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Yihua Jin,1,* Zhimin Geng,1,2,* Kun Lin,1 Xinyu Gu,1 Xiwei Feng,1 Songling Fu,1 Wei Wang,1 Chunhong Xie,1 Yujia Wang,1 Fangqi Gong1 1Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, People’s Republic of China; 2Pediatric Cardiovascular Diseases Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangqi Gong; Yujia Wang, Email gongfangqi@zju.edu.cn; wangyujia@zju.edu.cnPurpose: Kawasaki disease (KD) is an acute systemic vasculitis that is associated with dysregulated immune responses. Monocytes play a central role in innate immunity. Our previous single-cell RNA sequencing of peripheral blood mononuclear cells (PBMC) revealed a new subset of monocytes in children with KD called L-Selectin+ classical monocytes (SELL+ CM). Therefore, we aimed to investigate the correlation between KD and SELL+ CM.Patients and Methods: Peripheral blood samples were collected from 81 KD patients, 18 febrile patients and 36 healthy children before treatment. Among them, ten KD patients were followed up, and samples were obtained before and after intravenous immunoglobulin (IVIG) treatment. Analysis of SELL+ CM was performed using flow cytometry. Additionally, ROC curve analysis was conducted to assess the diagnostic value of SELL+ CM for KD.Results: Classical monocytes (CM) expressed the highest levels of L-selectin in children with KD. The ratio of SELL+ CM in CM was significantly higher in KD patients than in febrile and healthy children. Following IVIG treatment, the ratio of SELL+ CM in CM showed a downward trend. The receiver operating characteristic (ROC) curve analysis (the area under the curve, AUC = 0.71) indicated the potential diagnostic value of SELL+ CM in KD. The correlation analysis suggested that SELL+ CM may serve as a new clinical index for patients with KD.Conclusion: In KD, the ratio of SELL+ CM in CM significantly increases during the acute phase, which may become a potential biomarker and help facilitate KD diagnosis based on clinical features.Keywords: Kawasaki disease, monocyte subsets, L-Selectin, coronary artery lesions

Shengling Hu,1– 4 Jinqiang Guo,5 Zhe Chen,6 Fengyun Gong,1– 4 Qi Yu1– 4 1Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China; 2Hubei Clinical Research Center for Infectious Diseases, Wuhan, 430023, People’s Republic of China; 3Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Wuhan, 430023, People’s Republic of China; 4Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan, 430023, People’s Republic of China; 5Department of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 6Department of Thoracic Surgery, the Second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of ChinaCorrespondence: Qi Yu; Fengyun Gong, Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China, Email fishns123@163.com; 2020jy0008@hust.edu.cnBackground: Multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) with high mortality remains a public health crisis and health security threat. This study aimed to explore the predictive value of nutritional indices for all-cause mortality (ACM) in MDR/RR-TB patients.Methods: We retrospectively recruited MDR/RR-TB patients between January 2015 and December 2021, randomly assigning them to training and validation cohorts. Patients were divided into high nutritional risk groups (HNRGs) and low nutritional risk groups (LNRGs) based on the optimal cut-off value obtained from receiver operating characteristic (ROC) analyses of the hemoglobin-albumin-lymphocyte-platelet (HALP) score, prognostic nutritional index (PNI), and controlling nutritional status (CONUT) score. In the training cohort, Kaplan-Meier survival curves and Log rank tests were used to compare overall survival (OS) between the groups. Cox risk proportion regression analyses were used to explore the risk factors of ACM in patients with MDR/RR-TB. The predictive performance of ACM was assessed using area under the curve (AUC), sensitivity and specificity of ROC analyses.Results: A total of 524 MDR/RR-TB patients, with 255 in the training cohort and 269 in the validation cohort, were included. Survival analyses in the training cohort revealed significantly lower OS in the HNRGs compared to the LNRGs. After adjusting for covariates, multivariate analysis identified low HALP score, low PNI and high CONUT score were independent risk factors for ACM in MDR/RR-TB patients. ROC analyses demonstrated good predictive performance for ACM with AUCs of 0.765, 0.783, 0.807, and 0.811 for HALP score, PNI, CONUT score, and their combination, respectively. Similar results were observed in the validation set.Conclusion: HALP score, PNI, and CONUT scores could effectively predict ACM in patients with MDR/RR-TB. Hence, routine screening for malnutrition should be given more attention in clinical practice to identify MDR/RR-TB patients at higher risk of mortality and provide them with nutritional support to reduce mortality.Keywords: multidrug- and rifampicin- resistant tuberculosis, all- cause mortality, nutrition

Shengling Hu, Qi Yu, Fenfang Liu, Fengyun Gong Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology; Hubei Clinical Research Center for Infectious Diseases; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan, 430023, People’s Republic of ChinaCorrespondence: Fengyun Gong, Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology; Hubei Clinical Research Center for Infectious Diseases; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences; Joint Laboratory of Infectious Diseases and Health, Wuhan Institute of Virology and Wuhan Jinyintan Hospital, Chinese Academy of Sciences, Wuhan, 430023, People’s Republic of China, Email 2020jy0008@hust.edu.cnBackground: The development of chronic obstructive pulmonary disease (COPD) following tuberculosis (TB) is known as tuberculosis-associated obstructive pulmonary disease (TOPD). This study aimed to explore the predictive value of inflammatory indicators for TOPD in TB patients.Methods: Data for this cross-sectional study were collected between January 2014 and January 2022 at Wuhan Jinyintan Hospital. The ratio of inflammatory indicators, including Systemic Inflammatory Response Index (SIRI), C-reactive protein-to-lymphocyte ratio (CLR), eosinophil count-to-lymphocyte count ratio (ELR), were calculated. Univariate and multivariate logistic regression analyses were conducted to explore the association between the ratio of inflammatory indicators and TOPD. Furthermore, the relationship between the ratio of inflammatory indicators and TOPD was investigated using propensity score matching (PSM) and receiver operating characteristic (ROC) curve analysis was performed to evaluate their predictive value for TOPD.Results: The present study included a total of 737 patients, of whom 83 participants (11.26%) had TOPD. Sixty-nine TOPD patients and 69 non-TOPD (NTOPD) patients were successfully matched. Univariate and multivariable logistics regression analysis, conducted before and after PSM, revealed that SIRI was independently significantly associated with an increased risk of TOPD. The area under curve (AUC) of SIRI were 0.702 and 0.668 before and after PSM, respectively. Additionally, patients were stratified into four different groups based on SIRI quartiles for further analysis. The prevalence of TOPD in TB patients showed an increase with higher SIRI values, both before and after PSM.Conclusion: Levels of inflammatory indicators were higher in TOPD patients when compared to NTOPD patients. SIRI may be a simple and useful inflammatory index for assessing TOPD, and TB patients with higher values of SIRI are more likely to be high-risk group for TOPD.Keywords: tuberculosis-associated obstructive pulmonary disease, systemic inflammatory response index, ratio inflammatory indicator, propensity score matching

Fangmin Gong,1 Zhuliu Gong,1 Haimeng Liu,2 Pei Yi,1 Yuhan Jia,3 Jingwen Zhuang,1 Jilin Shu,1 Xincheng Huang,4 Yibo Wu5 1College of Literature and Journalism Communication, Jishou University, Jishou, People’s Republic of China; 2College of Minority Preparatory Education, Jishou University, Zhangjiajie, People’s Republic of China; 3Office of the Party and Administration, Hebei Academy of Fine Arts, Shijiazhuang, People’s Republic of China; 4School of Economics and Management, Beijing Institute of Graphic Communication, Beijing, People’s Republic of China; 5School of Public Health, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Haimeng Liu, Zhangjiajie Campus, Jishou University, Dayongqiao Street, Ziwu Road, Yongding District, Zhangjiajie, Hunan Province, 427000, People’s Republic of China, Tel +86 15074328922, Email Liu.Haimeng@outlook.com Yibo Wu, Peking University School of Public Health, No.38 Xueyuan Road, Haidian District, Beijing, 100191, People’s Republic of China, Tel +86 18810169630, Email bjmuwuyibo@outlook.comPurpose: To explore the relationship between adolescents’ problematic Internet use and loneliness and the mediating roles of social support and family communication.Methods: A questionnaire survey of 2483 adolescents aged 12– 17 years in 148 cities in China was conducted using the Problematic Internet Use Scale, the Collaborative Social Support Scale, the Family Communication Scale, and the Loneliness Scale. The data were statistically analyzed by SPSS 26.0 and validated by AMOS 28.0. Structural equation modelling (SEM) was conducted to test the effects of problematic Internet use on adolescents’ loneliness and the mediating effects of perceptions of social support and family communication.Results: There was a significant positive effect of adolescents’ problematic Internet use on loneliness (B-0.471, P< 0.001), and the mediating effects of perceptual social support (0.003, 0.012) and family communication (0.008, 0.019) were found to play a chain effect between adolescents’ problematic Internet use and loneliness, respectively. Use and feelings of loneliness played a chain mediating role (0.002, 0.006).Conclusion: This study identified the effects of adolescent problematic Internet use on loneliness and its mechanism of action, emphasized the importance of social support and family communication, and provided practical insights for improving family parenting styles and preventing and intervening in adolescent loneliness problems.Keywords: problematic internet use, adolescents, loneliness, perceived social support, family communication

Ling Yang,1,2 Maolin Cao,3 Jing Tian,1 Peijin Cui,1 Ling Ai,3 Xue Li,4 Hua Li,5 Menghan Gao,1 Liang Fang,1,2,6 Libo Zhao,1,2 Fang Gong,2,6 Chanjuan Zhou1,3,4,6 1Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Cerebrovascular Disease Research, Chongqing, People’s Republic of China; 3Department of General Practice, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Central Laboratory, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 5Department of Ophthalmology, Yongchuan Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 6Chongqing Clinical Research Center for Geriatric Disease, Chongqing, People’s Republic of ChinaCorrespondence: Fang Gong; Chanjuan Zhou, Yongchuan Hospital of Chongqing Medical University, No. 439 Xuanhua Road, Yongchuan, Chongqing, 402160, People’s Republic of China, Email 1512367841@qq.com; chanjuanzhou@hospital.cqmu.edu.cnPurpose: The quality of life of worldwide adolescents has been seriously affected by depression. Notably, the inflammatory response is closely associated with the pathophysiology of depression. The present study applied a novel targeted proteomics technology, Olink proximity extension assay (PEA), to profile circulating immune-related proteins in adolescents with depression.Methods: In the present study, the expression levels of 92 inflammation-related proteins were compared between adolescents with depression (ADs) (n=15) and healthy controls (HCs) (n=15), using the OLINK PEA inflammation panel. We further validated 5 top proteins that were identified through KEGG and GO analyses between 40 HCs and 50 ADs, including CCL4, CXCL5, CXCL6, CXCL11, and IL-18 using enzyme linked immunosorbent assay (ELISA).Results: We identified 13 differentially expressed proteins between the two cohorts, including 5 up-regulated and 8 down-regulated proteins. Among them, the TRAIL protein levels were significantly negatively correlated with the HAMA-14 score (r=− 0.538, p= 0.038), and the levels of transforming growth factor α (TGF-α) were significantly associated with a change in appetite (r = -0.658, p = 0.008). After validation by ELISA, CCL4, CXCL5, CXCL11, and IL-18 showed significant changes between ADs and HCs (p < 0.05), while CXCL6 showed an up-regulated tendency in ADs (p=0.0673). The pooled diagnostic efficacy (area under the curve [AUC]) of these five inflammation markers in clinical diagnosis for adolescent depression was 0.819 (95% CI: 0.735– 0.904).Conclusion: We report a number of inflammation-related plasma biomarkers, which uncover a potential involvement of chemokines, cytokines, and cytokine receptors in adolescent depression. Their roles in the pathophysiology of depression need to be further elucidated.Keywords: olink proximity extension assay, biomarkers, adolescent depression, inflammation

Qi Yu,1,&ast; Jinqiang Guo,2,&ast; Fengyun Gong1 1Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China; 2Department of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qi Yu; Fengyun Gong, Department of Infectious Diseases, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430023, People’s Republic of China, Email fishns123@163.com; 2020jy0008@hust.edu.cnIntroduction: Tuberculosis (TB) is a life-threatening single infectious disease, which remains a major global public health concern. This study was to establish and validate a clinically practical diagnostic scoring system for predicting active pulmonary tuberculosis (APTB) in patients with positive tuberculosis T cell spot test [T-SPOT] using indicators associated with coagulation and inflammation.Methods: A single-center retrospective cross-sectional study was performed to include patients with positive T-SOPT registered and hospitalized at Wuhan Jinyintan Hospital between January 2017 and December 2019. All patients were separated into the active pulmonary tuberculosis (APTB) group and the inactive pulmonary tuberculosis (IPTB) group, according to the diagnostic criteria from China’s Expert Consensus for APTB and IPTB. Subsequently, the patients were randomized into a training set and a validation set at a ratio of 2:1. Indicators associated with coagulation and inflammation, including prothrombin time activity (PTA), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration (Fbg-C), C-reactive protein/albumin ratio (CAR), C-reactive protein/prealbumin ratio (CPR), neutrophils count/lymphocyte count ratio (NLR), platelet count/lymphocyte count ratio (PLR), monocyte count/lymphocyte count ratio (MLR), and erythrocyte sedimentation rate (ESR) were obtained from electronic medical record system (EMRS). Stepwise logistic regression was performed in the training set to build a diagnostic model for predicting APTB, which was transformed into an easily applicable scoring system via nomogram. Receiver operating characteristic (ROC) analysis, calibration curve (CC), and decision curve analysis (DCA) were conducted to evaluate the predictive performance of the established diagnostic scoring system.Results: A total of 508 patients [training set (211 cases of APTB and 116 cases of IPTB) and validation set (103 cases of APTB and 78 cases of IPTB)] with positive T-SPOT were recruited in the study. Stepwise logistic regression showed that CPR, MLR, ESR, APTT and Fbg-C were independent predictors for APTB. The scoring system was subsequently formulated based on the abovementioned predictors, which correspond to scores of 10, 6, 7, 5, and 5, respectively. In addition, patients are more likely to be diagnosed as APTB when the cut-off score was ≥ 16 scores, while patients with < 16 scores are more likely to be diagnosed as IPTB. The scoring system showed good predictive efficacy in both the training set [area under the curve (AUC): 0.887] and the validation set (AUC: 0.898). Furthermore, both CC and DCA confirmed the clinical utility of the scoring system.Conclusion: The data suggest that the combination of indicators associated with coagulation and inflammation could serve as biomarkers to identify APTB in patients with positive T-SPOT. In addition, patients with positive T-SPOT were more prone to be diagnosed with APTB when having a combined total of scores ≥ 16 in the scoring system.Keywords: coagulation indices, inflammatory biomarkers, scoring system, active pulmonary tuberculosis

Fan Gong,1 Zhikui Chen,2 Jianyuan Chang,1 Jinlong Liu,2 Xiaobin Wang,1 Weisong Mo,1 Mengqin Tan,1 Tao Jiang1 1Department of Emergency Medicine, Hunan University of Medicine General Hospital, Huaihua, 418000, People’s Republic of China; 2Department of Respiratory Medicine, Hunan University of Medicine General Hospital, Huaihua, 418000, People’s Republic of ChinaCorrespondence: Tao Jiang, Department of Emergency Medicine, Hunan University of Medicine General Hospital, Jinxi South Road 144, Hecheng District, Huaihua, 418000, People’s Republic of China, Email 306056340@qq.comBackground: Chlamydia abortus is generally considered as the main cause of ruminants abortion, but it rarely causes human infection resulting in abortion or pneumonia.Case Presentation: We report a case of male patient with pneumonia caused by Chlamydia abortus. Results of next generation sequencing (NGS) in the bronchoalveolar lavage fluid (BALF) indicated Chlamydia abortus infection. The patient was treated with intravenous infusion of doxycycline. The clinical symptoms of this patient were ameliorated significantly, and all these improvement were indicated by laboratory parameters significantly. Shown as chest computed tomography (CT), most of the inflammation had been absorbed after doxycycline treatment.Conclusion: Chlamydia abortus mainly infects ruminants and occasionally humans. NGS has its own advantages of rapidity, sensitivity and specificity in detecting Chlamydia abortus. Doxycycline exhibits a great therapeutic effect on pneumonia caused by Chlamydia abortus.Keywords: Chlamydia abortus, pneumonia, human, metagenomic next-generation sequencing, case report

Shaoyan Li,1,2,&ast; Fengyan Gong,1,2 Zekun Zhou,1,2,&ast; Xu Gong1,2 1Department of Hand and Podiatric Surgery, Orthopedics Center, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China; 2Jilin Province Key Laboratory on Tissue Repair, Reconstruction and Regeneration, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xu Gong, Department of Hand and Podiatric Surgery, Orthopedics center, The First Hospital of Jilin University, Changchun, 130021, People’s Republic of China, Tel +86-13944099151, Email gongxu@jlu.edu.cnIntroduction: Topical verapamil has been demonstrated to reduce the fibroproliferative scar. Therefore, it was hypothesized that topical verapamil could reduce adhesion formation after tendon repair. The current study aimed to examine the effects of verapamil-loaded polydopamine nanoparticles (VP-PDA NPs) on the adhesion formation of Achilles tendon laceration and repair in a rat model.Methods: We randomly assigned 72 male Sprague-Dawley rats to the control, the PDA NPs, and the VP-PDA NPs groups (n = 24 per group). The quality of tendon healing was evaluated by the maximal tensile strength four and six weeks after surgery. The degree of tendon adhesion was scored on days 4, 15, 29, and 43 after surgery. The expressions of transforming growth factor-beta 1 (TGF-β 1), vimentin, α-smooth muscle actin (α-SMA), and collagens type I and III were detected through Western blotting or immunohistochemistry at four weeks after surgery.Results: In vitro release tests revealed that 61.3% of verapamil was released from VP-PDA NPs in four weeks. There was a significant increase in average failure to load in the VP-PDA NPs group (89.27 ± 5.09 N) compared with the PDA NPs group (65.52 ± 2.04 N) (p = 0.003) and the control group (74.52 ± 4.24 N) (p = 0.029). Adhesion scores were significantly reduced in the VP-PDA NPs group at six weeks (3.175 ± 0.08) and four weeks (3.35 ± 0.25) compared with the other groups. Moreover, VP-PDA NPs significantly reduced the expression of vimentin, α-SMA, TGF-β 1, and collagens type I and III.Conclusion: These data suggest that VP-PDA NPs reduced adhesion formation and enhanced tendon healing during rat tendon injury. Since topical verapamil has been used in clinics without side effects, VP-PDA NPs would have direct translation implications. However, its anti-adhesive effects on intrasynovial tendon injury must be examined.Keywords: tendon injury, adhesion formation, verapamil, nanoparticle

Wenkai Chen,1,2,&ast; Wenping Lin,3,&ast; Naichun Yu,1,2,&ast; Linlin Zhang,1,2,&ast; Zuoxing Wu,2 Yongjie Chen,1,2 Zongguang Li,1,2 Fengqing Gong,1,2 Na Li,2 Xiaohui Chen,4 Xu He,3 Yue Wu,5 Xiangchen Zeng,1,2 Yuting Yueh,1,2 Ren Xu,2,4,6,&ast; Guangrong Ji1,2,&ast; 1Department of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, Xiamen Key Laboratory of Regeneration Medicine, Organ Transplantation Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 3Department of Spine Surgery, Shenzhen Pingle Orthopedic Hospital, Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Shenzhen, People’s Republic of China; 4Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China; 5Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, People’s Republic of China; 6Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangrong Ji; Ren Xu, Department of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, No. 2000, Xiang’an East Road, Xiang’an District, Xiamen, 361000, People’s Republic of China, Tel +86-15710667257, Fax +86592-2889000, Email jiguangrong@xmu.edu.cn; xuren526@xmu.edu.cnPurpose: To investigate induction of cell death in Osteosarcoma (OS) using the anti-tuberculosis drug, rifampicin, loaded into exosomes.Patients and Methods: BMSC-exosomes were isolated by ultracentrifugation and loaded ultrasonically with rifampicin. Nanoparticle exosome-rifampicin (EXO-RIF) was added to the OS cell-lines, 143B and MG63, in vitro, to observe the growth inhibitory effect. In vivo experiments were conducted by injecting fluorescently labeled EXO-RIF through the tail vein of 143B cell xenograft nude mice and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically.Results: Sonication resulted in encapsulation of rifampicin into exosomes. Exosome treatment accelerated the entry of rifampicin into OS cells and enhanced the actions of rifampicin in inhibiting OS proliferation, migration and invasion. Cell cycle arrest at the G2/M phase was observed. Dynamin-related protein 1 (Drp1) was activated by EXO-RIF and caused mitochondrial lysis and apoptosis. Exosome treatment targeted rifampicin to the site of OS, causing OS apoptosis and improving mouse survival in vivo.Conclusion: The potent Drp1 agonist, rifampicin, induced OS apoptosis and exosome loading, improving OS targeting and mouse survival rates. EXO-RIF is a promising strategy for the treatment of diverse malignancies.Graphical Abstract: Keywords: bone tumor, drug delivery, exosomes, mesenchymal stem cells, survival

Fang-xue Gong,1 Xin Zhou,2 Zhao-he Niu,1 Yan Mao,1 Yong-mei Wang,1 Meng Lv,1 Xue-qiang Gao,1 Wen-jing Liu,1 Hai-bo Wang1 1Department of Breast Disease Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, People’s Republic of China; 2Qingdao Medical College of Qingdao University, Qingdao, Shandong Province, People’s Republic of ChinaCorrespondence: Hai-bo Wang, Department of Breast Disease Center, The Affiliated Hospital of Qingdao University, No. 59 Haier Road, Laoshan District, Qingdao City, Shandong Province, People’s Republic of China, Tel +86 18661805787, Email hbwang66@126.comPurpose: Autologous fat grafting (AFG) is a technique that can improve the appearance of breasts in surgical patients. There are currently few studies on breast-conserving surgery (BCS) combined with immediate AFG, although we believe that it could achieve satisfactory effects. Therefore, the purpose of this study is to observe the effects of BCS combined with immediate AFG on oncologic safety, satisfaction and psychology of breast cancer patients.Patients and Methods: We retrospectively collected the data of 85 breast cancer patients from February 2018 to October 2018. After screening, 40 patients in AFG group (AG, BCS combined with immediate AFG) and 40 patients in control group (CG, BCS alone) were finally included in the study. The primary outcomes were the survival, tumor recurrence and metastasis, and BREAST-Q score of patients. The secondary outcomes were short and long-term complications, degree of depression and anxiety of patients.Results: A total of 80 patients were included in the analysis. There was no significant difference in the clinicopathological data between the two groups (P> 0.05). The average follow-up time of the two groups was 40.58± 2.630 and 40.28± 2.679 months. In the analysis of oncologic safety, no patients died in AG and 1 patient died in CG. In addition, there was no significant difference between the two groups in terms of the overall recurrence rate and the distribution of recurrence types (P> 0.05). As for satisfaction, the BREAST-Q score of AG was significantly higher than that of CG (57.85± 4.833 vs 51.93± 5.045, P< 0.001). In the secondary outcomes, there was no short-term complication specified in the study; in the long-term complications, the incidence of calcification in AG was not significantly higher than that in CG (P=0.065). In the analysis of depression and anxiety, there was no significant difference between the two groups (P> 0.05).Conclusion: BCS combined with immediate AFG can significantly improve patients’ satisfaction without increasing the risk of death and tumor recurrence. However, it does not seem to play a role in improving the conditions of depression and anxiety.Keywords: breast cancer, breast-conserving surgery, autologous fat grafting, oncologic safety, BREAST-Q, psychology

Fangchen Gong,1,&ast; Ranran Li,2,&ast; Xiangtao Zheng,1,&ast; Weiwei Chen,1 Yanjun Zheng,1 Zhitao Yang,1 Ying Chen,1 Hongping Qu,2 Enqiang Mao,1 Erzhen Chen1 1Department of Emergency, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Erzhen Chen; Ying ChenDepartment of Emergency, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Ruijin 2# Road No. 197, Shanghai, 200025, People’s Republic of ChinaTel +862164370045Fax +862164333548Email rjchenerzhen@163.com; bichatlion@163.comBackground: Acute respiratory distress syndrome (ARDS) is one of the leading causes of death in patients with sepsis. As such, early and accurate identification of sepsis-related ARDS is critical.Methods: Bioinformatic analysis was used to explore the GEO datasets. ELISA method was used to detect the plasma or cellular supernatant of relevant proteins. Quantitative real-time PCR was used for mRNA measurements and Western blot was applied for protein measurements. Immunohistochemistry staining and Immunofluorescence staining were used to identify the localization of OLFM4. Cecal ligation and puncture (CLP) model was used to establish sepsis model.Results: The bioinformatic analysis results identified ten genes (CAMP, LTF, RETN, LCN2, ELANE, PGLYRP1, BPI, DEFA4, MPO, and OLFM4) as critical in sepsis and sepsis-related ARDS. OLFM4, LCN2, and BPI were further demonstrated to have diagnostic values in sepsis-related ARDS. Plasma expression of OLFM4 and LCN2 was also upregulated in sepsis-related ARDS patients compared to septic patients alone. OLFM4 expression was significantly increased in the lung tissues of septic mice and was co-localized with Ly6G+ neutrophils, F4/80+ macrophages and pro-surfactant C+ lung epithelial cells. In vitro data showed that OLFM4 expression in lung epithelial cells was downregulated upon LPS stimulation, whereas neutrophil media induced OLFM4 expression in lung epithelial cells. Overexpression of OLFM4 and treatment with recombinant OLFM4 effectively suppressed LPS-induced pro-inflammatory responses in lung epithelial cells. Furthermore, the increased levels of LDHA phosphorylation and the downstream NF-κB activation induced by LPS in epithelial cells were effectively diminished by OLFM4 overexpression and recombinant OLFM4 treatment via a reduction in ROS production and HIF1α expression.Conclusion: OLFM4 may regulate the pro-inflammatory response of lung epithelial cells in sepsis-related ARDS by modulating metabolic disorders; this result could provide new insights into the treatment of sepsis-induced ARDS.Keywords: sepsis, ALI/ARDS, lung epithelial cells, inflammation, OLFM4, LDHA

Yanqi Qi,&ast; Jiawen Xu,&ast; Zhe Lin,&ast; Yijing Tao, Fenglei Zheng, Yujia Wang, Yameng Sun, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People’s Republic of ChinaTel/Fax +86-571-88873008Email gongfangqi@zju.edu.cnIntroduction: Kawasaki disease (KD) is an acute febrile systemic vasculitis, but the etiology remains unknown. We studied serum levels of CD147, DcR3, and IL33 in different stages of KD to explore the value of CD147, DcR3, and IL33 in the pathophysiology of KD.Methods: We measured serum levels of CD147, DcR3, and IL33 by enzyme-linked immunosorbent assay (ELISA) at different stages with 71 KD patients and 66 healthy control children. We apply for network tools GeneMANIA and Cytoscape APP to analyze the functions of these pro-inflammatory factors at the gene and protein level.Results: Serum levels of CD147, DcR3, and IL33 were significantly increased in KD patients before IVIG treatment. Serum levels of CD147, DcR3, and IL33 gradually decreased over time after the treatment of IVIG. Eight cases were IVIG non-responders, while nine KD patients got CALs, but they did not overlap. And there were no statistical differences between group IVIG responders and IVIG non-responders or between groups without CALs and with CALs. We explored the functions of CD147, DcR3, and IL33 from GeneMANIA and Cytoscape APP and found these third pro-inflammatory factors were coexpressed, physical interactions, genetic interactions with other KD-related factors.Conclusion: CD147, DcR3, and IL33 are involved in the pathophysiology of KD, which provides novel evidence for diagnosing and treating KD with their inhibitors.Keywords: Kawasaki disease, coronary artery lesions, CD147, DcR3, IL33, PI3K/AKT pathway

Susan Gong,1 Lakshay Khosla,1 Fred Gong,1 Nikhil Kasarla,1 Karel Everaert,2 Jeffrey Weiss,1 Abdo Kabarriti1 1Department of Urology, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA; 2Department of Uro-Gynecology, Ghent University Hospital, Ghent, BelgiumCorrespondence: Susan GongDepartment of Urology, State University of New York Downstate Health Sciences University, 450 Clarkson Ave., Brooklyn, NY, 11203, USATel +1 845-891-6642Email Susan.Gong@downstate.eduPurpose: Current literature has suggested a relationship between nocturnal enuresis (NE) in childhood and the development of nocturia later in life as both disorders have similar underlying etiologies, comorbidities, and treatments. The objective was to synthesize the available evidence on the association between childhood NE and later presentation of nocturia.Methods: PubMed, CINAHL, Scopus, and Google Scholar were searched for peer-reviewed studies published between January 1980 and April 2021. Case–control and cohort studies that reported on childhood NE and current nocturia were included. The PRISMA protocol was followed (PROSPERO ID: CRD42021256255). A random-effects model was applied to calculate the pooled odds ratio (OR) and 95% confidence interval (CI). Risk of bias was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria and with a funnel plot.Results: Of the 278 articles identified, 8 studies met inclusion criteria. The 6 case–control and 2 prospective cohort studies resulted in a total sample size of 26,070 participants. In a random-effect pooled analysis, childhood NE was significantly associated with the development of nocturia (OR: 1.75, 95% CI: 1.11– 2.40). Significant heterogeneity (I2 = 92.7%, p < 0.01) was identified among the included studies, which was reflected in an asymmetrical funnel plot. NE and nocturia have similar underlying etiologies of hormonal abnormalities, sleep disorders, physiological disorders, and psychological disorders.Conclusion: The history of childhood NE is significantly associated with nocturia later in life. The data in this meta-analysis support this transition and identify potential similarities between the two disorders. The sparse number of articles relevant to this topic is a strong indicator of the need for more work on this transition from childhood to maturity. More studies are warranted to further explore the association between NE and nocturia.Keywords: LUTS, pediatric urology, incontinence, nocturnal polyuria

Kun Zhang,1,2 Hui Pan,1 Linjie Wang,1 Hongbo Yang,1 Huijuan Zhu,1 Fengying Gong1 1Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Endocrinology, Shijiazhuang People’s Hospital, The People Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Huijuan Zhu; Fengying GongKey Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1# Shuai Fu Yuan Hu Tong, Dong Dan, Beijing, 100730, People’s Republic of ChinaTel +86-10-69155100Fax +86-10-69155073Email shengxin2004@163.com; fygong@sina.comObjective: Adipose tissue insulin resistance is a common feature of obesity-related metabolic diseases. However, the relationship between adipose tissue insulin resistance and metabolic syndrome (MS) has not been fully elucidated. Here, we explored the relationship between the adipose tissue insulin resistance index (Adipo-IR) (fasting insulin × free fatty acids) and MS and the predictive power of Adipo-IR for MS in northern Chinese populations.Methods: A total of 312 subjects, 186 subjects with MS, 80 nonmetabolic syndrome (NMS) subjects with central obesity, and 46 normal controls were recruited. The general clinical information, biochemical measurements, and oral glucose tolerance tests were evaluated. Serum adiponectin levels were determined using enzyme linked immunosorbent assay (ELISA).Results: Adipo-IR was 2.32-fold higher in NMS subjects and 2.62-fold higher in MS subjects than in normal controls in male subjects; in female subjects, it was 1.75-fold and 3.58-fold higher, respectively (P < 0.05). Female subjects with MS had higher Adipo-IR than male subjects (P < 0.001). Adipo-IR was independently positively correlated with waist circumference, triglyceride, aspartate aminotransferase, and fasting blood glucose and negatively correlated with adiponectin (P < 0.05). Subjects with the highest Adipo-IR tertile had a 2.758-fold higher risk of MS than subjects with the lowest tertile after adjusting for potential confounders (95% confidence interval: 1.552– 9.096; P = 0.003). Receiver operating characteristic curve analysis showed that the predictive power of Adipo-IR for MS was 73.1% and 79.2% in male and female subjects, respectively, with optimal cutoff values of 3.84 and 5.92 mU/L×mmol/L.Conclusion: Adipo-IR provides a simple method to study adipose tissue insulin sensitivity. Adipo-IR is associated with MS and is an important predictor of MS.Keywords: adipose tissue insulin resistance, Adipo-IR, metabolic syndrome, obesity

Fenglei Zheng,* Yijing Tao,* Jingjing Liu, Zhimin Geng, Ying Wang, Yujia Wang, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine; National Clinical Research Center for Child Health, No. 3333, Binsheng Road, Hangzhou, 310052, People’s Republic of ChinaTel/Fax +86-571-86670008Email gongfangqi@zju.edu.cnPurpose: Macrophages-mediated inflammation is linked with endothelial damage of Kawasaki disease (KD). KCa3.1, a calcium-activated potassium channel, modulates inflammation of macrophages. However, little is known about the role of KCa3.1 in inflammation by macrophages involved in KD. Hence, this study is aimed to explore the potential role of KCa3.1 in regulating inflammatory response by macrophages and subsequent vascular injury in an in vitro model of KD.Methods: RAW264.7 cells were stimulated with Lactobacillus casei cell wall extract (LCWE) with or without TRAM-34 or PDTC or AG490. Subsequently, mouse coronary artery endothelial cells (MCAECs) were incubated with RAW264.7 cells-conditioned medium to mimic local inflammatory lesions in KD. CCKi8 assay was used to evaluate cell viability. The mRNA levels of inflammatory mediators were detected by qRT-PCR. Expressions of KCa3.1, MCAECs injury-associated molecules, proteins involved in signal pathways of nuclear factor-κB (NF-κB), signal transducers and activators of transcription (STAT) 3 and p38 were evaluated by Western blot.Results: Our study showed that LCWE increased KCa3.1 protein level in RAW264.7 macrophages and KCa3.1 inhibition by TRAM-34 notably suppressed the expression of pro-inflammatory molecules in LCWE-treated macrophages via blocking the activation of NF-κB and STAT3 pathways. Besides, the inflammation and damage of MCAECs were attenuated in the TRAM-34-treated group compared with the KD model group. This vascular protective role was dependent on the down-regulation of NF-κB and STAT3 signal pathways, which was confirmed by using inhibitors of NF-κB and STAT3.Conclusion: This study demonstrates that KCa3.1 blockade of macrophages suppresses inflammatory reaction leading to mouse coronary artery endothelial cell injury in a cell model of KD by hampering the activation of NF-κB and STAT3 signaling pathway. These findings imply that KCa3.1 may be a potential therapeutic target for KD.Keywords: Kawasaki disease, macrophages, inflammation, KCa3.1, vascular damage

Zhimin Geng,* Yijing Tao,* Fenglei Zheng, Linlin Wu, Ying Wang, Yujia Wang, Yameng Sun, Songling Fu, Wei Wang, Chunhong Xie, Yiying Zhang, Fangqi Gong Department of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fangqi GongDepartment of Cardiology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, People’s Republic of ChinaTel/Fax +86 571 86670008Email gongfangqi@zju.edu.cnBackground: Kawasaki disease (KD) is characterized by a disorder of immune response, and its etiology remains unknown. Monocyte is an important member of the body’s innate immune system; however its role in KD is still elusive due to its ambiguous heterogeneity and complex functions. We aim to comprehensively delineate monocyte heterogeneity in healthy and KD infants and to reveal the underlying mechanism for KD.Methods: Peripheral monocytes were enriched from peripheral blood samples of two healthy infants and two KD infants. scRNA-seq was performed to acquire the transcriptomic atlas of monocytes. Bio-information analysis was utilized to identify monocyte subsets and explore their functions and differentiation states. SELL+CD14+CD16- monocytes were validated using flow cytometry.Results: Three monocyte subsets were identified in healthy infants, including CD14+CD16- monocytes, CD14+CD16+ monocytes, and CD14LowCD16+ monocytes. Cell trajectory analysis revealed that the three monocyte subsets represent a linear differentiation, and possess different biological functions. Furthermore, SELL+CD14+CD16- monocytes, which were poorly differentiated and relating to neutrophil activation, were found to be expanded in KD.Conclusion: Our findings provide a valuable resource for deciphering the monocyte heterogeneity in healthy infants and uncover the altered monocyte subsets in KD patients, suggesting potential biomarkers for KD diagnosis and treatment.Keywords: Kawasaki disease, monocyte subsets, scRNA-seq

Fang Gong,1 Quan Zhou,2 Chunmei Gui,1 Shaohua Huang,1 Zuoan Qin3 1Department of Intensive Care Unit, The First People’s Hospital of Changde, Changde City, Hunan Province, 415000, People’s Republic of China; 2Department of Science and Education Section, The First People’s Hospital of Changde, Changde City, Hunan Province, 415000, People’s Republic of China; 3Cardiovascular Medicine Department, The First People’s Hospital of Changde, Changde City, Hunan Province, 415000, People’s Republic of ChinaCorrespondence: Fang GongDepartment of Intensive Care Unit, The First People’s Hospital of Changde, 818 Renmin Road, Changde City, Hunan Province, 415000, People’s Republic of ChinaTel +86-0736-7788035Email gficu2009@163.comPurpose: We aimed to investigate the relationship between the serum anion gap (AG) and all-cause mortality in patients with acute pancreatitis (AP) in intensive care units (ICUs).Patients and Methods: In this retrospective cohort analysis, data of patients with AP were extracted from the Medical Information Mart for Intensive Care database (version III). We collected the maximum serum AG value within the first 24 hours of ICU admission. The main outcome was 90-day all-cause mortality. A multivariate Cox proportional hazard regression model was used to examine the association between the serum AG and mortality. The restricted cubic spline curve was used to confirm a non-linear relationship between serum AG values and mortality.Results: Of the 279 patients included in the study, 87 (31.18%) died. The serum AG value was positively associated with 90-day all-cause mortality (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.02– 1.14), after adjusting for age, sex, alcohol consumption, congestive heart failure, diabetes mellitus, hypertension, eGFR, albumin, and the SOFA score. There was a non-linear relationship between serum AG values and mortality after adjusting for potential confounders. We used a two-piecewise regression model to obtain a threshold inflection point value of 13.8 mmol/L. The HR and the 95% CI on the left inflection point were 0. 82 (0.61– 1.09; p = 0.1719), and on the right inflection point were 1.15 (1.08– 1.23; p < 0.0001).Conclusion: The relationship between all-cause mortality in patients with acute pancreatitis and serum AG values was non-linear. All-cause mortality and serum AG values were positively correlated when the serum AG value was > 13.8 mmol/L.Keywords: anion gap, all-cause mortality, acute pancreatitis, MIMIC III database

Meijuan Liu, Kun Zhang, Linjie Wang, Hongbo Yang, Kemin Yan, Hui Pan, Huijuan Zhu, Fengying Gong Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, People’s Republic of ChinaCorrespondence: Fengying Gong; Huijuan ZhuKey Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1# Shuaifuyuan, Wangfujing, Beijing 100730, People’s Republic of ChinaTel +86 10 69155100Fax +86 10 69155073Email fygong@sina.com; shengxin2004@163.comIntroduction: To explore serum zinc-α 2-glycoprotein (ZAG) and adiponectin in metabolically healthy non-obese (MHNO), metabolically healthy obesity (MHO), metabolically abnormal obesity (MAO) and metabolically abnormal diabetic obese (MADO) subjects and the relationship with metabolically phenotypes of obesity.Methods: Two hundred twenty-five subjects including 32 with MHNO, 40 with MHO, 104 with MAO and 49 with MADO were enrolled. Baseline clinical data and biochemical variables were collected. Serum ZAG and adiponectin levels were measured by enzyme-linked immunosorbent assay (ELISA) kits. Metabolically healthy (< 3 metabolic abnormalities) or abnormal (≥ 3 metabolic abnormalities) subjects were classified based on the National Cholesterol Education Program–Adult Treatment Panel III (NCEP/ATP III) criteria. Obesity (body mass index ≥ 28 kg/m2) was recommended by China Obesity Task Force.Results: Serum ZAG levels were higher in the MHO group, but were progressively lower in MAO and MADO groups (P all< 0.05). In all subjects, total cholesterol, 2-hour postprandial blood glucose and homeostasis model assessment of adiponectin were independent variables to serum ZAG levels. Compared with subjects in the highest tertile of ZAG, the odds ratio (OR) of metabolically abnormal risks of subjects in the lowest and median tertiles of ZAG were higher both in a univariate and three adjustment models (P all< 0.05). Serum ZAG could discriminate the metabolically abnormal phenotype with receiver operating characteristic (ROC) curve area of 0.622 (95% CI, 0.539– 0.706, P< 0.05). Combination of ZAG and adiponectin had improved diagnosis value accuracy, with ROC curve area of 0.703 (95% CI, 0.629– 0.776, P< 0.05), and 62.7% sensitivity and 73.6% specificity.Conclusion: Serum ZAG levels were higher in MHO subjects, but lower in MAO and MADO subjects. The decreased serum ZAG levels were closely related to the metabolically abnormal phenotype of obese patients. Serum ZAG, especially the combination with adiponectin might be the potential diagnostic biomarkers for metabolically abnormal obese patients.Keywords: zinc-α 2-glycoprotein, ZAG, metabolically healthy non-obese, MHNO, metabolically healthy obese, MHO, metabolically abnormal obese, MAO, metabolically abnormal diabetic obese, MADO

Yuluo Rong,* Yongjun Luo,* Wei Liu, Fangyi Gong, Pengyu Tang, Weihua Cai Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China *These authors contributed equally to this work Objective: To investigate the early and mid-term efficacy and safety of the bridge-type ROI-C interbody fusion cage system in the treatment of cervical spondylosis with osteoporosis during anterior cervical discectomy and fusion (ACDF). Patients and methods: The clinical data from 24 cervical spondylosis patients with osteoporosis treated with ACDF were retrospectively analyzed. All patients were treated with ROI-C cage. Double-energy X-ray absorptiometry (DEXA) was used to measure the bone mineral density (BMD). The cervical sagittal radiographic parameters were measured and compared using X-ray including C2–C7 Cobb angle, segmental angle (SA), cervical vertebral bow depth, and height of operation segment (HOS). Postoperative dysphagia was recorded according to the Bazaz score. The Japanese Orthopedic Association (JOA) scores and Neck Disability Index (NDI) scores were used to evaluate the clinical outcomes at different time points. Odom and Vaccaro criteria were used to assess the surgical effects and to evaluate the fusion of the bone graft. Results: The mean duration of the postoperative follow-up was 27.4±5.7 months (ranging from 21 to 36 months). The JOA scores and NDI scores at 3 months post operation and at the time of final follow-up were significantly different from those before surgery (P0.05). Conclusion: The ROI-C cage system is safe and effective for use in patients undergoing anterior cervical spondylosis surgery for osteoporosis treatment. It results in a positive effect on bone graft fusion, is able to effectively improve cervical curvature, restores intervertebral height, and reduces the incidence of postoperative dysphagia. The clinical effects were positive at the early and middle postoperative stages. Keywords: cervical spondylosis, ROI-C, osteoporosis, imaging parameters, dysphagia

Hui Liu,1 Hui Xu,1 Yunxia Jiang,1 Shengyuan Hao,1 Feirong Gong,2 Hongjie Mu,1 Ke Liu3 1School of Pharmacy, Yantai University, Yantai, People’s Republic of China; 2Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Suzhou Nanomedicine R&D Co, Ltd, Suzhou, People’s Republic of China Abstract: Dimethoxycurcumin (DMC) is an analog of curcumin with superior efficacy in various disease models. Currently, drug delivery system research on DMC is very limited, and it has become a huge challenge to realize further developments and clinical applications. In the present study, a kind of amphiphilic block copolymer, N-t-butoxycarbonyl-phenylalanine terminated monomethoxyl poly (ethylene glycol)-b-poly (ε-caprolactone), or mPEG-PCL-Phe(Boc), was prepared from monomethoxyl poly (ethylene glycol)-b-poly (ε-caprolactone) (mPEG-PCL) with its hydroxyl terminal chemically converted into N-t-butoxycarbonyl-phenylalanine (Boc-Phe). This copolymer was determined to have a fairly low critical micelle concentration (2.56×10-3 mg/mL) and passive targeting potential to tumor tissue, and thus was applied to develop a polymeric micellar formulation of DMC for the first time. The DMC-loaded micelles prepared by thin-film hydration method had typical shell–core structure, with an average particle size of 17.9±0.4 nm and a polydispersity index of 0.045±0.011. The drug loading capacity and entrapment efficiency were 9.94%±0.15% and 97.22%±0.18%, respectively, indicating a high-affinity interaction between DMC and the copolymer. At a concentration of 2 mg/mL, the reconstituted micelle solution could be maintained for at least 10 days at room temperature, and displayed a low initial burst release followed by a sustained release in vitro. Pharmacokinetic study in rats revealed that in vivo drug exposure of DMC was significantly increased and prolonged by intravenously administering DMC-loaded micelles when compared with the same dose of free DMC dissolved in dimethyl sulfoxide. Furthermore, in vivo distribution results from tumor-bearing nude mice demonstrated that this micellar formulation significantly changed the biodistribution profile of DMC and increased drug accumulation in tumors. Therefore, the polymeric micellar formulation of DMC, based on the amphiphilic block copolymer, mPEG-PCL-Phe(Boc), could provide a desirable method for delivering DMC, especially for applications in cancer therapy. Keywords: dimethoxycurcumin, polymeric micelles, characterization, pharmacokinetic profile, biodistribution, tumor targeting

Lei Zhang,1 Faming Gong,2 Fang Zhang,3 Jing Ma,1 Peidong Zhang,1 Jun Shen3 1Department of Hepatobiliary and Pancreatic Surgery, 2PCFM Laboratory of Ministry of Education, School of Chemistry and Chemical Engineering, 3Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China Background: The purpose of this study was to evaluate the inhibitory effect of targeted folate-functionalized micelles containing superparamagnetic iron oxide nanoparticles (SPIONs) and sorafenib on human hepatic carcinoma (HepG2) cells in vitro, and to observe the feasibility of surveillance of this targeting therapeutic effect by magnetic resonance imaging. Methods: Sorafenib and SPIONs were loaded into polymeric micelles. The targeted nanocarrier was synthesized by functionalizing the micelles with folate. Folate-free micelles loaded with sorafenib and SPIONs were used as control (nontargeted) micelles. Uptake of the nanocarrier by cells was assessed using Prussian blue staining after 1 hour of incubation with the polymeric micelles. The inhibitory effect of the targeted micelles on HepG2 cell proliferation at various concentrations of sorafenib was assessed in vitro using the methyl thiazolyl tetrazolium (MTT) assay and apoptotic analysis using flow cytometry. Magnetic resonance imaging using a clinical 1.5 T scanner was performed to detect changes in the signal intensity of cells after incubation with the targeted micelles. Results: Prussian blue staining showed significantly more intracellular SPIONs in cells incubated with the targeted micelles than those incubated with nontargeted micelles. The MTT assay showed that the average inhibitory ratio in the targeted group was significantly higher than that in the nontargeted group (38.13% versus 22.54%, P = 0.028). The mean apoptotic rate in the targeted cells, nontargeted cells, and untreated cells was 17.01%, 11.04%, and 7.89%, respectively. The apoptotic rate in the targeted cells was significantly higher than that in the nontargeted cells (P = 0.043). The T2 signal intensity on magnetic resonance imaging of cells treated with the targeted micelles decreased significantly with increasing concentrations of sorafenib in the cell culture medium, but there was no obvious decrease in signal intensity in cells treated with the nontargeted micelles. Conclusion: Folate-functionalized polymeric micelles loaded with SPIONs and sorafenib inhibited proliferation and induced apoptosis of HepG2 cells in vitro. The inhibitory events caused by targeted micelles can be monitored using clinical magnetic resonance. Keywords: folic acid, sorafenib, magnetic resonance imaging, superparamagnetic iron oxide nanoparticles

Majority of practical multivariate statistical analysis and optimizations model interdependence among random variables in terms of the linear correlation. Though linear correlation is simple to use and evaluate, in several cases non-linear dependence between random variables may be too strong to ignore. In this paper, we propose polynomial correlation coefficients as simple measure of multi-variable non-linear dependence and show that the need for modeling non-linear dependence strongly depends on the end function that is to be evaluated from the random variables. Then, we calculate the errors in estimation resulting from assuming independence of components generated by linear de-correlation techniques, such as PCA and ICA. The experimental results show that the error predicted by our method is within 1% error compared to the real simulation of statistical timing and leakage analysis. In order to deal with non-linear dependence, we further develop a target-function-driven component analysis algorithm (FCA) to minimize the error caused by ignoring high order dependence. We apply FCA to statistical leakage power analysis and SRAM cell noise margin variation analysis. Experimental results show that the proposed FCA method is more accurate compared to the traditional PCA or ICA. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The undesired uncertainties in circuit performance can lead to analog/mixed-signal circuit failures and yield loss at nanoscale. As such, it has become extremely critical for high precision analog/RF circuits such as phase-locked loop (PLL) and custom/mixed-signal circuits such as SRAM arrays, which both have tight operating margin due to lower power supply and higher operating frequency. Many performance-domain techniques have become available in past few decades: the Monte Carlo (MC) method repeatedly draws samples, runs simulations, and evaluates the yield rate, which can be easily applied to high-dimensional problems. However, it is extremely time consuming. IS can reduce the number of samples required to achieve a desired accuracy, especially in the case where the failure region is small for rare failure events. However, it is always challenging to obtain an optimal sampling distribution or shift vector efficiently.

Measures relating word frequencies and expectations have been constantly of interest in Bioinformatics studies. With sequence data becoming massively available, exhaustive enumeration of such measures have become conceivable, and yet pose significant computational burden even when limited to words of bounded maximum length. In addition, the display of the huge tables possibly resulting from these counts poses practical problems of visualization and inference. VERBUMCULUS is a suite of software tools for the efficient and fast detection of over- or under-represented words in nucleotide sequences. The inner core of VERBUMCULUS rests on subtly interwoven properties of statistics, pattern matching and combinatorics on words, that enable one to limit drastically and a priori the set of over- or under-represented candidate words of all lengths in a given sequence, thereby rendering it more feasible both to detect and visualize such words in a fast and practically useful way. This paper is devoted to the description of the facility at the outset and to report experimental results, ranging from simulations on synthetic data to the discovery of regulatory elements on the upstream regions of a set of genes of the yeast.

Nanoparticles, distinguished by their unique chemical and physical properties, have emerged as focal points within the realm of materials science. Traditional theoretical approaches for atomic simulations mainly include empirical force field and ab initio simulations, with the former offering efficiency but limited reliability, and the latter providing accuracy but restricted to systems of relatively small sizes. Herein, we propose a systematic strategy and automated workflow designed for collecting a diverse types of atomic local environments within a training dataset. This includes small nanoclusters, nanoparticles, as well as surface and bulk systems with periodic boundary conditions. The objective is to construct a machine learning potential tailored for pure metal nanoparticle simulations of varying sizes. Through rigorous validation, we have shown that our trained machine learning potential is capable of effectively driving molecular dynamics simulations of nanoparticles across a wide temperature range, especially within the nanoscale regime. Remarkably, this is achieved while preserving the accuracy typically associated with ab initio methods.