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Yongsheng Zhao,* Xianlei Xin,* Bin Wang, Lei He, Qinghua Zhao, Weizheng Ren Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weizheng Ren; Qinghua Zhao, Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China, Email rwz301@163.com; zhaoqinghuabj@163.comPurpose: In this paper, we observed the use of contezolid in patients with complex intra-abdominal infections in the intensive care unit of the Hepatobiliary Surgery department at the Chinese PLA General Hospital.Patients and Methods: The study collected data on complex intra-abdominal infections patients who received the antibiotic contezolid between January 2022 and April 2023.Results: Contezolid was administered to 12 patients, including 8 with severe acute pancreatitis, 3 with intra-abdominal infections following abdominal surgery, and 1 with complicated intra-abdominal infection after trauma. Gram-positive bacteria, such as Enterococcus faecium, Enterococcus casseliflavus, Staphylococcus capitis, and Staphylococcus haemo-lytica, were detected in 11 patients. All patients who received contezolid had previously been treated with other anti-Gram-positive agents, including linezolid for 9 patients, teicoplanin for 6 patients, and vancomycin for 3 patients. The treatment with contezolid began 20.0 (15.0, 34.5) days after admission and lasted for 8.0 (6.0, 10.0) days. At the end of the treatment, the patients’ body temperature showed a significant decrease. After concomitant therapy, IL-6 levels decreased, and platelet count increased.Conclusion: Contezolid has shown potential in treating complex intra-abdominal infections caused by Gram-positive bacteria by reducing fever and inflammatory response.Keywords: intra-abdominal infection, contezolid, multiple drug-resistant bacteria, gram-positive bacteria

Rui Zhou,1,2,* Lijuan Fu,2,* Shu Liu,2,* Sanjie Gao,2 Zhifu Zhao,2 Wencai Jiang,2 Li Liu,2 Weiqiao Ren,2 Dongmei Xiang,2 Xing You,2 Chunyong Tang,2 Yukai Zhou,2 Yanqing Song,2 Juan Xie,2 Li Xie,2 Ru Yu,2 Xianjie Zhang,2 Dan Zhou,2 Jia Han,2 Leqiang Xia,2 Lize Xiong1 1Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Translational Research Institute of Brain and Brain-Like Intelligence, Clinical Research Center for Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China; 2Department of Anesthesiology, Deyang People’s Hospital, Deyang, 618000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Leqiang Xia, Department of Anesthesiology, Deyang People’s Hospital, No. 173, Section 1, North Taishan Road, Deyang, Sichuan, 618000, People’s Republic of China, Tel +8613547098458, Email xialq123184@163.com Lize Xiong, Shanghai Fourth People’s Hospital, No. 1279, Sanmen Road, Shanghai, 200434, People’s Republic of China, Tel +86-21-55603002, Fax +86-21-56660851, Email mzkxlz@126.com; lizexiong@tongji.edu.cnPurpose: To compare the influences of propofol, ciprofol and remimazolam on dreaming during painless gastrointestinal endoscopy.Methods: This study was a single-center, prospective, parallel-design, double-blind, randomized clinical trial. Between May 2023 and October 2023, patients undergoing elective painless gastrointestinal endoscopy were recruited and randomly allocated into one of the three groups. Demographic data, intraoperative information, incidence of dreaming, insufficient anesthesia and intraoperative awareness, type of dream, patient satisfaction score, adverse events, and improvement of sleep quality were collected.Results: The difference in incidence of dreaming among the three groups was not significant (33.33% vs 48.33% vs 41.67%, p=0.061). The number of patients with intraoperative hypotension in the propofol group was larger than that of the remimazolam group (32 vs 12, p=0.001). However, the cases of intraoperative hypotension between propofol group and ciprofol group or ciprofol group and remimazolam group were comparable (32 vs 22, p=0.122; 22 vs 12, p=0.064). The percentage of insufficient anesthesia between propofol group and remimazolam group was significant (13.33% vs 1.67%, p=0.001), while no statistical difference was detected between propofol group and remimazolam group or ciprofol group and remimazolam group (13.33% vs 5.00%, p=0.025; 5.00% vs 1.67%, p=0.150). The ability of propofol to improve sleep quality at 1st post-examination day was significantly better than that of remimazolam (86.21% vs 72.88%, p=0.015), while it was not significant between propofol group and ciprofol group or ciprofol group and remimazolam group (86.21% vs 80.36%, p=0.236; 72.88% vs. 72.88%, p=0.181). Incidence of intraoperative awareness, intraoperative hypoxia, type of dream, satisfaction score, adverse events during recovery, and sleep improvement on the 7th post-examination day was not significant among the groups.Conclusion: Anesthesia with propofol, ciprofol and remimazolam, respectively, for gastrointestinal endoscopy did not induce statistical difference in the incidence of dreaming, despite that all of them are more likely to induce pleasant dreams.Keywords: propofol, ciprofol, remimazolam, endoscopic sedation, dreaming

Ziyu Ren,1 Jiangchuan Long,1 Wenzhen Deng,1 Yuanyuan Jing,1 Jingwen Qiu,1 Wei Ren,2 Dongfang Liu1 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Wei Ren, Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No. 1. You-Yi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012755, Email renwei67@sina.com Dongfang Liu, Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing, 400010, People’s Republic of China, Tel +86-23-63832133, Email 300306@hospital.cqmu.edu.cn; ldf023023@qq.comBackground: In recent years, multiple observational studies have confirmed the association between sleep traits and various human physiopathological states. However, the causal relationship between sleep traits and hypothalamic-pituitary-target gland axis (HPTGA) function remains unknown.Methods: We obtained summary statistics on sleep traits (insomnia, chronotype, and sleep duration (long and short)) from the UK Biobank database. Data related to the HPTGA functions were obtained from the publicly available database. Subsequently, a two-sample Mendelian randomization (MR) analysis was performed to investigate the causal relationship between different sleep traits and the HPTGA function. Reverse MR analysis was conducted to examine the direction of causality.Results: The MR analysis results suggested that chronotype is associated with decreased levels of six hormones in HPTGA. Sleep duration was causally associated with decreased levels of free thyroxine and progesterone. Both long and short sleep durations are detrimental to the secretion of prolactin-releasing peptide, somatostatin, and plasma cortisol, while short sleep duration can promote progesterone secretion. After gender stratification, we found that female reproductive function is more susceptible to the influence of unfavorable sleep traits.Conclusion: Our MR analysis indicated a significant causal association between chronotype and suppressed gonadal function in healthy adult humans, with no apparent gender-specific effect. Extreme sleep durations were also found to be detrimental to the maintenance of normal HPTGA secretion function. Compared to males, gonadal function in the female cohort is more susceptible to extreme sleep habits. Subsequent observational studies are urgently needed to confirm the underlying mechanisms.Keywords: hypothalamo-hypophyseal-target gland axis, sleep traits, causal inference, Mendelian randomization

Yuxin Tan,1 Xiuyun Lin,1,2 Hui Chen,1 Min Xu,1 Yingying Tang,1 Pengfei Gao,1 Wei Ren,1 Di Zhang1 1Faculty of Psychology, Beijing Normal University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Applied Experimental Psychology, Faculty of Psychology, Beijing Normal University, Beijing, People’s Republic of ChinaCorrespondence: Xiuyun Lin, Faculty of Psychology, Beijing Normal University, Beijing, 100875, People’s Republic of China, Email linxy@bnu.edu.cnIntroduction: During emergencies, individuals and communities often react in a variety of ways, including panic response. However, the study of panic response is limited due to narrow assessment tools that measure only one or two dimensions of human response (eg, physiology, cognition, emotion, and behavior). To address this limitation and to explore the risk and protective factors of panic response during the global spread of the Coronavirus Disease 2019 (COVID-19), the current study developed and evaluated the Panic Response Scale (PRS).Methods: Four samples were recruited for the following purposes: interview analysis (n = 26); item analysis and exploratory factor analysis (n = 604); confirmatory factor analysis and reliability analysis (n = 603); and retest reliability, validity analysis, and regression analysis (n = 349).Results: The PRS consists of 21 items with four subscales: Physical Discomfort, Anxious Fluster, Sensitive Depression, and Excessive Prevention. Each of these subscales demonstrated good internal consistency (rs > 0.73), test-retest reliability (rs > 0.77), criterion validity (r = 0.69, p < 0.01), and convergent validity (rs = 0.31– 0.65, p < 0.01). Regression analysis revealed significant predicting effects of COVID-19 knowledge and neuroticism on panic response. Additionally, cognitive reappraisal moderated the association between neuroticism and panic response.Discussion: Following a traumatic event, the PRS offers a potential tool for identifying individuals in need of mental health services. Moreover, during the COVID-19 pandemic, knowledge and neuroticism served as risk factors for heightened panic response, while cognitive reappraisal served as a protective factor for coping with panic response.Keywords: COVID-19, panic response, knowledge, neuroticism, cognitive reappraisal

Kang Zou,1,2,&ast; Shu Huang,3,4,&ast; Wensen Ren,1,2,&ast; Huan Xu,1,2 Wei Zhang,1,2 Xiaomin Shi,1,2 Lei Shi,1,2 Xiaolin Zhong,1,2 Yan Peng,1,2 Muhan Lü,1,2 Xiaowei Tang1,2 1Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, People’s Republic of China; 3Department of Gastroenterology, Lianshui County People’ Hospital, Huaian, People’s Republic of China; 4Department of Gastroenterology, Lianshui People’ Hospital of Kangda College Affiliated to Nanjing Medical University, Huaian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaowei Tang; Muhan Lü, Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Street Taiping No. 25, Region Jiangyang, Luzhou, Sichuan Province, 646099, People’s Republic of China, Tel +86 8303165200, Fax +86 83061641541, Email solitude5834@hotmail.com; lvmuhan@swmu.edu.cnPurpose: The aim of this study is to develop and validate a predictive model for the prediction of in-hospital mortality in patients with acute pancreatitis (AP) based on the intensive care database.Patients and Methods: We analyzed the data of patients with AP in the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database and Electronic Intensive Care Unit Collaborative Research Database (eICU-CRD). Then, patients from MIMIC-IV were divided into a development group and a validation group according to the ratio of 8:2, and eICU-CRD was assigned as an external validation group. Univariate logistic regression and least absolute shrinkage and selection operator regression were used for screening the best predictors, and multivariate logistic regression was used to establish a dynamic nomogram. We evaluated the discrimination, calibration, and clinical efficacy of the nomogram, and compared the performance of the nomogram with Acute Physiology and Chronic Health Evaluation II (APACHE-II) score and Bedside Index of Severity in AP (BISAP) score.Results: A total of 1030 and 514 patients with AP in MIMIC-IV database and eICU-CRD were included in the study. After stepwise analysis, 8 out of a total of 37 variables were selected to construct the nomogram. The dynamic nomogram can be obtained by visiting https://model.sci-inn.com/KangZou/. The area under receiver operating characteristic curve (AUC) of the nomogram was 0.859, 0.871, and 0.847 in the development, internal, and external validation set respectively. The nomogram had a similar performance with APACHE-II (AUC = 0.841, p = 0.537) but performed better than BISAP (AUC = 0.690, p = 0.001) score in the validation group. Moreover, the calibration curve presented a satisfactory predictive accuracy, and the decision curve analysis suggested great clinical application value of the nomogram.Conclusion: Based on the results of internal and external validation, the nomogram showed favorable discrimination, calibration, and clinical practicability in predicting the in-hospital mortality of patients with AP.Keywords: acute pancreatitis, medical information mart for intensive care-IV, MIMIC-IV, electronic intensive care unit collaborative research database, eICU-CRD, dynamic nomogram

Xiufen Wang,1– 3 Ying Wang,1,2 Li Luo,3 Liuting Tan,4 Wenzhi Cai,1 Ling Chen,1 Wei Ren1 1Department of Nursing, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, People’s Republic of China; 2School of Nursing, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Department of the Third Pulmonary Disease, The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, People’s Republic of China; 4Department of Endocrine, The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Wei Ren; Ling Chen, Department of Nursing, Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Baoan District, Shenzhen, Guangdong Province, 518101, People’s Republic of China, Tel +86-755-23360006, Fax +86-755-23323777, Email renwei196911@163.com; dangdang601@smu.edu.cnIntroduction: Diabetic neurogenic bladder is one of the common complications in patients with diabetic neuropathy. However, studies reporting the prevalence and associated factors of urinary tract infections (UTIs) in patients with diabetic neuropathy are rare. Therefore, the present study aimed to explore the prevalence and influencing factors of UTI in patients with diabetic neuropathy.Methods: A hospital-based cross-sectional study that recruited patients with diabetic neuropathy was conducted from January 2019 to December 2021. Collected data included patient demographic information (age, sex, education level, body mass index), clinical data (duration of diabetes, method of administration), and laboratory tests. Multivariable logistic regression models were used to identify the factors associated with UTI risk. The strength of association was expressed as the odds ratio (OR) and 95% confidence interval (95% CI).Results: A total of 579 patients were recruited (male, 68.2%; overall average age, 57.89 years). Using multivariate analysis with adjustment for confounding factors, female sex (odds ratio [OR]: 4.12; 95% CI: 2.24– 7.60; P < 0.001), hypodermic insulin injection (OR: 2.10; 95% CI: 1.02– 4.35; P = 0.045), chronic kidney disease (OR: 3.12; 95% CI: 1.11– 8.80; P = 0.032), history of UTI (OR = 45.92; 95% CI: 8.62– 244.76; P < 0.001), positive urinary nitrite (OR: 32.87; 95% CI: 7.37– 146.70; P < 0.001), and high residual urine volume (OR: 2.19, 95% CI: 1.17– 4.10; P = 0.014) were independent risk factors for UTI in patients with diabetic neuropathy. Compared with the patients aged < 45 years, UTI prevalence increased 2.91-fold in patients aged 45– 54 years (OR: 3.91; 95% CI: 1.02– 15.03; P = 0.047) and 3.87-fold in those aged ≥ 65 years (OR: 4.87; 95% CI: 1.23– 19.25; P = 0.024).Conclusion: The main findings of this study showed that older age, female sex, hypodermic insulin injection, CKD, history of UTI, and positive urinary nitrite were independent risk factors for UTI in patients with diabetic neuropathy. To minimize the occurrence and resulting disease burden of UTI, knowledge regarding UTI risk factors in patients with diabetic neuropathy is critical to designate interventions.Keywords: epidemiology, prevalence, urinary tract infection, diabetic neuropathy, risk factors

Chen Liang,1,2,&ast; Shanshan Li,1,&ast; Jinfeng Yuan,1 Yanhua Song,3 Weicong Ren,1 Wei Wang,1 Yuanyuan Shang,1 Shenjie Tang,2 Yu Pang1 1Department of Bacteriology and Immunology, Beijing Key Laboratory on Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University /Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China; 2Tuberculosis Clinical Medical Center, Beijing Chest Hospital, Capital Medical University /Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China; 3Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shenjie Tang; Yu Pang, Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86 010 8950 9367 ; +86 010 8950 9359, Email tangsj1106@vip.sina.com; pangyupound@163.comPurpose: This study aimed to investigate the phenotype, proliferation and functional alterations of cytokine-induced memory-like natural killer (CIML NK) cells from healthy subjects and TB patients, and assessed the efficacy of CIML NK cells in response to H37Rv-infected U937 cells in vitro.Methods: Fresh peripheral blood mononuclear cells (PBMCs) were isolated from healthy people and tuberculosis patients and activated for 16h using low-dose IL-15, or IL-12, IL-15, IL-18 combination or IL-12, IL-15, IL-18 and MTB H37Rv lysates, respectively, followed by low-dose IL-15 maintenance for another 7 days. Then, the PBMCs were co-cultured with K562 and H37Rv-infected U937, and the purified NK cells were co-cultured with H37Rv infected U937. The phenotype, proliferation and response function of CIML NK cells were assessed using flow cytometry. Finally, colony forming units were enumerated to confirm the survival of intracellular MTB.Results: CIML NK phenotypes from TB patients were similar to healthy controls. CIML NK cells undergo higher rates of proliferation after IL-12/15/18 pre-activation. Moreover, the poor expansion potential of CIML NK cells co-stimulated with MTB lysates. CIML NK cells from healthy individuals showed enhanced IFN-γ functional to H37Rv infected U937 cells, along with significantly enhanced killing of H37Rv. However, the CIML NK cells from TB patients show attenuated IFN-γ production and now enhanced the ability of killing intracellular MTB compared to those from healthy donors after co-cultured with H37Rv infected U937.Conclusion: CIML NK cells from healthy individuals exist the increased ability of IFN-γ secretion and boosted anti-MTB activity in vitro, which from TB patients show impaired IFN-γ production and no enhanced anti-MTB activity compared to those from healthy donors. Additionally, we observe the poor expansion potential of CIML NK cells co-stimulated with antigens from MTB. These results open up new possibilities for NK cell-based anti-tuberculosis immunotherapeutic strategies.Keywords: Mycobacterium tuberculosis, cytokines, NK cells, memory-like NK cells, IFN-&#x03B3

Weicong Ren,1,&ast; Haoran Li,1,&ast; Can Guo,1,2 Yuanyuan Shang,1 Wei Wang,1 Xuxia Zhang,1 Shanshan Li,1 Yu Pang1 1Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 2Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu Pang; Shanshan Li, Email pangyupound@163.com; lss9011@126.comBackground: Aspergillus fumigatus-induced chronic pulmonary aspergillosis (CPA), the most common pulmonary tuberculosis (TB) sequela, tends to occur after pulmonary infection with the intracellular pathogen Mycobacterium tuberculosis (Mtb). Timely and accurate detection of A. fumigatus infection of pulmonary TB patients would undoubtedly greatly improve patient prognosis. Currently, the galactomannan (GM) antigen test is commonly used to detect A. fumigatus infection but has poor sensitivity that renders this assay inadequate for use in clinical practice.Design or Methods: Given the fact CPA and TB induce different host immune responses, we evaluated serum cytokine level profiles of CPA, TB patients and patients with both diseases (CPA-TB) for multiple cytokines and cytokine combinations.Results: The results revealed significantly higher serum levels of numerous proinflammatory cytokines, including IL-1β, IL-6, IL-8, IL-12p70, IFN-α, IFN-γ and TNF-α, in peripheral blood of CPA-TB patients versus that of TB patients. IL-8 levels alone provided the best discriminatory performance for distinguishing between TB and either CPA-TB patients (AUC = 0.949) or CPA patients (AUC = 0.964). Moreover, both IL-8 and TNF-α (AUC = 0.996) levels could be used to distinguish between TB and CPA-TB patients. Likewise, IL-8, TNF-α and IL-6 levels together could be used to distinguish between CPA-TB and TB patients.Conclusion: In this study, multiple cytokines were identified that may serve as potential biomarkers for use in detecting TB patients with CPA. Furthermore, our results should enhance understanding of how immune system dysfunctions influence susceptibility to Mtb and/or A. fumigatus infections.Keywords: Aspergillus fumigatus, Mycobacterium tuberculosis, cytokine profiles, IL-8, galactomannan

Tianhui Gao,1,&ast; Cong Yao,1,&ast; Yuanyuan Shang,1 Renchun Su,1 Xuxia Zhang,1 Weicong Ren,1 Shanshan Li,1 Wei Shu,2 Yu Pang,1 Qi Li2 1Department of Bacteriology and Immunology, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China; 2Clinical Center on Tuberculosis Control, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qi Li; Yu Pang, Beijing Chest Hospital, Capital Medical University, No. 97, Machang, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86 010 6954 6690 ; +86 10 8950 9366, Email lq0703@hotmail.com; pangyupound@163.comPurpose: Unsatisfactory efficacies of currently recommended anti-Mycobacterium abscessus complex (MABC) treatment regimens have led to development of novel drugs to combat MABC infections. In this study, we evaluated in vitro antimicrobial activities of bedaquiline (BDQ) and four oxazolidinones against MABC isolates.Methods: The resazurin microplate assay was performed to determine minimum inhibitory concentrations (MICs) of BDQ and four oxazolidinones, including tedizolid (TZD), sutezolid (SZD), delpazolid (DZD), and linezolid (LZD), against 65 MABC isolates. A checkerboard method was used to investigate efficacies of various antimicrobial drug combinations.Results: BDQ MICs for MABC isolates ranged from < 0.031 to 1 μg/mL, while MIC50 and MIC90 values were 0.125 μg/mL and 0.25 μg/mL, respectively. TZD MIC50 and MIC90 values for MABC isolates were 1 μg/mL and 4 μg/mL, respectively, which were fourfold lower than corresponding LZD values (P < 0.001). DZD MIC90 values for MABC isolates was 8 μg/mL, which were 0.5-fold lower than corresponding LZD values (P < 0.01). MICs of BDQ, SZD, and LZD for M. abscessus subspecies massiliense isolates were significantly lower than corresponding MICs for M. abscessus subspecies abscessus isolates (P < 0.05). Notably, use of oxazolidinones (DZD, SZD, LZD, or TZD) with BDQ against MABC isolates led to reduction of the oxazolidinone median MIC range from 4 to 0.125 μg/mL to 1– 0.031 μg/mL.Conclusion: These results demonstrated excellent BDQ inhibitory activity against MABC isolates. TZD exhibited stronger antimicrobial efficacy against MABC isolates as compared to efficacies of DZD, SZD, and LZD. Importantly, MICs of oxazolidinones were markedly decreased when they were combined with BDQ, thus suggesting that combinations of BDQ and oxazolidinones may be effective treatments for MABC infections.Keywords: bedaquiline, tedizolid, oxazolidinones, susceptibility testing, Mycobacterium abscessus complex, delpazolid

Wei Lin,1,2 Wenjun Ren,1,2 Hao Chen,1,2 Yong Wei1,2 1School of Ophthalmology and Optometry, Eye Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2State Key Laboratory of Optometry, Ophthalmology, and Vision Science, Affiliated Eye Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Yong Wei, School of Ophthalmology and Optometry, Eye Hospital of Wenzhou Medical University, No. 270, Xueyuan West Road, Wenzhou, 325027, People’s Republic of China, Email weiyongdoctor@163.comBackground: To explore the impacts of surgeons’ experience in patients with epiretinal membrane (ERM).Methods: Patients with idiopathic ERM (334 eyes) who underwent PPV and membrane peeling were included in this study. The surgeries were performed by 9 surgeons. Patients were categorized into the experienced group (surgeons who had performed more than 5000 cases of PPV) and the regular group (surgeons who had performed less than 1000 cases of PPV). The patients were also categorized into five groups according to different preoperative best corrected visual acuity (BCVA): 20/100 or worse, 20/70-20/50, 20/40-20/30, 20/25 and 20/20. Impacts of preoperative BCVA, surgeons’ experience, lens status, and internal limiting membrane (ILM) peeling on postoperative BCVA were analyzed.Results: The postoperative BCVA was significantly better at 1 week and 1 month in the experienced group compared to the regular group (p = 0.022 and 0.045, respectively). There were no significant differences in postoperative BCVA at 3 months and 6 months between the two groups (p = 0.268 and 0.233, respectively). Postoperative BCVA at 6 months was similar in the 20/25 group and 20/20 group (p = 0.063); both groups had better BCVA compared to the other three groups. The 20/100 or worse group had the greatest visual improvement among the 5 groups at 6 months.Conclusion: This study suggested that although the experience of surgeons had no significant impact on the final BCVA following PPV and ERM removal, the BCVA during the early postoperative phase appeared to be better in the experienced group.Keywords: surgeons’ experience, epiretinal membrane, pars plana vitrectomy, best corrected visual acuity

Meiling Jin,1,2,&ast; Wenwen Ren,3,&ast; Weiguang Zhang,2 Linchang Liu,2,4 Zhiwei Yin,2,5 Diangeng Li6 1Department of Nephrology, Beijing-Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China; 2Department of Nephrology, Chinese People’s Liberation Army General Hospital, Chinese People’s Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases (2011DAV00088), National Clinical Research Center for Kidney Diseases, Beijing, 100853, People’s Republic of China; 3Department of Nephrology, Beijing Ditan Hospital,Capital Medical University, Beijing, 100015, People’s Republic of China; 4Department of Nephrology, Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing, 100039, People’s Republic of China; 5College of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 6Department of Academic Research, Beijing-Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Diangeng LiDepartment of Academic Research, Beijing-Chaoyang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of ChinaTel/Fax +86 10-85231049Email lidiangeng@126.comZhiwei YinCollege of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; Department of Nephrology, Chinese People’s Liberation Army General Hospital, Chinese People’s Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases (2011DAV00088), National Clinical Research Center for Kidney Diseases, Beijing, 100853, People’s Republic of ChinaTel/Fax +86 10-66937010Email zhiwei_yin@126.comPurpose: This study aimed to explore the underlying mechanisms of Shenyankangfu tablet (SYKFT) in the treatment of glomerulonephritis (GN) based on network pharmacology, machine learning, molecular docking, and experimental validation.Methods: The active ingredients and potential targets of SYKFT were obtained through the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the targets of GN were obtained through GeneCards, etc. Perl and Cytoscape were used to construct an herb-active ingredient–target network. Then, the clusterProfiler package of R was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. We also used the STRING platform and Cytoscape to construct a protein–protein interaction (PPI) network, as well as the SwissTargetPrediction server to predict the target protein of the core active ingredient based on machine-learning model. Molecular-docking analysis was further performed using AutoDock Vina and Pymol. Finally, we verified the effect of SYKFT on GN in vivo.Results: A total of 154 active ingredients and 255 targets in SYKFT were screened, and 135 targets were identified to be related to GN. GO enrichment analysis indicated that biological processes were primarily associated with oxidative stress and cell proliferation. KEGG pathway analysis showed that these targets were involved mostly in infection-related and GN-related pathways. PPI network analysis identified 13 core targets of SYKFT. Results of machine-learning model suggested that STAT3 and AKT1 may be the key target. Results of molecular docking suggested that the main active components of SYKFT can be combined with various target proteins. In vivo experiments confirmed that SYKFT may alleviate renal pathological injury by regulating core genes, thereby reducing urinary protein.Conclusion: This study demonstrated for the first time the multicomponent, multitarget, and multipathway characteristics of SYKFT for GN treatment.Keywords: shenyankangfu tablet, glomerulonephritis, network pharmacology, machine learning, molecular docking

Clifford Silver Tarimo,1,2 Soumitra S Bhuyan,3 Quanman Li,1 Weicun Ren,4 Michael Johnson Mahande,5 Jian Wu1 1Department of Epidemiology and Health Statistics, Zhengzhou University, Zhengzhou, People’s Republic of China; 2Department of Science and Laboratory Technology, Dar es Salaam Institute of Technology, Dar es Salaam, Tanzania; 3Edward J. Bloustein School of Planning and Public Policy, Rutgers University, New Brunswick, NJ, USA; 4College of Sanquan, Xinxiang Medical University, Xinxiang, People’s Republic of China; 5Department of Epidemiology and Applied Biostatistics, Kilimanjaro Christian Medical University College, Moshi, TanzaniaCorrespondence: Jian Wu Email jianwu17@163.comObjective: The goal of this study was to establish the most efficient boosting method in predicting neonatal low Apgar scores following labor induction intervention and to assess whether resampling strategies would improve the predictive performance of the selected boosting algorithms.Methods: A total of 7716 singleton births delivered from 2000 to 2015 were analyzed. Cesarean deliveries following labor induction, deliveries with abnormal presentation, and deliveries with missing Apgar score or delivery mode information were excluded. We examined the effect of resampling approaches or data preprocessing on predicting low Apgar scores, specifically the synthetic minority oversampling technique (SMOTE), borderline-SMOTE, and the random undersampling (RUS) technique. Sensitivity, specificity, precision, area under receiver operating curve (AUROC), F-score, positive predicted values (PPV), negative predicted values (NPV) and accuracy of the three (3) boosting-based ensemble methods were used to evaluate their discriminative ability. The ensemble learning models tested include adoptive boosting (AdaBoost), gradient boosting (GB) and extreme gradient boosting method (XGBoost).Results: The prevalence of low (< 7) Apgar scores was 9.5% (n = 733). The prediction models performed nearly similar in their baseline mode. Following the application of resampling techniques, borderline-SMOTE significantly improved the predictive performance of all the boosting-based ensemble methods under observation in terms of sensitivity, F1-score, AUROC and PPV.Conclusion: Policymakers, healthcare informaticians and neonatologists should consider implementing data preprocessing strategies when predicting a neonatal outcome with imbalanced data to enhance efficiency. The process may be more effective when borderline-SMOTE technique is deployed on the selected ensemble classifiers. However, future research may focus on testing additional resampling techniques, performing feature engineering, variable selection and optimizing further the ensemble learning hyperparameters.Keywords: low Apgar score, labor induction, machine learning, ensemble learning, resampling methods, imbalanced data

Haoming Mai,1,&ast; Jiaxuan Chen,1,&ast; Haitao Chen,1,2,&ast; Zhiwei Liu,3,&ast; Guanlin Huang,1 Jialin Wang,1 Qianyi Xiao,4 Weihua Ren,5 Bin Zhou,1 Jinlin Hou,1 Deke Jiang1 1State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, People’s Republic of China; 3Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; 4School of Public Health, Fudan University, Shanghai, 200032, People’s Republic of China; 5Central Laboratory, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan Province, 471009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Deke Jiang; Jinlin HouState Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of ChinaTel +86-20-62786533; +86-20-61641941Email dekejiang17@smu.edu.cn; jlhousmu@163.comIntroduction: Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive.Methods: With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) < 0.20). A total of 14,930 variants within the MHC region were genotyped or imputed.Results: We identified two variants, rs114401688 (P = 1.05 × 10− 6, PFDR = 2.43 × 10− 3) and rs115126566 (P = 9.04 × 10− 5, PFDR = 1.77 × 10− 1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1&ast;04 and HLA-DRB1&ast;04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥ 50, P = 0.03).Discussion: Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.Keywords: fine mapping, susceptibility, MHC, hepatocellular carcinoma, HBV

Shengsheng Liu,1– 3,&ast; Weicong Ren,1,&ast; Jiajia Yu,1,2 Chuanyou Li,1 Shenjie Tang2 1Department of Bacteriology and Immunology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China; 2Multidisciplinary Diagnosis and Treatment Centre for Tuberculosis, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China; 3Department of Tuberculosis, Anhui Chest Hospital, Anhui, 230022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shenjie Tang; Chuanyou Li Tel +8613621028338; +8613683140887Email tangsj1106@hotmail.com; lichuanyou6688@hotmail.comPurpose: To investigate the potential pathophysiological association between tuberculosis (TB) and diabetes mellitus (DM) using bioinformatic analyses.Patients and Methods: Gene expression datasets for healthy controls (HCs), TB patients, DM patients, TB+DM patients (GSE114192), and metformin-treated cells (GSE102677) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified from pairwise dataset comparisons TB vs HCs and DM vs HCs. DEGs were verified by comparing them to DEGs for TB+DM vs HCs. Enrichment analysis of DEGs common to all three dataset comparisons was conducted using DAVID. The protein–protein interaction (PPI) network was established via STRING and visualised in Cytoscape. Hub genes were identified using the Cytoscape plug-in cytoHubba and then were verified using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Targeted miRNA prediction analysis identified metformin treatment-induced gene expression changes in peripheral blood mononuclear cells.Results: A total of 422 DEGs were common to all three dataset comparisons. Functional enrichment analysis revealed these DEGs were enriched for functional terms of type I interferon signaling pathway, innate immune response, inflammatory response, and infectious diseases. Ten hub genes identified using PPI network analysis were screened for interactions with metformin target gene INS using cytoHubba based on maximal clique centrality (MCC) score. Subsequently, five hub genes were predicted to functionally interact with INS, including STAT1, IFIT3, RSAD2, IFI44L, and XAF1, as verified by RT-qPCR. Meanwhile, seven miRNAs (miR-3680-3p, miR-3059-5p, miR-629-3p, miR-29b-2-5p, miR-514b-5p, miR-4755-5p, miR-4691-3p) were associated with regulation of hub genes. Notably, six hub genes (STAT1, IFIT3, RSAD2, ISG15, IFI44, IFI6) were down-regulated in cells exposed to both metformin and Mycobacterium tuberculosis antigens.Conclusion: Network hub genes hold promise as disease status biomarkers and as metformin treatment targets for alleviating TB and DM. This study describes a strategy for exploring pathogenic mechanisms of diseases such as TB and DM.Keywords: diabetes mellitus, tuberculosis, differentially expressed gene, metformin, bioinformatics

Yuan Dang,1 Xiaojuan Ouyang,2 Wenjun Ren,3 Lie Wang,3 Qiaojia Huang1 1Laboratory of Basic Medicine, 900 Hospital of the Joint Logistics Team (Dongfang Hospital)(Former Fuzhou General Hospital), Xiamen University Medical College, Fuzhou, 350025, Fujian, People’s Republic of China; 2Department of Department of Pathology, 900 Hospital of the Joint Logistics Team (Dongfang Hospital) (Former Fuzhou General Hospital), Fuzhou, 350025, Fujian, People’s Republic of China; 3Department of General Surgery, 900 Hospital of the Joint Logistics Team (Dongfang Hospital) (Former Fuzhou General Hospital), Fuzhou, 350025, Fujian, People’s Republic of ChinaCorrespondence: Lie WangDepartment of General Surgery, 900 Hospital of the Joint Logistics Team (Dongfang Hospital) (Former Fuzhou General Hospital), 156 North Xi-er Huan Road, Fuzhou City, Fujian Province, 350025, People’s Republic of ChinaTel +86-591-22859790Fax +86-591-83796855Email fzptwk@xmu.edu.cnQiaojia HuangLaboratory of Basic Medicine, 900 Hospital of the Joint Logistics Team (Dongfang Hospital) (Former Fuzhou General Hospital), 156 North Xi-er Huan Road, Fuzhou City, Fujian Province, 350025, People’s Republic of ChinaTel +86-591-22859102Fax +86-591-83721105Email huangqj100@126.comPurpose: The present study investigated the expression and function of the long noncoding RNA (lncRNA) actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) related to gastric cancer (GC), based on previous results from a microarray analysis.Methods: Real-time quantitative polymerase chain reaction (qPCR) was used to verify the expression of AFAP1-AS1 in 97 fresh GC tissues and paired non-GC tissues, as well as in six different GC cell lines (BGC-823, SGC-7901, MGC-803, AGS, MKN-45, and MKN-28). The expression levels were subsequently correlated with the clinicopathological features of patients. siRNA against AFAP1-AS1 was transfected into GC cell lines, and cell proliferation, migration, and invasion were detected before and after silencing of AFAP1-AS1 expression. Luciferase reporter gene analysis was used to confirm the target gene of microRNA-205-5p (miR-205-5p) in 293T cells. The potential mechanism was subsequently investigated.Results: qPCR results showed that AFAP1-AS1 was significantly overexpressed in GC tumor tissues and also GC cell lines, comparing to their paired non-GC tissues. Furthermore, statistical analysis revealed that the overexpression of AFAP1-AS1 was significantly correlated with tumor size (p=0.018) and grade of differentiation (p=0.042). Subsequently, artificially decreasing the expression of AFAP1-AS1 with its specific siRNA dramatically inhibited the proliferation, migration and invasion of GC cell lines (SGC-7901 and BGC-823 cells). Mechanical analysis suggested that AFAP1-AS1 is involved in regulation of its maternal gene, AFAP1, at both mRNA level and protein level. Luciferase reporter gene assay indicated that lncRNA AFAP1-AS1, as a ceRNA, is able to sponge miR-205-5p. Moreover, miR-205-5p has been well demonstrated to participate in the regulation of AFAP1 expression and the phenotypes of GC cells, including proliferation, migration and invasion.Conclusion: AFAP1-AS1, as a novel biomarker of GC, promotes the proliferation migration and invasion of GC cells and function as ceRNA to target AFAP1 by sponging miR-205-5p.Keywords: gastric cancer, lncRNA, AFAP1-AS1, AFAP1, miR-205-5p

Jingjie Hu,&ast; Liuyuan Wang,&ast; Kaili Fan, Wenwei Ren, Qiongzhang Wang, Yiting Ruan, Chengxiang Yuan, Guiqian Huang, Jincai He Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jincai He; Guiqian HuangDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of ChinaTel +86 577-555780166; +86 577-555781380Fax +86 577-55578033; +86 577-55578999Email hjc@wmu.edu.cn; huangguiqian123@126.comObjective: Inflammation plays an important role in stroke. Many inflammatory markers in peripheral blood are proved to be associated with stroke severity or prognosis. But few comprehensive models or scales to evaluate the post-stroke depression (PSD) have been reported. In this study, we aimed to compare the level of systemic inflammation markers between PSD and non-PSD patients and explore the association of these inflammatory markers with PSD.Methods: Totally, 432 ischemic stroke patients were consecutively enrolled in the study and received 1 month follow-up. We used the 17-Hamilton Rating Scale to measure depressive symptoms at 1 month after stroke. With the Hamilton Depression Scale score of > 7, patients were diagnosed with PSD. Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR) and derived neutrophil-to-lymphocyte ratio (dNLR) were calculated from the admission blood work.Results: Finally, 129 patients (30.5%) were diagnosed with PSD at 1 month. PSD patients showed significantly higher levels of SII (501.27 (345.43– 782.58) vs 429.60 (315.64– 570.98), P=0.001), NLR (2.36 (1.77– 3.82) vs 2.17 (1.56– 2.80), P=0.010), dNLR (1.67 (1.30– 2.51) vs 1.54 (1.16– 1.99), P=0.009), PLR (124.65 (95.25– 155.15) vs 109.22 (92.38– 142.03), P=0.015), especially SII at admission as compared to non-PSD patients. In the logistic analysis, SII value (> 547.30) was independently associated with the occurrence of PSD (OR=2.181, 95% CI=1.274– 3.732, p =0.004), better than dNLR (OR=1.833, 95% CI=1.071– 3.137, p =0.027), PLR (OR= 1.822, 95% CI=1.063– 3.122, p =0.029) and NLR (OR =1.728, 95% CI=1.009– 2.958, p =0.046).Conclusion: Increased SII, PLR, dNLR, NLR, particularly SII at admission, are significantly correlated with PSD and may add some prognostic clues to find early discovery of PSD.Keywords: inflammatory markers, post-stroke depression, systemic immune-inflammation index, neutrophil-to-lymphocyte, platelet-to-lymphocyte, derived neutrophil-to-lymphocyte ratio

Hui Lv,1,2 Jingjing Wang,3 Xiaolin Xing,3 Wenjie Ren1 1Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, 453000, People’s Republic of China; 2Management Institute, Xinxiang Medical University, Xinxiang, 453000, People’s Republic of China; 3School of Public Health, Xinxiang Medical University, Xinxiang, 453000, People’s Republic of ChinaCorrespondence: Wenjie Ren Email rwj1571373@126.comPurpose: To explore the influencing factors of medical dissatisfaction experiences from the perspectives of patients, and provide corresponding strategies for its prevention.Patients and Methods: Using multistage random sampling, 43 hospitals in three provinces of China were surveyed using a self-designed questionnaire. There were 2065 valid questionnaires analyzed in our study.Results: 46.9% (n = 934) of participants had experienced medical dissatisfaction in the past year, mainly due to poor service quality, cumbersome procedures and high medical costs. There were statistically significant differences in the medical dissatisfaction experiences for these patients with different ages, marital status and levels of education (P< 0.05). According to structural equation modelling, health education and media reports had a positive and indirect influence (standardized coefficient = 0.046) on medical dissatisfaction experiences, while there was a negative correlation (standardized coefficient = − 0.399) between patients’ social recognition and medical dissatisfaction experiences. Also, our results also found that social relationships had a negative and indirect impact (standardized coefficient = − 0.166) on medical dissatisfaction experiences. Besides, health education and media reports had a negative impact (standardized coefficient = − 0.115) on patients’ social recognition, while social relationships have a positive effect (standardized coefficient = 0.416) on patients’ social recognition.Conclusion: Health education and media reports and social relationships, as antecedent variables, have an indirect effect on inducing the medical dissatisfaction experiences of patients. In addition, patients’ social recognition was an intermediate variable in inducing the medical dissatisfaction of patients.Keywords: social cognition, health care workers, HCWs, mistrust, patients satisfaction

Jia Li,1 Liang Feng,1 Qiqi Huang,2 Wenwei Ren1 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 2Department of Cardiac Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaCorrespondence: Wenwei RenDepartment of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of ChinaTel/Fax +86 577 555 54543Email rww037@126.comQiqi HuangDepartment of Cardiac Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, People’s Republic of ChinaTel/Fax +86 577 555 54543Email wyyyhqq@126.comObjective: Pneumonia is a common complication in patients with stroke. There was a close relationship between serum iron and inflammatory response. This study aimed to explore the relationship between serum iron levels and stroke-associated pneumonia (SAP).Methods: Patients with acute stroke were recruited from the First Affiliated Hospital of Wenzhou Medical University and divided into SAP group and Non-SAP group. The demographic and clinical data of the patients were collected via the medical records, and the blood samples were collected within 24 hours after admission. The predictive value of serum iron to SAP was evaluated by receiver operating characteristic curve (ROC) and binary Logistic regression models. A restricted cubic spline (RCS) was used to furtherly clarify the relationship between serum iron and the risk of SAP.Results: A total of 906 participants were enrolled, including Non-SAP group (n = 755) and SAP group (n = 151). Serum iron levels in the SAP group were significantly lower than those in the Non-SAP group (9.77± 5.61 vs 14.01± 6.80, P < 0.001). Logistic regression showed that patients with high serum iron levels (≥ 7.8μmol/L) showed a lower risk of SAP (OR=0.43, 95% CI, 0.27– 0.69, P < 0.001). Besides, the RCS model showed that there was an L-shaped relationship between the serum iron and risk of SAP (P for non-linearity: 0.014).Conclusion: Low serum iron level was a risk factor for SAP, and there was an L-shaped relationship between them. Stroke patients with low serum iron levels should be alert to the risk of SAP.Keywords: stroke, pneumonia, serum iron

Shuangkuan Du,1 Pengjie Zhang,2 Wei Ren,1 Fan Yang,1 Chun Du1 1Department of Urology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, People’s Republic of China; 2The Center of Kidney Diseases and Hemodialysis, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, People’s Republic of ChinaCorrespondence: Pengjie Zhang Email ls6uhp@163.comBackground: The development of radioresistance remains the obstacle for prostate cancer (PCa) treatment. Here, we explored the role and potential mechanism of circular RNA zinc finger protein 609 (circ-ZNF609) in the radioresistance of PCa cells.Materials and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of circ-ZNF609, microRNA-501-3p (miR-501-3p) and hexokinase 2 (HK2) messenger RNA (mRNA). The viability, apoptosis, metastasis and radioresistance of PCa cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, transwell assays and colony formation assay. The glycolytic rate was assessed through measuring the glucose consumption and lactate production using fluorescence-based glucose and lactate assay kits. The target interaction between miR-501-3p and circ-ZNF609 or HK2 was predicted by StarBase software and confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The protein level of HK2 was detected by Western blot assay. In vivo tumor growth assay was used to explore the role of circ-ZNF609 in the radioresistance of PCa in vivo.Results: Circ-ZNF609 was abnormally up-regulated in PCa tissues and cell lines. Circ-ZNF609 silencing hampered the viability, metastasis, radioresistance and promoted the apoptosis through suppressing cell glycolysis. MiR-501-3p was a direct target of circ-ZNF609, and si-circ-ZNF609-induced influence in PCa cells was partly alleviated by the addition of anti-miR-501-3p. MiR-501-3p functioned through directly interacting with and down-regulating HK2. HK2 was modulated by circ-ZNF609/miR-501-3p axis in PCa cells. Circ-ZNF609 silencing enhanced the radiosensitivity of PCa cells in vivo.Conclusion: Circ-ZNF609 promoted the progression and radioresistance of PCa cells through accelerating the glycolysis via miR-501-3p/HK2 axis, providing promising targets for improving the prognosis of PCa patients.Keywords: prostate cancer, circ-ZNF609, miR-501-3p, HK2, glycolysis, radioresistance

Ning Xie,1,* Tao Qin,1,* Wei Ren,1 Herui Yao,1,2 Yunfang Yu,1 Huangming Hong1 1Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, People’s Republic of China; 2Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunfang Yu; Huangming Hong Tel +86-20-34071337Fax +86-20-81332833Email yunfangyu@foxmail.com; honghm3@mail.sysu.edu.cnPurpose: To assess the efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors (CDKi) combined with endocrine therapy (ET) in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and compare the efficacy of different CDKi (palbociclib, ribociclib, or abemaciclib).Materials and Methods: This study based on randomized Phase 2 or 3 trials of CDKi plus ET compared with placebo plus ET for women with HR+/HER2−ABC and identify relevant randomized clinical trials (RCTs) published prior to February 2020. The primary endpoint was progression-free survival (PFS), the secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit response (CBR) and safety. The PROSPERO registry number is 42018081105.Results: The results from eight trials including 4580 participants were pooled. Evidence indicated that the PFS of CDKi group was significantly prolonged (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50– 0.60, P < 0.01) compared with placebo group. The ORR and CBR were better (risk ratio [RR] 1.47, 95% CI 1.30– 1.67, P < 0.01; 1.24, 95% CI 1.15– 1.35, P < 0.01) in the CDKi group. The OS of CDKi group (HR 0.75, 95% CI 0.67– 0.85, P < 0.01) was significantly longer than ET alone. Subgroup analyses confirmed that the benefit was consistent across most subgroups. Subgroup analyses showed no statistically significant difference of PFS among three CDKi: palbociclib vs ribociclib (HR 0.55, 95% CI 0.49– 0.60, P = 0.34), palbociclib vs abemaciclib (HR 0.53, 95% CI, 0.47– 0.59, P = 0.61), and ribociclib vs abemaciclib (HR 0.56, 95% CI, 0.51– 0.62, P = 0.72). Treatment-related grade 3 or 4 hematologic adverse events (AEs) were more frequently in CDKi group.Conclusion: CDKi combined with ET can significantly prolong PFS and improve the ORR, CBR and OS in patients with HR+/HER2− ABC. However, the advantage of different CDKi has not been established.Keywords: CDK4/6 inhibitor, HR-positive, HER2-negative, advanced breast cancer

Jing Zhang,1 Shuo Zhang,2 Song Gao,3 Yan Ma,1 Xueying Tan,1 Ye Kang,4 Weidong Ren1 1Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of China; 2Department of Neurology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of China; 3Department of Clinical Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of China; 4Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, People’s Republic of ChinaCorrespondence: Weidong RenDepartment of Ultrasound, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang City 110004, People’s Republic of ChinaEmail renwdcmu01@163.comPurpose: To investigate the relationship between hypoxia-inducible factor 1-alpha (HIF-1α), Twist family BHLH transcription factor 1 (TWIST-1), and β 1 integrin (ITGB-1) expression and tumor stiffness, and evaluate performance of HIF-1α, TWIST-1, and ITGB-1 alone and in combination with Ki-67 for predicting pathological responses to neoadjuvant chemotherapy (NACT) in breast cancer (BC).Patients and Methods: This was a prospective cohort study of 104 BC patients receiving NACT. Tumor stiffness and oxygen score (OS) were evaluated before NACT by shear-wave elastography and optical imaging; HIF-1α, TWIST-1, ITGB-1, and Ki-67 expression were quantitatively assessed by immunohistochemistry of paraffin-embedded tumor samples obtained by core needle biopsy. Indexes were compared among different residual cancer burden (RCB) groups, and associations of HIF-1α, TWIST-1, ITGB-1, and Ki-67 with tumor stiffness and OS were examined. The value of HIF-1α, TWIST-1, ITGB-1, and Ki-67, and a possible new combined index (predRCB) for predicting NACT responses was assessed by receiver operating characteristic (ROC) curves.Results: HIF-1α, TWIST-1, and ITGB-1 expression were positively correlated with tumor stiffness and negatively with OS. Area under the ROC curves (AUCs) measuring the performance of HIF-1α, TWIST-1, ITGB-1, and Ki-67 for predicting responses to NACT were 0.81, 0.85, 0.79, and 0.80 for favorable responses, and 0.83, 0.86, 0.84, and 0.85 for resistant responses, respectively. PredRCB showed better prediction than the other individual indexes for favorable responses (AUC = 0.88) and resistant responses (AUC = 0.92).Conclusion: HIF-1α, TWIST-1, ITGB-1, and Ki-67 performed well in predicting favorable responses and resistance to NACT, and predRCB improved the predictive power of the individual indexes. These results support individualized treatment of BC patients receiving NACT.Keywords: HIF-1α, TWIST-1, ITGB-1, neoadjuvant chemotherapy, breast cancer, prediction

Jiao Hu,1 Yu Cui,1 Peihua Liu,1 Xu Zhou,2 Wenbiao Ren,1 Jinbo Chen,1 Xiongbing Zu11Department of Urology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaPurpose: Inguinal lymph node metastasis (LNM) is one of the most significant prognostic factors for patients with penile cancer. This study aimed to identify potential predictors of inguinal LNM.Patients and methods: A comprehensive search of the PubMed, Embase, and Cochrane Library databases for studies that reported predictors of inguinal LNM in penile cancer was performed. Finally, we selected 42 eligible studies with 4,802 patients. Accumulative analyses of odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were performed. All analyses were performed by using Review Manager software version 5.3.Results: Among the 4,802 patients, 1,706 (36%) were diagnosed with inguinal LNM. Predictors of LNM included two categories: tumor-associated biomarkers and invasive clinicopathologic characteristics. Biomarker-specific predictors: the program death ligand 1 (PD-L1) overexpression (OR=2.55, p=0.002), higher neutrophil-to-lymphocyte ratio (NLR) (OR=4.22, p=0.010), higher C-reactive protein (CRP) (OR=4.78, p3 cm) (OR=2.00, p=0.002), LVI (OR=3.37, p5 mm) (OR=2.58, p=0.002), nerve invasion (OR=2.84, p

Cuiling Zhang,1 Weigang Ren,1 Qingxin Liu,2 Zhikai Tan,3 Junwei Li,1 Chunyi Tong3 1College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, People’s Republic of China; 2Jiangsu Vocational College of Agriculture and Forestry, Jurong 212400, People’s Republic of China; 3Hunan Province Key Laboratory of Plant Functional Genomics and Developmental Regulation, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, People’s Republic of China Introduction: In this study, we report on the development of an effective delivery system for siRNAs; a novel cell-penetrating peptide (CPP), T9(dR), obtained from transportan (TP), was used for in vivo and in vitro testing. Methods: In this study, toxicity of T9(dR) and TP and efficient delivery of siRNA were tested in 293T, MDCK, RAW, and A549 cells. Furthermore, T9(dR)- and TP-delivered siRNAs against nucleoprotein (NP) gene segment of influenza virus (siNP) were studied in both cell lines and mice. Results: Gel retardation showed that T9(dR) effectively condensed siRNA into nanoparticles sized between 350 and 550 nm when the mole ratio of T9(dR) to siRNA was ≥4:1. In vitro studies demonstrated that T9(dR) successfully delivered siRNA with low cellular toxicity into several cell lines. It was also observed that T9(dR)-delivered siRNAs inhibited replication of influenza virus more efficiently as compared to that delivered by TP into the MDCK and A549 cells. It was also noticed that when given a combined tail vein injection of siNP and T9(dR) or TP, all mice in the 50 nmol siNP group infected with PR8 influenza virus survived and showed weight recovery at 2 weeks post-infection. Conclusion: This study indicates that T9(dR) is a promising siRNA delivery tool with potential application for nucleotide drug delivery. Keywords: cell-penetrating peptide, CPP, siRNA, inhibition, influenza virus, IV, transportan, nucleoprotein, NP

Caijun Dai,1,* Huihua Qiu,2,* Qiqi Huang,2,* Pinglang Hu,2 Xianchai Hong,2 Junwei Tu,1 Qiangli Xie,2 Haiyan Li,2 Wenwei Ren,2 Shuhong Ni,1 Fujian Chen3 1Jinhua Municipal Central Hospital, Jinhua 321000, China; 2The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; 3Anji County People’s Hospital, Huzhou 313300, China *These authors contributed equally to this work Purpose: Night shift is associated with adverse physical and psychological health outcomes such as poor sleep quality and depressive symptoms. We aimed to compare sleep quality as well as depressive symptoms in nurses working night shifts to those working day shifts only and explore the association between sleep quality and depressive symptoms among nurses. Patients and methods: Eight hundred sixty-five nurses were enrolled in the current study. Sleep quality and depressive symptoms among nurses were evaluated by the Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depressive Disorders Rating Scale (HADS), respectively. Results: PSQI and HADS scores were both significantly higher in the nurses working night shifts (P

Huihua Qiu,1 Wenwei Ren,1 Yanjie Yang,2 Xiongzhao Zhu,3 Guangyun Mao,4 Shanping Mao,5 Yan Lin,6 Shanshan Shen,7 Changjin Li,8 Hongying Shi,4 Suo Jiang,8 Jingjing He,9 Ke Zhao,8 Ye Fu,10 Xiaoqu Hu,11 Yingying Gu,1 Kai Wang,12 Xiuchan Guo,13 Jincai He1,8 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Medical Psychology, Public Health Institute of Harbin Medical University, Harbin, People’s Republic of China; 3Medical Psychological Institute, Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China; 5Department of Neurology, RenMin Hospital of Wuhan University, Wuhan, People’s Republic of China; 6Department of Neurology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 7Department of Geriatrics, Zhejiang Hospital, Hangzhou, People’s Republic of China; 8Department of Psychology, Wenzhou Medical University, Wenzhou, People’s Republic of China; 9Department of Psychiatry, Tongde Hospital of Zhejiang Province, Hangzhou, People’s Republic of China; 10Yinzhou Hospital Affiliated To Medical School of Ningbo University, Ningbo, People’s Republic of China; 11Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 12Department of Psychiatry, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 13Key Laboratory of Laboratory Medicine, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, People’s Republic of China Purpose: Cognitive behavioral therapy (CBT) for depression had been found to be effective in reducing depressive and anxiety symptoms in breast cancer survivors. It is not known whether CBT for depression would also improve insomnia and quality of life (QOL). The aim of this study was to investigate whether CBT for depression would improve insomnia and QOL in a randomized controlled multicenter trial. Patients and methods: In this study, breast cancer survivors (n=392) were randomly allocated to the following three groups: CBT (n=98), self-care management (SCM, n=98), and usual care (UC, n=196) in a ratio of 1:1:2. CBT and SCM received a series of nine sessions for 12 weeks, whereas UC received UC only. Insomnia and QOL were evaluated using Athens Insomnia Scale (AIS) and Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire at baseline, 4, 12, and 24 weeks. Results: There was a significant intergroup difference in AIS and FACT-B scores (both P

Xiu-Chai Zheng,1,2,* Wei Ren,1,2,* Shuang Zhang,1,2 Ting Zhong,1,2 Xiao-Chuan Duan,1,2 Yi-Fan Yin,1,2 Mei-Qi Xu,1,2 Yan-Li Hao,1,2 Zhan-Tao Li,1,2 Hui Li,1,2 Man Liu,1,2 Zhuo-Yue Li,1,2 Xuan Zhang1,2 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China *These authors contributed equally to this work Background: In the present study, the tumor-specific, pH-responsive peptide H7K(R2)2 -modified, theranostic liposome-containing paclitaxel (PTX) and superparamagnetic iron oxide nanoparticles (SPIO NPs), PTX/SPIO-SSL-H7K(R2)2, was prepared by using H7K(R2)2 as the targeting ligand, SPIO NPs as the magnetic resonance imaging (MRI) agent, PTX as antitumor drug. Methods: The PTX/SPIO-SSL-H7K(R2)2 was prepared by a thin film hydration method. The characteristics of PTX/SPIO-SSL-H7K(R2)2 were evaluated. The targeting effect, MRI, and antitumor activity of PTX/SPIO-SSL-H7K(R2)2 were investigated detail in vitro and in vivo in human breast carcinoma MDA-MB-231 cell models. Results: Our results of in vitro flow cytometry, in vivo imaging, and in vivo MR imaging confirmed the pH-responsive characteristic of H7K(R2)2 in MDA-MB-231 cell line in vitro and in vivo. The results of in vivo MRI and in vivo antitumor activity confirmed the theranostic effect of PTX/SPIO-SSL-H7K(R2)2 in MDA-MB-231 tumor-bearing model. Conclusion: Considering all our in vitro and in vivo results, we conclude that we developed targeting modified theranostic liposome which could achieve both role of antitumor and MRI. Keywords: tumor-specific pH-responsive peptide, paclitaxel, superparamagnetic iron oxide nanoparticles, liposome, theranostic efficiency

Juan Song, Weifang Ren, Tingting Xu, Yi Zhang, Hongyu Guo, Shanshan Zhu, Li Yang Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, People’s Republic of China Abstract: Liposome-based drug delivery system would be an innovative and promising candidate to circumvent multidrug resistance (MDR) of cisplatin (CDDP). However, the reversal efficacy of liposomal CDDP was severely impaired by weak cellular uptake and insufficient intracellular drug release. In this study, 3-octadecylcarbamoylacrylic acid–CDDP nanocomplex (OMI–CDDP–N)-based liposomes (OCP-L) with high cellular uptake and sufficient intracellular drug release were designed to circumvent MDR of lung cancer. OMI–CDDP–N was synthesized through a pH-sensitive monocarboxylato and an O→Pt coordinate bond, which is more efficient than CDDP. Also, OCP-L incorporated with OMI–CDDP–N could induce effective cellular uptake, enhanced nuclear distribution, and optimal cellular uptake kinetics. In particular, OCP-L presented superior effects on enhancing cell apoptosis and in vitro cytotoxicity in CDDP-resistant human lung cancer (A549/CDDP) cells. The mechanisms of MDR reversal in A549/CDDP cells by OCP-L could attribute to organic cation transporter 2 restoration, ATPase copper-transporting beta polypeptide suppression, hypoxia-inducible factor 1 α-subunit depletion, and phosphatidylinositol 3-kinase/Akt pathway inhibition. These results demonstrated that OCP-L may provide an effective delivery of CDDP to resistant cells to circumvent MDR and enhance the therapeutic index of the chemotherapy. Keywords: 3-octadecylcarbamoylacrylic acid-cisplatin nanocomplexes, liposomes, cellular uptake, multidrug resistance, therapeutic index

Chao Wang,1* Xin Wang,1* Ting Zhong,1 Yang Zhao,1 Wei-Qiang Zhang,1 Wei Ren,1 Dan Huang,1 Shuang Zhang,1 Yang Guo,1 Xin Yao,1 Yi-Qun Tang,2 Xuan Zhang,1 Qiang Zhang1,3 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, 2Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, 3State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Clotted plasma proteins are present on the walls of tumor vessels and in tumor stroma. Tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA) could recognize the clotted plasma proteins in tumor vessels. Thermosensitive liposomes could immediately release the encapsulated drug in the vasculature of the heated tumor. In this study, we designed a novel form of targeted thermosensitive liposomes, CREKA-modified lysolipid-containing thermosensitive liposomes (LTSLs), containing doxorubicin (DOX) (DOX-LTSL-CREKA), to investigate the hypothesis that DOX-LTSL-CREKA might target the clotted plasma proteins in tumor vessels as well as tumor stroma and then exhibit burst release of the encapsulated DOX at the heated tumor site. We also hypothesized that the high local drug concentration produced by these thermosensitive liposomes after local hyperthermia treatment will be useful for treatment of multidrug resistance. The multidrug-resistant human breast adenocarcinoma (MCF-7/ADR) cell line was chosen as a tumor cell model, and the targeting and immediate release characteristics of DOX-LTSL-CREKA were investigated in vitro and in vivo. Furthermore, the antitumor activity of DOX-LTSL-CREKA was evaluated in MCF-7/ADR tumor-bearing nude mice in vivo. The targeting effect of the CREKA-modified thermosensitive liposomes on the clotted plasma proteins was confirmed in our in vivo imaging and immunohistochemistry experiments. The burst release of this delivery system was observed in our in vitro temperature-triggered DOX release and flow cytometry analysis and also by confocal microscopy experiments. The antitumor activity of the DOX-LTSL-CREKA was confirmed in tumor-bearing nude mice in vivo. Our findings suggest that the combination of targeting the clotted plasma proteins in the tumor vessel wall as well as tumor stroma by using CREKA peptide and temperature-triggered drug release from liposomes by using thermosensitive liposomes offers an attractive strategy for chemotherapeutic drug delivery to tumors. Keywords: clotted plasma protein, tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA), lysolipid-containing thermosensitive liposomes, targeting

Fei Gao,1,2 Zhiqiang Liu,3 Wei Ren,3 Wen Jiang1 1Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, People’s Republic of China; 2Department of Neurology, First Affiliated Hospital of Xi’an Medical University, Xi’an 710077, People’s Republic of China; 3College of Life Sciences, Shaanxi Normal University, Xi’an 710062, People’s Republic of China Abstract: Growing evidence indicates brain inflammation has been involved in the genesis of seizures. However, the direct effect of acute inflammation on neuronal circuits is not well known. Lipopolysaccharide (LPS) has been used extensively to stimulate brain inflammatory responses both in vivo and in vitro. Here, we observed the contribution of inflammation induced by 10 μg/mL LPS to the excitability of neuronal circuits in acute hippocampal slices. When slices were incubated with LPS for 30 minutes, significant increased concentration of tumor necrosis factor α and interleukin 1β were detected by enzyme-linked immunosorbent assay. In electrophysiological recordings, we found that frequency of epileptiform discharges and spikes per burst increased 30 minutes after LPS application. LPS enhanced evoked excitatory postsynaptic currents but did not modify evoked inhibitory postsynaptic currents. In addition, exposure to LPS enhanced the excitability of CA1 pyramidal neurons, as demonstrated by a decrease in rheobase and an increase in action potential frequency elicited by depolarizing current injection. Our observations suggest that acute inflammation induced by LPS facilitates epileptiform activity in vitro and that enhancement of excitatory synaptic transmission and neuronal excitability may contribute to this facilitation. These results may provide new clues for treating seizures associated with brain inflammatory disease. Keywords: lipopolysaccharide, hippocampus, inflammation, epileptiform activity, synaptic transmission, neuronal excitability

Ke-Fu Yu,1 Wei-Qiang Zhang,1 Li-Min Luo,1 Ping Song,1 Dan Li,1 Ruo Du,1 Wei Ren,1 Dan Huang,1 Wan-Liang Lu,1,2 Xuan Zhang,1 Qiang Zhang1,2 1Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China Abstract: Considering the fact that iRGD (tumor-homing peptide) demonstrates tumor-targeting and tumor-penetrating activity, and that B16-F10 (murine melanoma) cells overexpress both αv integrin receptor and neuropilin-1 (NRP-1), the purpose of this study was to prepare a novel doxorubicin (DOX)-loaded, iRGD-modified, sterically-stabilized liposome (SSL) (iRGD-SSL-DOX) in order to evaluate its antitumor activity on B16-F10 melanoma cells in vitro and in vivo. The iRGD-SSL-DOX was prepared using a thin-film hydration method. The characteristics of iRGD-SSL-DOX were evaluated. The in vitro leakage of DOX from iRGD-SSL-DOX was tested. The in vitro tumor-targeting and tumor-penetrating characteristics of iRGD-modified liposomes on B16-F10 cells were investigated. The in vivo tumor-targeting and tumor-penetrating activities of iRGD-modified liposomes were performed in B16-F10 tumor-bearing nude mice. The antitumor effect of iRGD-SSL-DOX was evaluated in B16-F10 tumor-bearing C57BL/6 mice in vivo. The average particle size of the iRGD-SSL-DOX was found to be 91 nm with a polydispersity index (PDI) of 0.16. The entrapment efficiency of iRGD-SSL-DOX was 98.36%. The leakage of DOX from iRGD-SSL-DOX at the 24-hour time point was only 7.5%. The results obtained from the in vitro flow cytometry and confocal microscopy, as well as in vivo biodistribution and confocal immunofluorescence microscopy experiments, indicate that the tumor-targeting and tumor-penetrating activity of the iRGD-modified SSL was higher than that of unmodified SSL. In vivo antitumor activity results showed that the antitumor effect of iRGD-SSL-DOX against melanoma tumors was higher than that of SSL-DOX in B16-F10 tumor-bearing mice. In conclusion, the iRGD-SSL-DOX is a tumor-targeting and tumor-penetrating peptide modified liposome which has significant antitumor activity against melanoma tumors. Keywords: tumor-targeting and tumor-penetrating, integrin receptor, NRP-1, iRGD, liposome, doxorubicin

Dan Li,1 Ke Yang,1 Jie-Si Li,1 Xi-Yu Ke,1 Yu Duan,1 Ruo Du,1 Ping Song,1 Ke-Fu Yu,1 Wei Ren,1 Dan Huang,1 Xing-Huo Li,1 Xin Hu,1 Xuan Zhang,1 Qiang Zhang1,21Department of Pharmaceutics, 2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, ChinaBackground: Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood–brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo.Methods: The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice.Results: The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC50 of the CLA-PTX microemulsion was 1.61 ± 0.83 µM for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol® had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD50 of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg.Conclusion: CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.Keywords: CLA-PTX, microemulsion, pharmacokinetics, brain tumor, antitumor efficacy, safety

Wei Song1, Xiaowei Yu2, Sunxi Wang5, Ralph Blasier4, David C Markel3, Guangzhao Mao5, Tong Shi1, Weiping Ren1,31Department of Biomedical Engineering, Wayne State University, Detroit, MI, USA; 2Department of Orthopedic Surgery, Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China; 3Detroit Medical Center and Providence Hospital Orthopedic Residency, Detroit, 4Orthopedic Section, St Francis Hospital, Escanaba, 5Department of Chemical Engineering, Wayne State University, Detroit, MI, USABackground: Erythromycin, a hydrophobic antibiotic used to treat infectious diseases, is now gaining attention because of its anti-inflammatory effects and ability to inhibit osteoclasts formation. The aim of this study was to explore a cyclodextrin-erythromycin (CD-EM) complex for sustained treatment of orthopedic inflammation.Methods and results: Erythromycin was reacted with ß-cyclodextrin to form a nonhost-guest CD-EM complex using both kneading and stirring approaches. Physiochemical measurement data indicated that erythromycin and cyclodextrin formed a packing complex driven by intermolecular forces instead of a host-guest structure due to the limited space in the inner cavity of ß-cyclodextrin. The CD-EM complex improved the stability of erythromycin in aqueous solution and had a longer duration of bactericidal activity than free erythromycin. Cytotoxicity and cell differentiation were evaluated in both murine MC3T3 preosteoblast cells and RAW 264.7 murine macrophage cells. The CD-EM complex was noncytotoxic and showed significant inhibition of osteoclast formation but had little effect on osteoblast viability and differentiation.Conclusion: These attributes are especially important for the delivery of an adequate amount of erythromycin to the site of periprosthetic inflammation and reducing local inflammation in a sustained manner.Keywords: erythromycin, cyclodextrin, drug stability, bactericidal activity, osteoclastogenesis

As far as design of direct injection spark ignited engine is concerned, the fuel injector is a key component for success. Internal flow simulation is the best adapted tool for the design of the internal geometry of the injector. First, simulations of the internal flow will be discussed, especially transient stages of an injection event as well as the prediction of the fuel characteristics at the nozzle exit. Second, a coupling between internal flow calculations and instability model in order to predict initial spray characteristics will be suggested. L'injecteur est un des éléments clés dans la conception des moteurs essence à injection directe. La modélisation de l'écoulement dans l'injecteur guide la conception de la géométrie interne. Dans une première partie, les aspects de cette modélisation seront soulevés, à savoir, l'écoulement transitoire en début et fin d'injection, ainsi que la prédiction des caractéristiques du carburant à la sortie de l'injecteur qui va conditionner les caractéristiques du spray. Dans une deuxième partie, nous évoquerons les théories d'instabilités à l'origine de la formation des sprays, ainsi que l'approche employée pour prédire les caractéristiques des gouttes générées.