparing data from CENAT with data from different self-efficacy scales: patient–physician interactions scale (PEPPI-10), self-efficacy for rehabilitation outcome scale (SER), and the self-efficacy for exercise scale (SEE). Results: The sample comprised 196 patients, with mean age 63.6±8.7 years, disease duration was 11.5 years, and 57.1% were female. The CENAT was found to have high internal consistency. The CENAT had weak correlations with the Chinese versions of PEPPI r=0.40, SER r=0.40, and SEE r=0.39. There were no correlations with age r=-0.03 or disease duration r=-0.11. Conclusion: The ENAT translated well into Chinese and has evidence of validity in KOA. Future studies will further inform its usefulness in clinics, community, and online settings. Keywords: assessment, educational needs, knee osteoarthritis, instrument validation

Hong-Yang Lu,1–3 Jing Qin,2,3 Na Han,2,3 Lei Lei,2 Fajun Xie,2,3 Chenghui Li31Department of Oncology, Wenzhou Medical University, Wenzhou, People's Republic of China; 2Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Zhejiang Cancer Hospital, Hangzhou, People's Republic of China; 3Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, P.R. China Background: Small cell lung cancer (SCLC) is an aggressive and deadly neuroendocrine tumor derived from bronchial epithelial cells. Although it results in a 95% mortality rate, the development of targeted therapies for SCLCs has lagged behind. The aim of this study is to better research mutation characteristics of SCLC and identify potential biomarkers for target therapy.Methods: We utilized high- resolution melting analysis to identify the mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-3-kinase catalytic (PIK3CA) from the blood. A cohort of 99 SCLC patients including 44 limited-stage disease patients and 55 extensive-stage disease patients were prospectively collected. Results: EGFR 18 (G719X) mutation was found in 5 patients, EGFR 19 (del) mutation in 2, EGFR 20 (T790M) in 3, EGFR 21 (L858R) in 2, KRAS 2 (G13D) in 5, BRAF 15 (V600E) in 1, PIK3CA 9 (E542K) in 1, and no mutations in PTEN 5 (R130G), PTEN 6 (R173C), PTEN 8 (T319fs*1), and PIK3CA 20 (H1047R) were identified. Among these patients, two harbored EGFR double mutation, one patient with EGFR double mutation and KRAS 2 (G13D) mutation. Conclusion: The mutation form of EGFR may differ from lung adenocarcinoma, and mutations of KRAS, BRAF, and PIK3CA were rare in SCLC. These results aided us in comprehensively analyzing genetic features and laid the foundation for exploring the possibility of target therapy.Keywords: epidermal growth factor receptor, small cell lung cancer, plasma, high-resolution melting

Fang Bai,1–3,* You Yin,4,* Ting Chen,1,* Jihui Chen,1 Meixin Ge,2 Yunshu Lu,2 Fangyuan Xie,5 Jian Zhang,1 Kejin Wu,3 Yan Liu1,6 1Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, 3Department of Breast Surgery, Obstetrics and Gynaecology Hospital, Fudan University, Shanghai, 4Department of Neurology, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, 5Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 6Department of Pharmacy, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR) in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) liposomes (liposomal pemetrexed) were developed as a strategy to overcome MDR to pemetrexed in breast cancer. Materials and methods: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated. Results: Liposomal pemetrexed was small in size (160.77 nm), with a small polydispersity of

Fei Xie,1,* Yuncang Yuan,1,* Luyang Xie,2,* Pengzhan Ran,1 Xudong Xiang,3 Qionglin Huang,1 Guoxiang Qi,1 Xiaopeng Guo,1 Chunjie Xiao,1 Shangyong Zheng1 1School of Medicine, Yunnan University, Kunming, Yunnan, 2Department of Stomatology, Shanghai Tenth People’s Hospital, Shanghai, 3Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China *These authors contributed equally to this work Background: Downregulated expression levels of microRNA-320a (miR-320a) were found in primary breast cancers and colorectal cancer. Previous findings indicated that miRNA-320a may involve in the cancer development. In this study, we explored the roles of miR-320a by targeting c-Myc in the tumor growth of hepatocellular carcinoma (HCC). Methods: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to detect the expression of miR-320a in 50 HCC tissues and four HCC cells. Luciferase reporter assay was conducted to confirm the direct downstream target of miR-320a in HEK-293 cells. The effect of miR-320a on endogenous c-Myc expression was investigated by transfecting miR-320a mimics into HepG2 and QGY-7703 cell lines. The c-Myc and miR-320a expressions were analyzed by immunohistochemistry (IHC) and qRT-PCR in the same HCC tissues. Furthermore, the biological functional correlation of miR-320a with c-Myc was determined by studying the effect of miR-320a mimics or c-Myc small interfering RNA (siRNA) on HCC cell proliferation and invasion. Results: The expression of miR-320a was downregulated in 50 HCC tissues and 4 HCC cells. Luciferase assay revealed that c-Myc is a direct target of miR-320a. IHC and Western blot analysis showed that the c-Myc expression was inhibited by miR-320a in HCC tissues and cell lines. Upregulation of miR-320a suppressed the HCC cell proliferation and invasion capacity induced by inhibiting c-Myc, and the results were consistent with the effects of c-Myc siRNA on tumor suppression. These results revealed that miRNA-320a inhibits tumor proliferation and invasion by targeting c-Myc in HCC cells.Conclusion: Our results showed that miR-320a functions as a tumor suppressor in HCC. By targeting c-Myc directly, miR-320a inhibits the HCC cell growth. Our studies provide evidence of miR-320a as a potentially target for HCC treatment. Keywords: miR-320a, hepatocellular carcinoma, c-Myc, tumor suppressors

Hongyang Lu,1,2 Haimiao Xu,3 Fajun Xie,2 Jing Qin,2 Na Han,2 Yun Fan,1,2 Weimin Mao1 1Zhejiang Cancer Hospital, Zhejiang Key Laboratory of Diagnosis & Treatment Technology on Thoracic Oncology (Lung and Esophagus), 2Department of Thoracic Medical Oncology, 3Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China Abstract: The prognosis of small-cell lung cancer (SCLC) is poor despite reports suggesting modest improvement in survival. To date, chemotherapy remains the cornerstone treatment for SCLC patients, and many studies have focused on identifying the molecular characteristics of SCLC, which serve as the basis for precision treatments that improve the prognosis of SCLC. For instance, the therapeutic effect of temozolomide, recommended for patients with relapsed SCLC, is linked to 1p/19q codeletion in anaplastic oligodendroglial tumors. A subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. In order to identify 1p/19q codeletion and RET rearrangement in SCLC patients, 32 SCLC resected specimens were retrospectively collected between 2008 and 2014 from the Zhejiang Cancer Hospital in People’s Republic of China. Fluorescence in situ hybridization was used to detect 1p/19q codeletion and RET rearrangement in the specimens. A 1p single deletion was detected in eight specimens, 19q single deletion was detected in three specimens, and only three specimens had a 1p/19q codeletion. None of the specimens had a RET rearrangement. The three patients whose specimens had a 1p/19q codeletion were alive after 58, 50, and 30 months of follow-up care. There was a trend toward prolonged overall survival for the patients with codeletion compared to no codeletion, 1p single deletion, 19q single deletion, and without 1p and 19q deletion (P=0.113, 0.168, 0.116, and 0.122, respectively). Our data showed that RET rearrangement may be not an ideal molecular target for SCLC therapies in People’s Republic of China. Instead, 1p/19q codeletion is a promising marker for a good prognosis and treatment with temozolomide in SCLC. Keywords: small-cell lung cancer, 1p/19q codeletion, RET rearrangement, FISH

Yingying Shen,1,2,* Yuanzhi Shao,3,* Haoqiang He,1 Yunpu Tan,4 Xiumei Tian,2 Fukang Xie,2 Li Li11Imaging Diagnostic and Interventional Center, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; 2Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China; 3Key Laboratory of Optoelectronic Materials and Technologies, School of Physics and Engineering, Sun Yat-sen University, Guangzhou, Guangdong, China; 4Department of Gastrointestinal Surgery, Sun Yat-sen University, Guangzhou, Guangdong, China *These authors contributed equally to this workAbstract: We investigated the tracking potential of a magnetic resonance imaging (MRI) probe made of gadolinium-doped mesoporous silica MCM-41 (Gd2O3@MCM-41) nanoparticles for transplanted bone mesenchymal stem cells (MSCs) and neural stem cells (NSCs) in vivo. The nanoparticles, synthesized using a one-step synthetic method, possess hexagonal mesoporous structures with appropriate assembly of nanoscale Gd2O3 clusters. They show little cytotoxicity against proliferation and have a lower effect on the inherent differentiation potential of these labeled stem cells. The tracking of labeled NSCs in murine brains was dynamically determined with a clinical 3T MRI system for at least 14 days. The migration of labeled NSCs identified by MRI corresponded to the results of immunofluorescence imaging. Our study confirms that Gd2O3@MCM-41 particles can serve as an ideal vector for long-term MRI tracking of MSCs and NSCs in vivo.Keywords: nanoparticles, gadolinium, magnetic resonance imaging, stem cells