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Sun P, Huang W, Kang L, Jin M, Fan B, Jin H, Wang Q, Gao Z. Int J Nanomedicine. 2017;12:3221–3234 At the authors request, the Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. An investigation by the Publisher found overlap in images from Figure 5. Specifically, The image from Figure 5, 0 h, Blank, has been duplicated with the same image for Figure 5, 0 h, H6R6-NP. The image from Figure 5, 0h, Naked siRNA, has been duplicated with the same image for Figure 5, 0 h, H6R6-NP. The image from Figure 5, 24 h, Naked siRNA, has been duplicated with the same image for Figure 5, 24 h, H6R6-NP. The image from Figure 5, 48 h, Naked siRNA, has been duplicated with the image for Figure 5, 48 h, CS-NP. The authors cooperated with the investigation and provided data associated with the study. However, despite the authors’ assistance, they were unable to provide a satisfactory explanation for how the images came to be duplicated, and the validity of the published work could not be verified. The decision was made to retract the article and the authors agreed with this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Mingji Jin,1,2,* Yan Hou,1– 3,* Xiuquan Quan,1,2,4,* Liqing Chen,1,2 Zhonggao Gao,1,2 Wei Huang1,2 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People’s Republic of China; 2Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, People’s Republic of China; 3Department of Pharmacy, Yanbian University, Yanji, Jilin, 133000, People’s Republic of China; 4Department of Emergency Medicine, Affiliated Hospital of Yanbian University, Yanji, Jilin, 133000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhonggao Gao; Wei Huang Tel +86 010 63028096; +86 010 63026505Email zggao@imm.ac.cn; huangwei@imm.ac.cnBackground: The dual-loaded nano-delivery system can realize chemotherapeutic drug and small interfering RNA (siRNA) co-loading as well as enhance the therapeutic effect of drugs on tumors through a synergistic effect, while reducing their toxic and side effects on normal tissues.Methods: Previously, we developed layered smart nanoparticles (NPs) to co-deliver survivin siRNA as well as small molecule drugs for lung cancer. In this study, we used such smart NPs to co-deliver paclitaxel (PTX) and siRNA against vascular endothelial growth factor (VEGF) gene for breast cancer therapy in mice models. For the prepared NPs, characterizations such as particle size, zeta potential, gel electrophoresis imaging and in vitro stability were investigated. Then, 4T1 cells were used to evaluate the in vitro VEGF silencing capacity, tumor cell inhibitory and anti-apoptotic abilities. Finally, an orthotopic model of mouse breast cancer was established to evaluate the in vivo antitumor effects and safety properties of PTX-siRNAVEGF-NPs.Results: We prepared PTX-siRNAVEGF-NPs with particle size of 85.25 nm, PDI of 0.261, and zeta potential of 5.25 mV. The NPs with VEGF siRNA effectively knocked down the expression of VEGF mRNA. Cell counting kit-8 (CCK-8) and apoptosis assays revealed that the PTX-siRNAVEGF-NPs exhibited antiproliferation effect of PTX on 4T1 cells. The in vivo anti-tumor study indicated that PTX-siRNAVEGF-NPs could exert an antitumor effect by inhibiting the formation and development of new blood vessels in tumor tissues, thereby cutting off nutrient and blood supplies required for tumor tissue growth. Both the anti-tumor efficacy and in vivo safety of the PTX-siRNAVEGF-NPs group were better than that of the PTX-NPs and siRNAVEGF-NPs groups.Conclusion: The combination of PTX and VEGF siRNA exerts good antitumor effect on 4T1 tumor cells. This study provides a theoretical and practical basis for breast cancer therapy.Keywords: paclitaxel, VEGF siRNA, breast cancer, co-delivery

ZongAn Chen,1,* Zhen Gao,1,* LingLing Xia,1 XiaoQing Wang,2,* LiMing Lu,3,* XiaoLi Wu1,* 1Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Orthopedics, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 3Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: XiaoLi WuDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of ChinaTel +86-2163089567Email wuxiaoli528@126.comPurpose: Recent studies have confirmed the important role of chronic inflammation in keloid; however, mechanism of chronic inflammation in keloid tissue remains largely unclear, especially the dynamic of infiltrated inflammatory cells.Patients and Methods: Tissue and blood samples collected from keloid patients and healthy subjects were studied by immunohistochemistry and flow cytometry. Fibroblasts from keloid scars and normal skin were isolated by enzymic digestion.Results: We found that CXCL12 expression was elevated which was correlated with decreased dipeptidyl peptidase-4 (DPP4) expression in keloid scars relative to mature scars. In vitro studies suggested that autocrine transforming growth factor β 1 (TGF-β 1) in keloid-derived fibroblasts negatively regulated DPP4 expression which inhibited the reduction of extracellular CXCL12 levels by DPP4. Furthermore, immunofluorescence showed that most fibroblasts in keloid scars were DPP4lowTGFβ 1high compared with DPP4highTGFβ 1low fibroblasts in normal skin tissue, which facilitated extracellular CXCL12 accumulation in fibroblasts in keloid scars. Furthermore, we found that most circulating leukocytes in peripheral blood and tissue-infiltrated inflammatory cells in keloid scars expressed the C-X-C motif chemokine receptor 4 (CXCR4) instead of CXCR7, indicating that the chemotaxis driven by CXCL12 is likely to be mediated mainly by CXCR4.Conclusion: Our study indicated that the TGF-β/DPP4/CXCL12 axis may contribute to chronic inflammation in keloid scars by recruiting inflammatory cells through the CXCR4 receptor.Keywords: keloid, chemokines, inflammation, DPP4, CXCL12, TGF-β 1

Di Mei,1,&ast; Xiaolong Guo,2,&ast; Yirong Wang,1 Xiaofei Huang,1 Li Guo,1 Pengfei Zou,3 Delong Ge,1 Xinxin Wang,1 Wenhui Lee,4 Tongyi Sun,1 Zhiqin Gao,1 Yuanyuan Gao3 1School of Life Science and Technology, Shandong Key Laboratory of Proteins and Peptides Pharmaceutical Engineering, Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of China; 2School of Basic Medicine, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of China; 3School of Pharmacy, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of China; 4Key Laboratory of Animal Models and Human Disease Mechanism, Institute of Zoology, Kunming, Yunnan, 650233, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiqin GaoSchool of Life Science and Technology, Shandong Key Laboratory of Proteins and Peptides Pharmaceutical Engineering, Shandong Universities Key Laboratory of Biopharmaceuticals, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of ChinaTel +86 5368462066Email zhiqingao2013@163.comYuanyuan GaoSchool of Pharmacy, Weifang Medical University, Baotong Road, Weifang, Shandong Province, 261053, People’s Republic of ChinaTel +86 536 846 2067Email yyg20062006@126.comBackground: The treatment of Staphylococcus aureus (S. aureus)-infected wounds is difficult. It causes extreme pain to tens of thousands of patients and increases the cost of medical care. The antimicrobial peptide OH-CATH30 (OH30) has a good killing activity against S. aureus and can play a role in accelerating wound healing and immune regulation. Therefore, it shows great potential for wound healing.Purpose: The aim of this study was to overcome the short half-life and easy enzymolysis of OH30 by using graphene oxide conjugated with polyethylene glycol to load OH30 (denoted as PGO-OH30), as well as to evaluate its effect on wounds infected by S. aureus.Methods: PGO-OH30 nanoparticles were prepared by π–π conjugation and characterized. Their cell cytotoxicity, cell migration, infectious full-thickness dermotomy models, and histopathology were evaluated.Results: Characterization and cytotoxicity experiments revealed that the PGO-OH30 drug-delivery system had good biocompatibility and excellent drug-delivery ability. Cell-migration experiments showed that PGO-OH30 could promote the migration of human immortalized keratinocytes (HaCaT) cells compared with the control group (P< 0.05). In a mouse model of skin wound infection, PGO-OH30 accelerated skin-wound healing and reduced the amount of S. aureus in wounds compared with the control group (P< 0.05). In particular, on day 7, the number of S. aureus was 100 times lower in the PGO-OH30 group than in the control group.Conclusion: The PGO-OH30 drug-delivery system had good biocompatibility and excellent drug-delivery ability, indicating its good therapeutic effect on a skin wound-infection model.Keywords: OH-CATH30, bacterial infection, graphene oxide, skin wound

Yating Jian,1 Lili Zhao,1 Baixue Jia,2 Xu Tong,2 Tao Li,1 Yulun Wu,1 Xiaoya Wang,1 Zhen Gao,1 Yu Gong,1 Xuelei Zhang,2 Huqing Wang,1 Ru Zhang,1 Lei Zhang,1 Zhongrong Miao,2 Guilian Zhang1 On behalf of ANGEL-ACT Study Group1Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, Shaanxi, People’s Republic of China; 2Department of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Guilian ZhangDepartment of Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwulu, Xi’an, 710004, Shaanxi, People’s Republic of ChinaTel +86 29 87679346Fax +86 29 87678599Email zhgl_2006@126.comZhongrong MiaoDepartment of Interventional Neuroradiology, Beijing Tiantan Hospital, Capital Medical University, No. 119 South West Road, Fengtai District, Beijing, People’s Republic of ChinaTel +8613601243293Email zhongrongm@163.comPurpose: Elderly people represent a growing stroke population with different pathophysiological states than younger. Whether intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) is beneficial for elderly patients remains unclear. This study compared the efficacy and safety between elderly patients treated with MT alone and those treated with both IVT and MT.Patients and Methods: Patients aged ≥ 65 years who were eligible for IVT within 4.5 h from symptom onset were selected from the ANGEL-ACT (Endovascular Treatment Key Technique and Emergency Work Flow Improvement of Acute Ischemic Stroke) registry, a prospective registry program for patients with endovascular treatment from 111 Chinese stroke centers. The primary efficacy outcome was the 90-day modified Rankin Scale score. We compared efficacy and safety outcomes using ordinal or binary logistic regression or a generalized linear model.Results: In total, 482 elderly patients were included: 187 (38.8%) received IVT and MT (bridging MT) and 295 (61.2%) received MT alone (direct MT). There was no significant difference in the 90-day modified Rankin Scale score between the two groups (median: 4 vs 4 points, respectively; adjusted β=− 0.048, P=0.822). The direct MT group had a shorter onset-to-puncture time (225 vs 255 min, respectively; adjusted β=− 55.074, P=0.002) and a lower rate of parenchymal hemorrhage type 2 within 24 h (2.80% vs 6.63%, respectively; adjusted odds ratio [OR]=0.287, 95% confidence interval [CI]=0.096– 0.856, P=0.025). In addition, the direct MT group showed a trend toward a lower incidence of sICH (5.67% vs 10.06%, adjusted OR=0.453, P=0.061), procedure-related complications (7.12% vs 12.30%, adjusted OR=0.499, P=0.052) and distal or new territorial embolization (4.07% vs 6.95%, adjusted OR=0.450, P=0.093).Conclusion: Direct MT had similar efficacy to bridging MT in terms of the 90-day functional outcome in elderly patients, whereas bridging MT had a longer onset-to-puncture time and increased risk of hemorrhagic transformation and procedure-related complications.Keywords: acute ischemic stroke, endovascular treatment, intravenous thrombolysis, elderly patients

Fangqing Wang, 1,* Yanying Li, 1,* Hong Jiang, 1,* Chenglei Li, 2 Zhaohuan Li, 2 Cuiping Qi, 3 Zhipeng Li, 1 Zhiqin Gao, 1 Bo Zhang, 2 Jingliang Wu 1 1School of Bioscience and Technology, Weifang Medical University, Weifang, 261053, People’s Republic of China; 2School of Pharmacy, Weifang Medical University, Weifang, 261053, People’s Republic of China; 3School of Nursing, Weifang Medical University, Weifang, 261053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Zhang; Jingliang Wu Email zhangbo@wfmc.edu.cn ; jlwu2008@163.comBackground: Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy.Methods: Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel “BEL-7402+HUVEC” co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test.Results: The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery.Conclusion: CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.Keywords: dual-ligand-modified, liposomes, anti-angiogenesis, VEGF, co-delivery

Man Feng,1 Qinli Feng,2 Yujie Chen,3 Ge Liu,2 Zhuanglei Gao,4 Juan Xiao,5 Chang Feng2 1Department of Pathology, Affiliated Hospital of Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250000, People’s Republic of China; 2Department of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People’s Republic of China; 3Department of Anesthesiology, Affiliated Hospital of Shandong of TCM, Jinan, 250001, People’s Republic of China; 4Department of General Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People’s Republic of China; 5Department of Center of Evidence-Based Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, People’s Republic of ChinaCorrespondence: Chang FengDepartment of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Bei Yuan Street, Jinan, 250033, People’s Republic of ChinaTel +86-17660085521Email fengc2016@126.comPurpose: To evaluate the effect of dezocine on the postoperative ratio of Th1/Th2 cytokines in patients undergoing laparoscopic radical gastrectomy.Patients and Methods: Sixty patients undergoing laparoscopic radical gastrectomy were randomly divided into two groups (n=30): dezocine group (Group D) and sufentanil group (Group S). They received patient-controlled intravenous analgesia (PCIA) after the operation with either dezocine 0.8 mg/kg (Group D) or sufentanil 2 μg/kg (Group S). Both groups also received ondansetron 8 mg diluted to 100 mL with saline. The primary outcome was the Th1/Th2 cytokines ratio at predetermined intervals, 30 min before the induction of general anaesthesia and 0, 12, 24 and 48 h after surgery. The secondary endpoints were patients’ pain scores, measured on a visual analogue scale (VAS) at predetermined intervals (0, 12, 24 and 48 h after surgery), and side effects at follow-up 48 h after surgery.Results: The Th1/Th2 cytokines ratio in Group D was significantly higher than Group S (P< 0.05) 12, 24 and 48 h after the operation. There were no significant differences in VAS pain scores between groups at 0, 12, 24 and 48 h after surgery (P> 0.05). Compared to Group S, the incidence of postoperative nausea, vomiting and lethargy was significantly lower in Group D (P< 0.05).Conclusion: Dezocine increases the ratio of Th1/Th2 cytokines, relieves postoperative pain and causes fewer side effects in patients undergoing laparoscopic radical gastrectomy.Keywords: dezocine, gastric cancer, laparoscopic radical operation, postoperative analgesia, Th1/Th2 cytokines

Yang Liu,1,2,* Yun Wang,1,2,* Jie Wang,2 Kang Chen,2 Lingzi Jin,3 Weiqing Wang,4 Zhengnan Gao,5 Xulei Tang,6 Li Yan,7 Qin Wan,8 Zuojie Luo,9 Guijun Qin,10 Lulu Chen,11 Yiming Mu2 1Graduate School, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 3Department of International Medical Services, Peking Union Medical College Hospital (Xidan Campus), Beijing, People’s Republic of China; 4Shanghai National Research Centre for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Endocrinology, Dalian Central Hospital, Dalian, Liaoning, People’s Republic of China; 6Department of Endocrinology, First Hospital of Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 7Department of Endocrinology, Zhongshan University Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, People’s Republic of China; 8Department of Endocrinology, Southwest Medical University Affiliated Hospital, Luzhou, Sichuan, People’s Republic of China; 9Department of Endocrinology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 10Department of Endocrinology, First Affiliated Hospital of Zhengzhou University, Zhenzhou, Henan, People’s Republic of China; 11Department of Endocrinology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiming MuDepartment of Endocrinology, The First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, People’s Republic of ChinaTel +86-10-5549 9001Email muyiming@301hospital.com.cnBackground: Lipid accumulation product (LAP) as a powerful marker of visceral obesity is an independent risk factor of chronic kidney disease. The present study attempted to explore the association between LAP and albuminuria in prediabetic individuals.Methods: We conducted a cross-sectional study and enrolled 26,529 participants with prediabetes over 40 years old with prediabetes from seven provinces in China. LAP was calculated from waist circumference and fasting triglycerides. Elevated albuminuria was defined by urinary albumin-creatinine ratio (uACR) ≥ 30 mg/g. Propensity score matching was applied to reduce bias, comparison between LAP and other traditional visceral obesity indices was performed and multiple logistic regression models were conducted to assess the association between LAP and albuminuria in the prediabetic population.Results: Individuals with uACR ≥ 30 mg/g were older and had higher BP, BMI, WC, TG, fasting insulin, glycohemoglobin and LAP, as well as lower eGFR and HDL level. Multiple logistic regression analysis showed elevated LAP was associated with increased odds of albuminuria (OR [95%CI]Q2 vs Q1 1.09 [0.94, 1.27], OR [95%CI]Q3 vs Q1 1.13 [0.97, 1.31], OR [95%CI]Q4 vs Q1 1.42 [1.21, 1.67], P for trend=0.018), and superior over waist-to-hip ratio or waist-to-height ratio. Stratification indicated that the prediabetic population with higher LAP level and characterized by female gender, middle age, being overweight, and rise in blood pressure were more likely to have increased uACR.Conclusion: Elevated level of LAP was associated with increased albuminuria in the prediabetic population in China.Keywords: albuminuria, lipid accumulation product, prediabetes, visceral obesity

Zheng Wang,1 Yuqiang Zuo,2 Zhihong Gao2 1Department of Respiratory Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 2Department of Physical Examination Center, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Zhihong GaoDepartment of Physical Examination Center, The Second Hospital of Hebei Medical University Tel +86-0311-87046901Email tjzx1234556@126.comBackground: Chronic obstructive pulmonary disease (COPD) is a major cause of death because of its high incidence and mortality, which is chiefly resulted from cigarette smoke exposure. A large number of studies show that circular RNA (circRNA) participates in regulating COPD process. This study aims to reveal the role of circRNA ankyrin repeat domain 11 (circANKRD11) in cigarette smoke extract (CSE)-induced cell apoptosis, inflammation, and oxidative stress.Methods: The expression of circANKRD11, microRNA-145-5p (miR-145-5p) and bromodomain-containing 4 (BRD4) mRNA was detected by quantitative real-time polymerase chain reaction. The expression of apoptosis-related proteins and BRD4 protein was determined by Western blot. Cell apoptosis was detected by flow cytometry and Western blot. Cell inflammation was demonstrated by determining the levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) through enzyme-linked immunosorbent assay. Oxidative stress was investigated by the reactive oxygen species (ROS) and malondialdehyde (MDA) determination assays as well as superoxide dismutase (SOD) activity assay. The binding relationship between miR-145-5p and circANKRD11 or BRD4 was predicted by circinteractome or MicroT_CDS online database, and identified by dual-luciferase reporter, RNA immunoprecipitation or RNA pull-down assay.Results: CircANKRD11 and BRD4 expression were increased, whereas miR-145-5p expression was decreased in the lung tissues of smokers with or without COPD and CSE-induced HPMECs compared with the lung tissues of non-smokers as well as untreated HPMECs, respectively. CircANKRD11 silencing ameliorated CSE-induced cell apoptosis, inflammation, and oxidative stress. CircANKRD11 acted as a sponge of miR-145-5p, and regulated CSE-induced cell injury via sponging miR-145-5p. Additionally, miR-145-5p mimics protected against CSE-induced cell injury through targeting BRD4.Conclusion: CircANKRD11 absence protected HPMECs from CSE-induced injury by regulating BRD4 through associating with miR-145-5p, which demonstrated that circANKRD11 had the potential to act as a diagnosis biomarker for smoker-caused COPD.Keywords: COPD, circANKRD11, miR-145-5p, BRD4

Zhen Gao,1 Jing Zhang,2 Gao-Feng Liu,3 Lai-Xi Ji4 1Acupuncture and Tuina School/The 3rd Teaching Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 2Affiliated Hospital of Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi, People’s Republic of China; 3Graduate Faculty, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 4Graduate Faculty, Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Lai-Xi JiShanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi, People’s Republic of ChinaTel +86 13509714277Email tyjilaixi@126.comBackground: Given that acupuncture treatment for pain has gradually been accepted by researchers from various countries. However, few bibliometric analyses have been performed on the published articles. The objective of this research was to review its application for pain in recent 10 years and analyze, demonstrate and evaluate the trends, major research hotspots and frontier areas.Methods: The Web of Science retrieved literature from 2010 to 2020 on acupuncture for pain. The CiteSpace and Excel were used to analyze annual volumes of publications, journals, cited journals, countries, institutions, authors, cited authors, references and keywords and to draw collaborative networks and reference co-citation network maps.Results: The search finally included 4227 related studies. Results show that the number of annual publications has been increasing gradually. Evid Based Complement Alternat Med (366) was the most productive journal, while Pain (2270/0.04) ranked first in terms of frequency and centrality of cited journals, respectively. Among countries/institutions, the China (1252) and the Kyung Hee University (228) ranked first. Lee MS (51 articles) was the most effective author while MacPherson H (577) was the most cited author. The most frequently cited reference was a systematic review of individual patient data on acupuncture for chronic pain (322). “Burden” was identified as a frontier research item for 2017– 2020.Conclusion: This study provides a new and in-depth understanding of current acupuncture used for the treatment of pain. We anticipate that this study will stimulate international cooperation among research teams to advance the field.Keywords: acupuncture, pain, CiteSpace, co-citation analysis, co-occurrence analysis

Min Zhou,1,* Yadi Zhang,2,* Rui Tang,1 Haiyan Liu,1 Min Du,1 Zhi Gao,1 Zongshu Ji,1 Haoshu Fang3 1Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2Department of Respiratory Medicine, The Second People’s Hospital of Hefei and Hefei Hospital Affiliated with Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 3Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haoshu FangDepartment of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of ChinaTel +86 551-65161129Email fang.haoshu@hotmail.comBackground: High-mobility group box-1 protein (HMGB1) serves as the prototypic damage-associated molecular pattern molecule, and TLR4 is considered a receptor for HMGB1. Regulatory T cells (Tregs) play a crucial role in infectious diseases. The role of HMGB1 in the modulation of Tregs is of great interest.Methods: Serum HMGB1 and Treg proportions were detected in 58 patients with acute lung injury (ALI) and 36 healthy volunteers. The correlations of these parameters with disease severity were analyzed. The WT and TLR4-/- mice were administered HMGB1 by intratracheal injection. After 48 h, the mice were sacrificed. The morphological changes and wet/dry ratio of the lung were measured. Spleen CD4+CD25+ Tregs were sorted from spleen cells, the expression of FOXP3 and CTLA-4, and releasing of cytokines was detected. CD4+CD25+ Tregs were cocultured with effector T cells, the inhibitory effect, and release of cytokines was detected.Results: Significantly increased plasma levels of HMGB1 and reduced CD4+CD25+CD127low Tregs were detected in ALI patients. In the mouse model, lung injury was significantly increased after HMGB1 instillation in the WT and TLR4-/- groups compared with control group. The lung wet/dry ratio and the TNF-α and IL-1β contents in BALF were significantly increased, and the severity of WT mice was higher than that of TLR4-/- mice. The expression of FOXP3 and CTLA-4 in TLR4-/- mice was significantly increased compared with that in WT mice and was associated with a similar trend of IL-10 and TGF-β levels (p< 0.05). In coculture with effector T cells, Tregs isolated from TLR4-/- mice exhibited decreased IL-2 and IFN-γ and increased IL-4 levels compared with Tregs from WT mice. Increased polarization of TLR4-/- CD4+CD25+ Treg cells to Th2 cells was observed.Conclusion: In HMGB1-induced lung injury, HMGB1 affects the expression of FOXP3 and CTLA-4 through TLR4, thus reducing the immunosuppressive function of Treg cells.Keywords: HMGB1, TLR4, Treg, acute lung injury

Hongyan Li,1,2 Xiaomin Chen,1,2 Yajing Zhang,1,2 Kun Wang,1,2 Zairong Gao1,2 1Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, People’s Republic of ChinaCorrespondence: Zairong GaoDepartment of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, People’s Republic of ChinaTel/Fax +86-27-85726426Email gaobonn@163.comPurpose: To evaluate the diagnostic performance of 18F-FDG PET/MR in detecting recurrent or metastatic disease in patients with differentiated thyroid cancer (DTC) who have increased thyroglobulin (Tg) levels but a negative 131I whole-body scan (WBS). The relationship between 18F-FDG PET/MR and serum Tg levels was explored. We also evaluated the therapeutic impact of PET/MR on patient clinical management.Patients and Methods: Twenty-nine DTC patients with a negative 131I-WBS of the last post-therapeutic and increased Tg levels under thyroid-stimulating hormone suppression treatment who underwent 18F-FDG PET/MR examination were retrospectively analyzed.Results: Of those 29 patients, 18F-FDG PET/MR findings were true positive, true negative, false positive, and false negative in 18, 7, 2, and 2 patients, respectively. The overall sensitivity, specificity, and accuracy were 90.0%, 77.8%, and 86.2%, respectively. We noticed significant differences in serum Tg levels between the PET/MR-positive and PET/MR-negative patient groups (P=0.049). Receiver operating characteristic curve analysis showed that a Tg level of 2.4 ng/mL was the optimal cut-off value for predicting PET/MR results. The sensitivity, specificity, and accuracy of PET/MR were higher in patients with Tg levels greater than 2.4 ng/mL than in patients with lower levels. By detecting recurrent or metastatic disease, 18F-FDG PET/MR altered the clinical management in 7 patients (24.1%) of the overall population.Conclusion: 18F-FDG PET/MR has high diagnostic accuracy for detecting recurrent or metastatic diseases in DTC patients and is useful for clinical management.Keywords: 18F-FDG, PET/MR, differentiated thyroid cancer, thyroglobulin

Jiansong Wang, Jianjun Luo, Xuecheng Wu, Zhiyong Gao Department of Urology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410005, Hunan, People’s Republic of ChinaCorrespondence: Zhiyong GaoDepartment of Urology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, No. 61, Jie Fang Xi Road, Changsha, 410005, Hunan, People’s Republic of ChinaTel/Fax +86 0731-83929411Email Gaozhiyong831@163.comBackground: Recent studies showed circular RNAs (circRNAs) played regulatory roles in bladder cancer (BC). However, the relevance of circ_0000629, a newly identified circRNA, has not been determined yet. We aimed to characterize the function of circ_0000629 in BC and the relevant mechanism.Methods: First, we downloaded circRNA-related microarrays GSE147985 and GSE92675 from the GEO database, followed by a validation in our clinically obtained samples. We then overexpressed circ_0000629 in T24 and SW780 cells and evaluated the effects of circ_0000629 on BC cell proliferatory, apoptotic, and metastatic abilities. We further detected the subcellular localization of circ_0000629 in T24 and SW780 cells by the fractionation and export assay and FISH experiments. Integrated microarray analyses and bioinformatics website prediction were utilized to screen out the downstream microRNA (miRNA)/mRNA. The effects of miR-1290 and CDC73 on BC cell growth and metastasis was verified by functional rescue experiments. In addition, mice xenografts were built to measure the effect of circ_0000629 on tumor growth in vivo.Results: Circ_0000629 and CDC73 were reduced, and miR-1290 was significantly overexpressed in BC tissues and cells. Moreover, circ_0000629 significantly inhibited the development and metastasis of BC cells, but further overexpression of miR-1290 or knockdown of CDC73 attenuated the inhibitory effect of circ_0000629 on BC cells. Circ_0000629 localized in the cytoplasm and regulated CDC73 expression by sponging miR-1290. Further, overexpressed circ_0000629 reduced the BC tumor growth in vivo.Conclusion: Circ_0000629 promotes the expression of CDC73 by competitively binding to miR-1290, thereby inhibiting the growth and metastasis of BC cells.Keywords: bladder cancer, circular RNA_0000629, microRNA-1290, CDC73, epigenetics

Dan Yu,1,2,* Qilong Yin,1,3,* Jiwei Wang,1,* Jian Yang,1 Zimeng Chen,1 Zihan Gao,1 Qingli Huang,1,4 Shibao Li1,3 1Medical Technology School of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 2Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People’s Republic of China; 3Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 4Public Experimental Research of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingli HuangPublic Experimental Research of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of ChinaTel +86 15150043097Fax +86 516 83262091Email qlhuang@xzhmu.edu.cnShibao LiDepartment of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of ChinaTel +86 15895212960Fax +86 516 83353651Email sdjnshlb@xzhmu.edu.cnPurpose: Developing a sensitive SERS-based method to quantitatively detect serum biomarkers (Aβ 1-42 and P-Tau-181) for the early diagnosis of Alzheimer’s disease (AD).Methods: In this study, a novel SERS-based sandwich immunoassay, which consists of tannin-capped silver nanoparticles and magnetic graphene oxide (Fe3O4@GOs), was developed. We firstly applied this method for the detection of protein standards in buffer solution, obtaining the regression equation. Then, its potential value on real serum samples of AD was further explored.Results: The detection linear range of Aβ 1-42 and P-Tau-181 protein standards were observed to range from 100 pg mL− 1 to 10 fg mL− 1, 100 pg mL− 1 to 1 fg mL− 1 respectively. We finally explored clinical application of the proposed method in 63 serum samples. As a result, P-tau-181 differentiated AD from non-AD dementia patients (AUC = 0.770), with a more favored ROC than Aβ 1-42 (AUC =  0.383).Conclusion: The developed SERS-based immunoassay is successfully applied to the determination of Aβ 1-42 and P-Tau-181 in human serum specimens, which provides a promising tool for the early diagnosis of AD.Keywords: surface-enhanced Raman scattering, silver probe, Alzheimer’s disease, biomarker, diagnosis

Qingchao Tang,1 Yihao Zhu,1 Huan Xiong,1 Xiangzong Sheng,1 Zhiqiao Hu,1 Hanqing Hu,1 Rui Huang,1 Qian Zhang,1 Ziming Yuan,1 Lei Xie,2 Zhifeng Gao,1 Yuliuming Wang,1 Guiyu Wang,1 Xishan Wang3 1Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 2Heilongjiang Agricultural Reclamation General Hospital, Harbin, People’s Republic of China; 3Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Xishan WangDepartment of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Beijing, People’s Republic of ChinaTel +86 135 52367779Email wxshan1208@126.comGuiyu WangDepartment of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, People’s Republic of ChinaTel +86 451 86296599Email guiywang@163.comBackground: Natural orifice specimen extraction surgery (NOSES) has been successfully applied to the treatment of gastric, colorectal cancer (CRC). However, the development of NOSES is still in the exploratory stage, and there is still no strong evidence-based medical evidence.Patients and Methods: From January 2013 to June 2017, consecutive patients with colorectal cancer who underwent transluminal resection, anastomosis, and specimen extraction and those who underwent conventional laparoscopic resection were enrolled. Propensity score matching was used to align clinicopathological features between the two groups.Results: A total of 372 patients were eventually included in this study, 186 in each group. According to perioperative information and postoperative follow-up in both groups, the NOSES group had less blood loss (P = 0.011), shorter time to recovery of gastrointestinal function (P < 0.001), shorter postoperative hospital stay (P = 0.037). The NOSES group had fewer postoperative analgesics (P < 0.001), lower postoperative pain scores (P < 0.001), and lower incidence of postoperative complications (P = 0.017). Compared with the LA (laparoscopic) group, the NOSES group had better physical function (P< 0.05), role function (P< 0.001), emotional function (P< 0.001) and global health status than LA group, while symptoms such as pain (P< 0.001), insomnia (P< 0.001), constipation (P< 0.001) and diarrhea (P< 0.05) were less severe in the NOSES group. In addition, the NOSES group had higher body image scores. Overall survival (OS) and disease-free survival (DFS) were not significantly different between the two groups.Conclusion: For surgical treatment of colorectal cancer, NOSES has advantages in reducing postoperative pain, recovery of gastrointestinal function, postoperative quality of life, and improving patients’ satisfaction with abdominal wall aesthetics. There was no difference in long-term survival between NOSES and conventional laparoscopic surgery.Keywords: colorectal cancer, laparoscopic surgery, perioperative efficacy, natural orifice specimen extraction, survival

Dan Chen,1,* Zhi-qi Gao,1,* Ying-ying Wang,1 Bin-bin Wan,1 Gang Liu,1 Jun-liang Chen,1 Ya-xian Wu,1 Qin Zhou,2 Shan-yu Jiang,2 Ren-qiang Yu,2 Qing-feng Pang1 1Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, People’s Republic of China; 2Department of Neonatology, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, 214002, Jiangsu Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ren-qiang Yu 48 Huaishu Lane, Liangxi District, Wuxi, Jiangsu Province, People’s Republic of ChinaTel +86510-82709790Fax +86-510-82725094Email yurenqiang553@163.comQing-feng Pang 1800 Lihu Avenue, Binhu District, Wuxi, Jiangsu Province, People’s Republic of ChinaTel +8651052430172Fax +86-510-85329042Email qfpang@jiangnan.edu.cnBackground: Alveolar arrest and the impaired angiogenesis caused by chronic inflammation and oxidative stress are two main factors in bronchopulmonary dysplasia (BPD). Short-chain fatty acids (SCFAs), especially propionate, possess anti-oxidant and anti-inflammatory effects. The present study was designed to examine the roles of sodium propionate (SP) on lipopolysaccharide (LPS)-challenged BPD and its potential mechanisms.Methods: WT, Nrf2-/- mice and pulmonary microvascular endothelial cells (HPMECs) were used in this study. LPS was performed to mimic BPD model both in vivo and vitro. Lung histopathology, inflammation and oxidative stress-related mRNA expressions in lungs involved in BPD pathogenesis were investigated. In addition, cell viability and angiogenesis were also tested.Results: The increased nuclear factor erythroid 2-related factor (Nrf2) and decreased Kelch-like ECH-associated protein-1 (Keap-1) expressions were observed after SP treatment in the LPS-induced neonatal mouse model of BPD. In LPS-induced wild-type but not Nrf2-/- neonatal mice, SP reduced pulmonary inflammation and oxidative stress and exhibited obvious pathological alterations of the alveoli. Moreover, in LPS-evoked HPMECs, SP accelerated Nrf2 nuclear translocation presented and exhibited cytoprotective and pro-angiogenesis effects. In addition, SP diminished the LPS-induced inflammatory response by blocking the activation of nuclear factor-kappa B pathway. Moreover, pretreatment with ML385, an Nrf2 specific inhibitor, offsets the beneficial effects of SP on inflammation, oxidative stress and angiogenesis in LPS-evoked HPMECs.Conclusion: SP protects against LPS-induced lung alveolar simplification and abnormal angiogenesis in neonatal mice and HPMECs in an Nrf2-dependent manner.Keywords: sodium propionate, lipopolysaccharide, Nrf2, angiogenesis, bronchopulmonary dysplasia

Wu H, Liu Y, Chen L, et al. Int J Nanomedicine. 2022;17:6377–6398. The authors have advised there is an error in Figure 8A on page 6392. Due to an error that occurred inadvertently at the time of figure assembly, the images of the fluorescence intensity of RVG15-PEG@IR-820@ZIF-8 at the 8 h are incorrect. The correct Figure 8 is as follows Figure 8 Continued. Figure 8 Biodistribution of free IR-820, IR-820@ZIF-8, and RVG15-PEG@IR-820@ZIF-8 in vivo. (A) In vivo fluorescence imaging of orthotopic glioma-bearing mice treated with free IR-820, IR-820@ZIF-8, and RVG15-PEG@IR-820@ZIF-8 at 1, 4, 8, and 24 h. (B) Ex vivo fluorescence images of the excised brains and major organs at 24 h after injection. (C) Quantitative region-of-interest analysis of (B). Means ± SD, n = 3; *P < 0.05. . The authors wish to apologize for this error and advise it does not affect the interpretation of the data and the conclusion of the study.

Guixiang Wang,1 Yajun Li,1 Hufei Zhu,1 Guoqiang Huo,1 Jingying Bai,1 Zhiyong Gao2 1Department of Colorectal Surgery, Yan’an People’s Hospital, Yan’an, Shaanxi, People’s Republic of China; 2Department of General Surgery, Yanchuan County People’s Hospital, Yan’an, Shaanxi, People’s Republic of ChinaCorrespondence: Zhiyong Gao Tel +86-911-2888754Email diavze@163.comBackground: Circular RNAs (circRNAs) play a crucial role in a variety of cancers, including colorectal cancer (CRC). This study aimed to explore the role of hsa_circ_0136666 (circ-PRKDC) in CRC and its potential mechanism.Methods: The levels of circ-PRKDC, miR-198 and discoidin domain receptor 1 (DDR1) were measured using quantitative real-time polymerase chain reaction or Western blot. Cell viability was detected using cell counting kit-8 (CCK-8) assay. Cell apoptosis and cycle were evaluated via flow cytometry. Cell migration and invasion were examined using transwell assay. CyclinD1 protein level was determined via Western blot. The interaction among circ-PRKDC, miR-198 and DDR1 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation assay. Xenograft assay was performed to analyze tumor growth in vivo.Results: Circ-PRKDC and DDR1 levels were increased, and miR-198 level was decreased in CRC tissues and cells. Circ-PRKDC depletion inhibited proliferation, migration and invasion, and expedited apoptosis and cell cycle arrest in SW480 and HCT116 cells. Silence of circ-PRKDC impeded CRC progression by sponging miR-198. Overexpression of miR-198 hindered CRC development via targeting DDR1. Moreover, circ-PRKDC silencing suppressed tumor growth in vivo.Conclusion: Knockdown of circ-PRKDC inhibited CRC progression via modulating miR-198/DDR1 pathway.Keywords: colorectal cancer, circ-PRKDC, miR-198, DDR1, cell cycle

Lingdun Zhuge,1,2,* Binhao Huang,1,2,* Juntao Xie,1,2 Zhendong Gao,1,2 Difan Zheng,1,2 Shanbo Zheng,1,2 Jiaqing Xiang,1,2 Jie Zhang3 1Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie ZhangDepartment of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaTel +86 189 30598097Email zhangjie2289@hotmail.comObjective: The aim of this study was to construct the immunoscore (IS) to facilitate the prediction of postoperative survival and benefit from adjuvant chemotherapy (ACT) in esophageal squamous cell carcinoma (ESCC).Methods: A total of 249 patients who received radical esophagectomy at Fudan University Shanghai Cancer Center were divided into training set and testing set. Eighty-nine patients with ESCC from TCGA database were enrolled into the validation set. Myeloid cells in tumor microenvironment were evaluated by immunohistochemistry or CIBERSORT, and then were included into a LASSO Cox regression model to construct the immunoscore. The predictive value of the immunoscore for prognosis after surgery or ACT was analyzed.Results: The immunoscore was constructed by four types of myeloid cells including macrophages, neutrophils, mast cells, and dendritic cells and was demonstrated as IS=2^(0.527719*M&phis; − 0.2604269*MC-0.4812935*DC-0.4519706*Neu). The overall survival was significantly different between two immunotypes, which were divided according to the immunoscore, in all sets (P< 0.001, P=0.005, and P=0.002, respectively). Immunotype A was identified as an independent predictor for survival benefit in all three sets (HR=2.068, P=0.005; HR=2.028, P=0.007; HR=6.474, P=0.007; respectively). In patients who received ACT, immunotype A was significantly related to longer overall survival both in the training set (P< 0.001) and in the testing set (P=0.011). The nomogram based on immunotype and other clinicopathological factors showed good efficiency of predicting response to ACT. Finally, several important cytokines and pathways were highly enriched in immunoscore A subgroup.Conclusion: The immunoscore was an effective prognostic predictor in ESCC for patients undergoing surgical resection and receiving ACT.Keywords: adjuvant chemotherapy, prognosis, immunoscore, esophageal squamous cell carcinoma

Yunxia Wu, Zhiqiang Gao, Jiang Zhang Department of Neurology, Linyi Central Hospital, Linyi, Shandong 276400, People’s Republic of ChinaCorrespondence: Jiang Zhang Department of Neurology, Linyi Central Hospital, No. 17, Jiankang Road, Yishui County, Linyi 276400, Shandong, People’s Republic of ChinaTel/Fax +86-0539-22260223Email Jiangzhang3241@163.comBackground: It has been documented that microRNAs (miRs) assume a pivotal role in the development of ischemic stroke (IS). However, it remains poorly identified about the role of miR-122 in IS. Herein, this study was intended to explore the mechanism of E2F1-orchestrated miR-122 in IS.Patients and Methods: E2F1, miR-122, and SPRY2 expression in serum from patients with IS and oxygen-glucose deprivation (OGD)-treated N2a cells was detected by RT-qPCR. After gain- and loss-of-function approaches in OGD-induced N2a cells, GAFP staining, flow cytometry, and Western blot analysis were adopted to assess neuronal viability, cell cycle and apoptosis, and expression of apoptosis- and autophagy-related proteins, respectively. Meanwhile, mice with IS were induced, in which E2F1, miR-122, and SPRY2 were overexpressed, followed by evaluation of neurological deficit and cerebral infarction area. The MAPK pathway activity in tissues of mice and cells was determined.Results: miR-122 was down-regulated, and E2F1 and SPRY2 were up-regulated in IS patients and OGD-induced N2a cells. E2F1 inhibited miR-122 transcription, while miR-122 targeted SPRY2. Overexpression (OE) of miR-122 or down-regulation of E2F1 or SPRY2 increased viability, but decreased apoptosis, cell cycle arrest, and autophagy in OGD-induced N2a cells. In IS mice, the neurological deficit score and cerebral infarction area were elevated, which was aggravated by up-regulating E2F1 or SPRY2 but attenuated by overexpressing miR-122. E2F1/miR-122/SPRY2 axis mediated the MAPK pathway in vivo and in vitro.Conclusion: Collectively, E2F1 reduced miR-122 transcription to up-regulate SPRY2, which inactivated MAPK pathway and promoted neurological deficit in IS.Keywords: ischemic stroke; IS, E2F1, microRNA-122, SPRY2, MAPK pathway, neurological injury

Jin-Feng Huang,1,2 Xuan-Qi Zheng,1,2 Jia-Liang Lin,3 Kai Zhang,4 Hai-Jun Tian,4 Wen-Xian Zhou,1,2 Hui Wang,1,2 Ze Gao,5 Hai-Ming Jin,1,2,* Ai-Min Wu1,2,* 1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2The Second School of Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Orthopaedics, Peking University Third Hospital, Beijing, People’s Republic of China; 4Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai, People’s Republic of China; 5Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ai-Min Wu; Hai-Ming JinDepartment of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 109# Xueyuan Road, Wenzhou, Zhejiang 325027, People’s Republic of ChinaTel +86 0577 88002814Fax +86 057788002823Email aiminwu@wmu.edu.cn; kkjinhaiming@126.comBackground: Low back pain (LBP) is a very common condition and leads to serious pain, disability, and price tag all over the world. Intervertebral disk degeneration (IDD) is one of the major reasons that contributed to LBP. The levels of interleukin 1 beta (IL-1β) increase significantly in degenerative disks. IL-1β also accelerates IDD. Sinapic acid (SA) has the effect of anti‐inflammatory, antioxidant and antimicrobial. However, the effect of SA on IDD has never been studied. Therefore, the aim of this study was to figure out whether SA has protective effect on nucleus pulposus (NP) cells and further explore the possible underlying mechanism.Methods: The nucleus pulposus (NP) tissues of rats were collected and cultured into NP cells. The NP cells were stimulated by IL-1β and treated with SA. In vitro treatment effects were evaluated by ELISA, Western blot assay, immunofluorescence, TUNEL method and real-time PCR. We conducted percutaneous needle puncture in the rat tail to build intervertebral disk degeneration model and treated rats with SA. In vivo treatment effects were evaluated by hematoxylin and eosin (HE) and safranin O (SO) staining and magnetic resonance imaging (MRI) method.Results: Our results showed that SA not only inhibited apoptosis but also suppressed inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS) interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in IL-1β-stimulated NP cells. As to extracellular matrix (ECM), SA could increase collagen II and aggrecan levels and reduce the expression of MMP13 and ADAMTS5 during the stimulation of IL-1β. Furthermore, SA could activate nuclear factor‐erythroid 2‐related factor‐2 (Nrf2) to inhibit nuclear factor κB (NF‐κB) induced by IL‐1β. Nrf2 knockdown partly reduced the protective effect of SA on NP cells. Correspondingly, SA ameliorated IDD by promoting Nrf2 expression. In vivo results also showed that SA could delay the progression of IDD.Conclusion: In conclusion, we demonstrated that SA could protect the degeneration of NP cells and revealed the underlying mechanism of SA on Nrf2 activation in NP cells.Keywords: intervertebral disk degeneration, sinapic acid, apoptosis, Nrf2, inflammation

Weiqing Wang,1,2 Zhenhua Gao,2 Lu Wang,2 Jianing Li,2 Jinming Yu,1,2 Shumei Han,2 Xue Meng2 1School of Clinical Medicine, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China; 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, People’s Republic of ChinaCorrespondence: Xue MengDepartment of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong, People’s Republic of ChinaTel/Fax +86 0531-67627081Email mengxue123999@163.comAbstract: Recently, immunotherapies that target the interactions of programmed cell death 1 (PD-1) with its major ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2), have achieved significant success. To date, several immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have been developed to treat melanoma, non-small cell lung cancer, head and neck cancer, renal cell carcinoma, and urothelial carcinoma. Despite promising outcomes with immunotherapy, there are many limitations to several current immune biomarkers for predicting immune benefits and to traditional imaging for evaluating the efficacy and prognosis of immunotherapy and monitoring adverse reactions. In this review, we recommend a novel imaging method, molecular imaging. This paper reviews the application and prospects of molecular imaging in the context of current immunotherapies in regard to the following aspects: 1) detecting the expression of PD-1/PD-L1; 2) evaluating the efficacy of immunotherapy; 3) assessing patient prognosis with immunotherapy; 4) monitoring the toxicity of immunotherapy; and 5) other targets imaging.Keywords: tumor, immunotherapy, PD-1, PD-L1, PET, SPECT

Joseph Emil Amegadzie,1 John-Michael Gamble,2 Jamie Farrell,1 Zhiwei Gao1 1Faculty of Medicine, Memorial University of Newfoundland, Newfoundland, Canada; 2Faculty of Science, School of Pharmacy, University of Waterloo, Waterloo, Ontario, CanadaCorrespondence: Zhiwei GaoFaculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, CanadaTel +1 7098646523Email zhiwei.gao@med.mun.caPurpose: Gender differences in the incidence, susceptibility and severity of many obstructive airway diseases (OADs) have been well recognized. However, gender differences in the inhaled pharmacotherapy profile are not well characterized.Methods: We conducted a retrospective cohort study to investigate gender differences in new-users of inhaled corticosteroids (ICS), short-or long-acting beta2-agonist (SABA or LABA), ICS/LABA, short-or long-acting muscarinic antagonist (SAMA or LAMA) among patients with asthma, COPD or asthma-COPD overlap (ACO). We used Clinical Practice Research Datalink to identify OAD patients, 18 years and older, who were new-users (1-year washout period) from 01-January-1998 to 31-July-2018. Multivariable logistic regression was used to examine gender differences in each of the inhaled pharmacotherapies after controlling for potential confounders.Results: A total of 242,079 new-users (asthma: 84.93%; COPD: 10.19%; ACO: 4.88%) of inhaled pharmacotherapies were identified. The multivariable analyses showed that males with COPD were more likely to be a new user of a LABA (odds ratio [OR] 1.29; 95% confidence interval [CI], 1.12– 1.49), LAMA (OR 1.21; 95% CI 1.10– 1.33), SAMA (OR 1.11; 95% CI 1.01– 1.21) and less likely to be a new user of a SABA (OR 0.84; 95% CI, 0.80– 0.89) compared to females. Similar patterns were also observed for patients with ACO; males were more likely to be prescribed with LABA (OR 1.26; 95% CI 1.03– 1.55), LAMA (OR 1.28; 95% CI 1.11– 1.48), SAMA (OR 1.28; 95% CI 1.11– 1.48), and less likely to be a new user of a SABA (OR 0.89; 95% CI, 0.82– 0.96). Also, males with asthma were more likely to be a new-user of ICS/LABA (OR 1.15; 95% CI, 1.08– 1.23) and less likely to start an ICS (OR 0.97; 95% CI, 0.95– 0.99) in comparison with females.Conclusion: Our study showed significant gender differences in new-users of inhaled pharmacotherapies among OAD patients. Adjusting for proxies of disease severity, calendar year, smoking and socioeconomic status did not change the association by gender.Keywords: inhaled pharmacotherapies, asthma, COPD, asthma-COPD overlap, gender, drug utilization

Yan Yu,1,* Lili Zhao,1,* Yu Xie,1 Yu Xu,1 Weike Jiao,2 Jianhui Wu,2 Xinyu Deng,2 Guiju Fang,2 Qing Xue,2 Yali Zheng,1,3 Zhancheng Gao1,3 1Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing 100044, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Ningde Municipal Hospital Affiliated to Fujian Medical University, Ningde, Fujian 352100, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Xiang’An Hospital of Xiamen University, Xiamen, Fujian 361100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhancheng Gao; Yali Zheng Tel +86 18810900430; Tel +86 15011451515Email zcgao@bjmu.edu.cn; yali_zheng@126.comBackground: T helper (Th) cell cytokine imbalances have been associated with the pathophysiology of chronic obstructive pulmonary disease (COPD), including the Th1/Th2 and Th17/T regulatory cells (Treg) paradigms. Clarifying cytokine profiles during COPD acute exacerbation (AE) and their relationships with clinical manifestations would help in understanding the pathogenesis of disease and improve clinical management.Materials and Methods: Eighty seven patients admitted to the hospital with AEs of COPD were included in this study, and follow-up was conducted after discharge (every 30 days, for a total of 120 days). Sputum samples of patients at different time points (including at admission, discharge, and follow-up) were collected, and sputum cytokine profiling (12 cytokines in total) was performed using a Luminex assay.Results: According to the cytokine profiles at admission, patients were divided into three clusters by a k-means clustering algorithm, namely, Th1high Th17high (n=26), Th1lowTh17low (n=56), and Th1high Th17low (n=5), which revealed distinct clinical characteristics. Patients with Th1high Th17low profile had a significantly longer length of non-invasive ventilation time and length of hospital stay than patients with Th1high Th17high profile (7 vs 0 days, 22 vs 11 days, respectively, p < 0.05), and had the highest AE frequency. Sputum levels of Th17 cytokines (IL-17A, IL-22, and IL-23) during AE were negatively correlated with AE frequency in the last 12 months (r = − 0.258, − 0.289 and − 0.216, respectively, p < 0.05). Moreover, decreased sputum IL-17A levels were independently associated with increased AE frequency, with an OR (95% CI) of 0.975 (0.958– 0.993) and p = 0.006.Conclusion: Th1/Th17 imbalance during AE is associated with the severity of COPD. Decreased Th17 cytokine expression is correlated with increased AE frequency. The Th1/Th17 balance may be a specific target for the therapeutic manipulation of COPD.Keywords: chronic obstructive pulmonary disease, acute exacerbation, Th1 cytokines, Th17 cytokines, therapeutic

Zhenming Gao,1,* Jidong Sui,1,* Rong Fan,2 Weikun Qu,1 Xuepeng Dong,1 Deguang Sun1 1Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People’s Republic of China; 2Department of International Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenming Gao; Rong FanDepartment of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Dalian Medical University Department of International Medicine, The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, Liaoning 116027, People’s Republic of ChinaEmail gaozhenmingdl@163.com; fanrongdl@126.comAim: Lung injury is a common complication of acute pancreatitis (AP), which leads to the development of acute respiratory distress syndrome and causes high mortality. In the present study, we investigated the therapeutic effect of emodin on AP-induced lung injury and explored the molecular mechanisms involved.Materials and Methods: Thirty male Sprague-Dawley rats were randomly divided into AP (n=24) and normal (n=6) groups. Rats in the AP group received a retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and then randomly assigned to untreated, emodin, combined emodin and ML385, and dexamethasone (DEX) groups. Pancreatic and pulmonary injury was assessed using H&E staining. In in vitro study, rat alveolar epithelial cell line L2 cells were exposed to lipopolysaccharide and treated with emodin. Nrf2 siRNA pool was applied for the knockdown of Nrf2. The contents of the pro-inflammatory cytokines in the bronchoalveolar lavage fluid and lung were determined using enzyme-linked immunosorbent assay. The expressions of related mRNAs and proteins in the lung or L2 cells were detected using real-time polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence.Key Findings: Emodin administration alleviated pancreatic and pulmonary injury of rats with AP. Emodin administration suppressed the production of proinflammatory cytokines, downregulated NLRP3, ASC and caspase-1 expressions and inhibited NF-κB nuclear accumulation in the lung. In addition, Emodin increased Nrf2 nuclear translocation and upregulated HO-1 expression. Moreover, the anti-inflammatory effect of emodin was blocked by Nrf2 inhibitor ML385.Conclusion: Emodin effectively protects rats against AP-associated lung injury by inhibiting NLRP3 inflammasome activation via Nrf2/HO-1 signaling.Keywords: emodin, acute pancreatitis, lung injury, Nrf2, NLRP3 inflammasome

Minhu Cui,1,2 Mingji Jin,2 Mingfeng Han,2 Yingda Zang,2 Chuangjun Li,2 Dongming Zhang,2 Wei Huang,2 Zhonggao Gao,2 Xuezhe Yin3 1Department of Gastroenterology, Yanbian University Hospital, Yanji 133000, Jilin, People’s Republic of China; 2State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China; 3Department of Respiratory Medicine, Yanbian University Hospital, Yanji 133000, Jilin, People’s Republic of ChinaCorrespondence: Zhonggao GaoState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of ChinaTel/Fax +86 10-63028096Email zggao@imm.ac.cnXuezhe YinDepartment of Respiratory Medicine, Yanbian University Hospital, Yanji 133000, Jilin, People’s Republic of ChinaTel/Fax +86-433-2817019Email yinxz1234@163.comBackground: LA67 is a derivative of triptolide that exhibits strong antitumor activity. This derivative has a better safety profile than triptolide, but is limited by poor aqueous solubility.Aim and Methods: To improve solubility and further increase therapeutic efficacy, we prepared LA67-loaded polymeric micelles (LA67-PMs) using a film hydration method. The physicochemical properties of LA67-PMs were investigated, and the antitumor activity of this formulation against Colon26 (C26) cancer cell line was evaluated in vitro and in vivo with LA67 as a control.Results: Polymeric micelles containing LA67 had a particle size of 17.88 nm and a drug entrapment efficiency of 94.84%. This formulation dispersed completely in aqueous solution and exhibited slow, sustained release of LA67. Cellular uptake assay showed that LA67-PMs delivered LA67 to cancer cells with greater efficiency than free LA67, which resulted in increased LA67 accumulation in cancer cells. Cell counting kit 8 (CCK-8) assay showed that blank polymeric micelles (PMs) exhibited low toxicity and LA67-PMs exerted pronounced anti-proliferation effects against C26 cells. Furthermore, LA67-PMs induced apoptosis and repressed migration more effectively than free LA67. In vivo evaluation of antitumor activity showed that LA67-PMs inhibited tumor growth and distant organ metastasis to a greater extent than LA67, which resulted in improved survival rate. The potential mechanisms of these effects may have been induction of apoptosis, inhibition of cell proliferation, and neovascularization.Conclusion: Our study showed that LA67-PMs may be a promising formulation for treatment of colon cancer.Keywords: triptolide derivatives, polymeric micelles, small size, tumor therapy

Shuting Yu,1 Yingying Zhu,1 Xiaohua Shi,2 Ke Hu,3 Chunmei Bai,4 Wenwen Diao,1 Xiaoli Zhu,1 Zhiqiang Gao,1 Xingming Chen1 1Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Radiotherapy, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Department of Oncology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Xingming Chen Tel +86 13901077778Email xingming.chen@hotmail.comPurpose: To date, no guidelines have been proposed for the ideal treatment of postoperative larynx squamous cell carcinoma (LSCC) patients with lymphovascular invasion due to a lack of similar studies. The present study was conducted to compare the survival and toxicity in LSCC patients with lymphovascular invasion receiving either postoperative radiotherapy (PORT) or postoperative chemoradiotherapy (POCRT). The results can be applied for more appropriate treatment of these patients.Patients and Methods: Three hundred eighty-eight eligible LSCC patients with lymphovascular invasion were enrolled in this retrospective study. Survival and treatment-related toxicities were compared in the POCRT and PORT group using propensity score matching (PSM) methodology (1:1).Results: Five-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) of all patients were 48.7%, 58.2%, and 56.0%, respectively. Significantly, higher RFS rates (P=0.040) were found in the POCRT group than the PORT group in the PSM cohort. In the multivariate analysis, higher OS, DSS, and RFS rates were observed in the POCRT group than the PORT group (P=0.049, 0.024, and 0.011 respectively). Patients in the POCRT group presented more acute toxicities than those in the PORT group such as hematological toxicities (25.0% vs 0.9%, P< 0.001) and mucositis (35.0% vs 19.1%, P=0.002).Conclusion: In the context of no ideal treatment for LSCC patients with lymphovascular invasion, the present study proposes POCRT as a preferable modality compared with PORT, as POCRT was associated with higher RFS rates. Higher RFS, DFS, and OS rates were also observed in the POCRT group in the multivariate analysis.Keywords: head and neck carcinoma, larynx carcinoma, lymphovascular invasion, propensity score, chemoradiotherapy, survival

Yutong He,1 Jin Shi,1 Bernd Schmidt,2 Qingyi Liu,3 Gaofeng Shi,4 Xiaoli Xu,5 Congmin Liu,1 Zhaoyu Gao,1 Tiantian Guo,1 Baoen Shan1 1Cancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, Hebei 050011, People’s Republic of China; 2Department of Internal Medicine - Pneumology and Sleep Medicine, Central Emergency Room, Palliative Medicine, DRK Kliniken Berlin, Berlin 13359, Germany; 3Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, Hebei 050011, People’s Republic of China; 4Department of Radiology, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, Hebei 050011, People’s Republic of China; 5Follow-Up Centre, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, Hebei 050011, People’s Republic of ChinaCorrespondence: Baoen ShanCancer Institute, The Fourth Hospital of Hebei Medical University/The Tumor Hospital of Hebei Province, Shijiazhuang, Hebei 050011, People’s Republic of ChinaTel/Fax +86 311 86095613Email baoenshan62@sina.comBackground and Objective: Compared with tissue biopsy, liquid biopsy is the most preferable non-invasive promising method in personalized medicine, although it has many limitations in isolating circulating tumor cells (CTC). Lung cancer associated mortality is drastically increased due to a shortfall of early-stage detection, which remains a challenge. Herein, we aimed to detect lung cancer at an early-stage using CellCollector device.Methods: 39,627 volunteers underwent low-dose computed tomography; 2508 cases with pulmonary nodules and 7080 with no pulmonary nodules were chosen. After follow-up, 24 patients were diagnosed with early-stage non-small cell lung cancer (NSCLC), and subjected to CTC detection using CellCollector, along with 72 healthy volunteers. Immunofluorescence staining for EpCAM/CKs and CD45 were performed for CTC validation.Results: Fifteen out of twenty-four (stage I, n = 18; stage II, n = 6) early-stage lung cancer patients were found to be CTC-positive, whereas no CTC was found in the control group. Genetic mutation of TP53, ERBB2, PDGFRA, CFS1R and FGFR1 in the CTC revealed 71.6% of the mutation sites similar to the tumor tissues of 13 patients. Molecular characterization revealed higher expression of protein PD-LI in CTC (40%) as compared to tumor tissue (26.7%). Moreover, CTC clusters were detected in 40% of patients.Conclusion: CTC detection using the CellCollector in early-stage NSCLC had a relative high capture rate. Moreover, CTC analysis is a prospective setting for molecular diagnostic in cases when tumor tissue biopsy is not desirable.Keywords: CellCollector, in vivo detection, PD-L1, gene mutation, next generation sequencing

Zhi-peng Li,1,* Gui-xiang Tian,1,* Hong Jiang,1,* Rui-yan Pan,2 Bo Lian,1 Min Wang,1 Zhi-qin Gao,1 Bo Zhang,2 Jing-liang Wu1 1School of Bioscience and Technology, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2School of Pharmacy, Weifang Medical University, Weifang, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo ZhangSchool of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of ChinaEmail bozh315@163.comJing-liang WuSchool of Bioscience and Technology, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of ChinaTel +86 536 846 2541Email jlwu2008@163.comBackground: The tumor-targeting ability and pH-sensitive properties of intelligent drug delivery systems are crucial for effective drug delivery and anti-tumor therapy.Methods: In this study, sHA-DOX/HA-GA mixed micelles were designed with the following properties: sulfated hyaluronic acid (sHA) was synthesized to block cell migration by inhibiting HAase; sHA-DOX conjugates were synthesized via pH-sensitive hydrazone bond to realize DOX-sensitive release. The introduction of HA-GA conjugate could improve active-targeting ability and cellular uptake.Results: The results showed that the mixed micelles possessed a nearly spherical shape, nanoscale particle size (217.70±0.89 nm), narrow size distribution (PDI=0.07±0.04), negative zeta potential (−31.87±0.61 mV) and pH-dependent DOX release. In addition, the sHA-DOX/HA-GA micelles exhibited concentration-dependent cytotoxicities against liver carcinoma cells (HepG2) and HeLa cells, and were shown to be effectively taken up by HepG2 cells by confocal microscopy analysis. Furthermore, the in vivo anti-tumor study showed that mixed micelles had a superior anti-tumor effect compared to that of free DOX. Further evidence obtained from the hematoxylin–eosin staining and immunohistochemistry analysis also demonstrated that sHA-DOX/HA-GA exhibited stronger tumor inhibition and lower systemic toxicity than free DOX.Conclusion: The sHA-DOX/HA-GA mixed micelles could be a potential drug delivery system for anti-hepatoma therapy.Keywords: hyaluronic acid, glycyrrhetinic acid, hepatoma-targeting, pH-sensitive, micelles, anti-tumor therapy

Zhan Su,1,2 Duanqin Liu,1,2 Liying Chen,2 Jun Zhang,1,2 Lu Ru,2 Zhiyu Chen,2 Zhennan Gao,1,2,* Xuxia Wang1,2,* 1Shandong Provincial Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong 250012, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, Jinan, Shandong 250012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhennan Gao;Xuxia WangDepartment of Oral and Maxillofacial Surgery, School of Stomatology, Shandong University, 44-1 West Wenhua Road, Jinan, Shandong 250012, People’s Republic of ChinaTel +86 531 15169070891; +86 531 13906410670Email zngao@sdu.edu.cn; wxx@sdu.edu.cnBackground: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignant tumor in the world. Studies in recent years have demonstrated that cancer stem cells (CSCs) are present in many tumor tissues, including HNSCC, and CSCs are the root cause of tumor recurrence and metastasis. Thus, taking new treatment measures to target the killing of CSCs that are resistant to chemotherapy and radiotherapy is key to the success of cancer treatment.Methods: We explored a method for preparing anti-CD44 antibody-modified superparamagnetic iron oxide nanoparticles (SPIONPs). Biocompatibility was evaluated by a CCK-8 assay. The CSCs were obtained by a 3D cell culture technique from Cal-27 (human oral squamous cell carcinoma) cells, and then the CSCs were identified by quantitative real-time polymerase chain reaction (qRT-PCR). The targeting efficiency of the CD44-SPIONPs to CSCs was confirmed by Prussian blue staining and visualized by laser scanning confocal microscopy (LSCM). Flow cytometry was used to detect the apoptosis of CSCs after alternating magnetic field (AMF) treatment. The efficacy of tumor growth inhibition by CD44-SPIONP-mediated magnetic hyperthermia therapy was evaluated with tumor xenografts in nude mice.Results: The CD44-SPIONPs exhibited no negative effect on CSCs, indicating good biocompatibility. After SPIONPs were cocultured with stem cells, the majority of CD44-SPIONPs labeled with FITC penetrated the cell membrane into the cytoplasm. After AMF treatment, CD44-SPIONPs induced CSCs to undergo programmed death. The inhibitory ratio of the treated group was 33.43%, and necrotic areas in the tumor tissue were mainly distributed around the magnetic fluid.Conclusion: These results demonstrate that it is possible to kill CSCs using targeted magnetic nanoparticles and an AMF and that magnetic fluid hyperthermia significantly inhibited the growth of grafted Cal-27 tumors in mice.Keywords: magnetic nanoparticles, cancer stem cells, alternating magnetic field, tumor targeting

Zhongbao Zhou,1,2,* Shiqiang Song,3,* Zhenli Gao,2 Jitao Wu,2 Jiajia Ma,2 Yuanshan Cui2 1School of clinical medicine, Binzhou Medical University, Yantai, Shandong, China; 2Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China; 3Department of Urology, Qingdao Chengyang People’s Hospital, Qingdao, Shandong, China *These authors contributed equally to this work Aim: We performed a meta-analysis to evaluate the efficacy and safety of dutasteride and finasteride in treating men with androgenetic alopecia (AGA) during a 24-week treatment cycle.Methods: Randomized controlled trials of dutasteride and finasteride for treating AGA were searched using MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The data were calculated using Rev Man v5.3.0. The reference lists of retrieved studies were also investigated.Results: Three articles including 576 participants which compared dutasteride with finasteride were selected for our analysis. The mean change in total hair count (mean difference [MD], 28.57; 95% CI, 18.75–38.39; P

Jin Liu,1,* Chengyong Dong,2,* Haibo Wang,2 Deguang Sun,2 Rui Liang,2 Zhenming Gao,2 Liming Wang1,2 1General Surgery, Center for New Material and New Precision Technology of Cancer Therapy, Dalian Medical University, Dalian, Liaoning, China; 2Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China *These authors contributed equally to this work Abstract: A horseshoe appendix is a subtype of duplex appendix, in which the appendix is shaped like a circle that may lead to an internal hernia and result in intestinal necrosis. This subtype is extremely rare, with only 13 cases reported worldwide to date, and easily triggers a series of medico-legal consequences due to the neglect of another infection base of the appendix. We describe a 22-year-old man who presented with a 3-day history of fever and was diagnosed with pneumonia. After receiving antibiotics for 3 days in the Department of Pneumology, he was found to have a periappendiceal abscess. He underwent appendectomy after 3 days of conservative treatment failure in the Department of General Surgery. During the operation, we found that he had a horseshoe appendix with the two bases forming a circle, each communicating with the cecum. We provide a review of 13 cases presented in the literature, with a discussion of the clinical features, diagnosis, and surgical approach of the horseshoe appendix to make the general surgeon get a clear concept of this type of appendicitis. Keywords: appendix malformation, hernia, intestinal obstruction, embryonic development, appendix neoplasm

Xiuran Niu,1,* Zhihui Gao,1,* Shanshan Qi,1 Linjia Su,1 Nan Yang,1 Xiuli Luan,1 Jia Li,1 Qing Zhang,2 Yingli An,3 Sihe Zhang1 1Department of Cell Biology, School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2Department of Clinical Laboratory, Cancer Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3State Key Laboratory of Medicinal Chemical Biology and Institute of Polymer Chemistry, Nankai University, Tianjin, People’s Republic of China *These authors contributed equally to this work Background: Successful implementation of gene therapy heavily relies on efficiently delivering genetic materials and specific targeting into cells. Oncogene-driven endocytosis stimulates nutrient uptake and also develops an endocytosis-mediated defense against therapeutic agents. Cell-penetrating peptides, typically HIV-Tat, are well known for efficient delivery of nucleic acid drugs but lack targeting specificity. Various passive targeting strategies were pursued to enhance the tumor targeting efficiency; however, they are still limited by complicated cellular endocytosis routes and the heterogeneity of cancer types. Methods: Tat/pDNA complexes were noncovalently compacted and their physiochemical properties were determined. The siRNA pool and pLV-RNAi-GFP lentivirus were used to knock down dbl oncogene (originally isolated from diffuse B-cell lymphoma) expression, and its overexpression was performed by plasmid transient transfection. The cellular uptake of fluorescent ligands was quantified by confocal imaging and flow cytometry analysis. The transgene efficiency was determined by the Luciferase expression assay. Rho GTPase activation was checked by the GST-Rho GTPase-binding domain pull-down assay. Results: pGL3 plasmid DNA was noncovalently compacted with the Tat peptide into nano-size complexes at high N/P ratios. Macropinocytosis, a clathrin- and caveolin-independent endocytosis process, was shown to contribute to the uptake of middle-sized (~600 nm) Tat/pGL3 complexes. Cell-type-specific variation in macropinocytosis was essentially controlled by the action of the Dbl oncogene. Onco-Dbl presentation constantly induced a high level of macropinocytosis activity in ovarian cancer cells. Onco-Dbl overexpression hyperstimulated macropinocytosis enhancement in cells mainly through actin cytoskeleton reorganization mediated by the PH domain and Rac1 activation. The Dbl-driven Rho GTPase signaling collectively determined the cell-type-specific macropinocytosis phenotype. Conclusion: Such an aspect can be exploited to selectively confer targeted delivery of Tat/pDNA nano-complexes into ovarian cancer cells. Our work provides a novel alternative for targeted delivery of cell-penetrating peptide-based nucleic acid drugs into certain tumor types if specific endocytosis pathways are used. Keywords: onco-Dbl, macropinocytosis, Rac1, Tat/pDNA complex, targeting delivery

Jicai Zhang, Xiang Xiao, Jianming Zhu, Ziyun Gao, Xianliang Lai, Xingen Zhu, Guohua Mao Department of Neurosurgery, Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China Purpose: Glioblastoma multiforme (GBM) is the most common malignant brain tumor originating in the central nervous system in adults. Based on nanotechnology such as liposomes, polymeric nanoparticles, and lipid nanoparticles, recent research efforts have been aimed to target drugs to the brain. Methods: In this study, lactoferrin- and arginine–glycine–aspartic acid (RGD) dual-ligand-comodified, temozolomide and vincristine-coloaded nanostructured lipid carriers (L/R-T/V-NLCs) were introduced for GBM combination therapy. The physicochemical properties of L/R-T/V-NLCs such as particle size, zeta potential, and encapsulated efficiency are measured. The drug release profile, cellular uptake, cytotoxicity, tissue distribution, and antitumor activity of L/R-T/V-NLCs are further investigated in vitro and in vivo. Results: L/R-T/V-NLCs were stable with nanosize and high drug encapsulation efficiency. L/R-T/V-NLCs exhibited sustained-release behavior, high cellular uptake, high cytotoxicity and synergy effects, increased drug accumulation in the tumor tissue, and obvious tumor inhibition efficiency with low systemic toxicity. Conclusion: L/R-T/V-NLCs could be a promising drug delivery system for glioblastoma chemotherapy. Keywords: gliomatosis cerebri, combination therapy, nanostructured lipid carriers, lactoferrin, arginine–glycine–aspartic acid peptide, vincristine, temozolomide

Mingji Jin,1 Guangming Jin,2 Lin Kang,1 Liqing Chen,1 Zhonggao Gao,1 Wei Huang11State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Department of Diagnostic Radiology 2, Yanbian University Hospital, Yanji, Jilin, China Background: The co-delivery of chemotherapeutic agents and small interfering RNA (siRNA) within one cargo can enhance the anticancer outcomes through its synergistic therapeutic effects. Materials and methods: We prepared smart polymeric nanoparticles (NPs) with pH-responsive and poly(ethylene glycol) (PEG)-detachable properties to systemically co-deliver paclitaxel (PTX) and siRNA against survivin gene for lung cancer therapy. The cationic polyethyleneimine-block-polylactic acid (PEI-PLA) was first synthesized and characterized, with good biocompatibility. PTX was encapsulated into the hydrophobic core of the PEI-PLA polymers by dialysis, and then the survivin siRNA was loaded onto the PTX-loaded NPs (PEI-PLA/PTX) through electrostatic interaction between siRNA and PEI block. Finally, the negatively charged poly(ethylene glycol)-block-poly(l-aspartic acid sodium salt) (PEG-PAsp) was coated onto the surface of NPs by electrostatic interaction to form final smart polymeric NPs with mean particle size of 82.4 nm and zeta potential of 4.1 mV. After uptake of NPs by tumor cells, the PEG-PAsp segments became electrically neutral owing to the lower endosome pH and consequently detached from the smart NPs. This process allowed endosomal escape of the NPs through the proton-sponge effect of the exposed PEI moiety. Results: The resulting NPs achieved drug loading of 6.04 wt% and exhibited good dispersibility within 24 h in 10% fetal bovine serum (FBS). At pH 5.5, the NPs presented better drug release and cellular uptake than at pH 7.4. The NPs with survivin siRNA effectively knocked down the expression of survivin mRNA and protein owing to enhanced cell uptake of NPs. Cell counting kit-8 (CCK-8) assay showed that the NPs presented low systemic toxicity and improved antiproliferation effect of PTX on A549 cells. Moreover, in vivo studies demonstrated that accumulated NPs in the tumor site were capable of inhibiting the tumor growth and extending the survival rate of the mice by silencing the survivin gene and delivering PTX into tumor cells simultaneously. Conclusion: These results indicate that the prepared nano-vectors could be a promising co-delivery system for novel chemo/gene combination therapy. Keywords: PEG detachable, co-delivery, survivin siRNA, paclitaxel, pH responsive

Zhuanglei Gao,1 Zhaoxia Li,2 Jieke Yan,3 Peilin Wang1 1Department of General Surgery, 2Department of Pediatrics, 3Department of Renal Transplantation, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China Abstract: For targeted gastric carcinoma therapy, hyaluronic acid (HA)-modified layer-by-layer nanoparticles (NPs) are applied for improving anticancer treatment efficacy and reducing toxicity and side effects. The aim of this study was to develop HA-modified NPs for the co-loading of irinotecan (IRN) and 5-fluorouracil (5-FU). A novel polymer–chitosan (CH)–HA hybrid formulation (HA–CH–IRN/5-FU NPs) consisting of poly(D,L-lactide-co-glycolide) (PLGA) and IRN as the core, CH and 5-FU as a shell on the core and HA as the outmost layer was prepared. Its morphology, average size, zeta potential and drug encapsulation ability were evaluated. Human gastric carcinoma cells (MGC803 cells) and cancer-bearing mice were used for the testing of in vitro cytotoxicity and in vivo antitumor efficiency of NPs. HA–CH–IRN/5-FU NPs displayed enhanced antitumor activity in vitro and in vivo than non-modified NPs, single drug-loaded NPs and drugs solutions. The results demonstrate that HA–CH–IRN/5-FU NPs can achieve impressive antitumor activity and the novel targeted drug delivery system offers a promising strategy for the treatment of gastric cancer. Keywords: gastric carcinoma, irinotecan, 5-fluorouracil, hyaluronic acid, layer-by-layer nanoparticles

Ping Sun,1 Wei Huang,1 Lin Kang,1 Mingji Jin,1 Bo Fan,1 Hongyan Jin,2 Qi-Ming Wang,1 Zhonggao Gao1 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 2Yanbian University Hospital, Jilin, People’s Republic of China Abstract: An ideal carrier that delivers small interfering RNA (siRNA) should be designed based on two criteria: cellular-mediated internalization and endosomal escape. Poly(histidine-arginine)6(H6R6) peptide was introduced into chitosan (CS) to create a new CS derivative for siRNA delivery, 6-polyarginine (R6) as cell-penetrating peptides facilitated nanoparticle cellular internalization has been proved in our previous research, and 6-polyhistidine (H6) mediated the nanoparticle endosome escape resulted in the siRNA rapid releasing into tumor cytoplasm. H6R6-modified CS nanoparticles showed higher transfection efficiency and better endosomal escape capacity compared to ungroomed CS nanoparticle in vitro. Noticeably, H6R6-modified CS nanoparticles effectively inhibited tumor cell growth and metastases in vivo and significantly improved survival ratio. Therefore, we concluded that H6R6-modified CS copolymer can act as an ideal carrier for siRNA delivery and as a promising candidate in breast cancer therapy. Keywords: poly(histidine-arginine)6-peptide-modified chitosan nanoparticle, cell-penetrating peptides, endosome/lysosome escape, gene delivery, breast carcinoma

Ping Sun,1,2 Wei Huang,1,2 Mingji Jin,1,2 Qiming Wang,1,2 Bo Fan,1,2 Lin Kang,1,2 Zhonggao Gao1,2 1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, 2Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China Abstract: Nanoparticle-mediated small interfering RNA (siRNA) delivery is a promising therapeutic strategy in various cancers. However, it is difficult to deliver degradative siRNA to tumor tissue, and thus a safe and efficient vector for siRNA delivery is essential for cancer therapy. In this study, poly(ethylene glycol)-modified chitosan (PEG-CS) was synthesized successfully for delivering nucleic acid drug. We deemed that PEGylated CS could improve its solubility by forming a stable siRNA loaded in nanoparticles, and enhancing transfection efficiency of siRNA-loaded CS nanoparticles in cancer cell line. The research results showed that siRNA loaded in PEGylated CS (PEG-CS/siRNA) nanoparticles with smaller particle size had superior structural stability in the physical environment compared to CS nanoparticles. The data of in vitro antitumor activity revealed that 4T1 tumor cell growth was significantly inhibited and cellular uptake of PEG-CS/siRNA nanoparticles in 4T1 cells was dramatically enhanced compared to naked siRNA groups. The results from flow cytometry and confocal laser scanning microscopy showed that PEG-CS/siRNA nanoparticles were more easily taken up than naked siRNA. Importantly, PEG-CS/siRNA nanoparticles significantly reduced the growth of xenograft tumors of 4T1 cells in vivo. It has been demonstrated that the PEG-CS is a safe and efficient vector for siRNA delivery, and it can effectively reduce tumor growth and prevent metastasis. Keywords: PEGylated chitosan, non-viral vector, siRNA delivery, breast anti-tumor therapy

Zhiqiang Wang,1 Lei Yuan,1 Yongchuan Wang,2 Baizhi Yang,1 Xiaohong Dong,1 Zhaowang Gao3 1Department of Urology, Shouguang Hospital of Traditional Chinese Medicine, Shouguang, 2Department of Urology, Weifang Traditional Chinese Hospital, Weifang, 3Department of Urology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Shandong, People’s Republic of China Objective: The aim of this meta-analysis and systematic review is to evaluate the safety and efficacy of Chinese herbal medicine (CHM) for chronic prostatitis (CP) associated with damp-heat and blood-stasis syndromes.Methods: An electronic search of 13 databases up to May 2016 was screened to identify randomized controlled trials comparing the safety and efficacy of CHM for the treatment of CP associated with damp-heat and blood-stasis syndromes. Studies reporting on effective rates, adverse events, National Institutes of Health chronic prostatitis symptom index (NIH-CPSI) scores, and symptom index of Chinese medicine for chronic prostatitis (SI-CM) scores as outcomes were included in the analysis. Data were analyzed by fixed- or random-effect models using the Review Manager software.Results: Thirteen articles with the modified Jadad score ≥4 were identified. It was found that CHM was superior to placebo in increasing the efficacy (odds ratio: 6.72, 95% confidence interval [CI]: 2.78–9.48, P

Nan Zeng, Zan Gao College of Education and Human Development, School of Kinesiology, University of Minnesota, Minneapolis, MN, USA Abstract: Although exergaming has been used as a physical activity modality among various populations, the evidence regarding its effectiveness on health-related outcomes in overweight/obese individuals remains unclear. The current study systematically reviewed literature and summarized findings of exergame-based interventions in overweight/obese populations with the goal of clarifying the current perspectives on exergaming and obesity. The initial search yielded 202 articles from six databases; 12 studies were included after evaluating for inclusion criteria and removing duplicates. Among these studies, seven were randomized controlled trials, two were control trials, and three were comparison studies. Overall, exergaming has the potential to attenuate weight gain and shows promise when used for physical activity and physical fitness promotion. Further, exergame play is positively associated with psychological well-being, but its effects on physiological outcomes are inconclusive. Finally, effects of exergaming on energy intake are not clear. Existing evidence supports that exergaming may elicit some health benefits in people who are overweight or/and obese. The limited number of available randomized controlled trials, however, restrict the ability to draw a conclusion that exergaming can trigger a change in all health-related outcomes. More research is warranted to make definitive conclusions regarding the effects of exergaming on health-related outcomes in such populations. Keywords: active video game, weight loss, children and adolescents, systematic review

The generation of angular momentum in the fission process is still an open question. To shed light on this topic, we started a series of measurements at the IGISOL-JYFLTRAP facility in Finland. Highprecision measurements of isomeric yield ratios (IYR) are performed with a Penning trap, partly with the aim to extract average root-mean-square (rms) quantities of fragment spin distributions. The newly installed Phase-Imaging Ion-Cyclotron Resonance (PI-ICR) technique allows the separation of masses down to tens of keV, which is suffcient to disentangle many isomers. In this paper, we first summarize the previous measurements on the neutron and proton-induced fission of uranium and thorium, e.g. the odd cadmium and indium isotopes (119 ≤ A ≤ 127). The measurements revealed systematic trends as function of mass number, which stimulated further exploration. A recent measurement was performed at IGISIOL and several new IYR data will soon be published, for the first time. Secondly, we employ the TALYS nuclear-reaction code to model one of the newly measured isomer yields. Detailed GEF and TALYS calculations are discussed for the fragment angular momentum distribution in 134I.

Wenjie Tian,1,2,* Hongen Lei,1,* Ruili Guan,1 Yongde Xu,1 Huixi Li,1 Lin Wang,1 Bicheng Yang,1 Zhezhu Gao,1 Zhongcheng Xin1 1Andrology Center, Peking University First Hospital, Peking University, Beijing, 2Department of Urology, The Second Hospital of Jilin University, Jilin University, Changchun, People’s Republic of China *These authors contributed equally to this work Purpose: To investigate the therapeutic effects and potential mechanisms of icariside II (ICA II) on reversing diabetic nephropathy in streptozotocin (STZ)-induced type I diabetic rats.Methods: Newborn male Sprague Dawley rats were labeled with thymidine analog 5-ethynyl-2-deoxyuridine (EdU) for tracking endogenous label retaining progenitor cells (LRCs). At age of 8 weeks, 48 rats were randomly divided into three groups: normal control group (n=16), diabetes mellitus group (DM; n=16), and diabetes mellitus plus ICA II therapy group (DM+ICA II, n=16). Eight weeks induced for diabetes with STZ, rats in DM group and DM+ICA II group were treated with vehicle or ICA II (5 mg/kg/day) for another 8 weeks, respectively. Then, blood creatinine, 24-hour urine protein, blood urea nitrogen, and glycosylated hemoglobin were measured, as well as the expression of von Willebrand factor, malondialdehyde, transforming growth factor-β/drosophila mothers against decapentaplegic protein/connective tissue growth factor (TGF-β/Smad/CTGF) signaling, marker of proliferation Ki-67, and EdU+ LRCs in renal tissues.Results: Increased levels of creatinine, 24-hour urine protein, and blood urea nitrogen and remarkably decreased proportion of normal glomeruli and increased proportions of I, IIa, IIb, and III glomeruli were observed in diabetic rats, while ICA II could reverse these changes. Interestingly, ICA II could significantly downregulate the levels of malondialdehyde and TGF-β/Smad/CTGF signaling and increase the expression of von Willebrand factor, Ki-67, and EdU+ LRCs in the kidney.Conclusion: ICA II treatment could ameliorate diabetic nephropathy in STZ-induced diabetic rats by increasing endothelial cell contents, downregulating TGF-β/Smad/CTGF signaling pathway and oxidative stress level, and promoting cell proliferation both in kidney cortex and medulla. These beneficial effects appear to be mediated by its antioxidant capacity and recruitment of endogenous EdU+ progenitor cells into the kidney tissue. Keywords: diabetic nephropathy, icariside II, EdU, diabetes mellitus, label retaining progenitor cells

X Zhou,1 X Chen,2 JJ Cai,2 LZ Chen,3 YS Gong,4 LX Wang,5 Z Gao,1 HQ Zhang,1 WJ Huang,1 H Zhou1 1Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, 2Wenzhou Medical University, 3Department of Clinical Laboratory, Wenzhou Central Hospital, 4Institute of Hypoxia Medicine, Wenzhou Medical University, 5Department of Respiratory Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China Background: Relaxin (RLX) can prevent cardiac fibrosis. We aimed to investigate the possible mechanism and signal transduction pathway of RLX inhibiting cardiac fibrosis.Methods: Isoproterenol (5 mg·kg-1·d-1) was used to establish the cardiac fibrosis model in rats, which were administered RLX. The cardiac function, related targets of cardiac fibrosis, and endothelial–mesenchymal transition (EndMT) were measured. Transforming growth factor β (TGF-β) was used to induce EndMT in human umbilical vein endothelial cells, which were pretreated with RLX, 200 ng·mL-1, then with the inhibitor of Notch. Transwell cell migration was used to evaluate cell migration. CD31 and vimentin content was determined by immunofluorescence staining and Western blot analysis. Notch protein level was examined by Western blot analysis.Results: RLX improved cardiac function in rats with cardiac fibrosis; it reduced the content of collagen I and III, increased the microvascular density of the myocardium, and suppressed the EndMT in heart tissue. In vitro, RLX decreased the mobility of human umbilical vein endothelial cells induced by TGF-β, increased the expression of endothelial CD31, and decreased vimentin content. Compared to TGF-β and RLX co-culture alone, TGF-β + RLX + Notch inhibitor increased cell mobility and the EndMT, but decreased the levels of Notch-1, HES-1, and Jagged-1 proteins.Conclusion: RLX may inhibit the cardiac fibrosis via EndMT by Notch-mediated signaling. Keywords: relaxin, endothelial to mesenchymal transition, transforming growth factor β, myocardial fibrosis, Notch

Yunqing Li,1 Xisheng Li,1 Guodong Feng,2 Zhiqiang Gao,2 Peng Shen21School of Automation and Electrical Engineering, University of Science and Technology, Beijing, 2Department of Otolaryngology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China Abstract: Surgeons are continuing to strive toward achieving higher quality minimally invasive surgery. With the growth of modern technology, intelligent medical devices are being used to improve the safety of surgery. Milling beyond the bone tissue wall is a common abnormal milling state in ear surgery, as well as entanglement of the drill bit with the cotton swab, which will do harm to the patient's encephalic tissues. Various methods have been investigated by engineers and surgeons in an effort to avoid this type of abnormal milling state during surgery. This paper outlines a new method for identifying these two types of abnormal milling states. Five surgeons were invited to perform experiments on calvarial bones. The average recognition rate for otological drill milling through a bone tissue wall was 93%, with only 2% of normal millings being incorrectly identified as milling faults. The average recognition rate for entanglement of the drill bit with a cotton swab was 92%, with only 2% of normal millings being identified as milling faults. The method presented here can be adapted to the needs of the individual surgeon and reliably identify milling faults. Keywords: intelligent system, otological drill, multi-sensor information fusion

Ping Yang,1 Zhenyong Gao,1 Handi Zhang,1 Zeman Fang,1 Cairu Wu,1 Haiyun Xu,1,2 Qing-Jun Huang1 1Mental Health Center, 2Department of Anatomy, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China Abstract: Although the pathogenesis of depression, an incapacitating psychiatric ailment, remains largely unknown, previous human and animal studies have suggested that both proinflammatory cytokines and altered oligodendrocytes play important roles in the condition. This study examined these two factors in the brains of rats following unpredictable chronic mild stress for 4 weeks, with the hypothesis that chronic stress may affect oligodendrocytes and elevate proinflammatory cytokines in the brain. After suffering unpredictable stressors for 4 weeks, the rats showed depression-like behaviors, including decreased locomotion in the open field, increased immobility time in the forced swim test, and decreased sucrose consumption and less sucrose preference when compared with controls. Immunohistochemical staining of brain sections showed higher immunoreactivity of proinflammatory cytokines in certain brain regions of stressed rats compared with controls; lower immunoreactivity of myelin basic protein and fewer mature oligodendrocytes were seen in the prefrontal cortex, but no demyelination was detected. These results are interpreted and discussed in the context of recent findings from human and animal studies. Keywords: cytokines, depression, myelination, oligodendrocytes, stress