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Jun-Peng Liu,1 Yatong Zhang,2 Zinan Zhao,2 Tianqi Zhang,2 Yifan Na,2 Yao Luo,1 Yuhao Wan,1 Ning Sun,1 Cheng Wu,1 Hua Wang,1 Jiefu Yang1 1Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Pharmacy, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Hua Wang, Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1, Da Hua Road, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86 13911680467, Email wh74220@aliyun.comObjective: To evaluate the impact of adverse health conditions, including multimorbidity, frailty, malnutrition, cognitive impairment, and polypharmacy, on clinical outcomes in older people with atrial fibrillation (AF).Patients and Methods: This prospective cohort study focused on patients aged 65 years and older with AF. They were admitted to the hospital between September 2018 and April 2019 and followed up for 1 year. We evaluated these participants for adverse health conditions including multimorbidity, frailty, malnutrition, cognitive impairment, and polypharmacy. The primary clinical outcome measured was a combination of all-cause mortality or rehospitalization.Results: 197 older patients (≥ 65 years) with AF (mean age, 77.5± 7.1 years; 57.4% men) were enrolled. During 1-year follow-up, Primary endpoint events (all-cause mortality or rehospitalization) occurred in 82 patients (41.6%). Compared with the non-event group, the Charlson comorbidity index (CCI) was higher (2.5± 1.9 vs 1.7± 1.3, p=0.004), more heart failure (32.9% vs 17.4%, p=0.01) and chronic kidney disease (17.1% vs 7.0%, p=0.03), with lower systolic blood pressure (125.3± 18.3 mmHg vs 132± 17.9 mmHg, p=0.005) in the event group. On multivariate Cox regression showed that the CCI was associated with a higher odds ratio of the composite outcome of all-cause mortality and rehospitalization (HR: 1.26; 95% CI: 1.02– 1.56, p=0.03). Other adverse health conditions showed no significant association with the composite outcome of all-cause mortality and rehospitalization.Conclusion: Among adverse health conditions in older people with AF, multimorbidity appears to be a significant determinant of adverse clinical outcomes.Clinical Trial Registration: ChiCTR1800017204; date of registration: 07/18/2018.Keywords: atrial fibrillation, older people, multimorbidity, prognosis

Na Sun,1,2 Yanhong Gu1,2 1Department of Nursing, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, People’s Republic of China; 2School of Nursing, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Yanhong Gu, Director of Nursing Department, Shanghai Fifth People’s Hospital, Fudan University, 801 Heqing Road, Minhang District, Shanghai, 200240, People’s Republic of China, Tel +86-18516261081, Email reddy_gu@163.comObjective: This study aimed to explore the experiences and challenges of prostate cancer patients suffering from urinary incontinence following radical prostatectomy.Methods: A descriptive qualitative research design was employed. Purposeful sampling was used to select 22 prostate cancer patients who underwent radical prostatectomy and experienced urinary incontinence after surgery. These patients were interviewed between August to October 2023 at a tertiary B-grade hospital’s pelvic floor center in Shanghai. The data were collected through semi-structured in-depth interviews and analyzed using content analysis to identify and refine themes.Results: The experiences of urinary incontinence in patients can be categorized into four main themes: (1) Daily life disturbances (including 4 sub-themes: sleep disorders, fluid intake restriction, travel inconvenience, loss of sexual life); (2) Negative emotional experiences (including 4 sub-themes: perceived discrimination, concerns about recovery, loss of confidence in life, doubts about the surgical decision); (3) Social withdrawal (including 2 sub-themes: reduced desire for social interaction, decreased ability to socialize); (4) Limited support obtained (including 4 sub-themes: reliance on personal experience, seeking help from relatives and friends, difficulty discerning online information, lack of professional guidance).Conclusion: Postoperative urinary incontinence in prostate cancer patients presents a multidimensional experience. Healthcare professionals need to pay attention to these patients’ daily life, psychological state, and social interactions. Integrating various resources to provide professional support and rehabilitation guidance is crucial.Keywords: prostate cancer, qualitative research, radical prostatectomy, urinary incontinence, patient experience

Dan Li,1,* Na Sun,1,* Li Xiang,2 Jingjie Liu,2 Xueying Wang,1 Lin Yang,1,* Shaoping Huang1,* 1Department of Pediatrics, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China; 2Department of Neurology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaoping Huang; Lin Yang, Department of Pediatrics, the Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xiwu Road, Xi’an, Shaanxi, 710004, People’s Republic of China, Tel +86-18681852505, Email zhengtu1127@163.com; zahp78@163.comObjective: This study aimed to observe the neurophysiological characteristics of type II and type III 5q spinal muscular atrophy (SMA) patients and the changes in peripheral motor nerve electrophysiology after Nusinersen treatment, as well as the influencing factors.Methods: This single-center retrospective case–control study collected clinical data and peripheral motor nerve CMAP parameters from 42 5qSMA patients and 42 healthy controls at the Second Affiliated Hospital of Xi’an Jiaotong University (January 2021 to December 2022). It evaluated changes in motor function and CMAP amplitude before and after Nusinersen treatment.Results: Our investigation encompassed all symptomatic and genetically confirmed SMA patients, consisting of 32 type II and 10 type III cases, with a median age of 57 months (29.5 to 96 months). Comparative analysis with healthy controls revealed substantial reductions in CMAP amplitudes across various nerves in both type II and type III patients. Despite the administration of Nusinersen treatment for 6 or 14 months to the entire cohort, discernible alterations in motor nerve amplitudes were not observed, except for a significant improvement in younger patients (≤ 36 months) at the 14-month mark. Further scrutiny within the type II subgroup unveiled that individuals with a disease duration ≤ 12 months experienced a noteworthy upswing in femoral nerve amplitude, a statistically significant difference when compared to those with > 12 months of disease duration.Conclusion: Motor nerve amplitudes were significantly decreased in type II and type III 5q SMA patients compared to healthy controls. Nusinersen treatment showed better improvement in motor nerve amplitudes in younger age groups and those with shorter disease duration, indicating a treatment-time dependence.Keywords: 5q spinal muscular atrophy, neurophysiology, peripheral motor nerve, Nusinersen

Zhisheng Huang,1,2 Zuowang Cheng,3 Xia Deng,4 Ying Yang,5 Na Sun,5 Peibin Hou,5 Ruyue Fan,5 Shuai Liu6,7 1Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, National Regional Center for Respiratory Medicine, Jiangxi Hospital of China-Japan Friendship Hospital, Nanchang, Jiangxi, People’s Republic of China; 3Department of Clinical Laboratory, Zhangqiu District People’s Hospital Affiliated to Jining Medical University, Jinan, Shandong, People’s Republic of China; 4School of Public Health, Shandong Second Medical University, Weifang, Shandong, People’s Republic of China; 5Shandong Center for Disease Control and Prevention, Jinan, Shandong, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 7Shandong Key Laboratory of Infectious Respiratory Disease, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Shuai Liu; Ruyue Fan, Email liushuai_sam@163.com; fanruyue2022@163.comBackground: Coronavirus disease 2019 (COVID-19) is a respiratory infectious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The objective of this study is to identify reliable and accurate biomarkers for the early stratification of disease severity, a crucial aspect that is currently lacking for the impending phases of the next COVID-19 pandemic.Methods: In this study, we identified important module and hub genes related to clinical severe COVID-19 using differentially expressed genes (DEGs) screening combing weighted gene co-expression network analysis (WGCNA) in dataset GSE213313. We further screened and confirmed these hub genes in another two new independent datasets (GSE172114 and GSE157103). In order to evaluate these key genes’ stability and robustness for diagnosing or predicting the progression of illness, we used RT-PCR validation of selected genes in blood samples obtained from hospitalized COVID-19 patients.Results: A total of 968 and 52 DEGs were identified between COVID-19 patients and normal people, critical and non-critical patients, respectively. Then, using WGCNA, 10 modules were constructed. Among them, the blue module positively associated with clinic disease severity of COVID-19. From overlapped section between DEGs and blue module, 12 intersected common differential genes were obtained. Subsequently, these hub genes were validated in another two new independent datasets as well and 9 genes that overlapped showed a highly correlation with disease severity. Finally, the mRNA expression levels of these hub genes were tested in blood samples from COVID-19 patients. In severe cases, there was increased expression of MCEMP1, ANXA3, CD177, and SCN9A. In particular, MCEMP1 increased with disease severity, which suggested an unfavorable development and a frustrating prognosis.Conclusion: Using comprehensive bioinformatical analysis and the validation of clinical samples, we identified four major candidate genes, MCEMP1, ANXA3, CD177, and SCN9A, which are essential for diagnosis or development of COVID-19.Keywords: COVID-19, differentially expressed genes, WGCNA, hub genes, neutrophil

Nan Sun,1 Dan Dai,1 Shihang Deng,2 Xun Cai,3 Ping Song1 1Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China; 2Department of Dermatology, Shenzhen Bao’an Authentic TCM Therapy Hospital, Shenzhen, 518126, People’s Republic of China; 3Department of Dermatology, The Fifth People’s Hospital of Suzhou, Suzhou, 215131, People’s Republic of ChinaCorrespondence: Nan Sun; Ping Song, Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People’s Republic of China, Email dr-sue@foxmail.com; songping@vip.126.comBackground: Atopic dermatitis (AD) is an allergic inflammatory skin disease caused by aberrant and over-reactive immune response. Although circadian rhythm disruption is implicated in multiple immunoinflammatory conditions, including AD, the mechanisms at the molecular level underlying AD and circadian rhythms remain elusive.Methods: Bulk and single-cell RNA-sequencing data of AD patients were acquired from the Gene Expression Omnibus, including GSE121212, GSE120721, and GSE153760 datasets. A single-sample gene set enrichment analysis was performed to estimate circadian rhythm gene expression levels. A differential expression analysis was utilized to identify the key candidate genes in AD. CIBERSORT was used to quantify the proportions of immune cells, and the R package “Seurat” was utilized to investigate single-cell RNA-sequencing data.Results: Circadian rhythm gene expression levels were lower in AD skin samples than in normal skin samples. Dendritic cells were significantly upregulated and negatively correlated with circadian rhythm gene expression levels in AD patients. Compared with circadian rhythm-related genes in the control samples, ARNTL2, NOCT, and RORC were differentially expressed in AD; ARNTL2 and NOCT were significantly upregulated, whereas RORC was significantly downregulated in AD. ARNTL2, NOCT, and RORC also showed robust abilities to diagnose AD. We validated that the abundance of the dendritic cell was positively correlated with the ARNTL2 and NOCT expression levels using bulk RNA-sequencing data of the GSE121212 and single-cell RNA-sequencing data of the GSE153760. Moreover, the functional enrichment analysis showed that the IL-17 and NF-κB signaling pathways, Th1 and Th2 cell differentiations, and primary immunodeficiency, were enriched in AD patients.Conclusion: The findings of this study suggested that the circadian rhythm is involved in the progression of AD, and RNTL2, NOCT, and RORC as well as dendritic cells are differentially expressed in AD. These findings could be used to introduce diagnostic and chronotherapeutic modalities for AD.Keywords: atopic dermatitis, circadian rhythms, dendritic cells, ARNTL2, NOCT, RORC

Mingzhen Li,1 Bing Zhang,2 Lichuan Guo,2 Yuan Zhang,2 Xiaoyan Du,3 Bingyi Wang,3 Zheng Xu,4 Ning Sun,4 Ruibin Chen,4 Wanwen Han,4 Liming Chen,1 Zhenqiang Song1 1Department of Endocrinology, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of China; 2Department of Information Management, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of Medical, Happy Life Technology Co Ltd, Beijing, People’s Republic of China; 4Department of Yutang, Andon Health Co., Ltd, Tianjin, People’s Republic of ChinaCorrespondence: Zhenqiang Song, Department of Endocrinology, NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, No. 6 North Huanrui Road, Beichen District, Tianjin, People’s Republic of China, Tel +86-18602276218, Fax +86-022-59562017, Email zsong@tmu.edu.cnBackground: Our previous study demonstrated that digital diabetes care model (DDCM) created by multidisciplinary care team (MDCT) can improve glycemic control for patients with diabetes than usual care. Therefore, we aimed to explore long-term glycemic control with DDCM and influencing factors in type 2 diabetic cohort, in order to make a portrait for diabetes with goal-achieved HbA1c in clinics.Methods: A total of 1198 outpatients with type 2 diabetes using DDCM for at least 12 months were recruited as a cohort. Medical records and specific DDCM indexes were collected. The influencing factors for glycemic control were explored by multivariate logistic regression analysis, followed by an internal and external validation.Results: A total of 887 patients were finally included. HbA1c target-achieving rate was increased from 39.83% at baseline to 71.79% after 3-month follow-up. A shorter duration of diabetes, more frequent self-monitoring of blood glucose, lower HbA1c level at baseline, and less frequent emergency out-of-hospital follow-ups were influencing factors for HbA1c < 7% at 12-month follow-up. AUC of the prediction model was 0.790, with a sensitivity of 69.7% and specificity of 76.1%. Internal and external validation in patients using the DDCM monitored by MDCT indicated that the DDCM was robust (AUC =0.783 and 0.723, respectively).Conclusion: Our findings made a portrait for T2DM with goal-achieved HbA1c in our DDCM. It is important to recognize associated factors for health providers to make personalized intervention in clinical practice.Keywords: digital diabetes care model, glycemic control, type 2 diabetes management

Sitong Feng,1,2 Linrui Dong,1,2 Bin Yan,3 Sisi Zheng,1,2 Zhengtian Feng,1,2 Xue Li,1,2 Jiajia Li,1,2 Ning Sun,3 Yanzhe Ning,1,2 Hongxiao Jia1,2 1Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of China; 3Department of Andrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Hongxiao Jia; Yanzhe Ning, Beijing Anding Hospital, Capital Medical University, No. 5 Ankang Hutong, Xicheng District, Beijing, 100088, People’s Republic of China, Tel +86 010-58303065, Email jhxlj@ccmu.edu.cn; ningzy0923@mail.ccmu.edu.cnPurpose: Several studies have demonstrated that psychogenic erectile dysfunction (pED) patients potentially suffer from cognitive dysfunction. Despite that previous neuroimaging studies have reported abnormal functional connections of brain areas associated with cognitive function in pED, the underlying mechanisms of cognitive dysfunction in pED remain elusive. This study aims to investigate the underlying mechanisms of cognitive dysfunction by analyzing large-scale brain networks.Patients and Methods: A total of 30 patients with pED and 30 matched healthy controls (HCs) were recruited in this study and scanned by resting-state functional magnetic resonance imaging. The Dosenbach Atlas was used to define large-scale networks across the brain. The resting-state functional connectivity (FC) within and between large-scale brain networks was calculated to compare pED patients with HCs. The relationship among cognitive performances and altered FC of large-scale brain networks was further explored in pED patients.Results: Our results showed that the decreased FC within visual network, and between visual network and default mode network, visual network and frontoparietal network, and ventral attention and default mode network were found in pED patients. Furthermore, there was a positive correlation between immediate memory score and FC within visual network. The visuospatial score was negatively correlated with decreased FC between ventral attention network and default mode network.Conclusion: Taken together, our findings revealed the relationship between cognitive impairments and altered FC between large-scale brain networks in pED patients, providing the new evidence about the neural mechanisms of cognitive dysfunction in pED patients.Keywords: large-scale brain network, functional connectivity, cognitive impairment, psychogenic erectile dysfunction

Wanyang Dong,1,&ast; Qi Peng,1,&ast; Xiaohua Tang,1,2,&ast; Tian Zhong,1 Shunan Lin,1 Ziling Zhi,1 Jingyi Ye,1 Bixia Yang,1 Ning Sun,1,3 Wenchang Yuan1 1Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, 510180, People’s Republic of China; 2Third Affiliated Hospital of Guangzhou Medical University, Department of Clinical Laboratory, Guangzhou, 510150, People’s Republic of China; 3Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Sun; Wenchang Yuan, Email ning.sun@connect.polyu.hk; yuanwenchang95@163.comBackground: Staphylococcus haemolyticus is an opportunistic pathogen that belongs to coagulase-negative Staphylococci (CoNS). Increasing infection and multi-drug resistance cases caused by this strain have been reported and thus it poses a great health threat.Methods: The third-generation sequencing technology was performed on a S. haemolyticus SH-1 isolated from a clinical sample to analyze the drug resistance genes, which included vancomycin resistance related genes. In addition, antimicrobial susceptibility tests, transmission electron microscopy and Triton X-100 stimulated autolysis were conducted to understand its biological characteristics.Results: The study shows that this clinical isolate is a vancomycin intermediate-resistant strain. Genome comparison also revealed that WalK(N70K) and WalK(R280Q) mutations may contribute to the vancomycin resistant phenotype. Besides, S. haemolyticus SH-1 exhibit common features of thicker cell wall and decreased autolytic activity.Conclusion: S. haemolyticus SH-1 with WalKR mutations shows typical characteristics of vancomycin resistant strains. Combining the genome features and biological properties, our findings may provide important information for the understanding of the molecular mechanism of S. haemolyticus to vancomycin intermediate-resistance.Keywords: Staphylococcus haemolyticus, drug resistance gene, vancomycin intermediate-resistance, whole genome sequencing

Qilong Wang,1,2 Nannan Sun,3 Mingzhi Zhang1 1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2The Academy of Medical Science of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Mingzhi Zhang, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Road, Zhengzhou, Henan, 450052, People’s Republic of China, Email mingzhi_zhang1@163.comBackground: Lung adenocarcinoma (LUAD) is an aggressive cancer that has an extremely poor prognosis. As well as facilitating the detachment of cancer cells from the primary tumor site, anoikis plays an important role in cancer metastasis. Few studies to date, however, have examined the role of anoikis in LUAD, in patient prognosis.Methods: A total of 316 anoikis-related genes (ANRGs) integrated from Genecards and Harmonizome portals. LUAD transcriptome data were retrieved from the Genotype-Tissue Expression Project (GEO) and The Cancer Genome Atlas (TCGA). Anoikis-related prognostic genes (ANRGs) were primarily screened by univariate Cox regression. All ANRGs were included in the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model to construct the powerful prognostic signature. This signature was validated and assessed using the Kaplan-Meier method as well as univariate and multivariate Cox regression analyses. Anoikis-related regulators of risk score were identified using a XG-boost machine learning model. The expression of ITGB4 protein was examined in a ZhengZhou University (ZZU) tissue cohort by immunohistochemistry, and the potential mechanisms of action of ITGB4 in LUAD were explored by GO, KEGG, and ingenuity pathway analyses and by GSEA.Results: A risk score signature was constructed based on eight ANRGs, with high risk scores found to closely correlate with unfavorable clinical features. ITGB4 expression may be associated with 5-year over survival, with immunohistochemistry showed that the expression of ITGB4 was higher in LUAD than in nontumor tissues. Enrichment analysis suggested that ITGB4 may promote LUAD development by targeting E2F, MYC, and oxidative phosphorylation signaling pathways.Conclusion: Our anoikis-related signature from RNA-seq data may be a novel prognostic biomarker in patients with LUAD. It may help physicians develop personalized LUAD treatments in clinical practice. Moreover, ITGB4 may affect the development of LUAD through the oxidative phosphorylation pathway.Keywords: anoikis, lung adenocarcinoma, ITGB4, machine learning, prognosis

Changjiang Yu,1,&ast; Wei Guo,1,2,&ast; Zhulai Zhang,1,&ast; Yuting Ma,3,&ast; Xiaobei Cao,1 Na Sun,1 Yingyao Cui,1 Yunshen Wang,1 Wenyu Cui,1 Yongsheng Xu,1 Jianghua Zhan2,4 1Department of Pediatric Respiratory Medicine, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, People’s Republic of China; 2Graduate School of Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of Infection, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, People’s Republic of China; 4Department of Pediatric Surgery, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongsheng Xu, Department of Pediatric Respiratory Medicine, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, 300134, People’s Republic of China, Email xxyyss@126.com Jianghua Zhan, Graduate School of Tianjin Medical University, Department of Pediatric Surgery, Tianjin Children’s Hospital, Tianjin University Children’s Hospital, Tianjin, 300134, People’s Republic of China, Email zhanjianghuatj@163.comPurpose: Metagenomic next-generation sequencing (mNGS) is an emerging technique for pathogen detection. However, most literature on the clinical application of pediatrics generally comprises case reports or small-scale cohort studies.Patients and Methods: A total of 101 children with community-acquired severe pneumonia admitted to Tianjin Children’s Hospital from November 2021 to February 2022 were included. Pathogens in bronchoalveolar lavage fluid (BALF) specimens were detected using mNGS. The performances of mNGS and conventional tests on pulmonary infection diagnosis and pathogen identification were compared.Results: According to our data, mNGS had a broader spectrum for pathogen detection. The mNGS results of BALF showed that the number of children with severe pneumonia hospitalized for mycoplasma pneumoniae infection was more than that for other bacterial infections during the COVID-19 epidemic. In addition, 43 cases (42.6%) had been identified with mixed infection, including 36 cases (35.6%) of Mycoplasma pneumoniae mixed with other pathogenic bacteria. Analytically, the mNGS exhibited significantly enhanced detection in the BALF as compared with the conventional laboratory pathogenic detection approaches (P < 0.05). The Pearson correlation analysis revealed positive correlation between the time of fever during hospitalization and the number of mycoplasma sequences (P < 0.05).Conclusion: Compared with traditional methods, mNGS has a higher etiological detection rate and can comprehensively detect various pathogens of severe pneumonia. Therefore, mNGS of bronchoalveolar lavage fluid should be performed in children with severe pneumonia, which is of great significance for guiding treatment.Keywords: mNGS, severe pneumonia, pathogen, BALF, children

Meimei Wang,1,&ast; Zhenzhen Zhang,2,&ast; Ning Sun,3 Baolin Yang,4 Jihao Mo,5 Daping Wang,2 Mingqin Su,1 Jian Hu,1 Miaomiao Wang,6 Lei Wang7,8 1Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China; 2Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, People’s Republic of China; 3Institute of Clinical Laboratory Science, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu, 210002, People’s Republic of China; 4Institute of Technical Biology & Agriculture Engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230032, People’s Republic of China; 5Department of Medical Laboratory, Luoyang Orthopedic Hospital of Henan Province, Orthopedic Institute of Henan Province, Luoyang, Henan, 459001, People’s Republic of China; 6School of Medical Science, Huang He Science and Technology University, Zhengzhou, Henan, 459001, People’s Republic of China; 7School of Biological Sciences, Nanyang Technological University, Singapore, 639798, Singapore; 8Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA&ast;These authors contributed equally to this workCorrespondence: Lei Wang, Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA, Tel +1 786-620-1400, Email lxw561@miami.eduIntroduction: The increasing use of gold nanoparticles (Au NPs) in the medical field has raised concerns about the potential adverse effect of Au NPs exposure. However, it is difficult to assess the health risks of Au NPs exposure at the individual organ level using current measurement techniques.Methods: The physical and chemical properties of Au NPs were characterized by transmission electron microscope (TEM), Fourier transform infrared (FTIR), and zeta sizer. The RNA-seq data of Au NPs-exposed worms were analyzed. The food intake was measured by liquid culture and Pharyngeal pumping rate. The function of the smell and taste neurons was evaluated by the chemotaxis and avoidance assay. The activation of ASE neurons was analyzed by calcium imaging. The gene expression of ins-22 and egl-19 was obtained from the C. elegans single cell RNA-seq databases.Results: Our data analysis indicated that 62.8% of the significantly altered genes were functional in the nervous system. Notably, developmental stage analysis demonstrated that exposure to Au NPs interfered with animal development by regulating foraging behavior. Also, our chemotaxis results showed that exposure to Au NPs reduced the sensation of C. elegans to NaCl, which was consistent with the decrease in calcium transit of ASEL. Further studies confirmed that the reduced calcium transit was dependent on voltage-gated calcium channel EGL-19. The neuropeptide INS-22 was partially involved in Au NPs-induced NaCl sensation defect. Therefore, we proposed that Au NPs reduced the calcium transit in the ASEL neuron through egl-19-dependent calcium channels. It was partially regulated by the DAF-16 targeting neuropeptide INS-22.Discussion: Our results demonstrate that Au NPs affect food sensation by reducing the calcium transit in ASEL neurons, which further leads to reduced pharynx pumping and feeding defects. The toxicology studies of Au NPs from worms have great potential to guide the usage of Au NPs in the medical field such as targeted drug delivery.Graphical Abstract: Keywords: gold nanoparticles, RNA sequencing, ASEL neuron, voltage-gated calcium channel, developmental toxicity, Caenorhabditis elegans

Qianqian Zhao,1,&ast; Yongliang Tang,2,&ast; Luyu Zhang,1 Na Sun,3 Qiling Liu,3 Rongqiang Zhang3 1School of Nursing, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China; 2The Second Department of Orthopedics, Xi’an Central Hospital, Xi’an, Shaanxi, People’s Republic of China; 3School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongqiang Zhang, School of Public Health, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, Shaanxi, 712046, People’s Republic of China, Tel/Fax +86-029-38185219, Email zhangrqxianyang@163.comPurpose: In order to further study the biological functions of glutathione peroxidases (GPXs) and their expression level in patients with osteoarthritis (OA), we fully explored the potential relationship between GPXs and OA. This will provide new ideas for basic biological studies and therapeutic strategies for OA patients.Patients and Methods: In this study, bioinformatics techniques were used to explore the biological functions of five GPXs. The core genes related to the biological functions of GPXs were identified by constructing a protein-protein interaction network (PPI). In addition, we utilized microarray data in public databases to analyze the expression levels of GPXs in OA patients and healthy controls. Finally, we used quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of GPXs in OA patients and controls to validate our bioinformatic analysis results.Results: Enrichment analysis showed GPXs were mainly enriched in the glutathione metabolic pathway and participate in the biological process of oxidative stress response, and further play an antioxidant role. The PPI network indicated that superoxide dismutase 1 (SOD1), superoxide dismutase 2(SOD2) and catalase (CAT) were the core proteins of this network. GPX1 was regulated by the greatest number of miRNAs. Experiments showed that the expression of GPX1 was elevated in OA patients compared with controls.Conclusion: GPXs play an important antioxidant role in oxidative stress response. The expression of GPX1 was elevated in peripheral blood mononuclear cells (PBMCs) of OA patients. The changes of GPXs in OA patients may regulate the level of oxidative stress, which may influence synovial lesions and chondrocyte apoptosis.Keywords: glutathione peroxidase, biological functions, osteoarthritis

Hao Tian,1,&ast; Tingting Zhao,1,&ast; Yanling Li,1,&ast; Na Sun,1 Dandan Ma,1 Qiyun Shi,1 Guozhi Zhang,1 Qingqiu Chen,1 Kongyong Zhang,1 Ceshi Chen,2,&ast; Yi Zhang,1 Xiaowei Qi1 1Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, People’s Republic of China; 2Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaowei Qi; Yi Zhang, Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Gaotanyan Street 29, Chongqing, 400038, People’s Republic of China, Tel/Fax +86-23-68754160, Email qxw9908@foxmail.com; zhangyi1489@sina.comBackground: Epigenetic modification of chromatin is an important step in the regulation of gene expression. The chromobox family proteins (CBXs), as epigenetic modifier, may play a vital role in tumorigenesis and cancer progression. Herein we explored the correlation between CBXs and breast cancer (BC) via the bioinformatics approach and qRT-PCR validation.Methods: Several databases, including GEPIA, TCGA, GEO, K-M plotter, STRING, DAVID, cBioPortal, CIBERSORT, and HPA were employed to analyze the expression levels of CBXs and the correlations between CBXs and prognosis (overall and recurrence-free survival) in BC. We analyzed molecular functions, genetic variations, transcription factors of CBXs, and immune cell infiltration status. ROC curve analysis was performed to determine the predictive value of CBXs. RNA extracted from 11 human BC and paired adjacent normal tissues were subjected to qRT-PCR.Results: The mRNA expression level of CBX1– 5 was significantly upregulated, while that of CBX7 was significantly downregulated in BC; no expression disparities were observed in CBX6/8 expression. Further, high mRNA expression of CBX1/2/3/4/8 correlated with advanced BC, whereas high mRNA expression of CBX6/7 correlated with early BC. High mRNA expressions of CBX1/2/3/5 predict poor OS and RFS, while higher mRNA expressions of CBX6/7 predict better OS and RFS in patients with BC. ROC curve analysis revealed that CBX3 showed excellent discriminatory ability. Gene ontology enrichment analysis showed that CBXs primarily participated in SUMOylation and post-/transcriptional regulation. Moreover, they presented varying degrees of amplification in BC tissues and were related to the infiltration of various immune cells.Conclusion: CBXs can serve as putative biomarkers for BC. Further studies are warranted to determine the exact molecular mechanisms underlying the action of CBXs in BC, particularly CBX1/2/3/5/7.Keywords: chromobox family proteins, breast cancer, prognosis, bioinformatics, qRT-PCR

Junshuai Xue,1 Nianfeng Sun,2 Yang Liu3 1Department of General Surgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, People’s Republic of China; 2Women’s and Children’s Hospital Affiliated to Qingdao University, Qingdao, 266001, People’s Republic of China; 3Department of General Surgery, Vascular Surgery, Qilu Hospital of Shandong University, Jinan City, Shandong Province, People’s Republic of ChinaCorrespondence: Nianfeng Sun; Yang Liu, Tel +86 18561810688 ; +86 18560088317, Email sunnianfeng@126.com; liuyang_sdu@126.comBackground: Non-healing skin wounds are a common complication in diabetic patients. Vector biomaterials embedded with mesenchymal stem cells (MSCs) are considered a promising treatment approach. In this study, we presented a novel and effective approach to accelerate diabetic skin wound healing.Methods and Materials: Human umbilical cord mesenchymal stem cells (hUC-MSCs) were shaped into spheres. RADA16-I, KLT, and RGD nanopeptides were selected for self-assembly into hydrogels. hUC-MSCs spheroids (hUC-MSCsp) were combined in vitro with self-assembled nanopeptide hydrogels and subsequently transplanted into a mouse model of diabetic skin trauma.Results: Compared with the PBS, hUC-MSCs, hUC-MSCsp, and hUC-MSCs with hydrogel groups, hUC-MSCsp with hydrogel significantly accelerated wound healing (p< 0.01) and shortened the healing time (10 vs 14 vs 21 days). The expressions of IL-6, IL-10, IL-1β, and TNF-α were significantly decreased (p< 0.001). The expression of VEGF was significantly higher in the hUC-MSCsp with hydrogel group (p< 0.05), and the density of neovascularization in the fresh skin tissue at the wound was also remarkably increased (p< 0.01).Conclusion: Nanopeptide hydrogels loaded with hUC-MSCsp accelerated diabetic skin wound healing by inhibiting inflammation and promoting angiogenesis compared with conventional stem cell transplantation, which deserves further investigation.Keywords: diabetic wound, human umbilical cord mesenchymal stem cell, spheroid, nanopeptide hydrogels, treatment

Abstract Bacteria often reside in sessile communities called biofilms, where they adhere to a variety of surfaces and exist as aggregates in a viscous polymeric matrix. Biofilms are resistant to antimicrobial treatments, and are a major contributor to the persistence and chronicity of many bacterial infections. Herein, we determined that the CpxA-CpxR two-component system influenced the ability of enteropathogenic Yersinia pseudotuberculosis to develop biofilms. Mutant bacteria that accumulated the active CpxR~P isoform failed to form biofilms on plastic or on the surface of the Caenorhabditis elegans nematode. A failure to form biofilms on the worm surface prompted their survival when grown on the lawns of Y. pseudotuberculosis. Exopolysaccharide production by the hms loci is the major driver of biofilms formed by Yersinia. We used a number of molecular genetic approaches to demonstrate that active CpxR~P binds directly to the promoter regulatory elements of the hms loci to activate the repressors of hms expression and to repress the activators of hms expression. Consequently, active Cpx-signalling culminated in a loss of exopolysaccharide production. Hence, the development of Y. pseudotuberculosis biofilms on multiple surfaces is controlled by the Cpx-signalling, and at least in part this occurs through repressive effects on the Hms-dependent exopolysaccharide production.

Wei-Ying Diao,1,&ast; Cheng-Long Ding,1,&ast; Bo-Yang Yuan,2 Zan Li,3 Na Sun,4 Jia-Bin Huang5 1Department of Pathology, The First Affiliated Hospital of Jiamusi University, Jimusi City, Heilongjiang Province, 154002, People’s Republic of China; 2Department of Acupuncture and Moxibustion, The First Affiliated Hospital of Jiamusi University, Jimusi City, Heilongjiang Province, 154002, People’s Republic of China; 3Department of Analytical Chemistry Teaching and Research, Jiamusi University, Jiamusi City, Heilongjiang Province, 154002, People’s Republic of China; 4Graduate Department, Jiamusi University, Jiamusi, Heilongjiang Province, 154002, People’s Republic of China; 5Department of Geratology, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang Province, 154002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia-Bin Huang Email jiadupinglu54972@163.comIntroduction: We aim to investigate the relationship between HER2 gene phenotype and clinical characteristics, distribution and prognosis of non-small cell lung cancer (NSCLC) patients.Methods: A total of 249 NSCLC patients admitted to the oncology department of our hospital from January 2015 to January 2018 were retrospectively analyzed. The clinicopathological information, CT signs, clinical efficacy and long-term prognosis were collected and compared.Results: A total of 249 NSCLC patients underwent HER2 gene testing, 21 of them (8.43%) complied with HER2 alterations [HER2 (+)], and there were significant differences in tumor stages among patients with different HER2 phenotypes (P< 0.05). Among 21 NSCLC patients with HER2 (+), HER2 gene mutation was found in 17 patients (81%), and HER2 gene amplification in 4 patients (19%). Among the HER2 mutations, 12 cases (57%) were 20 exon mutations, and 5 cases (19%) were other mutations. Analysis of CT signs showed that border lobulation/burr, necrosis sign and pleural depression were correlated with HER2 gene mutation (P< 0.05). The incidence of EGRF mutation in HER (+) patients was significantly lower than that in HER (-) patients (P< 0.05), but there was no significant difference in the incidence of ALK gene mutation among different HER phenotypes (P> 0.05). The disease control rate of HER2 (+) patients was significantly lower than that of HER2 (-) patients, and the 12-month progression-free survival rate and survival rate of HER2 (+) patients were significantly higher than those of HER2 (-) patients (P< 0.05). There was no significant difference in the incidence of ADR among HER2 patients with different phenotypes, but the incidence of ADR (adverse drug reaction) in HER2 (+) patients with Grade 3 or 4 was significantly higher than that in the control group (P< 0.05).Discussion: The incidence of HER2 gene mutations in NSCLC patients is relatively low, but it is far commoner in patients with stage IIIB∼IV, among which exon 20 mutations are the most prevalent. In CT signs, the lesion lobulated sign/spiculated sign, necrosis signs, and pleural depression signs are related to HER2 gene mutations. In addition, HER2 gene mutations play a crucial role in the clinical prognosis and treatment safety of patients.Keywords: non-small cell lung cancer, HER2 genotype, CT signs, afatinib

Ning Sun,1,&ast; Yan Zhuang,1,&ast; Junling Zhang,2 Shiqing Chen,2 Yuwen Dai,2 Renhong Guo1 1Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2The Medical Department, 3D Medicines Inc., Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Renhong GuoDepartment of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, People’s Republic of ChinaEmail guorh610@sina.comBackground: With the development of next-generation sequencing (NGS), several anaplastic lymphoma kinase (ALK) fusion partner genes have been identified. However, ALK fusion is extremely rare in small cell lung cancer (SCLC), and there is no standard treatment option. Here, we report a patient with SCLC who carried an ALK- Intergenic Region (IR) rearrangement and responded to Alectinib.Case Presentation: A 26-year-old man was pathologically diagnosed with extensive-stage SCLC. After 2 cycles of first-line chemotherapy, CT showed a large soft tissue mass in the middle lobe of the right lung and increased liver nodules, left kidney lesions and right kidney lesions. To seek potential therapeutic regimens, ALK rearrangement was identified. The patient achieved a rapid and durable partial response with Alectinib (600 mg BID). The patient experienced a significant clinical response with a progression-free survival of more than 6 months. There were no grade 3 or more adverse events reported, and there was no dose reduction during treatment. Following Alectinib treatment, the allele frequency of ALK rearrangement and RB1 and TP53 mutations in plasma circulating tumor DNA decreased with the reduction in tumor size.Conclusion: This case provides a meaningful reference for the treatment of SCLC patients with ALK rearrangement. This case also provides valuable information on the response to ALK inhibitors in patients with ALK-IR rearrangement and better understanding of ALK-TKI applications in the future.Keywords: small-cell lung cancer, ALK rearrangement, ALK inhibitor, immunohistochemistry, genetics

Luyu Zhang,1 Qianqian Zhao,1 Leilei Mao,2 Huanze Li,1 Miaoqing Zhuang,1 Jiayi Wang,1 Yue Liu,1 Meng Qi,3 Xiaoping Du,3 Zengrun Xia,3 Na Sun,4 Qiling Liu,4 Hongfang Chen,1,5,6 Rongqiang Zhang4 1School of Nursing, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China; 2School of Information Engineering, Chang’an University, Xi’an, Shaanxi, People’s Republic of China; 3Ankang R & D Center of Se-enriched Products, Ankang, Shaanxi, People’s Republic of China; 4School of Public Health, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People’s Republic of China; 5Shaanxi Academy of Tradional Chinese Medicine, Xi’an, Shaanxi, People’s Republic of China; 6Shaanxi Provincial Hospital of Chinese Medicine, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Hongfang ChenShaanxi Academy of Tradional Chinese Medicine, Shaanxi Provincial Hospital of Chinese Medicine, No. 4 Xihua Gate, Xi’an, Shaanxi, 710003; School of Nursing, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, Shaanxi, 712046, People’s Republic of ChinaEmail 13892881695@163.comRongqiang ZhangSchool of Public Health, Shaanxi University of Chinese Medicine, No. 1 Middle Section of Century Avenue, Xianyang, Shaanxi, 712046, People’s Republic of ChinaTel/Fax +86-029-38185219Email Zhangrqxianyang@163.comPurpose: Selenophosphate synthetase 2 (SEPHS2) has been shown to regulate selenoprotein biosynthesis by catalyzing the synthesis of active selenium donor selenophosphate. SEPHS2 influences the survival of tumor cells. However, few studies have explored the expression level and prognostic of SEPHS2 in various cancers.Methods: The expression of SEPHS2 in human tumor tissues and normal adjacent tissues was analyzed in The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), and UALCAN databases. Cox regression analysis and Kaplan–Meier curve analysis were performed to analyze the association of SEPHS2 expression with the prognosis of cancer patients. The expression and prognosis of SEPHS2 in gliomas were further verified using the Chinese Glioma Genome Atlas (CGGA) dataset. The relationship between SEPHS2 and immune infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens was comprehensively explored using a TCGA cohort. The mechanism by which SEPHS2 regulates tumor progression was explored by using the STRING database. A nomogram was constructed using the R software to predict the overall survival (OS) of patients with brain lower grade glioma (LGG).Results: SEPHS2 was highly expressed in many cancers including LGG. Its high expression was significantly associated with poor OS, disease-free survival (DFS), and progression-free survival (PFS). Univariate and multivariate Cox analyses showed that SEPHS2 was an independent prognostic factor for LGG. Concordance index and calibration curves revealed that the nomogram had good predictive performance (concordance index: 0.791; 95% CI: 0.732– 1). A significant correlation was found between SEPHS2 and immune infiltration, TMB, MSI, and tumor neoantigens across diverse cancers. Enrichment analysis showed that SEPHS2 may regulate the PPAR signaling pathway.Conclusion: SEPHS2 expression regulates tumor development and it is a potential treatment target and prognostic biomarker, especially for lower grade glioma.Keywords: SEPHS2, selenoprotein, cancer, prognosis, biomarker

Yalin Cheng, Ke Chai, Wanrong Zhu, Yuhao Wan, Yaodan Liang, Minghui Du, Yingying Li, Ning Sun, Jiefu Yang, Hua Wang Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Hua WangDepartment of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaTel/Fax +86-10-85133852Email wanghua2764@bjhmoh.cnPurpose: Elderly heart failure (HF) patients have different clinical characteristics and poorer prognosis compared with younger patients. Prognostic risk scores for HF have not been validated well in elderly patients. We aimed to validate the Seattle Heart Failure Model (SHFM) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score in an elderly Chinese HF cohort.Patients and Methods: This retrospective study enrolled 675 elderly HF patients (age≥ 70 years) discharged from our hospital between 2012 and 2017. The performance of the two risk scores was evaluated in terms of discrimination, using receiver-operating characteristic analysis, and calibration using a calibration plot and Hosmer–Lemeshow (H-L) test. Absolute risk reclassification was used to compare the two scores.Results: During the mean follow-up time of 32.6 months, 193 patients (28.6%) died, and 1-year mortality was 10.5%. The predicted median 1-year mortality was 8% for the SHFM and 18% for the MAGGIC score. A Kaplan–Meier survival curve demonstrated that event rates of all-cause mortality significantly increased with increasing SHFM and MAGGIC scores. The discriminatory capacity of the SHFM was greater than that of the MAGGIC score (c-statistics were 0.72 and 0.67, respectively; P = 0.05). The calibration plot for the SHFM was better than that for MAGGIC score for 1-year mortality (SHFM: H-L χ2 =8.2, P = 0.41; MAGGIC: H-L χ2 =18.8, P =0.02). Compared with the MAGGIC score, the net reclassification index (NRI) of the SHFM was 2.96% (Z=5.88, P< 0.0001).Conclusion: The SHFM performs better than MAGGIC score, having good discrimination, calibration and risk classification for the prediction of 1-year mortality in elderly Chinese HF patients.Keywords: heart failure, risk score, prognosis, elderly patient

Xiaotong Song,1,2 Ning Sun,1– 3 Aixia Zhang,1– 3 Lei Lei,1 Xinrong Li,1 Zhifen Liu,1– 3 Yanfang Wang,1 Chunxia Yang,1– 3 Kerang Zhang1 1Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Mental Health, Shanxi Medical University, Taiyuan, People’s Republic of ChinaCorrespondence: Chunxia Yang; Kerang ZhangDepartment of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of ChinaEmail ychunxia2000@163.com; atomsxmu@vip.163.comObjective: Although the pathogenesis of major depressive disorder (MDD) is still unclear, studies have shown that the dopaminergic system of depressed patients is defective, and that NR4A2 is an important transcription factor affecting the development and maintenance of dopaminergic neurons. As such, NR4A2 levels affected by NR4A2 single nucleotide polymorphisms (SNPs) may be associated with MDD. This study examined whether NR4A2 SNPs are associated with depressive symptoms and antidepressant efficacy.Methods: A total of 441 patients with first-episode depression were enrolled in this study. We analysed three SNPs of NR4A2, using the 17-item Hamilton Depression Rating Scale (HAM-D) and its four factors to obtain scores at baseline and at the end of 6 weeks. UNPHASED software was employed for quantitative character analysis, and SPSS software was adopted for antidepressant efficacy analysis.Results: Patients with rs12803-A exhibited higher scores of retardation symptoms. Patients with the rs834834-C allele and rs834834-CC genotype had higher retardation symptom scores. Patients with rs3769340 exhibited greater antidepressant efficacy.Conclusion: NR4A2 gene polymorphisms are associated with retardation symptoms, somatic symptoms (gastro-intestinal), anxiety-based somatic symptoms, insight, and weight loss in patients with MDD. Additionally, rs3769340 may be a predictor of antidepressant efficacy in patients with major depressive disorder.Keywords: major depressive disorder, NR4A2, single nucleotide polymorphism, antidepressant treatment

Jinjie Yuan,1,2 Ning Sun,1 Xinying Feng,3 Huan He,1 Dong Mei,1 Guanghua Zhu,4 Libo Zhao1 1Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, Beijing, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Phase I Clinical Trials Centre, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, People’s Republic of China; 4Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Libo ZhaoClinical Research Center, Beijing Children’s Hospital, Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing, 100045, People’s Republic of ChinaEmail libozhao2011@163.comGuanghua ZhuHematology Oncology Center, Beijing Children’s Hospital, 56 Nanlishi Road, Xicheng District, Beijing, 100045, People’s Republic of ChinaEmail guangh.zhu@gmail.comPurpose: The aim of this study was to develop a novel busulfan dosing regimen, based on a population pharmacokinetic (PPK) model in Chinese children, and to achieve better area under the concentration-time curve (AUC) targeting.Patients and Methods: We collected busulfan concentration-time samples from 69 children who received intravenous busulfan prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). A population pharmacokinetic model for busulfan was developed by nonlinear mixed effect modelling and was validated by an external dataset (n=14). A novel busulfan dosing regimen was developed through simulated patients, and has been verified on real patients. Limited sampling strategy (LSS) was established by Bayesian forecasting. Mean absolute prediction error (MAPE) and relative root mean Squared error (rRMSE) were calculated to evaluate predictive accuracy.Results: A one-compartment model with first-order elimination best described the data. GSTA1 genotypes, body surface area (BSA) and aspartate aminotransferase (AST) were found to be significant covariates of Bu clearance, and BSA had significant impact of the volume of distribution. Moreover, two equations were obtained for recommended dose regimens: dose (mg)=34.14×BSA (m2)+3.75 (for GSTA1 *A/*A), Dose (mg)=30.99×BSA (m2)+3.21 (for GSTA1 *A/*B). We also presented a piecewise dosage based on BSA categories for each GSTA1 mutation. A two-point LSS, two hours and four hours after dosing, behaved well with acceptable prediction precision (rRMSE=1.026%, MAPE=6.55%).Conclusion: We recommend a GSTA1-BSA and BSA-based dosing (Q6 h) based on a PPK model for personalizing busulfan therapy in pediatric population. Additionally, an optimal LSS (C2h and C4h) provides convenience for therapeutic drug monitoring (TDM) in the future.Keywords: busulfan, individualized therapy, population pharmacokinetics, HSCT, GST mutations

Yaru Zou,1,2,* Dong Mei,1,* Jinjie Yuan,1,2 Jiaqi Han,1 Jiamin Xu,1 Ning Sun,1 Huan He,1 Changqing Yang,2 Libo Zhao1 1Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China*These authors contributed equally to this workCorrespondence: Libo ZhaoClinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of ChinaTel +86-010-59617018Email libozhao2011@163.comBackground: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP.Methods: We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice.Results: The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity.Conclusion: Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.Keywords: 6-mercaptopurine, nanomedicines, Jurkat cells, acute lymphoblastic leukemia, ALL, bioavailability

Nai Sun,* Wei Zhang,* Jiaying Liu, Xiaochen Yang, Qinjun Chu Department of Anesthesiology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou City, Henan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinjun ChuDepartment of Anesthesiology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, No. 16 Tongbai North Road, Zhongyuan District, Zhengzhou 450007, Henan Province, People’s Republic of ChinaTel/Fax +86 371-67690273Email yxchen615@163.comBackground: Propofol has been proposed to function as a tumor suppressor in various human cancers. In this study, we aimed to investigate the anti-tumor effect of propofol on cervical cancer (CC).Methods: Cell Counting Kit-8 (CCK-8) assay, colony formation assay, flow cytometry analysis, transwell assay and wound healing assay were conducted for cell viability, colony formation, apoptosis, invasion and migration, respectively. Western blot assay was used for protein levels. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for HOX antisense intergenic RNA (HOTAIR), miR-129-5p and RPL14 levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were executed to verify the interaction between miR-129-5p and HOTAIR or RPL14. Murine xenograft model assay was used for the role of propofol in tumor progression in vivo.Results: Propofol treatment suppressed CC cell viability, colony formation, invasion and migration and facilitated apoptosis. Propofol treatment led to a marked reduction in HOTAIR level in CC cells. HOTAIR overexpression promoted cell colony formation, invasion and migration and repressed apoptosis in CC cells and propofol-treated CC cells. For mechanism analysis, HOTAIR positively regulated RPL14 expression via acting as the sponge of miR-129-5p. MiR-129-5p overexpression reversed the impacts of HOTAIR on the malignant behaviors of propofol-treated CC cells. Furthermore, miR-129-5p inhibition accelerated the progression of CC cells, while RPL14 interference rescued the effect. In addition, propofol treatment restrained tumor growth of CC in vivo.Conclusion: Propofol inhibited CC development by modulation of HOTAIR/miR-129-5p/RPL14 axis.Keywords: propofol, cervical cancer, HOTAIR, miR-129-5p, RPL14

Baohua Liu,1,2,* Fei Gao,3,* Jianfeng Zhang,3,* Hongguo Zhou,1 Ning Sun,1 Laiyou Li,1 Libo Liang,2 Ning Ning,2 Qunhong Wu,2 Miaomiao Zhao4 1School of Health Services and Management, Ningbo College of Health Sciences, Ningbo 315100, Zhejiang, People’s Republic of China; 2Department of Social Medicine, School of Health Management, Harbin Medical University, Harbin 150081, Heilongjiang, People’s Republic of China; 3Institute of Food Safety and School Health, Heilongjiang Center for Disease Control and Prevention, Harbin 150030, Heilongjiang, People’s Republic of China; 4Department of Health Management, School of Public Health, Nantong University, Nantong 226019, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qunhong Wu; Miaomiao Zhao Tel +8618686825192; +8618860979901Email wuqunhong@163.com; zhaomiaomiao0201@163.comBackground: Sleep affects a wide array of health outcomes and is associated with the quality of life. Among students, sleep quality is affected by school stage and grade; however, data regarding the different sleep-related problems students experience at different school stages are limited. In this study, we aimed to explore sleep quality among a student sample ranging from elementary school to university level.Methods: Overall, data were examined for 9392 subjects aged 9– 22 years. Information on sociodemographic characteristics and other variables were collected through self-administered questionnaires. Sleep quality on school nights was evaluated using the standard Pittsburgh Sleep Quality Index; global score > 5 was classified as poor sleep quality. For the high school sample, logistic regression analysis was used to estimate associations between sleep quality and certain factors.Results: Of the elementary school, middle school, vocational high school, senior high school, and university students, 7.5%, 19.2%, 28.6%, 41.9%, and 28.5%, respectively, showed poor sleep quality. The high school students reported the highest prevalence of shorter sleep duration (70.8%), day dysfunction (84.7%), and subjective poor sleep quality (17.2%). The elementary school students showed the highest prevalence of poor sleep efficiency (17.9%). The university students showed the highest prevalence of sleep medication use (6.4%). The vocational high school students reported the highest prevalence of sleep latency (6.3%) and sleep disturbance (7.4%). Logistic regression modeling indicated that sleep quality is positively associated with school stage, grade, family atmosphere, academic pressure, and number of friends.Conclusion: Sleep quality and sleep features change greatly from elementary school to university. Interventions to improve sleep quality should consider targeting the specific issues students experience at each school stage. Alarmed by the high prevalence of poor sleep quality among high school students, it is recommended that high school students should be informed of their sleep matter and the consequences.Keywords: different school stages, sleep quality, students, PSQI

Efficient systemic pharmacological treatment of solid tumors is hampered by inadequate tumor concentration of cytostatics necessitating development of smart local drug delivery systems. To overcome this, we demonstrate that doxorubicin (DOX), a cornerstone drug used for osteosarcoma treatment, shows reversible accretion to hydroxyapatite (HA) of both nano (nHA) and micro (mHA) size. nHA particles functionalized with DOX get engulfed in the lysosome of osteosarcoma cells where the acidic microenvironment causes a disruption of the binding between DOX and HA. The released DOX then accumulates in the mitochondria causing cell starvation, reduced migration and apoptosis. The HA+DOX delivery system was also tested in-vivo on osteosarcoma bearing mice. Locally delivered DOX via the HA particles had a stronger tumor eradication effect compared to the controls as seen by PET-CT and immunohistochemical staining of proliferation and apoptosis markers. These results indicate that in addition to systemic chemotherapy, an adjuvant nHA could be used as a carrier for intracellular delivery of DOX for prevention of tumor recurrence after surgical resection in an osteosarcoma. Furthermore, we demonstrate that nHA particles are pivotal in this approach but a combination of nHA with mHA could increase the safety associated with particulate nanomaterials while maintaining similar therapeutic potential.

Wei He,1,2 Yao Luo,1 Jun-Peng Liu,1 Ning Sun,1 Di Guo,1 Ling-Ling Cui,1 Pei-Pei Zheng,1 Si-Min Yao,1 Jie-Fu Yang,1,2 Hua Wang1,2 1Department of Cardiology, Beijing Hospital, National Center of Gerontology, Beijing, People’s Republic of China; 2Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Hua Wang; Jie-Fu YangDepartment of Cardiology, Beijing Hospital, National Center of Gerontology, No. 1, Dahua Road, Dongcheng District, Beijing 100730, People’s Republic of ChinaTel +86 13911680467; +86 13601292259Fax +86 10-58115035Email wanghua2764@bjhmoh.cn; yangjiefu2011@126.comObjective: Our study aimed to explore the association between trimethylamine N-oxide and frailty in older adults with cardiovascular disease.Patients and Methods: This cross-sectional study analyzed a total of 451 people aged 65 years or older who underwent comprehensive geriatric assessments. Frailty status was determined using a frailty index constructed with 48 variables according to the cumulative deficits model. Physical frailty and cognitive frailty were also assessed in detail. Fasting plasma TMAO was measured by mass spectrometry.Results: The proportion of frail subjects was 29.9% (135/451). Plasma TMAO levels were significantly higher in frail patients than in nonfrail individuals (4.04 [2.84– 7.01] vs 3.21 [2.13– 5.03] μM; p< 0.001). Elevated plasma TMAO levels were independently associated with the likelihood of frailty (OR 2.12, 95% CI 1.01– 4.38, p=0.046). Dose–response analysis revealed a linear association between the TMAO concentration and the OR for frailty. A 2-unit increase in TMAO was independently correlated with physical frailty (OR 1.23, 95% CI 1.08– 1.41, p for trend 0.002) and cognitive frailty (OR 1.21, 95% CI 1.01– 1.45, p for trend 0.04).Conclusion: Elevated circulating TMAO levels are independently associated with frailty among older adults with cardiovascular disease.Keywords: older adults, frailty, TMAO, cardiovascular disease, physical frailty, cognitive frailty

Qingpeng Zeng,1 Bingzhi Wang,2 Jiagen Li,1 Jun Zhao,1 Yousheng Mao,1 Yushun Gao,1 Qi Xue,1 Shugeng Gao,1 Nan Sun,1 Jie He1 1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Jie HeDepartment of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Beijing 100021, People’s Republic of ChinaEmail prof.jiehe@gmail.comObjective: Spread through air spaces (STAS) has been reported to be an invasive histological pattern with poor prognosis in lung cancer; however, little is known about its intrinsic risk factors. This work analyzed the correlation between pathological and radiological features and STAS in resected lung adenocarcinomas.Patients and Methods: We retrospectively reviewed 1821 consecutive surgically treated patients with histologically diagnosed lung adenocarcinoma (174 positive for STAS and 1647 negative for STAS) from December 2017 to November 2018 at our institution. Propensity score matching identified 170 well-balanced pairs of patients. The correlations between pathological and radiological features and the presence of STAS were analyzed.Results: Before propensity matching, the incidence rate of STAS was 9.6% in all patients. In matched cohorts, multivariate analysis showed that the presence of STAS was significantly correlated with pure solid nodules (SNs) (p = 0.001) and solid/micropapillary patterns (SMPs) (p = 0.002). The odds ratio for STAS in SN-positive and SMP-positive adenocarcinoma against that in SN-negative and SMP-negative adenocarcinoma was 10.922 (95% confidence interval, 5.826– 20.475; p < 0.001). Tumor differentiation, visceral pleural invasion (VPI), lymphovascular invasion (LVI), invasive adenocarcinoma, and non-lepidic subtype were significantly associated with STAS in the univariate analysis (p < 0.05); however, the differences failed to reach a significant level in the multivariate analysis.Conclusion: We found that STAS was significantly correlated with several invasive clinicopathological patterns. The presence of SNs and SMPs were revealed as independent predictors for STAS, which could offer clinicians clues to identify STAS-positive adenocarcinoma.Keywords: lung adenocarcinoma, spread through air spaces, solid pulmonary nodule

Ning Sun,1,2 Chunxia Yang,1 Xiaoting He,1,3 Zhifen Liu,1 Sha Liu,1 Xinrong Li,1 Yanfang Wang,1 Ruihua Jin,2 Kerang Zhang1 1Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Nursing College of Shanxi Medical University, Taiyuan, People’s Republic of China; 3University-Town Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Ruihua Jin; Kerang Zhang Email jrh_xy@163.com; atomsxmu@vip.163.comBackground: Patients suffering from major depressive disorder (MDD) commonly demonstrate lower performance across multiple cognitive domains. Cognitive impairment is an intrinsic characteristic of MDD status and is often influenced by genetic factors. microRNAs (miRNAs or miRs) have been shown to have important implications in the etiology of MDD. Therefore, we aimed to identify and analyze the impact of expression and genetic variation of miR-34b/c on cognitive dysfunction in MDD.Methods: First, we analyzed miR-34c-5p expression in 48 cases of MDD and 54 healthy controls in a Chinese population using qRT-PCR. We assessed the relationship between the level of miR-34c-5p expression and cognitive performance by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Trail Making Test (TMT). Second, in order to characterize allelic effects of miR-34b/c on cognitive performance in MDD patients, we performed genetic association analysis of single-nucleotide polymorphism (SNP) loci of the MIR34B/C genes with cognitive function in a second group consisting of 531 MDD patients and 267 healthy controls.Results: We found a significant negative correlation between the level of miR-34c-5p expression and both the language and delayed memory index scores in patients with MDD. We also found a significant positive correlation between the level of miR-34c-5p expression and the time required to complete tests A and B of the TMT. The interaction between the rs2187473 genotype and the disease was significant for both immediate memory and delayed memory. In the patient group, the rs2187473 CC genotype was significantly associated with higher performance on immediate memory (F = 6.683, p < 0.05) and delayed memory tasks (F = 4.221, p < 0.05).Conclusion: Our findings suggest that changes in miR-34c expression level have important impacts on cognitive function in patients with MDD. In particular, the polymorphism rs2187473 is a potential genetic risk factor for cognitive function in MDD, which may be of clinical use.Keywords: major depressive disorder, MDD, microRNA-34c, single-nucleotide polymorphism, cognitive function

Penghong Liu,1,2 Qi Li,1,2 Aixia Zhang,1 Zhifen Liu,1 Ning Sun,1 Chunxia Yang,1 Yanfang Wang,1 Kerang Zhang1 1Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan 030001, People’s Republic of China; 2Department of Psychiatry, Shanxi Medical University, Taiyuan 030001, People’s Republic of ChinaCorrespondence: Yanfang Wang; Kerang ZhangDepartment of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan 030001, People’s Republic of ChinaTel +86-13934556065; +86-18834180209Email Wangyanfang12388@163.com; atomsxmu@vip.163.comObjective: To investigate the regional homogeneity (ReHo) between unipolar depression (UD) and bipolar disorder (BD), and to search for brain imaging markers for distinguishing UD and BD.Methods: A total of 58 patients who met the diagnosis criteria of UD in DSM–Ⅳ, 40 patients who met the diagnosis criteria of BD in DSM-Ⅳ and 54 healthy controls (HC) completed the resting-state functional magnetic resonance (rs-fMRI) scans. The ReHo of the three groups was compared and Pearson correlation analysis was performed between the ReHo values and the clinical symptoms.Results: (1) Significant differences were found in the right hippocampus, right parahippocampal gyrus, right Inferior orbitofrontal gyrus, right superior temporal gyrus, right inferior temporal gyrus, and right middle occipital gyrus across the three groups. (2) Compared to HC, the ReHo in the right parahippocampal gyrus in UD significantly increased. (3) When compared to HC, the ReHo in the right hippocampus in BD significantly increased. The ReHo in the right middle occipital gyrus decreased. (4) Compared to UD, BD exhibited significantly decreased ReHo in the right inferior temporal gyrus. No correlations were observed between the scores of 24-item Hamilton Depression Rating Scale (HDMD-24), Hamilton Anxiety Scale (HAMA), Young Mania Rating Scale (YMRS), and the ReHo values of altered brain regions between BD and UD.Conclusion: The results suggest that there was a considerable difference in the ReHo of brain among UD, BD, and HCs. ReHo in the right inferior temporal gyrus showed significant differences between BD and UD that might serve as neuroimaging markers to identify BD and UD.Keywords: bipolar depression, unipolar depression, rs-fMRI, regional homogeneity

Wenchang Yuan,*,1 Zhiwu Yu,*,2 Weiqi Song,*,3 Yanan Li,4 Zhiyuan Fang,1 Baizhen Zhu,1 Xiaomei Li,1 Hao Wang,5 Wei Hong,6 Ning Sun1,71The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, People’s Republic of China; 2Division of Laboratory Science, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, People’s Republic of China; 3School of Public Health, Guangzhou Medical University, Guangzhou 511436, People’s Republic of China; 4Department of Pharmacy, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, People’s Republic of China; 5School of Pharmacy, Ningxia Medical University, Yinchuan 750004, People’s Republic of China; 6School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan 750021, People’s Republic of China; 7State Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, People’s Republic of China*These authors contributed equally to this workBackground: The prevalence of drug-resistant bacterial infections urges the development of new antibacterial agents that possess a mechanism of action different from traditional antibiotics. FtsZ has been recognized as a key functional protein in bacterial cell division and it is currently believed to be a potential target for the development of novel antibacterial agents.Purpose: The primary aim of the study is to screen out an inhibitor targeting at FtsZ and followed to investigate its antibacterial activity and mode of action.Methods: Cell-based cell division inhibitory screening assay, antimicrobial susceptibility test, minimum bactericidal concentration assay, time-killing curve determination, FtsZ polymerization assay, GTPase activity assay, and molecular modeling were performed in the present study.Results: The screening study from a small library consisting of benzimidazole and indole derivatives discovered a compound (CZ74) with an indole-core structure. The compound exhibited strong cell division inhibitory effect. In addition, CZ74 shows high antibacterial potency against a number of tested Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. The minimum inhibitory concentration values obtained were within the range of 2–4 μg/mL. The results of biological study revealed that CZ74 at 2 μg/mL is able to disrupt FtsZ polymerization and inhibit GTPase activity and cell division. From molecular modeling study, CZ74 is found possibly binding into the interdomain cleft of FtsZ protein and then leads to inhibitory effects.Conclusion: This indole-cored molecule CZ74 could be a potential lead compound and could be further developed as a new generation of antibacterial agents targeting FtsZ to combat against multidrug-resistant bacteria.Keywords: indole-core-based derivative, antibacterial, cell division, FtsZ, antibiotic resistant

Ning Sun,1,2,* Dou Wang,3,* Guoqiang Yao,4 Xiaomei Li,1 Ting Mei,1 Xinke Zhou,1 Kwok-Yin Wong,2 Baishan Jiang,4 Zhiyuan Fang,11The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510500, People’s Republic of China; 2State Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong SAR, People’s Republic of China; 3Department of Hepatobiliary and Pancreatic Surgery, Shenzhen People‘s Hospital, Second Clinical Medical College of Jinan University, Shenzhen 518020, People’s Republic of China; 4Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, People’s Republic of China*These authors contributed equally to this work Background: The intraoperative visualization of tumor cells is a powerful modality for surgical treatment of solid tumors. Since the completeness of tumor excision is closely correlated with the survival of patients, probes that can assist in distinguishing tumor cells are highly demanded.Purpose: In the present study, a fluorescent probe JF1 was synthesized for imaging of tumor cells by conjugating a substrate of cathepsin B (quenching moiety) to Oregon Green derivative JF2 using a self-immolative linker.Methods: JF1 was then loaded into the folate-PEG modified CaCO3 nanoparticles. The folate receptor-targeted, pH-dependent, and cathepsin B activable CaCO3 nanoprobe was test in vitro and in vivo for tumor imaging.Results: CaCO3 nanoprobe demonstrated good stability and fast lighting ability in tumors under low pH conditions. It also showed lower fluorescence background than the single cathepsin B dependent fluorescent probe. The pH-dependent and cathepsin B controlled “turn-on” property enables precise and fast indication of tumor in vitro and in vivo.Conclusion: This strategy of controlled drug delivery enables in vivo imaging of tumor nodules with a high signal-to-noise ratio, which has great potential in surgical tumor treatment.Keywords: cathepsin B, activable probe, fluorescent probe, CaCO3 nanoparticle, tumor imaging

Na Sun,1,* Lingzhou Zhao,1,* Jingyi Zhu,2,* Yujie Li,1 Ningning Song,1 Yan Xing,1 Wenli Qiao,1 He Huang,2 Jinhua Zhao11Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, People’s Republic of China; 2State Key Laboratory of Material-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, People’s Republic of China*These authors contributed equally to this work Purpose: Polyethylenimine (PEI) has been widely used as a versatile template to develop multifunctional nanosystems for disease diagnosis and treatment. In this study, we manufactured iodine-131 (131I)-labeled PEI-entrapped gold nanoparticles (Au PENPs) as a novel nanoprobe for single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and radionuclide therapy.Materials and methods: PEI was PEGylated and sequentially conjugated with Buthus martensii Karsch chlorotoxin (BmK CT, a tumor-specific ligand which can selectively bind to MMP2), 3-(4′-hydroxyphenyl)propionic acid-OSu (HPAO), and fluorescein isothiocyanate to form the multifunctional PEI template for entrapment of Au NPs. Then, the PEI surface was radiolabeled with 131I via HPAO to produce the novel nanoprobe (BmK CT-Au PENPs-131I).Results: The synthesized multifunctional Au PENPs before and after 131I radiolabeling were well-characterized as follows: structure, X-ray attenuation coefficient, colloid stability, cytocompatibility, and radiochemical stability in vitro. Furthermore, BmK CT-Au PENPs-131I were suitable for targeted SPECT/CT imaging and radionuclide therapy of tumor cells in vitro and in a xenograft tumor model in vivo.Conclusion: The developed multifunctional Au PENPs are a promising theranostic platform for targeted imaging and treatment of different MMP2-overexpressing tumors.Keywords: polyethylenimine, BmK CT, gold nanoparticles, SPECT/CT imaging, radionuclide therapy

Wenchang Yuan,1,2,* Jianhua Liu,2,3,* Youchao Zhan,1,* Li Wang,2 Yanqiong Jiang,1 Yanling Zhang,1 Ning Sun,1,4 Ning Hou1,51Department of Clinical Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510700, People’s Republic of China; 2Department of Clinical Laboratory, General Hospital of Xinjiang Military Region, Urumqi 830001, People’s Republic of China; 3Department of Intensive Care Unit, the Fourth Hospital of Changsha, Changsha 410006, People’s Republic of China; 4State Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, People’s Republic of China; 5School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, People’s Republic of China*These authors contributed equally to this work Background: Staphylococcus aureus is among the most common causes of health care- and community-associated infections worldwide. The distributions of different S. aureus clones change over time and also vary geographically. The purpose of this study was to determine the molecular type and antimicrobial resistance profiles of clinical S. aureus strains isolated in Urumqi, Northwestern China.Methods: A total of 605 clinical S. aureus isolates were collected from Xinjiang Military General Hospital, in Urumqi. Protein A-encoding (spa) typing, multilocus sequence typing, staphylococcal chromosomal cassette mec typing, Panton-Valentine leucocidin (pvl) gene detection, and antimicrobial resistance profiling were performed.Results: Among these strains, 271 isolates (44.7%) were methicillin-resistant S. aureus (MRSA) and 334 (55.3%) were methicillin-susceptible S. aureus (MSSA). The MRSA strains consisted of 22 spa types and 14 sequence types (STs). ST239-MRSA-III-t030 (73.1%, 198/271) and ST59-MRSA-IV-t437 (11.8%, 32/271) were the most common, and ST22-MRSA-IV-t309 was the rarest (2.02%, 6/271). The MSSA strains consisted of 93 spa types and 29 STs. ST22, ST121, ST398, ST5, ST7, ST188, and ST15 were the main MSSA STs, and ST22-MSSA-t309 was most common (26.0%, 87/334). The pvl gene was present in 20.3% of all S.aureus strains, and 80.8% (88/99) of ST22-MSSA strains harbored the pvl gene. A total of 85.7% pvl-positive ST22-MSSA strains were spa t309 (85/99), and 87.5% of pvl-positive ST22-MSSA strains were from abscesses or wounds (skin and soft tissue infections). All ST239-MRSA strains were resistant to gentamicin (GEN), levofloxacin (LEV), ciprofloxacin (CIP), moxifloxacin (MXF), rifampicin (RIF), and tetracycline (TET). Among the ST59-MRSA strains, over 70.0% were resistant to erythromycin (ERY), clindamycin (CLI), and TET. ST22-MSSA remained susceptible to most antibiotics, but was resistant to PEN (97.0%), ERY (57.6%), and CLI (15.2%).Conclusion: Our major results indicated that the antimicrobial resistance profiles and pvl genes of S. aureus isolates from Urumqi were closely associated with clonal lineage. ST239-MRSA-III-t030 and pvl-positive ST22-MSSA-t309 were the most common clones in this region of Northwestern China.Keywords: Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, pvl gene, molecular typing

Penghong Liu,1,2 Gaizhi Li,1 Aixia Zhang,1 Ning Sun,1 Lijun Kang,2 Chunxia Yang,1 Yanfang Wang,1 Kerang Zhang11Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan 030001, People’s Republic of China; 2Department of Psychiatry, Shanxi Medical University, Taiyuan, 030001, People’s Republic of ChinaObjective: It is common that major depressive disorder (MDD) is accompanied by gastrointestinal (GI) symptoms. However, few studies have focused on the clinical characteristics and its possible mechanism, while brain gray matter (GM) structure is important in the pathogenesis of GI symptoms. In this study, we aimed to investigate the basic clinical characteristics and regional GM volume changes in MDD accompanied by GI symptoms.Method: Patients with MDD (n=49) and age, gender, and educational level-matched healthy controls (n=30) were recruited. Patients with MDD were divided into two groups based on the GI status: MDD with (n=27) and without (n=22) GI symptoms. The 24-item Hamilton Depression Rating Scale (HAMD) was administered. T1-weighted anatomical images were obtained and analyzed. Correlation analysis was used to identify the possible associations between changed regional GM volume and GI symptoms and depressive symptoms.Results: The HAMD reductive ratio for 2 weeks of treatment in the GI symptoms group was significantly higher than the non-GI symptoms group (P

Yongyu Bai,1 Kai Sun,1 Xiufang Xing,1 Fengjiang Zhang,1 Na Sun,2 Yibo Gao,1 Ling Zhu,3 Jie Yao,3 Junqiang Fan,3 Min Yan11Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of China; 2Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 221004, People’s Republic of China; 3Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, People’s Republic of ChinaObjective: To study the general efficacy of hydromorphone as a systemic analgesic in postoperative pain management following single-port video-assisted thoracoscopic surgery (VATS) and to explore the optimal administration regimen.Methods: A prospective, randomized, double-blind study was designed and conducted in a tertiary hospital. In total, 157 valid patients undergoing single-port VATS were randomly allocated into three groups. A total of 53 patients received morphine bolus only for postoperative analgesia (Group Mb); 51 patients received a hydromorphone background infusion plus bolus (Group Hb + i), and 53 patients received a hydromorphone bolus only (Group Hb). The primary outcomes were patient-reported static and dynamic pain levels; the secondary outcomes included side effects, sleep quality, and recovery indexes.Results: Patients in Group Hb + i experienced lower pain intensity (approximately 10 out of 100 on the visual analog scale) in both static pain and dynamic pain in the days following surgery (P

He W, Luo Y, Liu JP, et al. Clin Interv Aging. 2020;15:1809– 1820. The authors have advised affiliation 2 on page 1809 is incorrect, the text “Peking Union Medical College” should read “Graduate School of Peking Union Medical College”. The authors apologize for this error.Read the original article

Xiao-Ji Lin,1 Li-Meng Cai,2 Zi-Jun Qian,2 Chen-Yi Wang,2 Ni Sun,1 Xiao-Hai Sun,1 He Huang,1 Wen-Jian Guo,1 Hai-Yan Lin,1 Rong-Xin Yao1 1Department of Haematology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, 2Science and Technology of Students Association, The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China Objective: This study aims to investigate ectopic expression of histone deacetylase 6 (HDAC6) in diffuse large B-cell lymphoma (DLBCL). Methods: This study analyzed patients with DLBCL (n=132) and reactive lymph node hyperplasia (n=32) diagnosed in our hospital from December 2007 to May 2016. Correlation between HDAC6 expression and clinical pathologic features was analyzed by χ2 test. The significant differences between the 5-year overall survival (OS) or progression-free survival (PFS) and high HDAC6 expression as well as DLBCL clinic-pathological features including age, International Prognostic Index (IPI) score, Eastern Cooperative Oncology Group score, lactate dehydrogenase (LDH), and germinal center B-cell-like were assessed by univariate and multivariate analyses. Results: HDAC6 high-expression percentage in DLBCL was significantly higher than that in the control group. The proportion of IPI score of 0–2, 5-year OS, and PFS in the high-expression group, which had lower percentage of patients with increased LDH and β2-microglobulin, were significantly higher than those in the low-expression group. Moreover, HDAC6 mRNA expression in HDAC6 protein low expression was markedly lower than that in protein high expression. The multivariate analysis demonstrated that HDAC6 high expression was an independent prognostic factor for patients with DLBCL. Conclusion: HDAC6 high expression might be a prognostic factor for DLBCL. Keywords: diffuse large B-cell lymphoma, HDAC6, prognosis

Xiwen Liao,1,* Rui Huang,2,* Xiaoguang Liu,1,3 Chuangye Han,1 Long Yu,1,4 Shijun Wang,5 Na Sun,2 Bopei Li,6 Xin Ning,7 Tao Peng1 1Department of Hepatobiliary Surgery, 2Department of Hematology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 3Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, 4Department of Hepatobiliary and Pancreatic Surgery, 5Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 6Department of Gastrointestinal Surgery, 7Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China *These authors contributed equally to this work Background: Alcohol dehydrogenase (ADH) isoenzymes have been reported as a potential diagnostic marker for pancreatic cancer, but their prognostic value in pancreatic cancer remains unclear. The aim of this investigation was to identify the prognostic value of ADH genes in human patients with pancreatic adenocarcinoma (PAAD).Materials and methods: An RNA sequencing dataset and corresponding survival profiles of PAAD were obtained from The Cancer Genome Atlas. Survival analysis and gene set enrichment analysis were used to investigate the prediction value and potential mechanism of ADH genes in PAAD prognosis.Results: Survival analysis of ADH genes suggests that a high expression of ADH1A (adjusted P=0.037, adjusted hazard ratio [HR] =0.627, 95% CI =0.404–0.972) and ADH6 (adjusted P=0.018, adjusted HR =0.588, 95% CI =0.378–0.914) were associated with a significantly decreased risk of death, while a high expression of ADH5 was associated with a significantly increased risk of death (adjusted P=0.043, adjusted HR =1.564, 95% CI =1.013–2.414). Joint effects analysis of three ADH gene prognostic markers suggests that the prognosis difference for any marker combination was more significant than that for any individual marker. The potential mechanism of ADH1A and ADH6 in PAAD prognosis was that a high expression of ADH1A and ADH6 was involved in the P450 pathway and biological processes, while high ADH5 expression was involved in transforming growth factor β regulation-related pathways and biological processes, Wnt, the cell cycle, ErbB, and mitogen-activated protein kinase signaling pathways.Conclusion: Our data suggest that ADH1A, ADH5, and ADH6 expression may be potential prognostic markers of PAAD and in combination have a strong interaction and better predictive value for PAAD prognosis. Keywords: prognostic, alcohol dehydrogenase, pancreatic adenocarcinoma, TCGA, GSEA

Shu Liu,1,* Fuxi Zhen,2,* Nana Sun,3 Jiayan Chen,1 Yuandong Cao,1 Sheng Zhang,1 Hongyan Cheng,4 Xiaolin Ge,1 Xinchen Sun1 1Department of Radiation Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Thoracic Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Radiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 4Department of General Internal Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China *These authors contributed equally to this work Purpose: Previous studies have demonstrated that apparent diffusion coefficient (ADC) values measured by magnetic resonance imaging have prognostic value in patients with esophageal squamous cell carcinoma (ESCC). However, the role of ADC needs to be validated in a cohort of Chinese ESCC patients. This study assessed the role of ADC in predicting the outcome of patients with ESCC treated only by chemoradiation in the People’s Republic of China. Patients and methods: Seventy-three patients with local advanced ESCC were retrospectively analyzed in this study; none of the patients underwent surgery before or after chemoradiation. The ADC values of the primary tumors were determined by magnetic resonance imaging. The ADC values were then correlated with clinicopathological and other radiological parameters. Survival analysis was carried out to determine if ADC had an impact on survival of these patients. Results: The median ADC value of the esophageal cancer tissue was 1.256*10-3 mm2/sec (range: 0.657–2.354*10-3 mm2/sec, interquartile range 0.606*10-3 mm2/sec). No clinicopathological or radiological parameters were associated with the ADC values except the sites of tumor tissues. ADC

Staphylococcus aureus produces membrane-derived vesicles (MVs), which share functional properties to outer membrane vesicles. Atomic force microscopy revealed that S. aureus-derived MVs are associated with the bacterial surface or released into the surrounding environment depending on bacterial growth conditions. By using a comparative proteomic approach, a total of 131 and 617 proteins were identified in MVs isolated from S. aureus grown in Luria-Bertani and brain-heart infusion broth, respectively. Purified S. aureus MVs derived from the bacteria grown in either media induced comparable levels of cytotoxicity and neutrophil-activation. Administration of exogenous MVs increased the resistance of S. aureus to killing by whole blood or purified human neutrophils ex vivo and increased S. aureus survival in vivo. Finally, immunization of mice with S. aureus-derived MVs induced production of IgM, total IgG, IgG1, IgG2a, and IgG2b resulting in protection against subcutaneous and systemic S. aureus infection. Collectively, our results suggest S. aureus MVs can influence bacterial–host interactions during systemic infections and provide protective immunity in murine models of infection.

Protein lysine acetylation is recognized as an important reversible post translational modification in all domains of life. While its primary roles appear to reside in metabolic processes, lysine acetylation has also been implicated in regulating pathogenesis in bacteria. Several global lysine acetylome analyses have been carried out in various bacteria, but thus far there have been no reports of lysine acetylation taking place in the important human pathogen Vibrio cholerae. In this study, we analyzed the lysine acetylproteome of the human pathogen V. cholerae V52. By applying a combination of immuno-enrichment of acetylated peptides and high resolution mass spectrometry, we identified 3,402 acetylation sites on 1,240 proteins. Of the acetylated proteins, more than half were acetylated on two or more sites. As reported for other bacteria, we observed that many of the acetylated proteins were involved in metabolic and cellular processes and there was an over-representation of acetylated proteins involved in protein synthesis. Of interest, we demonstrated that many global transcription factors such as CRP, H-NS, IHF, Lrp and RpoN as well as transcription factors AphB, TcpP, and PhoB involved in direct regulation of virulence in V. cholerae were acetylated. In conclusion, this is the first global protein lysine acetylome analysis of V. cholerae and should constitute a valuable resource for in-depth studies of the impact of lysine acetylation in pathogenesis and other cellular processes.

Pei-Li Zhu,1 Si-Yuan Pan,1 Shu-Feng Zhou,2 Yi Zhang,1 Xiao-Yan Wang,1 Nan Sun,1 Zhu-Sheng Chu,1 Zhi-Ling Yu,3 Kam-Ming Ko41Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, People’s Republic of China; 4Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People’s Republic of ChinaBackground: Currently, combined therapy using herbs and synthetic drugs has become a feasible therapeutic intervention against some diseases. The purpose of this study was to assess the effects of supplementation with fenofibrate (FF), a chemical drug used for the treatment of hyperlipidemia, and the aqueous extract of Schisandrae Fructus (SF, a Chinese herb) pulp (AqSF-P) or an SF-related synthetic analog, bicyclol (BY), on serum/hepatic lipid levels and liver status in normal and hypercholesterolemic (HCL) mice.Methods: Male mice obtained from the Institute of Cancer Research (ICR) were fed on a normal diet (ND) or high cholesterol/bile salt (0.5%/0.15%, w/w) diet (HCBD) containing FF (0.03% or 0.1%, w/w) with or without AqSF-P (0.3%-9.0%, based on crude herbal material, w/w) or BY (0.025%, w/w) for 10 days. Then serum lipid levels and alanine aminotransferase (ALT) activity, as well as hepatic triglyceride (TG), total cholesterol (TC), and glucose levels, were measured.Results: Oral supplementation with FF significantly reduced serum and hepatic TG, TC, and hepatic glucose levels (approximately 79%) in mice fed with ND or HCBD. FF supplementation combined with AqSF-P or BY increased FF-induced reduction in hepatic TC and TG contents in ND-fed mice (up to 67%) and in HCBD-fed mice (up to 54%), when compared with FF supplementation alone. Hepatic glucose-lowering effect of FF was enhanced (up to 19%) by AqSF-P cosupplementation in both normal and HCL mice. FF supplementation enhanced the excretion of fecal TC (by 75%) in mice fed with HCBD. Fecal TC contents were increased by 14%/9% in the combination therapy with FF and AqSF-P in ND-/HCBD-fed mice. Serum ALT activity was elevated by 45% in HCBD-fed mice. FF caused a significant increase in ALT activity by 198% and 120% in normal and HCL mice, respectively. BY markedly attenuated the ALT activity by 54% in mice fed with ND supplemented with 0.1% FF and by 42% in mice fed with HCBD supplemented with 0.03% FF.Conclusion: AqSF-P cosupplementation augmented the hepatic lipid-/glucose-lowering effects of FF. BY ameliorated FF-induced liver injury in normal and HCL mice.Keywords: bicyclol, hepatotoxicity, synergist, fatty liver disease, fat index, interaction

Bacterial membrane vesicle (MV) production has been mainly studied in Gram-negative species. In this study, we show that Listeria monocytogenes, a Gram-positive pathogen that causes the food-borne illness listeriosis, produces MVs both in vitro and in vivo. We found that a major virulence factor, the pore-forming hemolysin listeriolysin O (LLO), is tightly associated with the MVs, where it resides in an oxidized, inactive state. Previous studies have shown that LLO may induce cell death and autophagy. To monitor possible effects of LLO and MVs on autophagy, we performed assays for LC3 lipidation and LDH sequestration as well as analysis by confocal microscopy of HEK293 cells expressing GFP-LC3. The results revealed that MVs alone did not affect autophagy whereas they effectively abrogated autophagy induced by pure LLO or by another pore-forming toxin from Vibrio cholerae, VCC. Moreover, Listeria monocytogenes MVs significantly decreased Torin1-stimulated macroautophagy. In addition, MVs protected against necrosis of HEK293 cells caused by the lytic action of LLO. We explored the mechanisms of LLO-induced autophagy and cell death and demonstrated that the protective effect of MVs involves an inhibition of LLO-induced pore formation resulting in inhibition of autophagy and the lytic action on eukaryotic cells. Further, we determined that these MVs help bacteria to survive inside eukaryotic cells (mouse embryonic fibroblasts). Taken together, these findings suggest that intracellular release of MVs from L. monocytogenes may represent a bacterial strategy to survive inside host cells, by its control of LLO activity and by avoidance of destruction from the autophagy system during infection.

Yi Zhang,1 Si-Yuan Pan,1 Shu-Feng Zhou,2 Xiao-Yan Wang,1 Nan Sun,1 Pei-Li Zhu,1 Zhu-Sheng Chu,1 Zhi-Ling Yu,3 Kam-Ming Ko4 1Department of Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3School of Chinese Medicine, Hong Kong Baptist University, 4Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, People's Republic of China Background: Schisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice. Methods: Institute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125–2 g/kg) or SFO (0.3–5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6–120 hours postdosing. Results: Serum ALT activity was elevated by 60%, with maximum effect (Emax) =45.77 U/L and affinity (KD) =1.25 g/kg at 48–96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (Emax =2.30 nmol/mg protein and KD =0.41 g/kg) and 22% (Emax =1.42 nmol/mg protein and KD =2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%–60% (Emax =11.01, KD =0.68 g/kg) and 8%–32% (Emax =9.88, KD =4.47 g/kg) at 12–120 hours and 24–120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%–158% and 35%–85%, respectively, at 12–96 hours and 6–48 hours after Sch B and SFO treatment, respectively. The values of Emax and KD for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 µmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of Emax =5.50/4.60 mmol/L and KD =0.43/2.84 g/kg, respectively. Conclusion: The findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time-dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The Emax and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO. Keywords: pharmacodynamics, hepatomegaly, alanine aminotransaminase, affinity, maximum effect

Antibiotic use on animals demonstrates improved growth regardless of whether or not there is clinical evidence of infectious disease. Antibiotics used for trachoma control may play an unintended benefit of improving child growth.In this sub-study of a larger randomized controlled trial, we assess anthropometry of pre-school children in a community-randomized trial of mass oral azithromycin distributions for trachoma in Niger. We measured height, weight, and mid-upper arm circumference (MUAC) in 12 communities randomized to receive annual mass azithromycin treatment of everyone versus 12 communities randomized to receive biannual mass azithromycin treatments for children, 3 years after the initial mass treatment. We collected measurements in 1,034 children aged 6-60 months of age.We found no difference in the prevalence of wasting among children in the 12 annually treated communities that received three mass azithromycin distributions compared to the 12 biannually treated communities that received six mass azithromycin distributions (odds ratio = 0.88, 95% confidence interval = 0.53 to 1.49).We were unable to demonstrate a statistically significant difference in stunting, underweight, and low MUAC of pre-school children in communities randomized to annual mass azithromycin treatment or biannual mass azithromycin treatment. The role of antibiotics on child growth and nutrition remains unclear, but larger studies and longitudinal trials may help determine any association.

Clinical examination of trachoma is used to justify intervention in trachoma-endemic regions. Currently, field graders are certified by determining their concordance with experienced graders using the kappa statistic. Unfortunately, trachoma grading can be highly variable and there are cases where even expert graders disagree (borderline/marginal cases). Prior work has shown that inclusion of borderline cases tends to reduce apparent agreement, as measured by kappa. Here, we confirm those results and assess performance of trainees on these borderline cases by calculating their reliability error, a measure derived from the decomposition of the Brier score.We trained 18 field graders using 200 conjunctival photographs from a community-randomized trial in Niger and assessed inter-grader agreement using kappa as well as reliability error. Three experienced graders scored each case for the presence or absence of trachomatous inflammation-follicular (TF) and trachomatous inflammation-intense (TI). A consensus grade for each case was defined as the one given by a majority of experienced graders. We classified cases into a unanimous subset if all 3 experienced graders gave the same grade. For both TF and TI grades, the mean kappa for trainees was higher on the unanimous subset; inclusion of borderline cases reduced apparent agreement by 15.7% for TF and 12.4% for TI. When we assessed the breakdown of the reliability error, we found that our trainees tended to over-call TF grades and under-call TI grades, especially in borderline cases.The kappa statistic is widely used for certifying trachoma field graders. Exclusion of borderline cases, which even experienced graders disagree on, increases apparent agreement with the kappa statistic. Graders may agree less when exposed to the full spectrum of disease. Reliability error allows for the assessment of these borderline cases and can be used to refine an individual trainee's grading.