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Ang Li,1,* Xushan Cai,2,* Dong Li,1,* Yimin Yu,1 Chengyu Liu,1 Jie Shen,1 Jiaqi You,3 Jianou Qiao,3 Feng Wang4 1Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, School of Life Science and Technology, Tongji University, Shanghai, People’s Republic of China; 2Department of Clinical Laboratory, Shanghai Jiading Maternal and Child Health Hospital, Shanghai, People’s Republic of China; 3Department of Respiratory, Shanghai Ninth People’s Hospital Affiliated Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Thoracic Surgery, Shanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ang Li, Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, School of Life Science and Technology, Tongji University, No. 389 Xincun Road, Shanghai, 200065, People’s Republic of China, Email liang@tongji.edu.cn Feng Wang, Department of Thoracic Surgery, Shanghai Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine, No. 639, Zhizaoju Road, Shanghai, 200011, People’s Republic of China, Email wangsongyi1997@163.comBackground: Lung metastasis is a leading cause of cancer-related death. mRNA-based cancer vaccines have been demonstrated to be effective at inhibiting tumor growth. Intranasal immunization has emerged as a more effective method of inducing local immune responses against cancer cells in the lungs.Methods: An innovative layered double hydroxide- and 5-OP-RU–based mRNA nanovaccine (Mg/Al LDH-5-OP-RU/mRNA) was synthesized via coprecipitation. The particle size distribution and zeta potential were measured, and the nanovaccine was observed by transmission electron microscopy. The functions and properties of the nanovaccine were evaluated via an mRNA-targeted delivery assay and measurement of dendritic cell (DC) and mucosa-associated invariant T (MAIT) cell maturation and activation. In addition, the cytotoxicity, antigen-specific T cell activation, cytokines, protective ability, and therapeutic ability of the nanovaccine were assessed in a mouse tumor model. Further, the immune cell composition was evaluated in tumors.Results: The Mg/Al LDH-5-OP-RU/mRNA nanovaccine was efficiently delivered into lung-draining mediastinal lymph nodes (MLNs), and it activated dendritic cells (DCs) and mucosa-associated invariant T (MAIT) cells after intranasal administration. Moreover, the optimized dual-activating mRNA nanovaccine efficiently transfected DC cells and expressed antigen proteins in DC cells. An HPV-associated tumor model revealed that the intranasal delivery of the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine significantly prevented the lung metastasis of tumors and had a therapeutic effect on established metastatic tumor nodules in the lungs. Mechanistically, the enhanced activation of DC and MAIT cells induced by the Mg/Al LDH-5-OP-RU/E7 mRNA nanovaccine increased the production of immune-stimulating cytokines and decreased the secretion of immunosuppressive cytokines, which led to the expansion and activation of memory T cells targeting the E7 antigen, a reduction in the population of neutrophils, and differentiation of tumor -associated macrophages to the M1 phenotype in the lungs.Conclusion: These results highlight the potential of the innovative nasal mRNA nanovaccine for both preventing and treating tumor metastasis in the lungs.Keywords: mRNA nanovaccine, layered double hydroxide, 5-OP-RU, dendritic cells, Mucosa-associated invariant T cells, lung metastasis

Shenghao Zhang,1,* Jiahui Ma,1,* Yilei Ma,1,* Jia Yi,1 Beier Wang,2 Hanbing Wang,3 Qinsi Yang,4 Kun Zhang,5 Xiaoqing Yan,6 Da Sun,1,7 Jinfeng You8 1Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, People’s Republic of China; 2Department of Hepatobiliary-Pancreatic Surgery, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 3Department of Biotechnology, The University of Hong Kong, Hong Kong SAR, 999077, People’s Republic of China; 4Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, People’s Republic of China; 5Chongqing Municipality Clinical Research Center for Endocrinology and Metabolic Diseases, Chongqing University Three Gorges Hospital, Chongqing, 404000, People’s Republic of China; 6The Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, People’s Republic of China; 7Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu hospital of Wenzhou Medical University, Yiwu, 322000, People’s Republic of China; 8Department of Obstetrics, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, 324000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinfeng You; Da Sun, Email Jincancanyjf@163.com; sunday@wzu.edu.cnBackground: Diabetes Mellitus (DM) is a substantial health concern worldwide, and its incidence is progressively escalating. Conventional pharmacological interventions frequently entail undesirable side effects, and while probiotics offer benefits, they are hindered by constraints such as diminished stability and effectiveness within the gastrointestinal milieu. Given these complications, the advent of bioengineered probiotics is a promising alternative for DM management.Aim of Review: The objective of this review is to provide an exhaustive synthesis of the most recent studies on the use of engineered probiotics in the management of DM. This study aimed to clarify the mechanisms through which these probiotics function, evaluate their clinical effectiveness, and enhance public awareness of their prospective advantages in the treatment of DM.Key Scientific Concepts of Review: Scholarly critiques have explored diverse methodologies of probiotic engineering, including physical alteration, bioenrichment, and genetic manipulation. These techniques augment the therapeutic potency of probiotics by ameliorating gut microbiota, fortifying the intestinal barrier, modulating metabolic pathways, and regulating immune responses. Such advancements have established engineered probiotics as a credible therapeutic strategy for DM, potentially providing enhanced results compared to conventional treatments. Keywords: engineered probiotics, diabetes mellitus, gut microbiota, genetic engineering, therapeutic efficacy

Bo Liu,1,2 Mengling Chen,1 Junjie You,1 Silin Zheng,3 Min Huang2 1School of Nursing, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China; 3Nursing Department, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of ChinaCorrespondence: Silin Zheng, Nursing Department, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China, Email 1400223549@qq.com Min Huang, Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China, Email hm20140313@163.comBackground: Gastroesophageal reflux disease (GERD) and Chronic Obstructive Pulmonary Disease (COPD) often coexist and have been associated in observational studies. However, the real potential causal relationship between GERD and COPD is unknown and not well established.Methods: In this study, we conducted a bidirectional two-sample Mendelian randomization(MR) to estimate whether GERD and COPD are causal. The GERD genetic data is from summary level data of a genome-wide association (GWAS) meta-analysis (Ncases = 71,522, Ncontrol=26,079). The COPD GWAS are available from the FinnGen (Ncases=16,410, Ncontrol=283,589). MR-Egger regression, Weighted Median, and Inverse-variance weighted (IVW) were used for MR analysis from the R package “TwoSampleMR”, and IVW was the dominant estimation method. Additionally, the MR pleiotropy residual sum and outlier (MR-PRESSO), Cochran Q statistic, and leave-one-out analysis were used to detect and correct for the effect of heterogeneity and horizontal pleiotropy.Results: MR analysis indicated that GERD was causally associated with an increased risk of COPD (IVW odds ratio (OR): 1.3760, 95% confidence interval (CI): 1.1565– 1.6371, P=0.0003), and vice versa (IVW OR: 1.1728, 95% CI:1.0613– 1.2961, P=0.0018). The analyses did not reveal any pleiotropy or heterogeneity.Conclusion: Our study revealed possible evidence for a bidirectional causal relationship between GERD and COPD. Implementing screening and preventive strategies for GERD in individuals with COPD, and vice versa, will be crucial in future healthcare management. Further studies are needed to elucidate the mechanisms underlying the causal relationship between GERD and COPD.Keywords: human genetics, Mendelian randomization, gastroesophageal reflux disease, causal relationship, chronic obstructive pulmonary disease

Lu Zhang,1,2 Jiaqian You,1 Huixin Lv,1 Manxuan Liu,1 Sezhen Quni,1 Xiuyu Liu,1 Yanmin Zhou1,2 1Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, People’s Republic of China; 2School of Stomatology, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Yanmin Zhou, Email zhouym@jlu.edu.cnAbstract: Antibiotics are the most commonly used means to treat bacterial infection at present, but the unreasonable use of antibiotics induces the generation of drug-resistant bacteria, which causes great problems for their clinical application. In recent years, researchers have found that nanomaterials with high specific surface area, special structure, photocatalytic activity and other properties show great potential in bacterial infection control. Among them, black phosphorus (BP), a two-dimensional (2D) nanomaterial, has been widely reported in the treatment of tumor and bone defect due to its excellent biocompatibility and degradability. However, the current theory about the antibacterial properties of BP is still insufficient, and the relevant mechanism of action needs to be further studied. In this paper, we introduced the structure and properties of BP, elaborated the mechanism of BP in bacterial infection, and systematically reviewed the application of BP composite materials in the field of antibacterial. At the same time, we also discussed the challenges faced by the current research and application of BP, which laid a solid theoretical foundation for the further study of BP in the future.Keywords: black phosphorus, antibacterial, nanometer material, photothermal therapy

Nai Mu,1,2,* Jie Li,3,* Li Zeng,4 Juan You,4 Rong Li,4 Anquan Qin,4 Xueping Liu,1 Fang Yan,3,5 Zheng Zhou1,2 1Department of Clinical Medicine, North Sichuan Medical College, Nanchong, Sichuan Province, People’s Republic of China; 2Geriatric Diseases Institute of Chengdu, Department of Orthopedics, Chengdu Fifth People’s Hospital, Chengdu, Sichuan Province, People’s Republic of China; 3Center for Medicine Research and Translation, Chengdu Fifth People’s Hospital, Chengdu, Sichuan Province, People’s Republic of China; 4Department of Pharmacy, Chengdu Fifth People’s Hospital, Chengdu, Sichuan Province, People’s Republic of China; 5Geriatric Diseases Institute of Chengdu, Department of Geriatrics, Chengdu Fifth People’s Hospital, Chengdu, Sichuan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang Yan; Zheng Zhou, Tel +86 134 0849 8904 ; +86 182 0810 1005, Email fangyan@cdutcm.edu.cn; zhouzheng@nsmc.edu.cnAbstract: Exosomes are small extracellular vesicles, ranging in size from 30– 150nm, which can be derived from various types of cells. In recent years, mammalian-derived exosomes have been extensively studied and found to play a crucial role in regulating intercellular communication, thereby influencing the development and progression of numerous diseases. Traditional Chinese medicine has employed plant-based remedies for thousands of years, and an increasing body of evidence suggests that plant-derived exosome-like nanovesicles (PELNs) share similarities with mammalian-derived exosomes in terms of their structure and function. In this review, we provide an overview of recent advances in the study of PELNs and their potential implications for human health. Specifically, we summarize the roles of PELNs in respiratory, digestive, circulatory, and other diseases. Furthermore, we have extensively investigated the potential shortcomings and challenges in current research regarding the mechanism of action, safety, administration routes, isolation and extraction methods, characterization and identification techniques, as well as drug-loading capabilities. Based on these considerations, we propose recommendations for future research directions. Overall, our review highlights the potential of PELNs as a promising area of research, with broad implications for the treatment of human diseases. We anticipate continued interest in this area and hope that our summary of recent findings will stimulate further exploration into the implications of PELNs for human health.Keywords: exosomes, nanocarriers, nanotherapeutics, plants, vesicles

Jae-Woo Ju,1 Jiwon You,1 Hyunsook Hong,2 Chang Kyung Kang,3 Won Ho Kim,1,4 Ho-Jin Lee1,4 1Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Republic of Korea; 3Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 4Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Ho-Jin Lee, Department of Anesthesiology and Pain Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea, Tel +82-2-2072-0039, Fax +82-2-747-8363, Email zenerdiode03@gmail.comPurpose: We aimed to investigate the impact of enhanced in-hospital infection prevention during the coronavirus disease 2019 (COVID-19) pandemic on postoperative pneumonia in older surgical patients.Patients and Methods: We retrospectively reviewed the electronic medical records of consecutive patients ≥ 70 years who underwent elective surgery between 2017 and 2021 at our institution. All perioperative variables were retrieved from the electronic medical records. The primary outcome was new-onset postoperative pneumonia during the hospitalization period. Since February 2020, our institution implemented a series of policies to enhance infection prevention, hence patients were divided into groups according to whether they underwent surgery before or during the COVID-19 pandemic. An interrupted time series analysis was performed to evaluate the difference between pre- and post-intervention slopes of the primary outcome.Results: Among the 29,387 patients included in the study, 10,547 patients underwent surgery during the COVID-19 pandemic. Although there was a decreasing trend of the monthly incidence rate of postoperative pneumonia compared to before the COVID-19 pandemic, there was no statistical significance in the trend (slope before COVID-19 period: β-coefficient, − 0.007; 95% CI, − 0.022 to 0.007).Conclusion: Our study revealed that enhanced in-hospital infection prevention implemented to manage the COVID-19 pandemic did not significantly affect the decreasing trend of postoperative pneumonia at our institution.Keywords: coronavirus, COVID-19, healthcare-associated pneumonia, pandemic, pneumonia, severe acute respiratory syndrome coronavirus 2

Bo Liu,1,2 Junjie You,1 Lingyi Huang,1 Mengling Chen,1 Yushan Shen,1 Longyu Xiong,1 Silin Zheng,3 Min Huang2 1School of Nursing, Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China; 3Nursing Department, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of ChinaCorrespondence: Silin Zheng, Nursing Department, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China, Tel +86 13002866667, Email 1400223549@qq.com Min Huang, Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China, Tel +86 18982482624, Email hm20140313@163.comPurpose: To perform a bibliometric analysis of the 100 most-cited articles (T100 articles) on COVID-19 vaccine hesitancy to characterize current trends.Methods: The data of the bibliometric analysis were retrieved from the Web of Science Core Collection (WoSCC) database on January 29, 2023, and the results were sorted in descending order by citations. Two researchers independently extracted the characteristics of the top 100 cited articles, including title, author, citations, publication year, institution, country, author keywords, Journal Cited Rank, and impact factor. Excel and VOSviewer were used to analyze the data.Results: The T100 articles ranged from 79 to 1125 citations, with a mean of 208.75. The T100 articles were contributed by 29 countries worldwide, of which the USA ranked first with 28 articles and 5417 citations. The T100 articles were published in 61 journals; the top three citations were VACCINES, NATURE MEDICINE, and EUROPEAN JOURNAL OF EPIDEMIOLOGY, and the number of citations was 2690, 1712, and 1644, respectively. Professor Sallam, M(n=4) from Jordan, is the author who participated in the most published articles. Catholic University of the Sacred Heart (n=8) had the most T100 articles.Conclusion: It is the first bibliometric analysis of the T100 articles in the field of COVID-19 vaccine hesitancy. We carefully analyzed and described the characteristics of these T100 articles, which provide ideas for further strengthening COVID-19 vaccination and fighting against the epidemic in the future.Keywords: COVID-19, vaccine hesitancy, bibliometric analysis, citation

Yan Li,1,&ast; Ensi Hong,1,2,&ast; Wenguo Ye,2 Jianyu You1 1Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China; 2The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenguo Ye, The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People’s Republic of China, Email 648957697@qq.com Jianyu You, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People’s Republic of China, Email youjytcm@163.comPurpose: Pain is one of the most common and feared symptoms among cancer patients. Unrelieved pain denies patients comfort and greatly affects their overall quality of life. Moxibustion is commonly used to manage chronic pain. However, its efficacy on cancer pain remains inconclusive. This study aimed to evaluate the efficacy of moxibustion for cancer pain.Methods: We searched seven databases to obtain articles about moxibustion combined with pharmacotherapy for cancer pain published before November 2022. All data extraction was carried out independently by two investigators. RevMan 5.4 software was used for data analysis.Results: A total of ten trials involving 999 cases were included. The results of the meta-analysis revealed that moxibustion combined with pharmacotherapy was significantly better than drug therapy alone in improving pain relief rate (RR =1.16, 95% CI = [1.04, 1.30], P = 0.01), reducing pain scores (SMD = − 1.43, 95% CI = [− 2.09, − 0.77], P < 0.0001), Shortening the onset of analgesia (MD = − 12.07, 95% CI = [− 12.91, − 11.22], P < 0.00001), prolonging the duration of analgesia (MD = 3.69, 95% CI = [3.21, 4.18], P < 0.00001), and improving quality of life (SMD = 2.48, 95% CI = [0.67, 4.29], P = 0.007). In addition, moxibustion combined with pharmacotherapy can effectively reduce adverse reactions of drugs (RR =0.35, 95% CI = [0.21, 0.57], P < 0.0001).Conclusion: The evidence in this review supports moxibustion as an effective adjuvant therapy for cancer pain management. However, high-quality RCTs are needed to further confirm these findings.Registration Number: PROSPERO CRD42022370942.Keywords: moxibustion, cancer pain, systematic review, meta-analysis

Jingjing Li,1 Jingyuan You,2 Guoping Yin,1 Jinkun Xu,1 Yuhuan Zhang,1 Xuemei Yuan,1 Qiang Chen,1 Jingying Ye1,3 1Department of Otorhinopharyngology–Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 2Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, People’s Republic of China; 3Institute of Precision Medicine, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Jingying Ye, Department of Otorhinopharyngology–Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Litang Road 168, Beijing, 102218, People’s Republic of China, Tel +86-13701396970, Email yejingying@mail.tsinghua.edu.cnPurpose: Accumulating evidence suggests that theta/beta ratio (TBR), an electroencephalographic (EEG) frequency band parameter, might serve as an objective marker of executive cognitive control in healthy adults. Obstructive sleep apnea (OSA) has a detrimental impact on patients’ behavior and cognitive performance while whether TBR is different in OSA population has not been reported. This study aimed to explore the difference in relative EEG spectral power and TBR during sleep between patients with severe OSA and non-OSA groups.Patients and Methods: 142 participants with in-laboratory nocturnal PSG recording were included, among which 100 participants suffered severe OSA (apnea hypopnea index, AHI > 30 events/hour; OSA group) and 42 participants had no OSA (AHI ≤ 5 events/h; control group). The fast Fourier transformation was used to compute the EEG power spectrum for total sleep duration within contiguous 30-second epochs of sleep. The demographic and polysomnographic characteristics, relative EEG spectral power and TBR of the two groups were compared.Results: It was found that the beta band power during NREM sleep and total sleep was significantly higher in the OSA group than controls (p < 0.001, p = 0.012, respectively), and the theta band power during NREM sleep and total sleep was significantly lower in the OSA group than controls (p = 0.019, p = 0.014, respectively). TBR during NREM sleep, REM sleep and total sleep was significantly lower in the OSA group compared to the control group (p < 0.001 for NREM sleep and total sleep, p = 0.015 for REM sleep). TBR was negatively correlated with AHI during NREM sleep (r=− 0.324, p < 0.001) and total sleep (r=− 0. 312, p < 0.001).Conclusion: TBR was significantly decreased in severe OSA patients compared to the controls, which was attributed to both increased beta power and decreased theta power. TBR may be a stable EEG-biomarker of OSA patients, which may accurately and reliably identify phenotype of patients.Keywords: sleep electroencephalography, spectral power, frequency band ratio, theta/beta ratio, OSA

Dongjiu Li,1,&ast; Jiayin You,2,&ast; Chengyu Mao,1,&ast; En Zhou,1,&ast; Zhihua Han,1 Junfeng Zhang,1 Tiantian Zhang,1 Changqian Wang1 1Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China; 2Department of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tiantian Zhang; Changqian Wang, Email ZhangTT2022Dr@163.com; wangcqdr17@163.comObjective: Cardiomyocyte apoptosis critically contributes to ischemia reperfusion injury (IRI), which lacks effective therapeutic strategies. Circular RNAs (circRNAs) serve as novel diagnostic and therapeutic targets in various cardiovascular diseases. CircRNA Fbxl5 is one of the abundantly expressed circRNAs in the heart and its role in myocardial IRI remains elusive.Materials and Methods: Wild-type (WT) mice and neonatal mice ventricular myocytes (NMVMs) were used and subjected to myocardial IRI and anoxia reoxygenation (AR), respectively. Molecular and histological analyses and echocardiography were used to determine the extent of apoptosis, infarct size, and cardiac function.Results: We found that circRNA Fbxl5 was significantly upregulated in the myocardium, as well as in NMVMs subjected to AR. Knockdown of circRNA Fbxl5 ameliorated cardiomyocyte apoptosis, thereby decreasing infarct size and preserving cardiac function. Additionally, in vitro knockdown of circRNA Fbxl5 in NMVMs subjected to AR recapitulated the in vivo findings. Mechanistically, we identified that circRNA Fbxl5 directly sponged and suppressed the endogenous microRNA-146a (miR-146a), thereby weakening its inhibitory effect on MED1, which could further promote the apoptosis of cardiomyocytes.Conclusion: Our findings revealed a novel and critical role for circRNA Fbxl5 in regulating cardiomyocyte apoptosis, and added additional insight into circRNAs mediated during myocardial IRI. The underlying miR-146a-MED1 signaling serves as an important cascade in regulating the apoptosis of cardiomyocytes.Keywords: myocardial ischemia reperfusion injury, circular RNA, microRNA-146a, cardiomyocyte apoptosis

Yiling Lu,1,&ast; Weichun Tang,2,3,&ast; Xiaoyu Wang,1 Xinyi Kang,1 Jun You,1 Liping Chen1 1Department of Obstetrics and Gynecology, Nantong First People’s Hospital, Nantong, Jiangsu, 226001, People’s Republic of China; 2NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, 211166, People’s Republic of China; 3Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liping ChenDepartment of Gynecology and Obstetrics, Nantong First People’s Hospital, Nantong, Jiangsu, 226001, People’s Republic of ChinaEmail 42770899@qq.comBackground: Endometrial cancer (EC) is a multifactorial disease, and its progression may be driven by abnormal genetic methylation. To clarify the underlying molecular mechanisms and sensitive biomarkers for EC, this study used an integrated bioinformatic analysis to explore the methylation-driven genes of EC.Methods: The mRNA expression data, methylation data and corresponding clinical information of EC samples were downloaded from The Cancer Genome Atlas (TCGA) database. MethylMix algorithm was used to screen out methylation-driven genes in EC. Functional and pathway enrichment analysis and the protein–protein interaction (PPI) analysis were conducted to demonstrate the functions and interactions between these genes. Then, prognosis-related methylated genes were screened out by using univariate and multivariate Cox analyses, and a prognostic risk assessment model for EC was constructed. The methylation sites and expression profiles of candidate genes were further investigated.Results: A total of 127 methylated genes were identified in EC. Four genes (RP11-968O1.5, DCAF12L1, MSX1 and ALS2CR11) were selected as candidate genes to construct a reliable prognostic risk model. The univariate and multivariate Cox proportional hazards regression analyses showed that the risk score based on four genes was an independent prognostic indicator for OS among EC patients. A nomogram was established and the calibration plot analysis indicated the good performance and clinical utility of the nomogram. In addition, the methylation and expression of MSX1 and DCAF12L1 were significantly associated with EC survival rate. The joint ROC analysis revealed that the AUC of DCAF12L1-MSX1 was 0.867, which suggested both have a good EC-diagnosing efficiency. We then coped DCAF12L1 and MSX1 with GESA analysis, finding both were mainly associated with the KRAS signaling pathway.Conclusion: This bioinformatic study combs the methylated genes involved in EC development for the first time, finding that MSX1 and DCAF12L1 could serve as EC prognostic markers and drug targets.Keywords: endometrial cancer, methylation-driven genes, integrated bioinformatic analysis, prognosis, biomarkers

Xiaoyu Wang,&ast; Weichun Tang,&ast; Yilin Lu, Jun You, Yun Han, Yanli Zheng Department of Obstetrics and Gynecology, Nantong First People’s Hospital, Nantong, Jiangsu, 226001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanli ZhengDepartment of Obstetrics and Gynecology, Nantong First People’s Hospital, Nantong, Jiangsu, 226001, People’s Republic of ChinaTel/Fax +86-513-85051875Email gaoshan1189@sina.comBackground: Alternative splicing (AS) acts on many tumors and its relationship with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) needs to be researched.Methods: RNA sequencing data and clinical information of CESC cohorts were obtained from the Cancer Genome Atlas (TCGA) and SpliceSeq was used to analyze the splicing profile of mRNA in CESC. UpSetR displayed the intersections among AS events and univariate analysis chose survival-associated AS and splicing factor (SF) genes. Functional analysis was operated on Enrichr, STRING database and MCODE analysis were used to evaluate protein–protein interaction (PPI) information. LASSO and multivariate analysis constructed prognostic model and risk analysis of tumor infiltrating immune cells was also conducted.Results: A total of 402 AS-generated genes were found to be associated with CESC prognosis. Functional analysis showed that Golgi to lysosome transport was enriched. PPI network suggested that UBA52 was most functional. Dendritic cells activated, dendritic cells resting, macrophages M0, mast cells resting, T cells CD4 memory activated and T cells CD8 were most correlative with the risk score.Conclusion: SFs and AS events can directly or indirectly affect the prognosis of CESC patients and this study identified SNRPA and CELF2 as two CESC-engaged SFs.Keywords: cervical squamous cell carcinoma and endocervical adenocarcinoma, CESC, alternative splicing, AS, prognosis, TCGA

Wei Liu,&ast; Wei Wang,&ast; Jiangmei Liu, Yunning Liu, Shidi Meng, Feixue Wang, Zheng Long, Jinlei Qi, Jinling You, Lin Lin, Lijun Wang, Maigeng Zhou, Peng Yin National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Peng YinNational Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, No. 27 Nanwei Road, Beijing, 100050, People’s Republic of ChinaTel +86 010-63015058Email yinpeng@ncncd.chinacdc.cnBackground: To examine trends in chronic obstructive pulmonary disease (COPD) mortality and years of life lost (YLL) due to COPD for all provinces in China during 2005– 2020.Methods: Data for COPD mortality were derived from China National Mortality Surveillance System (NMSS). We analyzed the numbers and age-standardized rates of death and YLL due to COPD in China, during 2005– 2020. We carried out decomposition analysis to analyze the drivers of change in COPD deaths during the study period.Results: The age-standardized mortality rate of COPD in China decreased significantly from 99.5/100,000 in 2005 to 50.5/100,000 in 2020. Similar trend was seen in the age-standardized YLL rate. The mortality rate increased with age. During 2005– 2020, the age-standardized mortality rate decreased in all provinces (except for Tibet) with the largest decline in Jilin (− 77.8%), Henan (− 68.4%) and Fujian (− 67.1%). The decreased number of deaths was decomposed as population growth (8.5%) and population ageing (69.7%) with offset by decline of age-specific mortality (− 87.5%).Conclusion: COPD remains an important public health problem in China, though significant reductions of COPD mortality and YLL rate were observed. Vigorous prevention and control strategies should be enhanced to improve the quality of life of COPD patients and reduce the premature death caused by COPD in Chinese population.Keywords: COPD, mortality, YLL

Jiale Sun,1,&ast; Xuedong Wei,1,&ast; Jiawei You,1 Wenchang Yue,1 Jun Ouyang,1 Zhixin Ling,1 Jianquan Hou1,2 1Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Urology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhixin Ling; Jianquan HouDepartment of Urology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu, People’s Republic of ChinaEmail lzx986084954@126.com; hjqsdfyy@163.comBackground: Stanniocalcin-1 (STC1) is a well-studied oncogene that promotes different types of cancer progression. However, the expression status of STC1, the values of STC1 on prognosis, and its immune characteristic in bladder cancer (BLCA) have not been well examined.Methods: The expression of STC1 and its clinicopathological as well as immune characteristics in BLCA samples were firstly identified in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) performed on the tissue microarray (TMA) slide was further used to validate the expression of STC1 and its relationship with immune features in 16 non-muscle invasive bladder cancer (NMIBC) samples and 42 muscle invasive bladder cancer (MIBC) samples.Results: The expression of STC1 was upregulated in higher stage BLCA. High STC1 expression also predicted poor prognosis in BLCA. Subsequently, the TMA validated the expression and prognostic value of STC1 in BLCA. Bioinformatics analysis demonstrated that STC1 and common immune checkpoints as well as immune markers of various immune cells were positively correlated in TCGA. In addition, IHC data from the TMA further validated that tumor cells with higher STC1 level tended to express higher PDL1 as well as increased infiltration of CD3+ T cells.Conclusion: To our knowledge, this is the first comprehensive study that investigates the clinical and immune characteristics of STC1 in BLCA. It may provide new insight into the function of STC1 in regulating tumor immune microenvironment. Further studies are warranted to uncover the potential mechanisms that mediate STC1 expression and tumor immunity in BLCA.Keywords: STC1, bladder cancer, tissue microarray, immune characteristics, immune checkpoints

Jie Wang,1,2 Lina Yang,2 Jialing You,2 Dada Wen,2 Bo Yang,2 Canhua Jiang1 1Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, 410078, People’s Republic of China; 2Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, 410078, People’s Republic of ChinaCorrespondence: Canhua JiangDepartment of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410078, Hunan, People’s Republic of ChinaTel/Fax +86-731-89753046Email wj0988@csu.edu.cnObjective: To explore the effect of platelet-derived growth factor (PDGF) on oral mucosal fibroblast autophagy and further elucidate the molecular mechanism by which PDGF-BB regulates the biological behavior of oral mucosal fibroblasts by inducing autophagy.Methods: Primary oral mucosal fibroblasts were isolated and cultured by the tissue block and trypsin methods and identified by indirect immunofluorescence vimentin detection. We detected the autophagy marker Beclin-1 and fibrosis marker Col-I of the primary oral mucosal fibroblasts at different time points after stimulating the fibroblasts with different PDGF-BB concentrations by Western blotting and determined the best experimental concentration and stimulation time of PDGF-BB. Then, indirect immunofluorescence, Western blotting, and quantitative real-time polymerase chain reaction (PCR) were used to detect the effect of PDGF-BB on the expression of autophagy-related and fibrotic proteins before and after 3-methyladenine (3-MA) intervention. Additionally, the effect of 3-MA on the proliferation and migration of primary oral mucosal fibroblasts stimulated by PDGF-BB was detected by the MTT method and a scratch experiment. The effect of PDGF-BB on Beclin-1 and phosphatidylinositol-3 kinase class 3 (PI3KC3) interaction was detected by co-immunoprecipitation.Results: The results demonstrated that PDGF-BB could induce autophagy of the oral mucosal fibroblasts, showing a certain time and dose correlation. It induced cell autophagy through Beclin-1 and PI3KC3 interaction to promote the proliferation, migration, conversion, and collagen synthesis of the fibroblasts. However, 3-MA inhibited the combination of Beclin-1 and PI3KC3 and weakened the fibroblasts’ proliferation, migration, conversion, and collagen synthesis activities.Conclusion: Overall, PDGF-BB induces autophagy through the Beclin-1 pathway to regulate the biological behavior of oral mucosal fibroblasts.Keywords: PDGF-BB, primary oral mucosal fibroblasts, autophagy, 3-MA, biological behavior, signaling pathway

Li J, You J, Wu C, et al. Int J Nanomedicine. 2018;13:4607-4625. An error during the preparation of Figure S1 for publishing led to the inadvertent creation of a duplicate region in figure part S1B on page 4622. The journal wishes to apologise for this error. The correct version of Figure S1 is as follows. Figure S1 Transmission electron microscopy characterizations of Fe3O4 nanoparticles (NPs) (A) and Fe3O4@mSiO2 NPs (B). The insert in (A) is the distribution of Fe3O4 NP size.

Junning You,1 Xiaolin Wang2 1Department of Emergency, Xianyang Hosptial, Yan’an University, XianYang, Shaanxi, People’s Republic of China; 2Department of General Surgery, Yulin No.2 Hospital, Yulin, Shaanxi, People’s Republic of ChinaCorrespondence: Xiaolin Wang Tel +86-912-3362049Email fuguren11@126.comBackground: The incidence of cholangiocarcinoma (CCA) is on the rise in recent years, and its pathogenesis may be associated with the deregulation of circular RNAs (circRNAs). Hence, we aimed to investigate the role of circRNA homeodomain interacting protein kinase 3 (circ_HIPK3) in CCA.Methods: The expression of circ_HIPK3, miR-148a-3p and unc-51 like kinase 3 (ULK1) mRNA was detected using quantitative real-time polymerase chain reaction (qPCR). The role of circ_HIPK3 in cell proliferation was detected by 3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide (MTT) assay and colony formation assay. Cell apoptosis and cell cycle progression were investigated using flow cytometry assay. Cell migration and invasion were detected by transwell assay. The protein levels of ULK1 and migration/invasion-associated markers were measured using Western blot. The putative relationship between miR-148a-3p and circ_HIPK3 or ULK1 was validated by dual-luciferase reporter assay. The role of circ_HIPK3 was also investigated in vivo.Results: Circ_HIPK3 was overexpressed in CCA tissues and cells. In function, circ_HIPK3 knockdown inhibited CCA cell proliferation, migration and invasion and induced apoptosis and cycle arrest. It was confirmed that miR-148a-3p was a target of circ_HIPK3, and ULK1 was a target of miR-148a-3p. Circ_HIPK3 regulated ULK1 expression by targeting miR-148a-3p. Rescue experiments showed that miR-148a-3p inhibition reversed the effects of circ_HIPK3 knockdown. Besides, miR-148a-3p enrichment-blocked cell proliferation, migration and invasion were recovered by ULK1 overexpression. In vivo, circ_HIPK3 knockdown inhibited solid tumor growth.Conclusion: Circ_HIPK3 knockdown blocked CCA malignant development partly via regulating the miR-148a-3p/ULK1 pathway.Keywords: circ_HIPK3, miR-148a-3p, ULK1, cholangiocarcinoma

Jinghai Gao,* Jianhong Dang,* Jing Chu,* Xiaojun Liu, Jing Wang, Jiahao You, Zhijun Jin Department of Obstetrics and Gynecology, Shanghai ChangZheng Hospital, Naval Medical University, Shanghai, 200003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaojun LiuDepartment of Obstetrics and Gynecology, Shanghai ChangZheng Hospital, Naval Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai, 200003, People’s Republic of ChinaTel +8621-81885873Email liuxiaojun@smmu.edu.cnPurpose: To compare perioperative outcomes between robotic single-site surgical technique and conventional laparoendoscopic single-site surgical technique.Methods: This was a retrospective cohort study involving 67 patients who received robotic single-site surgery or laparoendoscopic single-site surgery for the treatment of stage IB1 cervical squamous carcinoma. The robotic single-site radical hysterectomy technique combined with pelvic lymph node dissections were performed in 32 patients while the laparoendoscopic single-site radical hysterectomy technique combined with pelvic lymph node dissections were performed in 35 patients.Results: The enrolled patients had been diagnosed with stage IB1 cervical squamous carcinoma. The perioperative outcomes were mean age (51.63± 8.32 years in the lymph node dissection (RSS group) and 53.14± 8.14 years in the lymph node dissection (LESS group), p=0.453); BMIs (23.76± 2.72 in the RSS group and 23.46± 2.28 in the LESS group, p=0.629); shorter operative times (223.56± 15.43 min in the RSS group and 248.61± 20.89 min in the LESS group, p< 0.01) and less estimated blood loss (217.25± 16.77 mL in the RSS group and 294.74± 24.00 mL in the LESS group, p< 0.01). None of the study participants exhibited postoperative pain. There were no statistically significant differences in the length of hospital stay (p=0.865), perioperative complications (p=0.602), duration of closure and removal of catheter (p=0.518) as well as in pathological diagnoses between the two groups.Conclusion: Robotic single-site surgery can be used in the treatment of early stage cervical cancer as it exhibits acceptable operative times and perioperative outcomes. This surgical technique is feasible and safe.Keywords: cervical squamous cancer, robotic single-site surgery, laparoendoscopic single-site surgery

Dan Xie,* Ying Xian,* Jingya You, Wen Xu, Min Fan, Xiaogang Bi, Kouxing Zhang Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kouxing ZhangDepartment of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-Sen University, 2693 Kaichuang Avenue, Guangzhou, 510530, People’s Republic of ChinaEmail zhkoux@mail.sysu.edu.cnIntroduction: Co-infection pneumonia with Mycobacterium abscessus (M. abscessus) and Pneumocystis jirovecii (P. jirovecii) is rarely reported in previously healthy patients without HIV infection. The diagnosis of pneumonia of M. abscessus and P. jirovecii remains challenging due to its nonspecific clinical presentation and the inadequate performance of conventional diagnostic methods.Case Report: We report the case of a 44-year-old previously healthy male transferred to our hospital in February 2020 with a 4-month history of productive cough and one month of intermittent fever. At local hospital, the metagenomic next-generation sequencing(mNGS) detected P. jirovecii sequences in blood; with the antifungal therapy (Caspofungin, trimethoprim–sulfamethoxazole [TMP-SMX] and methylprednisolone [MP]), the patient still had hypoxemia, cough and fever. Then he was transferred to our hospital, the mNGS of bronchoalveolar lavage fluid (BALF) detected the sequences of M. abscessus and P. jirovecii. CD4+ T-lymphocytopenia in the peripheral blood cells was presented and HIV serology was negative. Caspofungin, TMP-SMX, clindamycin and MP were used to treat P. jirovecii pneumonia (PJP). Moxifloxacin, imipenem cilastatin and linezolid were used to treat M. abscessus infection. Clinical progress was satisfactory following antifungal combined with anti-M. abscessus therapy.Conclusion: Co-infection pneumonia with M. abscessus and P. jirovecii as reported here is exceptionally rare. mNGS is a powerful tool for pathogen detection. M. abscessus infection could be a risk factor for P. jirovecii infection. This case report supports the value of mNGS in diagnosing of M. abscessus and P. jirovecii, and highlights the inadequacies of conventional diagnostic methods.Keywords: Pneumocystis jiroveci, Mycobacterium abscessus, mNGS, co-infection, HIV negative

Yanjun Mi,1,* Yongwen Li,2,* Zhuo He,3,* Donghan Chen,2 Qingqi Hong,2 Jun You2 1Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, 361003, People’s Republic of China; 2Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Fujian Province, 361003, People’s Republic of China; 3Department of Gastropancreatoduodenal Surgery, Hunan Cancer Hospital, Changsha, Hunan Province, 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun YouDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, No. 55 Zhenhai Road, Si Ming District, Xiamen, Fujian Province, 361003, People’s Republic of ChinaTel +86 13906051681Email youjun1681@163.comBackground: Linc-ROR is a long non-coding RNA, that is found aberrantly expressed in various human cancers. We aim here to unveil the role of Linc-ROR in gastric cancer (GC) progression.Methods: qPCR was used to determine gene expression. Cell viability was measured by CCK-8 assay. Transwell assays were performed to evaluate the GC cells’ migratory and invasive abilities. Xenograft mouse model was conducted to measure tumor growth.Results: We found that Linc-ROR were overexpressed in GC tissues compared to the adjacent tissues. High Linc-ROR predicts poor prognosis of GC patients. The prediction of bioinformatics online revealed that Linc-ROR could bind to miR-212-3p. Further, dual-luciferase reporter assay confirmed a direct interaction between Linc-ROR and miR-212-3p. Overexpression of miR-212-3p facilitated GC cells’ migration and invasion, while the silencing of miR-212-3p attenuated GC cell migratory and invasive abilities. Moreover, Linc-ROR knockdown significantly suppressed the proliferation, migration, and invasion of GC cells, whereas miR-212-3p antagomir partially reversed Linc-ROR knockdown-induced phenotypes. Fibroblast growth factor 7 (FGF7), a downstream molecule of miR-212-3p, was overexpressed in GC cells. The recovery of FGF7 expression partially reversed the phenotypes caused by Linc-ROR silencing. Mechanistically, silencing of Linc-ROR contributed to the downregulation of CDK4, CDK6, Cyclin D1, N-Cadherin, Vimentin, MMP-9, MMP-2, but caused the upregulation of P21, P27, E-Cadherin, CK-19 in MGC-803 cells; however, FGF7 treatment could reverse the results induced by Linc-ROR silencing. Results in vivo further suggested that Linc-ROR knockdown repressed GC tumor growth, where the expression of miR-212-3p was up-regulated and FGF7 expression was downregulated in tumor tissues of mice.Conclusion: These findings indicated that Linc-ROR/miR-212-3p/FGF7 axis played an important role in gastric cancer progression. Linc-ROR expression level was associated with the prognosis of GC patients.Keywords: Linc-ROR, miR-212-3p, FGF7, gastric cancer

Dongjiu Li,1,* Chengyu Mao,1,* En Zhou,1,* Jiayin You,2,* Erhe Gao,3 Zhihua Han,1 Yuqi Fan,1 Qing He,1 Changqian Wang1 1Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 2Department of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 3Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA*These authors contributed equally to this workCorrespondence: Changqian Wang Email wangcqdr17@163.comObjective: Post myocardial infarction (MI) fibrosis has been identified as an important factor in the progression of heart failure. Previous studies have revealed that microRNA-21 (miR-21) plays an important role in the pathogenesis of fibrosis. The purpose of this study was to explore the role of miR-21 in post-MI cardiac fibrosis.Material and Methods: MI was established in wild-type (WT) and miR-21 knockout (KO) mice. Primary mice cardiac fibroblasts (CFs) were isolated from WT and miR-21 KO mice and were treated with angiotensin II (Ang II) or Sprouty1 (Spry1) siRNA. Histological analysis and echocardiography were used to determine the extent of fibrosis and cardiac function.Results: Compared with WT mice, miR-21 KO mice displayed smaller fibrotic areas and decreased expression of fibrotic markers and inflammatory cytokines. In parallel, Ang II-induced myofibroblasts transformation was partially inhibited upon miR-21 KO in primary CFs. Mechanistically, we found that the expression of Spry1, a previously reported target of miR-21, was markedly increased in miR-21 KO mice post MI, further inhibiting ERK1/2 activation. In vitro studies showed that Ang II activated ERK1/2/TGF-β/Smad2/3 pathway. Phosphorylated Smad2/3 further enhanced the expression of α-SMA and FAP and may promote the maturation of miR-21, thereby downregulating Spry1. Additionally, these effects of miR-21 KO on fibrosis were reversed by siRNA-mediated knockdown of Spry1.Conclusion: Our findings suggest that miR-21 promotes post-MI fibrosis by targeting Spry1. Furthermore, it mediates a positive feedback on Ang II, thereby inducing the ERK/TGF-β/Smad pathway. Therefore, targeting the miR-21–Spry1 axis may be a promising therapeutic option for ameliorating post-MI cardiac fibrosis.Keywords: cardiac fibrosis, myocardial infarction, microRNA-21, Sprouty1, ERK/TGF-β/Smad signaling pathway

Jingjing You,1,2 Chris Hodge,1,3– 5 Monira Hoque,4 Constantinos Petsoglou,1,4 Gerard Sutton1,3,4 1Save Sight Institute, Sydney Medical School, University of Sydney, Sydney, NSW, Australia; 2School of Optometry and Vision Science, UNSW Sydney, Sydney, NSW, Australia; 3Vision Eye Institute, Chatswood, Sydney, NSW, Australia; 4NSW Tissue Bank, Sydney, NSW, Australia; 5Graduate School of Health, University of Technology Sydney, Sydney, NSW, AustraliaCorrespondence: Jingjing YouSave Sight Institute, Sydney Medical School, University of Sydney, 8 Macquarie Street, Sydney 2001, AustraliaEmail jing.you@sydney.edu.auAbstract: Human platelet products have emerged as an alternative treatment for a range of ocular surface diseases such as dry eye and corneal ulceration. With significant therapeutic potential and increasing popularity, this study aimed to conduct a systematic review to detail the various production methods involved in generating platelet-derived products, compare and analyze clinical findings across available studies, and disseminate the relative advantages, limitations, and challenges of using platelet products to treat ocular surface disease. Thirty-eight clinical studies were identified, excluding studies conducted in animals and non-English language. Studies reported clinical outcomes, which included ocular surface disease index, best-corrected visual acuity, and corneal fluorescein staining. Most clinical studies reported improved patient signs and symptoms with an increasing variety of human platelet products including platelet rich plasma eye drops, human platelet lysate and platelet gels. However, due to variations in production methods, and study designs as well as confusing terminology, it was suggested that characterization of platelet products is needed for proper evaluation across studies.Keywords: platelet rich plasma, human platelet lysate, dry eye syndrome

Hexin Lin,1,2,* Jiabian Lian,3,4,* Lu Xia,4,5,* Guoxian Guan,2 Jun You1,4 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China; 2Department of Colorectal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 3Department of Laboratory Medicine, Xiamen Key Laboratory of Genetic Testing, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China; 4School of Clinical Medicine, Fujian Medical University, Fuzhou, People’s Republic of China; 5Laboratory of Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun YouDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, 55 Zhenhai Road, Xiamen, Fujian 361000, People’s Republic of ChinaTel +86-13906051681Email junyou_fahxm@163.comBackground: Chromobox 3 (CBX3) is a member of the chromobox family proteins, which plays a critical role in tumor progression, but the exact function of CBX3 in gastric cancer remains unknown. The current research mainly investigates the underlying mechanisms and clinical value of CBX3 in gastric cancer.Methods: Gene expression cohorts from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed to assess the effect of CBX3 in gastric cancer. CBX3 expression was further determined by immunohistochemistry (IHC). The function of CBX3 on proliferation, migration and the cell cycle was explored via colony-forming, cell cycle and transwell assays, respectively. Moreover, RNA sequencing (RNA-seq) in AGS cells and two cohorts was utilized to explore the specific mechanism of CBX3.Results: CBX3 expression was upregulated in human gastric cancer tissues and the expression level was closely associated with adverse signs. Knockdown of CBX3 in gastric cancer cells significantly inhibited the malignant phenotype. In addition, RNA-seq analysis revealed that CBX3 regulates genes related to the cell cycle, mismatch repair and immune-related pathways. Furthermore, the expression of CBX3 was significantly and inversely related to the abundance of tumor-infiltrating lymphocytes (TILs), PDCD1 and PDCD1LG2 expression and immunotherapy responses. Moreover, CBX3 influences the effectiveness of chemotherapy, thereby impacting the prognosis of gastric cancer patients.Conclusion: CBX3 contributes to gastric cancer progression and is associated with chemotherapy and immunotherapy response. CBX3 may serve as a new diagnostic biomarker and potential target for immunotherapy and chemotherapy in gastric cancer.Keywords: chromobox 3, gastric cancer, tumorigenesis, survival, chemotherapy, immunotherapy

You J, Wang X. Cancer Manag Res. 2021;13:3827–3839. At the authors request, the Editor and Publisher of Cancer Management and Research wish to retract the published article. The authors have informed the journal that they are unable to provide the original data for the study and are unable to verify the findings after failing to reproduce the results. The Editor agreed with the decision to retract. 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”. This retraction relates to this paper

Yunli Shen,1,* Shiyu Gong,1,* Jiming Li,1,* Yunkai Wang,1 Xumin Zhang,1 Hao Zheng,1 Qi Zhang,1 Jieyun You,1 Zheyong Huang,2 Yihan Chen11Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, People’s Republic of China; 2Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workPurpose: Myocardial delivery of magnetic iron oxide nanoparticles (MNPs) might produce iron overload-induced myocardial injury, and the oxidative stress was regarded as the main mechanism. Therefore, we speculated antioxidant modification might be a reasonable strategy to mitigate the toxicity of MNPs.Methods and results: Antioxidant N-acetylcysteine (NAC) was loaded into magnetic mesoporous silica coated Fe3O4 nanoparticles. Neonatal rat hypoxia/reoxygenation (H/R) cardiomyocytes were incubated with nanoparticles for 24 hrs. NAC can effectively mitigate iron-induced oxidative injury of cardiomyocytes, evidenced by reduced production of MDA, 8-iso-PGF2α, and 8-OHDG and maintained concentrations of SOD, CAT, GSH-Px, and GSH in ELISA and biochemical tests; downregulated expression of CHOP, GRP78, p62, and LC3-II proteins in Western Blot, and less cardiomyocytes apoptosis in flow cytometric analysis.Conclusions: NAC modifying could suppress the toxic effects of Fe3O4 nanoparticles in H/R cardiomyocytes model in vitro, indicating a promising strategy to improve the safety of iron oxide nanoparticles.Keywords: N-acetylcysteine (NAC), iron oxide nanoparticles, oxidative stress, cardiomyocytes, hypoxia-reoxygenation

Xiangkun Yuan1,*, Yongxia Zhang1,*, Mangmang Cui,1 Junjun Miao,1 Lei Gao,1 Jianwei Hu,1 Dandan Tian,1 Jinqiang You21Department of Radiation Oncology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, Hebei, People’s Republic of China; 2Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, People’s Republic of China*These authors contributed equally to this work Objective: This study aimed to investigate the dosimetry difference between a 3D printed minimally invasive guidance template and conventional free implantation in brachytherapy of postoperative recurrent cervical carcinoma under the guidance of computed tomography (CT).Methods: A total of 21 cases of patients with recurrent cervical cancer after operation were enrolled from January 2017 to June 2018. After external irradiation treatment in 1.8-Gy fractions to 45 Gy, patients were randomly divided into two groups to receive brachytherapy: 11 cases were assisted by a 3D-printed minimally invasive guidance template, and the other 10 cases were free implantation. In the template group, needles were inserted according to the main guide channel of the template commissioned in medical photosensitive resin, while patients in the other group were treated with bare hands under the guidance of CT, which was used in both groups to adjust the position and depth of the implant needles. After transmission of the CT images into the Oncentra® Brachy TPS system, the target organs and organs at risk were delineated for further treatment.Results: The D90 value of the high-risk clinical target volume in the template group was 6.30±0.21 Gy while that in the other group was 6.07±0.32 Gy (P

Xingwang Liu,1,2,* Chen Chen,3,* Hangzhou Zhang,4 Ang Tian,5 Junhua You,6 Lin Wu,7 Zeming Lei,8 Xi Li,8 Xizhuang Bai,8 Shiyi Chen1 1Department of Sports Medicine, Huashan Hospital of Fudan University, Shanghai 200040, China; 2State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200082, China; 3Department of Arthroscopic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China; 4Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital of China Medical University, Shenyang 110000, China; 5Liaoning Provincial Key Laboratory of Metallurgical Resources Circulation Science, Northeastern University, Shenyang 110819, China; 6School of Materials Science and Engineering, Shenyang University of Technology, Shenyang 110870, China; 7Department of Prosthodontics, School of Stomatology, China Medical University, Shenyang 110000, China; 8Department of Orthopaedics, The People’s Hospital of China Medical University, Shenyang 110000, China *These authors contributed equally to this work Background: Implant-related infection is a major problem postsurgery. As an alternative to a localized antibiotic release system, we used Ag to fabricate Ti–Ag alloys with nanotubular coatings (TiAg-NTs). Ag has excellent antibacterial properties, but its biological toxicity is a concern. Therefore, we performed biological experiments both in vitro and in vivo to evaluate the biocompatibility of TiAg-NTs with different concentrations of Ag (1%, 2%, and 4%). Methods: For in vitro experiments, cytocompatibility, including cell attachment, viability, and proliferation, was tested, and genes and proteins related to osteogenic differentiation were also evaluated. For in vivo assays, the rat femoral condylar insertion model was used, and micro-computed tomography (micro-CT) and histological analysis were conducted to analyze bone formation around implants at 1, 2, and 4 weeks after surgery. Results: Both in vitro and in vivo results indicate that Ti2%Ag-NT showed comparable cytocompatibility with commercially pure Ti (cp-Ti), and it could achieve good osseointegration with the surrounding bone tissue. Conclusion: We thus believe that Ti2%Ag-NT is a potential biomaterial for orthopedics. Keywords: Ag, Ti, alloy, nanotube, biocompatibility

Jingjing Li,1,2,* Jia You,2,3,* Chen Wu,2 Yue Dai,1 Meilin Shi,2 Lina Dong,2 Kai Xu1,2 1Department of Radiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, People’s Republic of China; 2School of Medical Imaging, Xuzhou Medical University, Xuzhou 221004, People’s Republic of China; 3Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People’s Republic of China *These authors contributed equally to this work Background: The development of T1–T2 dual contrast agent (CA) favors the visualization of the lesion in a more accurate and reliable manner by magnetic resonance imaging (MRI). The relaxivity and the interference between T1 and T2 CA are the main concerns for their design. Methods: In this work, we constructed an Fe3O4@mSiO2/PDDA/BSA-Gd2O3 nanocomplex where BSA-Gd2O3 NPs and Fe3O4 NPs were chosen as T1 and T2 MRI CAs and a 20 nm mesoporous silica (mSiO2) nanoshell was introduced to reduce the interference between them. We performed transmis­sion electron microscopy, X-ray powder diffraction, UV-vis absorption spectra, and Fourier transform infrared absorption (FTIR) spectra to characterize the prepared nanocomplex and MRI scanning to evaluate their MRI behaviors. Furthermore, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and hematologic and biochemical analyses were introduced to evaluate their in vitro and in vivo toxicity. Finally, the specific MRI of 786-0 cells with Fe3O4@mSiO2/PDDA/BSA-Gd2O3-AS1411 nanoprobe in vitro was realized. In vivo biodistribution of Fe3O4@mSiO2/PDDA/BSA-Gd2O3 nanocomplex in the mouse was determined by the quantification of the Gd element by inductively coupled plasma-mass spectrometry. Results: The prepared Fe3O4@mSiO2/PDDA/BSA-Gd2O3 nanocomplex possessed high longitudinal (r1=11.47 mM s-1 Gd) and transverse (r2=195.1 mM s-1 Fe) relaxivities, enabling its use as a T1–T2 dual contrast agent for MRI. MTT testing and hematologic and biochemical analysis indicated the good biocompatibility of Fe3O4@mSiO2/PDDA/BSA-Gd2O3 nanocomplex in vitro and in vivo. After further conjugation with AS1411 aptamer, they could target tumor cells successfully by T1 and T2 MRI in vitro. The possible metabolic pathway of the tail vein-injected Fe3O4@mSiO2/PDDA/BSA-Gd2O3 nanocomplex in mouse was mainly via kidney. Conclusion: A T1–T2 dual-mode contrast agent, Fe3O4@mSiO2/PDDA/BSA-Gd2O3 nanocomplex, was developed and its good performance for tumor cell targeting in vitro and kidney contrast-enhanced MRI in mice indicated its promising potential as an effective T1–T2 dual-mode contrast agent for in vivo MRI with self-confirmation. Keywords: molecular magnetic resonance imaging, nano-contrast agent, aptamer, T1–T2, MRI

Wei Chen, Jia You, Qi Zheng, Yue-Yong Zhu Center for Liver Diseases, The First Affiliated Hospital, Fujian Medicine University, Fuzhou 350005, Fujian Province, China Introduction: Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) play important roles in the progression of hepatocellular carcinoma (HCC) by regulating gene expression. However, the identification of functional lncRNAs in HCC remains insufficient. Our study aimed to investigate the function of lncRNA OGFRP1, which has not been functionally researched before, in Hep3B and HepG2 cells. Methods: lncRNA OGFRP1 in HCC cells was down-regulated by using RNAi technology. Quantitative real-time polymerase chain reaction was used to determine the mRNA expression of lncRNA OGFRP1. Cell proliferation was examined by CCK8 and clone formation assays. Cell cycle and apoptosis were analyzed by flow cytometry. Cell migration and invasion were assessed by using Scratch assay and transwell assay, respectively. Protein expression of signaling pathways was determined by using Western blot. Results: Cell proliferation of Hep3B was significantly inhibited by down-regulation of lncRNA OGFRP1 (P

Ying Li,1,2 Meng Wang,1,2 Bu-Wei Huang,1,2 Yuan Ping,3 Jian You,1 Jian-Qing Gao1,2 1Institute of Pharmaceutics, College of Pharmaceutical Sciences, 2Zhejiang Province Key Laboratory of Anticancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of China; 3School of Materials Science and Engineering, Nanyang Technological University, Singapore Abstract: Although widely used in chemotherapy, free doxorubicin (Dox) might enhance cell malignancy undesirably. Liposomal Dox (Doxlipo) has been clinically approved for the treatment of breast cancer due to reduced systematical toxicity and increased tumor targeting, yet the transcriptome-wide elucidation of the Doxlipo formulations remains elusive. To this end, we explored the impact of two Dox liposomal formulations, Doxlipo mainly containing hydrogenated soy phosphatidylcholine or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, on the transcriptional pattern of MCF-7 cells. The two types of Dox liposomal formulations with different drug release kinetics were investigated to reveal the relationship between the formulation and tumor malignancy. Interestingly, we found that liposomal formulation significantly altered the transcriptional pattern of a wide range of genes. Under equivalent dosage of Dox, free Dox substantially changed the expression of ANK1, ACTA2, GPR87, GDF15, FZD6, and WNT4 in MCF-7 cells. Notably, free Dox induced much higher expression of ABCB1 and significantly enhanced the cell migration behavior in comparison with HSPC Doxlipo under a similar level of cytotoxicity. Finally, siRNA targeting GPR87 was codelivered with cationic Doxlipo to reduce the expression of malignancy-related genes. Our study, for the first time, provides an overview of the influence of formulation on the malignancy at transcriptional level and reveals the relationship between cytotoxicity and cell malignancy from the formulation aspect, offering valuable reference for the future formulation design for anticancer drug delivery. Keywords: liposomes, doxorubicin, cellular uptake, cell malignancy, transcriptional profiling

Huiying Xue,1 Zhaoyang Yu,1 Yong Liu,1 Weigang Yuan,1 Tan Yang,1 Jia You,1 Xingxing He,2 Robert J Lee,3 Lei Li,1 Chuanrui Xu1 1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 2Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 3Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA Abstract: Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been shown that miR-375 inhibits P-gp expression via inhibition of astrocyte elevated gene-1 (AEG-1) expression in HCC, and induces apoptosis in HCC cells by targeting AEG-1 and YAP1. In this study, we prepared lipid-coated hollow mesoporous silica nanoparticles (LH) containing doxorubicin hydrochloride (DOX) and miR-375 (LHD/miR-375) to deliver the two agents into MDR HCC cells in vitro and in vivo. We found that LHD/miR-375 overcame drug efflux and delivered miR-375 and DOX into MDR HepG2/ADR cells or HCC tissues. MiR-375 delivered by LHD/miR-375 was taken up through phagocytosis and clathrin- and caveolae-mediated endocytosis. Following release from late endosomes, it repressed the expression of P-gp in HepG2/ADR cells. The synergistic effects of miR-375 and hollow mesoporous silica nanoparticles (HMSN) resulted in a profound increase in the uptake of DOX by the HCC cells and prevented HCC cell growth. Enhanced antitumor effects of LHD/miR-375 were also validated in HCC xenografts and primary tumors; however, no significant toxicity was observed. Mechanistic studies also revealed that miR-375 and DOX exerted a synergistic antitumor effect by promoting apoptosis. Our study illustrates that delivery of miR-375 using HMSN is a feasible approach to circumvent MDR in the management of HCC. It, therefore, merits further development for potential clinical application. Keywords: hollow mesoporous silica nanoparticle, doxorubicin, miR-375, AEG-1, hepatocellular carcinoma, multidrug resistance

Fei Gao,1–3 Jinming Zhang,3 Chaomei Fu,3 Xiaoming Xie,4 Fu Peng,1–3 Jieshu You,1,2 Hailin Tang,1,2,4 Zhiyu Wang,5 Peng Li,6 Jianping Chen1–3 1School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, 2Shenzhen Institute of Research and Innovation, University of Hong Kong, Shenzhen, 3College of Pharmacy, Chengdu University of Chinese Medicine, Chengdu, 4Department of Breast Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 5Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 6State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China Abstract: Isoliquiritigenin (ISL), a natural anti-breast cancer dietary compound, has poor delivery characteristics and low bioavailability. In order to promote the therapeutic outcome of ISL, a tumor-targeting lipid–polymer hybrid nanoparticle (NP) system modified by tumor-homing iRGD peptides has been developed. The hybrid NPs were prepared by a modified single-step nanoprecipitation method to encapsulate ISL. iRGD peptides were anchored on the surface by a postinsertion method (ISL-iRGD NPs). The stable lipid–polymer structure of ISL-iRGD NPs, with high encapsulation and loading efficiency, was confirmed. Compared to free ISL and non-iRGD-modified counterparts, ISL-iRGD NPs showed higher cytotoxicity and cell apoptosis against the different type of breast cancer cells. This was attributable to higher cellular accumulation mediated by the iRGD-integrin recognition and the nanoscale effect. More importantly, based on the active tumor-tissue accumulation by iRGD peptides and the prolonged in vivo circulation by the stealth nanostructure, ISL-iRGD NPs displayed higher tumor-growth inhibition efficiency in 4T1-bearing breast-tumor mouse models. Therefore, the constructed iRGD modified lipid–polymer hybrid NPs would provide a promising drug-delivery strategy to improve ISL in anti-breast cancer efficacy. Keywords: isoliquiritigenin, iRGD, lipid–polymer hybrid NPs, breast cancer

Xingwang Liu,1 Ang Tian,2 Junhua You,3 Hangzhou Zhang,4 Lin Wu,5 Xizhuang Bai,1 Zeming Lei,1 Xiaoguo Shi,2 Xiangxin Xue,2 Hanning Wang4 1Department of Orthopedics, The People’s Hospital of China Medical University, 2Liaoning Provincial Universities Key Laboratory of Boron Resource Ecological Utilization Technology and Boron Materials, Northeastern University, 3School of Materials Science and Engineering, Shenyang University of Technology, 4Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital of China Medical University, 5Department of Prosthodontics, School of Stomatology, China Medical University, Shenyang, People’s Republic of China Purpose: To endow implants with both short- and long-term antibacterial activities without impairing their biocompatibility, novel Ti–Ag alloy substrates with different proportions of Ag (1, 2, and 4 wt% Ag) were generated with nanotubular coverings (TiAg-NT). Methods: Unlike commercial pure Ti and titania nanotube, the TiAg-NT samples exhibited short-term antibacterial activity against Staphylococcus aureus (S. aureus), as confirmed by scanning electron microscopy and double staining with SYTO 9 and propidium iodide. A film applicator coating assay and a zone of inhibition assay were performed to investigate the long-term antibacterial activities of the samples. The cellular viability and cytotoxicity were evaluated through a Cell Counting Kit-8 assay. Annexin V-FITC/propidium iodide double staining was used to assess the level of MG63 cell apoptosis on each sample. Results: All of the TiAg-NT samples, particularly the nanotube-coated Ti–Ag alloy with 2 wt% Ag (Ti2%Ag-NT), could effectively inhibit bacterial adhesion and kill the majority of adhered S. aureus on the first day of culture. Additionally, the excellent antibacterial abilities exhibited by the TiAg-NT samples were sustained for at least 30 days. Although Ti2%Ag-NT had less biocompatibility than titania nanotube, its performance was satisfactory, as demonstrated by the higher cellular viability and lower cell apoptosis rate obtained with it compared with those achieved with commercial pure Ti. The Ti1%Ag-NT and Ti4%Ag-NT samples did not yield good cell viability. Conclusion: This study indicates that the TiAg-NT samples can prevent biofilm formation and maintain their antibacterial ability for at least 1 month. Ti2%Ag-NT exhibited better antibacterial ability and biocompatibility than commercial pure Ti, which could be attributed to the synergistic effect of the presence of Ag (2 wt%) and the morphology of the nanotubes. Ti2%Ag-NT may offer a potential implant material that is capable of preventing implant-related infection. Keywords: titanium, silver, nanotube, antibacterial, biocompatibility

Jing Li,1,2,* Sawitri Assanangkornchai,1,* Lin Lu,3 Manhong Jia,3,* Edward B McNeil,1,* Jing You,4,* Virasakdi Chongsuvivatwong1,* 1Epidemiology Unit, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand; 2School of Public Health, Kunming Medical University, 3Yunnan Center for Disease Prevention and Control, 4Infectious Diseases Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, People’s Republic of China *These authors contributed equally to this work Background: HIV/AIDS-related stigma is a major barrier of access to care for those infected with HIV. The aim of this study was to examine, validate, and adapt measuring scales of internalized, personal, and occupational stigma developed in Africa into a Chinese context. Methods: A cross-sectional study was conducted from January to September 2015 in Kunming, People’s Republic of China. Various scales were constructed on the basis of the previous studies with modifications by experts using exploratory and confirmatory factor analyses (EFA + CFA). Validation of the new scales was done using multiple linear regression models and hypothesis testing of the factorial structure invariance. Results: The numbers of subjects recruited for the development/validation samples were 696/667 HIV-positive patients, 699/667 non-HIV patients, and 157/155 health care providers. EFA revealed a two-factor solution for internalized and personal stigma scales (guilt/blaming and being refused/refusing service), which were confirmed by CFA with reliability coefficients (r) of 0.869 and 0.853, respectively. The occupational stigma scale was found to have a three-factor structure (blaming, professionalism, and egalitarianism) with a reliability coefficient (r) of 0.839. Higher correlations of factors in the HIV patients (r=0.537) and non-HIV patients (r=0.703) were observed in contrast to low-level correlations (r=0.231, 0.286, and 0.266) among factors from health care providers. Conclusion: The new stigma scales are valid and should be used to monitor HIV/AIDS stigma in different groups of Chinese people in health care settings. Keywords: HIV/AIDS-related stigma, exploratory factor analysis, confirmatory factor analysis, guilt, blaming, being refused, refusing service

Xue H, Yu Z, Liu Y, et al. Int J Nanomedicine.2017;12:5271–5287. The authors of this paper have advised that Figure 8E is incorrect. Because of the similar label of groups LHD/miR-375 and LH/miR-375, the authors uploaded the wrong figure by mistake. The authors have confirmed this correction will not make any change to the conclusion of their original research. Read the original article

Jun-Qing Situ,1 Yi-Qing Ye,2 Xiu-Liang Zhu,3 Ri-Sheng Yu,3 Jian You,1 Hong Yuan,1 Fu-Qiang Hu,1 Yong-Zhong Du11College of Pharmaceutical Sciences, 2Women’s Hospital, 3Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaAbstract: The delivery of chemotherapeutics into tumor cells is a fundamental knot for tumor-target therapy to improve the curative effect and avoid side effects. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA self-assembled to form micelles with a low critical micelle concentration of 16.79 µg·mL-1 and diameter of about 50 nm. With doxorubicin (DOX) base as a model antitumor drug, the drug-encapsulation efficiency of DOX-loaded A54-Dex-PLGA micelles (A54-Dex-PLGA/DOX) reached up to 75%. In vitro DOX release from the A54-Dex-PLGA/DOX was prolonged to 72 hours. The A54-Dex-PLGA micelles presented excellent internalization ability into hepatoma cells (BEL-7402 cell line and HepG2 cell line) in vitro, and the cellular uptake of the micelles by the BEL-7402 cell line was specific, which was demonstrated by the blocking experiment. In vitro antitumor activity studies confirmed that A54-Dex-PLGA/DOX micelles suppressed tumor-cell (BEL-7402 cell) growth more effectively than Dex-PLGA micelles. Furthermore, in vivo biodistribution testing demonstrated that the A54-Dex-PLGA micelles had a higher distribution ability to BEL-7402 tumors than that to HepG2 tumors.Keywords: homing peptide, polymeric micelles, doxorubicin, tumor-cell targeting

Feng-Ying Chen,1 Jing-Jing Yan,1 Han-Xi Yi,2 Fu-Qiang Hu,2 Yong-Zhong Du,2 Hong Yuan,2 Jian You,2 Meng-Dan Zhao1 1Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang University, Hangzhou, People’s Republic of China Abstract: Nowadays, a real challenge in cancer therapy is to design drug delivery systems that can achieve high concentrations of drugs at the target site for improved therapeutic effect with reduced side effects. In this research, we designed and synthesized a homing peptide-(TNYLFSPNGPIA, TNYL) modified chitosan-g-stearate (CS) polymer micelle (named T-CS) for targeting delivery. The peptide displayed specific binding affinity to EphB4 which is a member of the Eph family of receptor tyrosine protein kinases. The amphiphilic polymer T-CS can gather into micelles by themselves in an aqueous environment with a low critical micelle concentration value (91.2 µg/L) and nano-scaled size (82.1±2.8 nm). The drug encapsulation efficiency reached 86.43% after loading the hydrophobic drug doxorubicin (DOX). The cytotoxicity of T-CS/DOX against SKOV3 cells was enhanced by approximately 2.3-fold when compared with CS/DOX. The quantitative and qualitative analysis for cellular uptake indicated that TNYL modification can markedly increase cellular internalization in the EphB4-overexpressing SKOV3 cell line, especially with a short incubation time. It is interesting that relatively higher uptake of the T-CS/DOX micelles by SKOV3 cells (positive-EphB4) than A549 cells (negative-EphB4) was observed when the two cells were co-incubated. Furthermore, in vivo distribution experiment using a bilateral-tumor model showed that there was more fluorescence accumulation in the SKOV3 tumor than in the A549 tumor over the whole experiment. These results suggest that TNYL-modified CS micelles may be promising drug carriers as targeting therapy for the EphB4-overexpressing tumor. Keywords: chitosan-g-stearate, polymeric micelles, TNYL, active targeting, antitumor activity

Jing-Jing Yao, Yong-Zhong Du, Hong Yuan, Jian You, Fu-Qiang HuCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of ChinaAbstract: Cis-aconitate-modified chitosan-g-stearic acid (CA-CSO-SA) micelles were ­synthesized in this study to improve the gene transfection efficiency of chitosan-g-stearic acid (CSO-SA). The CA-CSO-SA micelles had a similar size, critical micelle concentration, and ­morphology, but their zeta potential and cytotoxicity were reduced compared with CSO-SA micelles. After modification with cis-aconitate, the CA-CSO-SA micelles could also compact plasmid DNA (pDNA) to form nanocomplexes. However, the DNA binding ability of CA-CSO-SA was slightly reduced compared with that of CSO-SA. The transfection efficiency mediated by CA-CSO-SA/pDNA against HEK-293 cells reached up to 37%, and was much higher than that of CSO-SA/pDNA (16%). Although the cis-aconitate modification reduced cellular uptake kinetics in the initial stages, the total amount of cellular uptake tended to be the same after 24 hours of incubation. An endocytosis inhibition experiment showed that the internalization mechanism of CA-CSO-SA/pDNA in HEK-293 cells was mainly via clathrin-mediated endocytosis, as well as caveolae-mediated endocytosis and macropinocytosis. Observation of intracellular trafficking indicated that the CSO-SA/pDNA complexes were trapped in endolysosomes, but CA-CSO-SA/pDNA was more widely distributed in the cytosol. This study suggests that modification with cis-aconitate improves the transfection efficiency of CSO-SA/pDNA.Keywords: chitosan-g-stearic acid, cis-aconitate, micelles, transfection efficiency, intracellular trafficking

Yong Zhang,1,2 Lesai Li,3 Jiliang You,2 Jianguo Cao,2 Xiaohua Fu2 1Department of Hematology, Xiangya Hospital, Central South University, Changsha, People's Republic of China; 2College of Medicine, Hunan Normal University, Changsha, People's Republic of China; 3Department of Gynecologic Oncology, Tumor Hospital Xiangya School of Medicine of Central South University, Changsha, People's Republic of China Purpose: 7-Difluoromethyl-5, 4΄-dimethoxygenistein (DFMG), prepared by the difluoromethylation and alkylation of Genistein, is an active new chemical entity. Its anti-atherosclerosis effect was found in a series of studies in vitro. In this article, we explored and evaluated the anti-atherosclerosis effect via its protection of endothelial function in ApoE-/- mice that were fed a high-fat diet. Methods: Five C57BL/6J mice were selected as a control group and were fed a 1% high-fat diet (control group, n = 5). Five ApoE-/- mice that were fed a high-fat diet for 16 weeks were selected as the atherosclerosis model group (model group, n = 5). In the phase I study, 25 ApoE-/- mice were provided a prophylactic treatment with different drugs at the beginning of the 16 week high-fat diet: 5 mg/gk genistein (genistein 1 group, n = 5), 5 mg/kg lovastatin (lovastatin1 group, n = 5), 2.5 mg/kg DFMG (DFMG L1 group, n = 5), 5 mg/kg DFMG (DFMG M1 group, n = 5), and 10 mg/kg DFMG (DFMG H1 group, n = 5). In the phase II study, 25 atherosclerosis model, ApoE-/- mice were treated with different drugs and fed a high-fat diet for 16 weeks: 5 mg/gk genistein (genistein 2 group, n = 5), 5 mg/kg lovastatin (lovastatin 2 group, n = 5), 2.5 mg/kg DFMG (DFMG L2 group, n = 5), 5 mg/kg DFMG (DFMG M2 group, n = 5), and 10 mg/kg DFMG (DFMG H2 group, n = 5). The plasma levels of lipids, von Willebrand factor (vWF), and nitrite were compared between phases I and II. Endothelium-dependent relaxation (EDR), aortic lesion development, and quantification in thoracic aortas were measured during these two phase studies. Results: Compared to the model group, the lipid and vWF plasma levels were significantly lower, the plasma nitrite levels were significantly higher, the fatty streaks of aortic lesions were significantly lower, and the endothelium dependent relaxation was significantly higher after both phase studies (P < 0.05). The DFMG supplementation led to significant plasma nitrite increment in all groups after both phase studies (P < 0.05).There were significantly decreased fatty streaks of aortic lesions in DFMG-prevented and DFMG-treated mice (P < 0.05). There was a significant increase in EDR in all prophylactic treatment groups and treatment groups (P < 0.05). We further demonstrated that the preventative effect was more obvious than the therapeutic effect. Conclusion: Our results suggest that DFMG could work in prophylactic and therapeutic treatments for atherosclerosis development. Keywords: 7-Difluoromethyl-5, 4΄-dimethoxygenistein (DFMG), atherosclerosis, ApoE-/- mice, endothelium dysfunction, prevention

Hong Yuan, Xin Bao, Yong-Zhong Du, Jian You, Fu-Qiang HuCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR ChinaPurpose: Both polymer micelles and mesoporous silica nanoparticles have been widely researched as vectors for small molecular insoluble drugs. To combine the advantages of copolymers and silica, studies on the preparation of copolymer-silica composites and cellular evaluation were carried out.Methods: First, a stearic acid-g-chitosan (CS-SA) copolymer was synthesized through a coupling reaction, and then silicone oxide (SiO2)-deposited doxorubicin (DOX)-loaded stearic acid-g-chitosan (CS-SA/SiO2/DOX) nanoparticles were prepared through the sol-gel reaction. Physical and chemical properties such as particle size, zeta potential, and morphologies were examined, and small-angle X-ray scattering (SAXS) analysis was employed to identify the mesoporous structures of the generated nanoparticles. Cellular uptake and cytotoxicity studies were also conducted.Results: CS-SA/SiO2/DOX nanoparticles with different amounts of SiO2 deposited were obtained, and SAXS studies showed that mesoporous structures existed in the CS-SA/SiO2/DOX nanoparticles. The mesoporous size of middle-ratio and high-ratio deposited CS-SA/SiO2/DOX nanoparticles were 4–5 nm and 8–10 nm, respectively. Based on transmission electron microscopy images of CS-SA/SiO2/DOX nanoparticles, dark rings around the nanoparticles could be observed in contrast with CS-SA/DOX micelles. Furthermore, CS-SA/SiO2/DOX nanoparticles exhibited faster release behavior in vitro than CS-SA/DOX micelles; cellular uptake research in A549 indicated that the CS-SA/SiO2/DOX nanoparticles were taken up by A549 cells more rapidly, and that CS-SA/SiO2/DOX nanoparticles entered the cell more easily when the amount of SiO2 was higher. IC50 values of CS-SA/DOX micelles, CS-SA/SiO2/DOX-4, CS-SA/SiO2/DOX-8, and CS-SA/SiO2/DOX-16 nanoparticles against A549 cells measured using the MTT assay were 1.69, 0.93, 0.32, and 0.12 µg/mL, respectively.Conclusion: SiO2-deposited stearic acid-g-chitosan organic–inorganic composites show promise as nanocarriers for hydrophobic drugs such as DOX.Keywords: doxorubicin, nanoparticles, SiO2-deposited, stearic acid-g-chitosan

Paraschos Archontakis Barakakis,1 Thuonghien Tran,2 Jee Young You,3 Gabriel J Hernandez Romero,4 Vipul Gidwani,1 Fernando J Martinez,5 Spyridon Fortis2,6 1Northeast Internal Medicine Associates, LaGrange, IN, USA; 2Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA; 3Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA; 4Department of Medicine, Albert Einstein College of Medicine/Jacobi Medical Center, Bronx, NY, USA; 5Departments of Medicine and Genetic Medicine, Weill Cornell Medicine, New York, NY, USA; 6Veterans Rural Health Resource Center, VA Office of Rural Health, and Center for Access and Delivery Research and Evaluation (CADRE) at the Iowa City VA Healthcare System, Iowa City, IA, USACorrespondence: Paraschos Archontakis Barakakis, Northeast Internal Medicine Associates, 4344 Love Grass Lane, Fort Wayne, LaGrange, IN, 46845, USA, Tel +1 929-422-4589, Email p.archontakis.barakakis@gmail.comBackground: Inhaled corticosteroids (ICSs) combined with bronchodilators have been identified to improve outcomes in COPD but also to be associated with certain adverse effects.Objective: We performed a systematic review and meta-analysis to compile and summarize data on the efficacy and safety of dosing levels (high versus medium/low) of ICS alongside ancillary bronchodilators following PRISMA guidelines.Data Sources: Medline and Embase were systematically searched until December 2021. Randomized, clinical trials (RCTs) that met predefined inclusion criteria were included.Data Extraction: Risk ratios (RRs) with 95% confidence intervals (CI) were extracted. Any acute exacerbation of COPD (AECOPD) risk was chosen as the primary efficacy outcome, mortality rate as the primary safety outcome, moderate/severe AECOPD risk as the secondary efficacy outcome and pneumonia risk as the secondary safety outcome. Subgroup analyses of individual ICS agents, of patients with baseline moderate/severe/very severe COPD and of patients with recent COPD exacerbation history were also performed. A random-effects model was used.Results: We included 13 RCTs in our study. No data on low doses were included in the analysis. High dose ICS was not associated with a statistically significant difference in any AECOPD risk (RR: 0.98, 95% CI: 0.91– 1.05, I2: 41.3%), mortality rate (RR: 0.99, 95% CI: 0.75– 1.32, I2: 0.0%), moderate/severe AECOPD risk (RR: 1.01, 95% CI: 0.96– 1.06, I2: 0.0%) or pneumonia risk (RR: 1.07, 95% CI: 0.86 − 1.33, I2: 9.3%) compared to medium dose ICS. The same trend was identified with the several subgroup analyses.Conclusion: Our study collected RCTs investigating the optimal dosing level of ICS prescribed alongside ancillary bronchodilators to patients with COPD. We identified that the high ICS dose neither reduces AECOPD risk and mortality rates nor increases pneumonia risk relative to the medium dose.Keywords: chronic obstructive lung disease, acute COPD exacerbation, mortality, pneumonia, inhaled corticosteroids

Yu Seob Shin, Jae Hyung You, Ji Won On, Myung Ki Kim Department of Urology, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University – Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, Republic of Korea Objective: To evaluate the association between the length of the female urethra and urodynamic study (UDS) parameters in patients presenting with stress urinary incontinence (SUI).Patients and methods: We retrospectively enrolled 391 women who underwent a transobturator adjustable tape sling implantation for the management of SUI between April 2009 and March 2016. All patients underwent a physical examination and UDS. Filling cystometry data that were evaluated included the Valsalva leak point pressure, and the cough leak point pressure. The maximal urethral closure pressure, the functional urethral length (FUL), and the length of the continence zone (LCZ) were measured using the urethral profile obtained from the UDS. The anatomical urethral length (AUL) was measured intraoperatively using a Foley catheter. We calculated the LCZ/FUL ratio to determine the anatomical continence length for this study.Results: We noted that 299 patients completed the study. The mean AUL was 26.25±3.59 mm. The mean FUL and LCZ were 41.37±15.05 mm and 24.15±13.90 mm, respectively. The mean LCZ/FUL was 0.57±0.19. Using the Pearson correlation coefficient, we observed that the AUL showed a correlation with the FUL (0.168, P=0.034), the LCZ (0.212, P=0.007), the LCZ/FUL ratio (0.190, P=0.016), the Valsalva leak point pressure (0.223, P=0.005), the cough leak point pressure (0.215, P=0.006), and the maximal urethral closure pressure (0.178, P=0.043).Conclusion: Our results show that the AUL in women is associated with UDS parameters relating to SUI. Keywords: stress urinary incontinence, urethral length, urodynamics, women

Yanping Gong, Genpeng Li, Jianyong Lei, Jiaying You, Ke Jiang, Zhihui Li, Rixiang Gong, Jingqiang Zhu Thyroid and Parathyroid Surgery Center, West China Hospital of Sichuan University, Chengdu, China Background: The optimal treatment strategy for papillary thyroid microcarcinoma (PTMC) has remained controversial. The purpose of this study was to provide a new reference value for PTMC to aid the selection of optimal management for minute lesions.Patients and methods: A pool of 1176 consecutive patients who met the inclusion criteria were ultimately enrolled in this study. The correlation of papillary thyroid carcinoma (PTC) tumor size and lymph node metastasis was analyzed. Receiver operating characteristic curve studies were conducted to identify the reference value by determining the optimal cut-off point of size related to lymph node metastasis. To validate our results, all selected patients were divided into two groups according to the cut-off point and some of the prognostic factors were compared.Results: A moderate significant correlation was found between the tumor size and the average number of lymph node metastases (r=0.502, P8.5 mm), a tumor size ≤8.5 mm in diameter may be favorable to discriminate PTMC from PTC and aid the selection of optimal management. Keywords: thyroid neoplasms, carcinoma, papillary, lymph nodes