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Siyuan Wang,1,* Beiyao Gao,1,* Minghui Shi,2– 6 Shiwei Qumu,2– 5 Fen Dong,2– 5,7 Peijian Wang,1 Ting Yang,2– 5 Shan Jiang1 1Department of Rehabilitation Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2National Center for Respiratory Medicine, Beijing, People’s Republic of China; 3National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 4Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 6Capital Medical University, Beijing, People’s Republic of China; 7Department of Clinical Research and Data management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shan Jiang; Ting Yang, China-Japan Friendship Hospital, 2 Yinghuayuan East St. Hepingli, Chaoyang District, Beijing, 100029, People’s Republic of China, Email landjiang@126.com; dryangting@qq.comObjective: Given the established impact of exercise in reducing arterial stiffness and the potential for intermittent hypoxia to induce its elevation, this study aims to understand how oxygen desaturation during exercise affects arterial stiffness in individuals with COPD.Methods: We enrolled patients with stable COPD from China-Japan Friendship Hospital from November 2022 to June 2023. The 6-minute walk test (6-MWT) was performed with continuous blood oxygen saturation (SpO2) monitoring in these patients. The patients were classified into three groups: non-exercise induced desaturation (EID), mild-EID and severe-EID, according to the changes in SpO2 during the 6-MWT. The Cardio-Ankle Vascular Index (CAVI) and the change in CAVI (ΔCAVI, calculated as CAVI before 6MWT minus CAVI after the 6MWT) were measured before and immediately after the 6MWT to assess the acute effects of exercise on arterial stiffness. GOLD Stage, pulmonary function, and other functional outcomes were also measured in this study.Results: A total of 37 patients with stable COPD underwent evaluation for changes in CAVI (ΔCAVI) before and after the 6-MWT. Stratification based on revealed three subgroups: non-EID (n=12), mild-EID (n=15), and severe-EID (n=10). The ΔCAVI values was − 0.53 (− 0.95 to − 0.31) in non-EID group, − 0.20 (− 1.45 to 0.50) in mild-EID group, 0.6 (0.08 to 0.73) in severe-EID group. Parametric tests indicated significant differences in ΔCAVI among EID groups (p = 0.005). Pairwise comparisons demonstrated significant distinctions between mild-EID and severe-EID groups, as well as between non-EID and severe-EID groups (p = 0.048 and p = 0.003, respectively). Multivariable analysis, adjusting for age, sex, GOLD stage, diffusion capacity, and blood pressure, identified severe-EID as an independent factor associated with ΔCAVI (B = 1.118, p = 0.038).Conclusion: Patients with COPD and severe-EID may experience worsening arterial stiffness even during short periods of exercise.Keywords: COPD, arterial stiffness, exercise-induced oxygen desaturation, rehabilitation

Zhi-yong Lyu, Jing-hui Zhen, Qing-ying Meng, Wei Zhou, Jing-yun An, Fang Dong Department of Clinical Laboratory Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of ChinaCorrespondence: Fang Dong, Department of Clinical Laboratory Center, Beijing Children’s Hospital Affiliated to Capital Medical University, No. 56 Nan Lishi Road, Beijing, 100045, People’s Republic of China, Email fangd32@163.comPurpose: Bloodstream infections (BSIs) was an essential cause of morbidity and mortality in children. Empiric broad-spectrum treatment of BSIs may be costly and unable to effectively eliminate the correct pathogenic microbes, resulting in downstream antimicrobial resistance. The purpose was to provide evidence for diagnosis and treatment of bloodstream infections in pediatrics, by revealing the pathogen distribution and antibiotic resistance pattern of BSIs.Methods: In this 5-year study, a total of 2544 pathogenic bacteria stains, isolated from 2368 patients with BSI, were retrospectively analyzed, to define the species distribution and the antimicrobial resistance pattern in Beijing.Results: The most frequently isolated pathogenic bacteria were K. pneumoniae (12.1%), S. aureus (11.5%), E. coli (11.2%), and E. faecium (11.2%). Hematological malignancies were the most common disease among patients with underlying conditions. Methicillin resistance was detected in 30.0% of S. aureus and 81.7% of coagulase-negative Staphylococcus (CoNS), respectively. The detection rates of carbapenem-resistant-E. coli (CRECO) and carbapenem-resistant-K. pneumoniae (CRKPN) were 10.8% and 50.8%, respectively. In terms of 122 isolates of S. pneumonia, 5 isolates (4.1%) were penicillin-resistant Streptococcus pneumoniae (PRSP); meanwhile, 50 isolates (41.0%) were penicillin-intermediate Streptococcus pneumoniae (PISP). Among the non-fermentative gram-negative bacilli isolates, 22.8% and 26.9% of the P. aeruginosa, were resistant to imipenem and meropenem. Furthermore, the resistance rates of A. baumannii to imipenem and meropenem both were 54.5%.Conclusion: In the study, we demonstrated the characteristics of bloodstream infections and antimicrobial susceptibility pattern of pediatrics in Beijing. Gram positive bacteria were the main pathogens of BSIs. CoNS strains presented even higher resistance to multiple antibiotics, including methicillin, than S. aureus. K. pneumoniae and E. coli represent the most common isolated gram-negative bacteria and exhibited high resistance to a variety of antimicrobial agents. Therefore, it was of critical importance to implement appropriate antimicrobial medication according to pathogen distribution and drug susceptibility test.Keywords: bloodstream infections, children, etiology, antimicrobial resistance, methicillin-resistant S. aureus, methicillin-resistant coagulase-negative staphylococci, S. pneumoniae, carbapenem-resistant Enterobacter

Zhiyong Lyu,1 Jing Li,2 Jinghui Zhen,1 Wei Shi,3 Qingying Meng,1 Wei Zhou,1 Jingyun An,1 Kaihu Yao,3,&ast; Fang Dong1,&ast; 1Department of Clinical Laboratory Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Department of Clinical Laboratory, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Dong; Kaihu Yao, Department of Clinical Laboratory Center, Beijing Children’s Hospital Affiliated to Capital Medical University, No. 56 Nan Lishi Road, Beijing, 100045, People’s Republic of China, Email fangd32@163.com; yaokaihu@bch.com.cnIntroduction: Streptococcus pneumoniae (S. pneumoniae) is a major pathogen causing death in children. Few studies have evaluated the importance of S. pneumoniae in the identified bacteria in clinical work. This retrospective study aimed to reveal the rank of S. pneumoniae in determined bacteria isolated from children in Beijing, China, as well as the antimicrobial resistance of this pathogen.Methods: The number of specimen for bacterial culture and of bacterial species were cumulated and ranked based on the data of the two largest children’s hospitals in Beijing from 2015 to 2021. The temporal change of S. pneumoniae culture, as well as the clinical data of S. pneumoniae isolates were collected and analyzed. The minimum inhibitory concentrations of antimicrobial agents were determined by BD Phoenix 100 automated system or Vitek 2 automated system for antimicrobial susceptibility testing. The breakpoints recommended by CLSI were adopted.Results: During the 7-year study period, a total of 45,631 bacterial isolates were cultured from 462,144 submitted specimens, in which S. pneumoniae was the third frequent agent following S. aureus and H. influenza, and accounting for 8.79% of the isolates (4011/45,631). In the 4011 S. pneumoniae isolates, 2239 and 997 ones were, respectively, isolated from sputum and bronchial lavage fluid. Most of S. pneumoniae strains were identified in winter (34.7%) and spring (26.1%), and were mainly isolated from patients under 5 years old (77.1%). Low susceptible rate (27.6%) of CSF isolates was determined to penicillin according to the parenteral meningitis breakpoints, while high susceptible rate (56.9%) of non-CSF isolates was obtained according to the parenteral non-meningitis breakpoints. The isolates showed low sensitivity to erythromycin and tetracycline (< 5%). All isolates were susceptible to vancomycin and linezolid.Conclusion: The present results demonstrated that S. pneumoniae was one of the most commonly detected bacteria in current pediatric clinical tests, especially in young children under 5 years old, which emphasized the importance of prevention. Penicillin could still be the first empiric choice to treat non-meningitis pneumococcal infections, while erythromycin should not be involved in the treatment.Keywords: Streptococcus pneumoniae, antimicrobial resistance, children, China

Jiachi Zhang,1 Shujuan Xiao,1,2 Lei Shi,1 Yaqing Xue,1,2 Xiao Zheng,1,2 Fang Dong,1 Benli Xue,1 Chichen Zhang1,3,4 1School of Health Management, Southern Medical University, Guangzhou, People’s Republic of China; 2School of Public Health, Southern Medical University, Guangzhou, People’s Republic of China; 3Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 4Institute of Health Management, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Chichen Zhang, School of Health Management, Southern Medical University, No. 1023 Shatai South Road, Baiyun District, Guangzhou, 510515, People’s Republic of China, Tel +86-20-61648756, Email zhangchichen@sina.comPurpose: Urban-rural health disparity is one of the most prominent challenges in China today. The goal of this study is to find differences in health-related quality of life (HRQoL) and its associated factors among older people in urban and rural areas.Methods: A multi-stage stratified sampling method was conducted in Shanxi Province, with a total of 3250 older adults participated in this cross-sectional survey. HRQoL was assessed using the Chinese version of the EQ-5D-5L. Tobit regression models were employed to identify associated factors for HRQoL.Results: The mean EQ-5D utility score of the total sample was 0.87± 0.23, with a statistically significant difference observed between urban (0.89 ± 0.22) and rural areas (0.86 ± 0.23). Obesity (Coe=− 0.10, p=0.021) and nutrition awareness (Coe=− 0.14, p=0.009) were two unique associated factors to rural older adults’ HRQoL. While, age (Urban: Coe=0.13, p=0.001; Rural: Coe=− 0.019, p< 0.001), socioeconomic status (Urban: Coe=0.13, p< 0.001; Rural: Coe=0.14, p< 0.001), number of chronic non-communicable diseases (Urban: Coe=− 0.20, p< 0.001; Rural: Coe=− 0.15, p< 0.001), sleep quality (Urban: Coe=− 0.22, p< 0.001; Rural: Coe=0.15, p< 0.001) and daytime sleepiness (Urban: Coe=− 0.13, p< 0.001; Rural: Coe=− 0.13, p< 0.001) were found to be associated with HRQoL regardless of the residential area.Conclusion: This study suggested that rural older adults are facing HRQoL disadvantages compared to those in urban area. Accordingly, more attention should be devoted to rural older adults’ HRQoL, particularly to the unique factors like body weight and nutrition awareness. Targeted policies and interventions should be implemented to improve HRQoL and bridge the urban-rural HRQoL gap.Keywords: health-related quality of life, HRQoL, older adults, urban and rural, health management

Lingyan You,1– 3 Hongtao Niu,1,2 Ke Huang,1,2 Fen Dong,1,2,4 Ting Yang,1,2 Chen Wang1,2,5 1Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Quanzhou First Hospital Affiliated Fujian Medical University, Quanzhou, Fujian, People’s Republic of China; 4Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Ting YangDepartment of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No. 2, East Yinghua Road, Chaoyang District, Beijing, 100029, People’s Republic of ChinaEmail zryyyangting@163.comChen WangChinese Academy of Medical Sciences and Peking Union Medical College, 9 Dongdan 3rd Alley, Dong Dan, Dongcheng, Beijing, 100730, People’s Republic of ChinaEmail cyh-birm@263.netPurpose: To identify clinical features and outcomes associated with pulmonary heart disease among patients with chronic obstructive pulmonary disease exacerbation (COPD), which may help reduce economic burden accrued over hospital stay and shorten length of stay (LOS).Patients and Methods: Totally, 4386 patients with acute exacerbation of COPD (AECOPD) classified into pulmonary heart disease (PHD) group and non-pulmonary heart disease group, were included from the ACURE registry, a prospective multicenter patient registry study. Clinical features and outcomes were compared between groups.Results: PHD patients had a more severe profile, including having higher scores of COPD assessment test and modified British Medical Research Council, worse lung function, more patients hospitalized more than once in the past year due to acute exacerbation of COPD, and more comorbidities. Furthermore, drug cost was higher and length of stay was longer in AECOPD patients with PHD.Conclusion: AECOPD patients with PHD had a more severe profile and worse clinical outcomes, including higher drug cost and longer LOS. PHD is an independent risk factor of drug cost and LOS. Complicated with PHD in COPD/AECOPD patients with PHD means heavier disease burden and worse prognosis. It merits further study to focus on PHD management in COPD/AECOPD patients.Keywords: chronic obstructive pulmonary disease, exacerbation, pulmonary heart disease, cost, length of stay

Jie Min,1 Fei Dong,1 Pin Wu,2 Xiaopei Xu,1 Yimin Wu,2 Yanbin Tan,1 Fan Yang,1 Ying Chai2 1Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang Province, People’s Republic of China; 2Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang Province, People’s Republic of ChinaCorrespondence: Ying ChaiDepartment of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, Zhejiang Province, People’s Republic of ChinaTel +86-57187783642Fax +86 571-87068001Email chaiy@zju.edu.cnPurpose: Immunotherapy has made breakthroughs in the treatment of non-small-cell lung cancer (NSCLC); however, only a subset of patients achieved long-term survival, so it is of great importance to find a biomarker of lung cancer thus guide immunotherapy. Studies have shown that the infiltration level of tissue resident memory CD8+ T cells (CD8+ TRMs) is positively correlated with lung cancer prognosis and can be an ideal biomarker for assessing the tumor local immune status. We screened the radiomic features associated with CD8+ TRMs as targets in NSCLC surgical specimens by radiomic approaches, and established a radiomic predictive model to assess the local immune status, which may provide a scientific reference for lung cancer treatment strategies.Patients and Methods: We retrospectively analyzed the NSCLC surgical specimens immune cell database and extracted CD8+ TRMs cell data, preoperative CT scan data were achieved. A total of 97 patients containing complete preoperative data were included, radiomic features were extracted from the preoperative CT image data. All the patients were divided into two groups, namely high-CD8+ TRMs infiltrated group and low-CD8+ TRMs infiltrated group, based on the proportion of CD8+ TRMs cells subset in the immune cell population. The most valuable radiomic features and semantic features were extracted and selected, and a neural network model was established to predict the level of CD8+ TRMs cell infiltration level to assess the tumor local immune status.Results: The NSCLC tumor immune status predictive model was built to discriminate high- from low-CD8+ TRMs with an area under the curve (AUC) of 0.788 (95% CI) in the training set and 0.753 (95% CI) in the validation set.Conclusion: The radiomic models using CT image data showed a good predictive performance for accessing NSCLC immune status thus has great potential for personalized therapeutic decision making.Keywords: non-small-cell lung cancer, NSCLC, radiomic, tumor immune status, tissue resident memory CD8+ T cells, CD8+ TRMs

Chen Liang,1 Xihua Mao,1 Hongtao Niu,2– 4 Ke Huang,2– 4 Fen Dong,2– 5 Yahong Chen,6 Kewu Huang,7,8 Qingyuan Zhan,2– 4 Yin Huang,1 Yaowen Zhang,1 Ting Yang,2– 4 Chen Wang2– 4,9 1Chinese Alliance for Respiratory Diseases in Primary Care, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 4Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, People’s Republic of China; 5Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 7Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Beijing, People’s Republic of China; 8Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China; 9Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Ting YangDepartment of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, No. 2, East Yinghua Road, Chaoyang District, Beijing, 100029, People’s Republic of ChinaEmail zryyyangting@163.comChen WangChinese Academy of Medical Sciences and Peking Union Medical College, 9 Dongdan 3rd Alley, Dong Dan, Dongcheng, Beijing, 100730, People’s Republic of ChinaEmail cyh-birm@263.netPurpose: The study aimed to give a comprehensive overview of characteristics and evaluate in-hospital clinical outcomes among hospitalized acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients in China using data from the AECOPD inpatient registry (ACURE).Patients and Methods: The ACURE is an ongoing, national, multicenter, observational registry. Participants enrolled during phase I stage (1st September 2017 to 25th February 2020) of ACURE with confirmed AECOPD diagnoses were studied. Descriptive analyses were conducted to describe features and occurrences of in-hospital clinical outcomes of AECOPD inpatients in real-world China.Results: A total of 5334 AECOPD inpatients from 163 sites in 28 provinces or province-level municipalities were included. Among all participants, 78.8% were males and the median age was 69.0 [interquartile range (IQR): 63.0– 76.0] years. The proportions of current and former smokers were 23.6% and 44.2%, respectively. The median age at COPD diagnosis was 64.0 (IQR: 57.0– 71.0) years and 88.7% participants demonstrated at least one comorbidity. During stable period, only 56.9% subjects received pharmacological therapies and the influenza vaccination rate was 2.9%. During hospitalization, 99.5% subjects received pharmacological treatments and antibiotics were prescribed to 90.9% participants. The all-cause in-hospital mortality was 0.1% and no significant difference was found across hospital categories.Conclusion: Clinical features of Chinese AECOPD inpatients were different from those of other populations. In real-world China, the clinical management during stable period was unsatisfied, whereas therapy during hospitalization was effective regarding in-hospital clinical outcomes regardless of hospital category.Keywords: registries, demography, therapeutics, disease management, hospital mortality, public health

Müller cells (MC) are considered dormant retinal progenitor cells in mammals. Previous studies demonstrated ephrin-As act as negative regulators of neural progenitor cells in the retina and brain. It remains unclear whether the lack of ephrin-A2/A3 is sufficient to promote the neurogenic potential of MC. Here we investigated whether the MC is the primary retinal cell type expressing ephrin-A2/A3 and their role on the neurogenic potential of Müller cells. In this study, we showed that ephrin-A2/A3 and their receptor EphA4 were expressed in retina and especially enriched in MC. The level of ephrinAs/EphA4 expression increased as the retina matured that is correlated with the reduced proliferative and progenitor cell potential of MC. Next, we investigated the proliferation in primary MC cultures isolated from wild-type and A2–/– A3–/– mice by 5-ethynyl-2′-deoxyuridine (EdU) incorporation. We detected a significant increase of EdU+ cells in MC derived from A2–/– A3–/– mice. Next, we investigated the role of ephrin-A2/A3 in mice undergoing photoreceptor degeneration such as Rhodopsin knockout (Rho–/–) mice. To further evaluate the role of ephrin-A2/A3 in MC proliferation in vivo, EdU was injected intraperitoneally to adult wild-type, A2–/– A3–/– , Rho–/– and Rho–/– A2–/– A3–/– mice and the numbers of EdU+ cells distributed among different layers of the retina. EphrinAs/EphA4 expression was upregulated in the retina of Rho–/– mice compared to the wild-type mice. In addition, cultured MC derived from ephrin-A2–/– A3–/– mice also expressed higher levels of progenitor cell markers and exhibited higher proliferation potential than those from wild-type mice. Interestingly, we detected a significant increase of EdU+ cells in the retinas of adult ephrin-A2–/– A3–/– mice mainly in the inner nuclear layer; and these EdU+ cells were co-localized with MC marker, cellular retinaldehyde-binding protein, suggesting some proliferating cells are from MC. In Rhodopsin knockout mice (Rho–/– A2–/– A3–/– mice), a significantly greater amount of EdU+ cells were located in the ciliary body, retina and RPE than that of Rho–/– mice. Comparing between 6 and 12 weeks old Rho–/– A2–/– A3–/– mice, we recorded more EdU+ cells in the outer nuclear layer in the 12-week-old mice undergoing severe retinal degeneration. Taken together, Ephrin-A2/A3 are negative regulators of the proliferative and neurogenic potentials of MC. Absence of ephrin-A2/A3 promotes the migration of proliferating cells into the outer nuclear layer and may lead to retinal cell regeneration. All experimental procedures were approved by the Animal Care and Use Committee at Schepens Eye Research Institute, USA (approval No. S-353-0715) on October 24, 2012.

Yuzhen Wang,1 Hong Li,2 Fakun Dong,3 Fang Yan,3 Min Cheng,4 Wanzhong Li,3 Qi Chang,3 Tianzi Song,3 Aoying Liu,3 Bo Song3 1Medical Imaging Specialty, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2Basic Medical School, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 3School of Pharmacy, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 4Clinical Medical College, Weifang Medical University, Weifang, Shandong, People’s Republic of ChinaCorrespondence: Bo SongWeifang Medical University, Baotong Street, No. 7166, Weifang, Shandong 261053, People’s Republic of ChinaTel/Fax +86-536-8462490Email songsbob@163.comPurpose: Many exopolysaccharides (EPS) have significant emulsifying activity. Some EPS produced by the marine bacterial strain FYS have stronger emulsifying activity in the form of nanoparticles, suggesting that they could potentially form Pickering emulsions. We prepared novel EPS/CT Pickering nanoemulsions (ECPN) with EPS as emulsifiers and assessed their ability to ameliorate the poor permeability of calcipotriol (CT) in skin affected by psoriasis vulgaris.Methods: A strain of marine bacterium FYS was identified. Molecular weight, monosaccharide composition and microstructure of EPS were determined by gel permeation chromatography, high-performance liquid chromatography and scanning electron microscopy. EPS nanoparticles were prepared by adjusting the pH, and the emulsifying activity was studied at different pH. ECPN were prepared by ultrasound and optimized by the response surface method. The size distribution, microstructure, stability and in vitro drug release of ECPN were studied. The therapeutic effect of ECPN on psoriasis vulgaris was explored by animal experiments and characterizing histomorphology in vivo.Results: A phylogenetic tree revealed that FYS was a Bacillus halodurans strain. EPS produced by the strain were heteropolysaccharides with a three-dimensional network composed of glucose, galactose, glucuronic acid, rhamnose, galacturonic acid and mannose (32.0:34.3:9.7:7.4:10.3:6.3). The EPS can form nanoparticles at pH = 4– 6 with enhanced emulsifying ability. Transmission electron microscopy revealed that EPS nanoparticles adhered to the surface of oil droplets to stabilize the emulsions via a Pickering emulsification mechanism. The prepared ECPN have high stability with a sustained-release effect. Finally, animal experiments showed that ECPN effectively shortened the treatment course of psoriasis vulgaris.Conclusion: EPS is highly possible to have the potential Pickering emulsification mechanism. The stability of the nanoemulsion was high. ECPN also showed potential for use in the treatment of psoriasis vulgaris. This study provides new insight into the medical applications of EPS and the treatment of psoriasis.Keywords: Bacillus halotolerans, exopolysaccharides, response surface method, psoriasis

Ying Liang,* Chun Chang,* Yahong Chen, Fawu Dong, Linlin Zhang, Yongchang Sun Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, 100191, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yongchang SunDepartment of Respiratory and Critical Care Medicine, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing, People’s Republic of ChinaTel +86 13910979132Fax +86 108 226 6989Email suny@bjmu.edu.cnBackground: Social distancing and restriction measures during the COVID-19 epidemic may have impacts on medication availability and healthcare utilization for COPD patients, and thereby affect standard disease management. We aimed to investigate the change of respiratory symptoms, pharmacological treatment and healthcare utilization of COPD patients during the epidemic in Beijing, China.Methods: We conducted a single-center, cross-sectional survey performed at Peking University Third Hospital and recruited patients with COPD who were interviewed by phone call. Clinical data, including respiratory symptoms, pharmacological treatment, management and healthcare access before and during the COVID-19 epidemic from January 25 to April 25, 2020, were collected.Results: A total of 153 patients were enrolled for analysis. Before the epidemic, 81.7% (125/153) had long-term maintenance medication and ICS/LABA (60.8%) and LAMA (57.5%) were most commonly used. During the epidemic, 75.2% (115/153) maintained their pharmacological treatment and 6.5% (10/153) had to reduce or stop taking medications, with a slight decrease of patients taking ICS/LABA (53.6%) and LAMA (56.9%). Most of the patients [76.5% (117/153)] had a low symptom burden, with a CAT score < 10 during the epidemic. Of 153 patients, 45 (29.4%) patients reported worsening of respiratory symptoms but only 15.6% (7/45) sought medical care in hospitals, while the remaining expressed concerns about cross-infection in the hospital (55.5%, 25/45) or had mild symptoms which were managed by themselves (28.8%, 13/45).Conclusion: During the COVID-19 epidemic in Beijing, most of our COPD patients maintained their long-term pharmacological treatment and had mild-to-moderate symptoms. Approximately, 30.0% of the patients experienced worsening of respiratory symptoms, but most of them did not seek medical care in the hospital due to concerns about cross-infection.Keywords: COVID-19, chronic obstructive pulmonary disease, exacerbation, management

Cunbo Jia,1,* Chunyu Zhang,1,* Fang Fang,1,* Ke Huang,2 Fen Dong,3 Xiaoying Gu,3 Hongtao Niu,2 Shan Li,4 Chen Wang,2,5 Ting Yang2 1Department of Health Reform and Development, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, People’s Republic of China; 3Data Platform, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 4School of Management, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this paperCorrespondence: Ting YangDepartment of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Science, Chaoyang District, Beijing 100029, People’s Republic of ChinaTel +8610-84205907Email dryangting@qq.comBackground: Chronic obstructive pulmonary disease (COPD) is prevalent and poses a heavy burden worldwide. However, patients know little about COPD, and primary health care providers have poor therapy capability in China. Enjoying Breathing Program aims to establish a new comprehensive COPD patient management system, including early detection, standardized therapy, and follow-up in China. The goal of the study is to 1) describe the intervention for physicians and patients and 2) to assess the effectiveness of this program.Methods: It is the first nationwide trial involving all levels of health care institutions from primary health care institutions to tertiary hospitals. It includes a series of structured but individualized intervention for both health care providers and COPD patients. Primary health care providers from pilot hospitals will take both online and face-to-face courses, including the procedure of COPD patients’ management and prevention, diagnosis and treatment. Once the patients are diagnosed with COPD, they will undertake standard therapy and self-management education program, perform rehabilitation exercises, and be followed up by primary health care providers every 3 months. The primary outcome will be exacerbation-related hospital/emergency admission and the change of patients’ awareness and primary health care providers’ knowledge of COPD within 36 months. Secondary outcome will include the change of pulmonary function test, structured COPD patients’ management, two-way referral, and standardized therapy.Conclusion: A comprehensive COPD patient management model to promote the standardized therapy will be established; this will improve COPD patients’ awareness and health quality.Trial Registration Number: This study has been registered at www.ClinicalTrials.gov (registration identifier: NCT04318912).Keywords: protocol, national prospective trial, COPD management

Na He,1,2 Fei Dong,3 Wei Liu,1 Suodi Zhai1 1Department of Pharmacy, Peking University Third Hospital, Beijing, People’s Republic of China; 2Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Science, Peking University, Beijing, People’s Republic of China; 3Department of Hematology, Peking University Third Hospital, Beijing, People’s Republic of ChinaCorrespondence: Suodi Zhai; Wei LiuDepartment of Pharmacy, Peking University Third Hospital, 49 Huayuan North Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel +86 10-82266686; +86 10-82265740Email zhaisuodi@163.com; andthen0023@163.comObjective: To provide a comprehensive review of vancomycin dosing in patients with hematologic malignancies or neutropenia.Methods: PubMed, Embase and the Cochrane Library were searched through April 2, 2020. Original studies relevant to vancomycin dosing regimen in adults with hematologic malignancies or neutropenia were included. No restriction was applied in study design and language. A descriptive analysis was performed.Results: Twenty-three studies were included eventually, of which eighteen were case series studies, four were cohort studies and another one was a randomized controlled trial. Five case series studies made a clinical audit of conventional vancomycin dosing in patients with malignancies or neutropenia, showing that the proportion of patients with sub-therapeutic trough levels remained high, ranging from 32% to 88%. Seven case series studies and four cohort studies demonstrated that vancomycin clearance (CLva) tended to be higher in patients with hematologic malignancies or neutropenia, whereas volume of distribution (V) seemed to be comparable to the control group. Five studies proposed individualized initial dosing regimen per the pharmacokinetic changes; however, no prospective validation has been conducted in clinical setting. Additionally, four case series studies suggested that the correlation between vancomycin clearance and estimated creatinine clearance was relatively poor, bringing a great challenge to proper dosing strategy. A randomized controlled trial stated that therapeutic drug monitoring (TDM) of vancomycin could decrease the incidence of nephrotoxicity in immunocompromised febrile patients with hematologic malignancies.Conclusion: The available evidence indicates that conventional vancomycin dosing leads to suboptimal concentration in patients with hematologic malignancy or neutropenia. TDM accompanied by pharmacokinetic interpretation can decrease the risk of nephrotoxicity. The individualization of the initial dosing regimen and mechanisms of augmented clearance require further research.Keywords: vancomycin, hematologic malignancy, neutropenia, pharmacokinetics, evidence-based practice

Ruiteng Song,1 Fang Yan,1 Min Cheng,2 Fakun Dong,1 Yongqi Lin,1 Yuzhen Wang,3 Bo Song1 1School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China; 2Clinical Medical College, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China; 3Medical Imaging Specialty, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of ChinaCorrespondence: Yuzhen Wang; Bo SongWeifang Medical University, Baotong Street, No. 7166, Weifang, Shandong 261053, People’s Republic of ChinaTel +86-536-8462490Email wangyz@wfmc.edu.cn; songsbob@163.comPurpose: As one of the classic anti-Canidia albicans (CA) and vulvovaginal candidiasis (VVC) drugs, nystatin (NYS) is limited by poor water solubility and easy aggregation. Traditional NYS vaginal delivery formulations do not fully adapt to the specific environment of the vaginal cavity. The use of exopolysaccharides (EPS) has great application potential in emulsifiers, but its use has not been reported in nanoemulsions. In this work, an EPS/NYS nanoemulsion (ENNE) was developed to improve the activities of NYS against CA and VVCMethods: The ENNE was prepared by ultrasonic method using EPS as an emulsifier, liquid paraffin oil as an oil phase, PEG400 as a co-emulsifier, and NYS as the loaded drug. ENNE preparation was optimized by response surface method. After optimization, in vitro and in vivo analysis of the anti-CA activity; animal experiments; staining with propidium iodide (PI), periodic acid-schiff (PAS), and hematoxylin-eosin (H&E); and cytokine experiments were performed to investigate the therapeutic ability against VVC.Results: The optimal formulation and preparation parameters of ENNE were determined as follows: EPS content of 1.5%, PEG400 content of 3.2%, NYS content of 700 μg/mL, paraffin oil content of 5.0%, ultrasonic time of 15 min, and ultrasonic amplitude of 35%. The ENNE showed an encapsulated structure with an average particle size of 131.1 ± 4.32 nm. ENNE exhibited high storage and pH stability, as well as slow release. The minimum inhibitory concentration (MIC) of ENNE against CA was only 0.125 μg/mL and the inhibition zone was 19.0 ± 0.5 mm, for greatly improved anti-CA effect. The prepared ENNE destroyed the membrane of CA cells, and exhibited good anti-CA effect in vivo and therapeutic ability against VVC.Conclusion: The results of this study will promote the application of EPS in nanotechnology, which should lead to new and effective local drug formulations for treating VVC.Keywords: Canidia albicans, ultrasonic, response surface method, antifungal

Yunxiang Zhang,1,2,* Yu Zheng,1,2,* Fangyi Dong,1,2,* Handong Ma,3 Liping Zhu,1 Dake Shi,4 Xiaoyang Li,1,2 Junmin Li,1,2 Jiong Hu1,2 1Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3John Hopcroft Center for Computer Science, Department of Computer Science and Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Clinical Microbiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junmin Li; Jiong Hu Tel +86 21 6437 0045 665 258Fax +86-21-64374756Email drlijunmin@126.com; hj10709@rjh.com.cnBackground: The epidemiology of Gram-negative bacteria in patients with febrile neutropenia (FN) and their susceptibility to initial empirical antibiotic therapy is key to successful treatment during the treatment of hematologic malignancies.Methods: A retrospective study was conducted. Patients with FN and confirmed laboratory results of Gram-negative bacteria infections were included. If no direct sensitivity of the identified pathogen to the initially prescribed antibiotic regimen was confirmed, it was defined as inappropriate initial antibiotic treatment (IIAT).Results: A total of 247 patients with FN were proven to be infected with Gram-negative bacteria, and 200 were diagnosed with acute leukemia. The most commonly detected bacteria were Escherichia coli (40%), Klebsiella pneumoniae (20%), and Pseudomonas aeruginosa (11%). In sum, 176 patients were classified as IIAT. The mortality rate in the IIAT group was significantly higher (37.7% vs 23.9%, P=0.038). With monotherapy as empirical treatment, high possibility of IIAT with fluoroquinolones (52%) and cephalosporins (35%) was detected, while more sensitivity to carbapenems (16%) and glycopeptides antibiotics (19%) was noticed. With combined treatment, cephalosporins/carbapenems had with the lowest percentage of IIAT (18%).Conclusion: In conclusion, inappropriate initial empirical antibiotic treatments were associated with higher mortality in patients with hematologic malignancies. The current empirical antibiotic regimen needs to be further optimized.Keywords: febrile neutropenia, Gram-negative bacteria, hematologic malignancy, empirical antibiotic treatment, inappropriate initial antibiotic treatment

Hui Liu,1 Fang Dong,2 Jinrong Liu,1 Jianhua Liu,3 Yu Pang,4 Shunying Zhao,1 Jie Lu,5 Huimin Li11Department of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Department of Laboratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 3Department of Pediatrics, Maternal and Child Health Care Hospital of Shunyi District, Beijing, People’s Republic of China; 4Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China; 5Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of ChinaAbstract: Mycobacterium abscessus complex (MABC) is an uncommon but increasingly important cause of invasive pulmonary disease, a condition associated with diagnostic and management challenges. MABC has mainly been reported in children with certain medical conditions, such as preexisting structural lung disorders and immunocompromised status. In this article, we describe a rare case of MABC pulmonary disease in an otherwise healthy infant. A 4-month-old female presented with cough and fever for 4 days. Computed tomography showed multiple masses and small nodules across both lungs. Isolated mycobacteria from her bronchoalveolar lavage fluid and gastric aspirate were identified as MABC by using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and M. abscessus subsp. massiliense was ultimately identified by DNA sequence analysis. Prolonged treatment with a combination of azithromycin, cefoxitin, and moxifloxacin achieved a successful treatment outcome.Keywords: nontuberculous mycobacteria, pulmonary, drug resistance, azithromycin, treatment outcome

Wei Shi,* Fang Dong,* Yujia Jiang, Linlin Lu, Changwen Wang, Jie Tan, Wen Yang, Hui Guo, Jie Ming,* Tao Huang* Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China *These authors contributed equally to this work Background: Despite the advances in early detection and treatment methods, breast cancer still has a high mortality rate, even in those patients predicted to have a good prognosis. The purpose of this study is to identify a microRNA signature that could better predict prognosis in breast cancer and add new insights to the current classification criteria. Materials and methods: We downloaded microRNA sequencing data along with corresponding clinicopathological data from The Cancer Genome Atlas (TCGA). Of 1,098 breast cancer patients identified, 253 patients with fully characterized microRNA profiles were selected for analysis. A three-microRNA signature was generated in the training set. Subsequently, the performance of the signature was confirmed in a validation set. After construction of the signature, we conducted additional experiments, including flow cytometry and the Cell Counting Kit-8 assay, to illustrate the correlation of this microRNA signature with breast cancer cell cycle, apoptosis, and proliferation. Results: Three microRNAs (hsa-mir-31, hsa-mir-16-2, and hsa-mir-484) were identified to be significantly and independently correlated with patient prognosis, and performed with good stability. Our results suggest that higher expression of hsa-mir-484 indicated worse prognosis, while higher expression of hsa-mir-31 and hsa-mir-16-2 indicated better prognosis. Moreover, additional experiments confirmed that this microRNA signature was related to breast cancer cell cycle and proliferation. Conclusion: Our results indicate a three-microRNA signature that can accurately predict the prognosis of breast cancer, especially in basal-like and hormone receptor-positive breast cancer subtypes. We recommend more aggressive therapy and more frequent follow-up for high-risk groups. Keywords: microRNA, breast cancer, TCGA, prognosis

Cheng-Ting Zi,1–3,* Liu Yang,2,* Feng-Qing Xu,2 Fa-Wu Dong,2 Dan Yang,2 Yan Li,2 Zhong-Tao Ding,3 Jun Zhou,2 Zi-Hua Jiang,4 Jiang-Miao Hu2 1Key Laboratory of Pu-er Tea Science, Ministry of Education, College of Science, Yunnan Agricultural University, Kunming 650201, China; 2State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China; 3Key Laboratory of Medicinal Chemistry for Nature Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China; 4Department of Chemistry, Lakehead University, Thunder Bay, ON P7B 5E1, Canada *These authors contributed equally to this work Background: Podophyllotoxin is a potent cytotoxic agent and serves as a useful lead compound for the development of antitumor drugs. Several podophyllotoxin-derived antitumor agents, including etoposide, are currently in clinical use; however, their therapeutic efficacy is often limited due to side effects and the development of resistance by cancer cells. Previous studies have shown that 4β-1,2,3-triazole derivatives of podophyllotoxin exhibit more potent anticancer activity and better binding to topoisomerase-II than etoposide. The effect of dimerization of such derivatives on the anticancer activity has not been studied. Methods: Two moieties of podophyllotoxin were linked at the C-4 position via 1,2,3-triazole rings to give a series of novel dimeric podophyllotoxin derivatives. 4β-Azido-substituted podophyllotoxin derivatives (23 and 24) were coupled with various dipropargyl functionalized linkers by utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to provide dimeric products in very good yield. The in vitro anticancer activity of the synthesized compounds was evaluated by MTT assay against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480). The normal BEAS-2B (lung) cell line was also included for study in order to evaluate the cancer selectivity of the most active compound as compared with normal cells. Results: A group of 16 dimeric podophyllotoxin derivatives with different linkers were synthesized and structurally characterized. Most compounds do not show significant cytotoxicity (IC50 > 40 mM) against all five cancer cell lines. However, one compound (29) which bears a perbutyrylated glucose residue on the glycerol linker is highly potent against all five cancer cell lines tested, with IC50 values ranging from 0.43 to 3.50 µM. This compound (29) also shows good selectivity towards cancer cell lines as compared with the normal BEAS-2B (lung) cell line, showing selec­tivity indexes from 4.4 to 35.7. Conclusion: The anticancer activity of dimeric podophyllotoxin derivatives is generally speaking not improved as compared to their monomeric counterparts, and the potency of these dimeric derivatives can be largely affected by the nature of the linker between the two moieties. Among the synthesized derivatives, compound 29 is significantly more cytotoxic and selective towards cancer cells than etoposide and cisplatin, which are currently in clinical use. Compound 29 is a promising anticancer drug and needs further studies. Keywords: podophyllotoxin, dimeric podophyllotoxin derivatives, CuAAC reaction, perbutytylated glucose, antitumor, synthesis

Retinal ischemia/reperfusion injury (RI) is a common cause of irreversible visual impairment and blindness in elderly and critical unmet medical need. While no effective treatment is available for RI, microglial activation and local immune responses in the retina are thought to play important roles in the pathophysiology of neurodegeneration. While survival and activation of microglia depend critically on colony-stimulating factor receptor (CSF-1R) signaling, it remains unclear if targeting the retinal immune microenvironments by CSF-1RAb after RI is sufficient to rescue vision and present a potentially effective therapy. Here we used rodent models of RI and showed that retinal ischemia induced by acute elevation of intraocular pressure triggered an early activation of microglia and macrophages in the retina within 12 h. This was followed by lymphocyte infiltration and increased production of pro-inflammatory cytokines. Intravitreal injection of CSF-1R neutralizing antibody (CSF-1RAb) after RI significantly blocked microglial activation and the subsequent T cell recruitment. This also led to improved retinal ganglion cell survival and function measured by cell quantification and electroretinogram positive scotopic threshold responses, as well as increased visual acuity and contrast sensitivity as assessed by optomotor reflex-based assays, when compared to the isotype-treated control group. Moreover, the administration of CSF-1RAb efficiently attenuated inflammatory responses and activation of human microglia in culture, suggesting a therapeutic target with human relevance. These results, together with the existing clinical safety profiles, support that CSF-1RAb may present a promising therapeutic avenue for RI, a currently untreatable condition, by targeting microglia and the immune microenvironment in the retina to facilitate neural survival and visual function recovery.

Glaucoma is a neurodegenerative disease of which the etiology is still unclear. Here the authors show that elevation of intraocular pressure induces T cell infiltration in the eyes. Furthermore, they show that T cell cross-reactivity between endogenous and commensal antigens contributes to disease onset in mice.

Mengyi Wang, Shengnan Ruan, Jie Ming, Fang Dong Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Abstract: An alternatively spliced transcription factor that participates in the unfolded protein response, XBP1 is a novel protein involved in cancer progression and outcome. This study aimed to investigate the relationship of spliced XBP1 (XBP1s) with the clinicopathological characteristics and prognosis of breast cancer by using tissue-microarray analysis. A consecutive series of 170 patients with breast cancer diagnosed between 2001 and 2004 in hospitals in eastern and southern China were included. Immunohistochemical staining for XBP1s was performed, and the expression of XBP1s was separately examined in nuclei and cytoplasm. We found that a higher expression of XBP1s in nuclei strongly correlated with poorer survival (46.7% versus 75%, P=0.018); however, the expression of XBP1s in the cytoplasm had no relationship with survival. Multivariate Cox regression analysis indicated that the expression of XBP1s was not an independent prognostic factor (RR 2.074, 95% CI 0.909–4.736; P=0.083). None of the other clinicopathological characteristics – age, pathology grade, T stage, N stage, TNM stage, estrogen receptor, progesterone receptor, or HER2 status – was found to be correlated with XBP1s expression in the nuclei. In conclusion, independently of other clinicopathological factors, the nuclear expression of XBP1s is correlated with shorter breast cancer survival; however, whether nuclear XBP1s is an independent prognostic biomarker needs to be confirmed by further studies with larger samples and detailed sample stratification. Keywords: breast cancer, tissue microarray, XBP1s, endoplasmic reticulum stress, biomarker

Fan Dong,1,* Yifan Shen,1,* Fengbin Gao,2 Tianyuan Xu,2 Xianjin Wang,1 Xiaohua Zhang,1 Shan Zhong,1 Minguang Zhang,1 Shanwen Chen,1 Zhoujun Shen1 1Department of Urology, Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, 2Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *These authors contributed equally to this work Background: We aimed to evaluate the prognostic value of site-specific metastases in patients with metastatic bladder cancer and analyze the roles that surgeries play in the treatment of this malignancy.Materials and methods: A population-based retrospective study using Surveillance, Epidemiology and End Results dataset was performed and metastatic bladder cancer patients were classified according to the sites of metastases (bone, brain, liver, lung and distant lymph nodes). Kaplan–Meier analysis with log-rank test was used for survival comparisons. Multivariate Cox regression model was employed to analyze the effect of distant metastatic sites on overall survival (OS) and cancer-specific survival (CSS).Results: A total of 1862 patients with metastatic bladder cancer from 2010 to 2014 were identified. Bone, lung and distant lymph nodes were the most common metastatic sites. Patients with bone, brain, liver and lung involvement had worse OS and CSS compared to patients without the corresponding sites of metastases. Multivariate analysis showed that bone, brain, liver and lung metastases were independent prognostic factors for both OS and CSS, while distant node metastasis was not. Moreover, patients with a single metastatic site had more favorable OS (p

Wei Zhang, Jing Wang, Yanfang Wang, Fei Dong, Mingxia Zhu, Wenli Wan, Haishen Li, Feifei Wu, Xinxing Yan, Xiaoyan Ke Department of Hematology and Lymphoma Research Center, Peking University Third Hospital, Beijing, People’s Republic of China Background: The role of B7-H3 in acute monocytic leukemia U937 cells has not been thoroughly investigated.Materials and methods: B7-H3 knockdown in the U937 cell line was performed using small hairpin (sh)RNA lentivirus transduction. The effects on cell proliferation, cycle, migration, and invasion were investigated by Cell Counting Kit-8 assay, methyl cellulose colony-forming assay, propidium iodide staining, and Transwell assays in vitro. Changes in cell growth inhibition and apoptosis, when combined with chemotherapy drugs, were determined using the Cell Counting Kit-8 and Annexin V-FITC/PI assays. U937 xenograft models were used to assess the effects of B7-H3 on tumorigenicity and the therapeutic effect of B7-H3 knockdown in combination with chemotherapy drugs in vivo.Results: Downregulation of B7-H3 significantly decreased U937 cell growth and colony-forming ability. The mean inhibition rate of tumor growth with B7-H3 knockdown was 59.4%, and the expression of both Ki-67 and PCNA in xenografts was significantly reduced. After B7-H3 silencing, the U937 cell cycle was arrested at the G0/G1 phase. The cell migration rate of B7-H3 knockdown cells was reduced more than fivefold, and invasion capacity decreased by 86.7%. B7-H3 RNAi profoundly increased the antitumor effect of chemotherapy in vitro and in vivo. On day 19, inhibition rates of tumor growth in B7-H3 shRNA combined with idarubicin, cytarabine, and idarubicin plus cytarabine were 70.5%, 80.0%, and 90.0%, respectively (P=0.006, P=0.004, and P=0.016, respectively).Conclusion: B7-H3 may promote U937 cell progression, and shRNA targeting B7-H3 significantly enhances sensitivity to chemotherapeutic drugs. These results may provide new insight into the function of B7-H3 and a promising therapeutic approach targeting B7-H3 in acute monocytic leukemia. Keywords: B7-H3, acute monocytic leukemia, cancer gene therapy, chemosensitivity

Fuxia Dong,1,2 Yunchang Xie,1 Jianping Qi,1 Fuqiang Hu,3 Yi Lu,1 Sanming Li,2 Wei Wu1 1School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery of Ministry of Education and PLA, Shanghai, People’s Republic of China; 2School of Pharmacy, Shenyang Pharmaceutical University, Liaoning, People’s Republic of China; 3School of Pharmacy, Zhejiang University, Hangzhou, People’s Republic of China Abstract: Bile salt/phospholipid mixed micelles (MMs) are potent carriers used for oral absorption of drugs that are poorly soluble in water; however, there are many limitations associated with liquid formulations. In the current study, the feasibility of preparing bile salt/phospholipid MM precursor (preMM) pellets with high oral bioavailability, using fluid-bed coating technology, was examined. In this study, fenofibrate (FB) and sodium deoxycholate (SDC) were used as the model drug and the bile salt, respectively. To prepare the MMs and to serve as the micellular carrier, a weight ratio of 4:6 was selected for the sodium deoxycholate/phospholipids based on the ternary phase diagram. Polyethylene glycol (PEG) 6000 was selected as the dispersion matrix for precipitation of the MMs onto pellets, since it can enhance the solubilizing ability of the MMs. Coating of the MMs onto the pellets using the fluid-bed coating technology was efficient and the pellets were spherical and intact. MMs could be easily reconstituted from preMM pellets in water. Although they existed in a crystalline state in the preMM pellets, FB could be encapsulated into the reconstituted MMs, and the MMs were redispersed better than solid dispersion pellets (FB:PEG = 1:3) and Lipanthyl®. The redispersibility of the preMM pellets increased with the increase of the FB/PEG/micellar carrier. PreMM pellets with a FB:PEG:micellar carrier ratio of 1:1.5:1.5 showed 284% and 145% bioavailability relative to Lipanthyl® and solid dispersion pellets (FB:PEG = 1:3), respectively. Fluid-bed coating technology has considerable potential for use in preparing sodium deoxycholate/phospholipid preMM pellets, with enhanced oral bioavailability for poorly water-soluble drugs. Keywords: mixed micelles, bile salts, phospholipids, fluid-bed coating, oral bioavailability

The originally published version of this Article contained an error in Figure 4. The bar chart in panel f was inadvertently replaced with a duplicate of the bar chart in panel e. This error has now corrected in both the PDF and HTML versions of the Article.