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Yuqin Pan,1,* Bangshun He,1,* Huiling Sun,1 Tao Xu,1 Bei Pan,1 Shukui Wang,1 Yanping Mei2 1General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, 210006, People’s Republic of China; 2Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shukui WangGeneral Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People’s Republic of ChinaEmail shukwang@163.comYanping MeiDepartment of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, People’s Republic of ChinaEmail 4940556@qq.comBackground: Paraoxonases (PONs) are a family of orphan enzymes with multiple functions, including anti-inflammatory, antioxidative, antiatherogenic activities. Studies have suggested that genetic variations in PON1 and PON2 are associated with ischemic stroke (IS) risk; however, the conclusion remains unclear in the Chinese population.Methods: To investigate the susceptibility of genetic variations in PON1 and PON2 to risk of IS and its subtypes, this case–control study was carried out on a Chinese population comprising 300 IS patients and 300 healthy controls. Genotypes of six genetic variations in PON1 and PON2 were identified with an improved multiplex ligase detection–reaction technique.Results: PON1 rs662 was associated with increased risk of IS (CT vs. TT — ORadjusted 1.79, 95% CI 1.08– 2.97; p=0.025). Stratified analysis for patients by sex revealed that the significant association of PON1 rs662 with IS risk was maintained in the male cohort (CT vs. TT — ORadjusted 2.59, 95% CI 1.29– 5.21 [p=0.009]; CT/CC vs. TT — ORadjusted 2.03, 95% CI 1.05– 3.93 [p=0.036]), but not in the female cohort. Analysis according to IS subtype revealed that PON1 rs662 genetic variation was an increased risk in the subcohort of patients with large-artery atherosclerosis (CT/CC vs. TT — ORadjusted 2.31, 95% CI 1.09– 4.91; p=0.029), but not in patients with other types of IS.Conclusion: This study suggested that PON1 rs662 presented a potential risk of IS, especially for males, and this association was more obvious for large-artery atherosclerosis.Keywords: ischemic stroke, genetic variation, PON1, PON2

Jie Gao,1,2,* Xiaohan Chen,1,* Tianjun Ma,1,* Bin He,1 Peng Li,1 Yucheng Zhao,1 Yuejin Ma,1 Jianhua Zhuang,1 You Yin1 1Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People’s Republic of China; 2Institute of Translational Medicine, Shanghai University, Shanghai 200444, People’s Republic of China*These authors contributed equally to this workCorrespondence: You Yin; Jianhua ZhuangDepartment of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People’s Republic of ChinaTel/Fax +86-21-63586818Email yinyou179@163.com; jianhuazh11@126.comPurpose: Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests as abnormal behavior and a progressive decline in memory. Although the pathogenesis of AD is due to the excessive deposition of amyloid β protein (Aβ) outside the neurons in the brain, evidence suggests that tau proteins may be a better target for AD therapy. In neurodegenerative diseases, a decrease in autophagy results in the failure to eliminate abnormally deposited or misfolded proteins. Therefore, induction of autophagy may be an effective way to eliminate tau proteins in the treatment of AD. We investigated the effects of polyethylene glycol (PEG)-ceramide nanomicelles on autophagy and on tau proteins in N2a, a murine neuroblastoma metrocyte cell line.Methods: Ceramide is a sphingolipid bioactive molecule that induces autophagy. PEG-ceramide is a polymer that is composed of the hydrophobic chain of ceramide and the hydrophilic chain of PEG-2000. In this study, we prepared PEG-ceramide nanomicelles that were 10– 20 nm in size and had nearly neutral zeta potential.Results: The results show that PEG-ceramide nanomicelles caused an increase in the LC3-II/LC3-I ratio, while p62 protein levels decreased. Confocal microscopy revealed a significant increase in the number of dots corresponding to autophagosomes and autolysosomes, which indicated autophagic activation. Moreover, PEG-ceramide nanomicelles induced tau degradation in N2a cells through autophagy.Conclusion: In summary, we have confirmed that PEG-ceramide nanomicelles enhanced autophagic flux and degraded overexpressed human tau proteins in N2a cells by regulating the autophagy pathway. Thus, PEG-ceramide nanomicelles show great promise as agents to induce autophagy and degrade tau proteins in the treatment of AD.Keywords: Alzheimer’s disease, autophagosomes, lysosome, nano-carrier, autophagic flux

Zakia Belhadj,1 Bing He,1 Jijun Fu,2 Hua Zhang,1 Xueqing Wang,1 Wenbing Dai,1 Qiang Zhang1 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People’s Republic of China; 2School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, People’s Republic of ChinaCorrespondence: Qiang Zhang; Wenbing Dai Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery SystemsState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, People’s Republic of ChinaTel +86-10-82802791; Tel +86-10-82802791Email zqdodo@bjmu.edu.cn; daiwb@bjmu.edu.cnPurpose: The mononuclear phagocyte system (MPS) presents a formidable obstacle that hampers the delivery of various nanopreparations to tumors. Therefore, there is an urgent need to improve the off-MPS targeting ability of nanomedicines. In the present study, we present a novel preconditioning strategy to substantially increase the circulation times and tumor targeting of nanoparticles by regulating nanocarrier-MPS interactions.Methods: In vitro, the effect of different vacuolar H+-ATPase inhibitors on macrophage uptake of targeted or nontargeted lipid vesicles was evaluated. Specifically, the clinically approved proton-pump inhibitor esomeprazole (ESO) was selected as a preconditioning agent. Then, we further investigated the blocking effect of ESO on the macrophage endocytosis of nanocarriers. In vivo, ESO was first intravenously administered into A549-tumor-bearing nude mice, and 24 h later, the c(RGDm7)-modified vesicles co-loaded with doxorubicin and gefitinib were intravenously injected.Results: In vitro, ESO was found to reduce the interactions between macrophages and c(RGDm7)-modified vesicles by interfering with the latter’s lysosomal trafficking. Studies conducted in vivo confirmed that ESO pretreatment greatly decreased the liver and spleen distribution of the targeted vesicles, enhanced their tumor accumulation, and improved the therapeutic outcome of the drug-loaded nanomedicines.Conclusion: Our findings indicate that ESO can regulate the nanoparticle-MPS interaction, which provides a feasible option for enhancing the off-MPS targeting of nanomedicines.Keywords: mononuclear phagocyte system, preconditioning strategy, esomeprazole, V-ATPase inhibitors, targeted lipid vesicles

Zeying Li,1,2 Bin He,2 Xu Sun2 1School of Computer Information Engineering, Hanshan Normal University, Chaozhou 521000, People’s Republic of China; 2School of Management, Guangdong University of Technology, Guangzhou 510520, People’s Republic of ChinaCorrespondence: Xu SunSchool of Management, Guangdong University of Technology, 161 Ying Long Road, Guangzhou 510520, People’s Republic of ChinaTel +86 158 133 613 64Fax +86 020 870 835 65Email tsunxu@gdut.edu.cnPurpose: From the perspective of affective events theory, the present study examines whether two distinct categories stressors (challenge-hindrance stressors) have different effects (hindrance or promotion) on abusive supervision.Materials and Methods: The data of 203 pairs of supervisor–subordinate have been collected from 12 different Chinese enterprises.We first conducted confirmatory factor analyses (CFA) in Lisrel software to test the model’s validity. And then, we used the descriptive statistics to example the correlations of variables. Finally, we conducted hierarchical regression analysis and bootstrap methods to test hypotheses.Results: The finding shows that two distinct categories stressors have different indirect effects (hindrance or promotion) on abusive supervision. Specifically, challenge stressors reduce abusive supervision through positive affective experience, while hindrance stressors increase abusive supervision through negative affective experience. In addition, locus of control plays a first-stage moderated-mediation role in the indirect effect of challenge stressors on abusive supervision and in the indirect effect of hindrance stressors on abusive supervision.Conclusion: This study offers some comprehensive insights for why and when challenge stressors and hindrance stressors have different effects on abusive supervision. This study extends the current literature by directly testing two different underlying psychological mechanisms (resource acquisition and resource depletion), which are responsible for the different effects of challenge stressors and hindrance stressors. Also, individuals’ cognitive attribution tendency is confirmed as boundary conditions of the direct effect of work stressors on affective experience and indirect effects of work stressors on abusive supervision.Keywords: challenge-hindrance stressors, affective experience, locus of control, abusive supervision, affective events theory

Chenxia Guo, Xiaoyan Sun, Wenqi Diao, Ning Shen,* Bei He* Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bei HePeking University Third Hospital, Beijing, People’s Republic of ChinaTel +86 13910125933Email puh3_hb@bjmu.edu.cnNing ShenPeking University Third Hospital, People’s Republic of ChinaTel +86 13693638871Email shenning1972@126.comAbstract: Short-term exposure to major air pollutants can increase the risk of acute exacerbation in chronic obstructive pulmonary disease (COPD) patients. However, evidence on the mechanism of acute exacerbation of COPD (AECOPD) caused by air pollutants is still limited. A total of 78 patients with stable COPD and 58 healthy controls were recruited in Peking University Third Hospital in China from December 2014 to January 2015. The correlation and lag effect over 7 days (lag1– 7) of 6 air pollutants with clinical symptoms and inflammatory markers in induced sputum were analyzed. PM2.5, NO2 and CO were positively correlated with the COPD assessment test (CAT) score at lag 5, PM10 was positively correlated with the CAT score at lag 3, MMP-9 and IL-8 were positively correlated with PM2.5, PM10 and NO2 at lag 2, and CO was positively correlated with each other marker at lag 4. Short-term exposure to PM2.5, PM10, NO2, and CO can cause a neutrophil-mediated airway inflammatory response, followed by increased clinical symptoms. If the PM2.5, PM10, NO2 and CO exposure levels increase during air pollution monitoring, the early usage of medication or reduction of exposure to pollutants can effectively reduce the clinical symptoms of patients.Keywords: chronic obstructive pulmonary disease, air pollution, matrix metalloproteinase 9, interleukin 8, induced sputum

Yujie Shi,1,* Dong Peng,2,* Dan Wang,1 Zongmin Zhao,3 Binlong Chen,1 Bing He,1 Yukun Zhu,2 Kun Wang,2 Jie Tian,2 Qiang Zhang1 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People’s Republic of China; 2CAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China; 3School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA*These authors contributed equally to this workCorrespondence: Jie TianCAS Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, People’s Republic of ChinaTel +86-10-82618465Email tian@ieee.orgQiang ZhangBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, People’s Republic of ChinaTel/Fax +86-10-82802791Email zqdodo@bjmu.edu.cnIntroduction: Though widely studied for biomedical applications, the lack of current systemic studies on the in vivo fate of single-walled carbon nanohorns (SWCNHs) largely restricts their further applications, as real-time monitoring of their biodistribution remains a big challenge. Here, we aim to customize a label-free multispectral optoacoustic tomography (MSOT) method and systematically survey the fate of oxidized SWCNHs (SWCNHox) following different exposure routes by whole body imaging.Methods: Mice were given a suspension of SWCNHox with an average size of 136.4 nm via four different administration routes, and then imaged by MSOT.Results: After oral gavage, SWCNHox were mainly distributed in the gastrointestinal tract then excreted through the gut. Compared with the observation post first dosing, the accumulation of SWCNHox in the gastrointestinal tract was not obvious even after four-time oral gavage. Almost no SWCNHox were found at detectable levels in kidney, liver, blood and spleen. Following intravenous (iv) injection, SWCNHox were mainly presented and persisted in the spleen and liver, while very little in the kidney and almost none detectable in the intestine. SWCNHox accumulated significantly in the liver and spleen after four IV administrations. Following hypodermic and intramuscular injections, almost no SWCNHox could cross biological barriers and transport to the spleen, kidney or liver, likely due to their very low absorption rate. Almost all SWCNHox remained around the injection sites. For the first time, we have systematically investigated the in vivo fate of SWCNHs in a label-free and real-time manner.Conclusion: The findings of this study provide insights into the selection of appropriate exposure routes for potential biomedical applications of carbon nanomaterials.Keywords: MSOT imaging, SWCNHox, exposure routes, biodistribution, in vivo fate

Cell fates are determined by specific transcriptional programs. Here we provide evidence that the transcriptional coactivator, Mediator 1 (Med1), is essential for the cell fate determination of ectodermal epithelia. Conditional deletion of Med1 in vivo con

Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy.

Wenqi Diao1, Wassim W Labaki2, MeiLan K Han2, Larisa Yeomans3, Yihan Sun4, Zyad Smiley4, Jae Hyun Kim3, Cora McHugh4, Pingchao Xiang5, Ning Shen6, Xiaoyan Sun6, Chenxia Guo6, Ming Lu6, Theodore J Standiford2, Bei He*,7, Kathleen A Stringer*,2,4 1Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, MI, USA; 3Biochemical Nuclear Magnetic Resonance Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; 4NMR Metabolomics Laboratory, Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; 5Department of Respiratory and Critical Care Medicine, Shou-Gang Hospital Affiliated to Peking University, Beijing, People’s Republic of China; 6Department of Respiratory Medicine, Peking University Third Hospital, Beijing 100191, People’s Republic of China; 7Department of Respiratory Medicine, Peking University Health Sciences Center, Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kathleen A StringerCollege of Pharmacy, University of Michigan, Ann Arbor, MI 48104, USATel +1 734 647 4775Email stringek@umich.eduBackground: Chronic obstructive pulmonary disease (COPD) is a systemic condition that is too complex to be assessed by lung function alone. Metabolomics has the potential to help understand the mechanistic underpinnings that contribute to COPD pathogenesis. Since blood metabolomics may be affected by sex and body mass index (BMI), the aim of this study was to determine the metabolomic variability in male smokers with and without COPD who have a narrow BMI range.Methods: We compared the quantitative proton nuclear magnetic resonance acquired serum metabolomics of a male Chinese Han population of non-smokers without COPD, and smokers with and without COPD. We also assessed the impact of smoking status on metabolite concentrations and the associations between metabolite concentrations and inflammatory markers such as serum interleukin-6 and histamine, and blood cell differential (%). Metabolomics data were log-transformed and auto-scaled for parametric statistical analysis. Mean normalized metabolite concentration values and continuous demographic variables were compared by Student’s t-test with Welch correction or ANOVA with post-hoc Tukey’s test, as applicable; t-test p-values for metabolomics data were corrected for false discovery rate (FDR). A Pearson association matrix was built to evaluate the relationship between metabolite concentrations, clinical parameters and markers of inflammation.Results: Twenty-eight metabolites were identified and quantified. Creatine, glycine, histidine, and threonine concentrations were reduced in COPD patients compared to non-COPD smokers (FDR ≤15%). Concentrations of these metabolites were inversely correlated with interleukin-6 levels. COPD patients had overall dampening of metabolite concentrations including energy-related metabolic pathways such as creatine metabolism. They also had higher histamine levels and percent basophils compared to smokers without COPD.Conclusion: COPD is associated with alterations in the serum metabolome, including a disruption in the histidine-histamine and creatine metabolic pathways. These findings support the use of metabolomics to understand the pathogenic mechanisms involved in COPD.Trial registration www.clinicaltrials.gov, NCT03310177.Keywords: China, metabolomics, histidine, energy homeostasis, inflammation, chronic obstructive pulmonary disease

Bei Pan,1,* Bangshun He,1,* Xueni Xu,1,2 Xiangxiang Liu,1 Tao Xu,1 Mu Xu,1 Xiaoxiang Chen,1,2 Kaixuan Zeng,1,2 Kang Lin,3 Xiuxiu Hu,1,2 Li Sun,4 Yuqin Pan,1 Huiling Sun,1 Shukui Wang,1,3,51General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People’s Republic of China; 2School of Medicine, Southeast University, Nanjing 210009, People’s Republic of China; 3Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, People’s Republic of China; 4Department of Laboratory Medicine, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, People’s Republic of China; 5Jiangsu Collaborative Innovation Center on Cancer Personalized Medicine, Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this work Purpose: To date, increasing evidences have demonstrated that the aberrant expression of miR-371–3 cluster has been verified in various cancers and could be potentially used as a biomarker for tumor diagnosis and prognosis. To explore the role of miR-371–3 cluster in tumor diagnosis and prognosis, we conducted this study based on the published data.Methods: We searched electronic databases (PubMed, EMBASE and Web of Science databases) (Jan 1, 2007 to Jun 1, 2018). The pooled sensitivity, specificity and area under the curve (AUC) of summary receiver operator characteristic (SROC) curve were used for diagnostic values, meanwhile the pooled hazard ration (HR) and 95% CI were used to explore the prognosis capacity of miR-372 and miR-373. In addition, the publication bias of the enrolled studies was tested and a sensitivity analysis of each study was performed to evaluate the stability of the pooled result.Results: A total of eleven eligible studies containing six eligible studies containing 870 participants for diagnosis and 1218 cancer cases for prognosis were selected for this study. For diagnosis, the pooled results revealed that the miR-371 (sensitivity: 0.85, specificity: 0.92, AUC: 0.92) and miR-373 (sensitivity: 0.81, specificity: 0.93, AUC: 0.93) could be used as diagnostic biomarkers. For prognosis, we observed that elevated miR-372 indicated poor prognosis (HR=2.31, 95% CI: 1.04–5.14), especially in the cutoff value subgroup of median (HR=2.62, 95% CI: 1.54–4.46). In addition, pooled results showed that expression of miR-373 was not related to prognosis because of the significant heterogeneity, and the high miR-373 expression presented favorable prognosis in Asians (HR=0.34, 95% CI: 0.23–0.50) after omitting the study of heterogeneity origin.Conclusion: The current studies demonstrated that miR-371 and miR-373 could be predictive tumor diagnostic biomarkers and the expression of miR-372 and miR-373 may indicate prognosis of cancer patients.Keywords: cancer, miR-371, miR-372, miR-373, diagnosis, prognosis, biomarkers

Zhongqi Li,1,2 Zhizhong Wang,3 Huan Song,1 Qiao Liu,1 Biyu He,1 Peiyi Shi,1 Ye Ji,1 Dian Xu,1 Jianming Wang1,21Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China; 2Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Epidemiology and Health Statistic, School of Public Health, NingXia Medical University, Yinchuan, People’s Republic of ChinaObjective: To investigate suitable forecasting models for tuberculosis (TB) in a Chinese population by comparing the predictive value of the autoregressive integrated moving average (ARIMA) model and the ARIMA-generalized regression neural network (GRNN) hybrid model.Methods: We used the monthly incidence rate of TB in Lianyungang city from January 2007 through June 2016 to construct a fitting model, and we used the incidence rate from July 2016 to December 2016 to evaluate the forecasting accuracy. The root mean square error (RMSE), mean absolute percentage error (MAPE), mean absolute error (MAE) and mean error rate (MER) were used to assess the performance of these models in fitting and forecasting the incidence of TB.Results: The ARIMA (10, 1, 0) (0, 1, 1)12 model was selected from plausible ARIMA models, and the optimal spread value of the ARIMA-GRNN hybrid model was 0.23. For the fitting dataset, the RMSE, MAPE, MAE and MER were 0.5594, 11.5000, 0.4202 and 0.1132, respectively, for the ARIMA (10, 1, 0) (0, 1, 1)12 model, and 0.5259, 11.2181, 0.3992 and 0.1075, respectively, for the ARIMA-GRNN hybrid model. For the forecasting dataset, the RMSE, MAPE, MAE and MER were 0.2805, 8.8797, 0.2261 and 0.0851, respectively, for the ARIMA (10, 1, 0) (0, 1, 1)12 model, and 0.2553, 5.7222, 0.1519 and 0.0571, respectively, for the ARIMA-GRNN hybrid model.Conclusions: The ARIMA-GRNN hybrid model was shown to be superior to the single ARIMA model in predicting the short-term TB incidence in the Chinese population, especially in fitting and forecasting the peak and trough incidence.Keywords: model, ARIMA, GRNN, tuberculosis, incidence, forecasting

Huan Song,1,* Dian Xu,1,* Peiyi Shi,1 Biyu He,1 Zhongqi Li,1 Ye Ji,1 Charles Kwaku Agbeko,1 Jianming Wang1,2 1Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China; 2Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing 211166, People’s Republic of China *These authors contributed equally to this work Background: As a new class of endogenous ncRNAs, circRNAs have been recently verified to be involved in the carcinogenesis and progression of human cancers. In the current study, we attempted to explore the potential function of a candidate circRNA (hsa_circ_0000337) in esophageal squamous cell carcinoma (ESCC). Patients and methods: The altered expression of hsa_circ_0000337 was validated in clinical samples from 48 patients with ESCC. The human esophageal carcinoma cell lines KYSE-150 and TE-1, and the normal human esophageal epithelial cell line (HET-1A) were applied for functional analysis of hsa_circ_0000337. Cell proliferation was measured using the Cell Counting Kit-8 assay and the colony formation assay. Cell invasion and migration were detected by Transwell and wound healing assays, respectively. We further performed bioinformatic analysis and luciferase reporter assays to explore the role of hsa_circ_0000337 as a miRNA sponge. Results: hsa_circ_0000337 was significantly upregulated in ESCC tissues compared to adjacent normal-appearing tissues (P0.05). Knockdown of hsa_circ_0000337 significantly inhibited cell proliferation, migration, and invasion in TE-1 and KYSE-150 cell lines. Bioinformatics predicted and luciferase reporter assay verified that hsa_circ_0000337 could bind to miR-670-5p, a ncRNA involved in carcinogenesis. It is estimated that 21 genes are regulated by miR-670-5p. Conclusion: hsa_circ_0000337 was found to be an upregulated circRNA that is related to ESCC and promotes the progression of disease by regulating cell proliferation, migration, and invasion. These findings suggest that this circRNA could be a promising diagnostic biomarker and potential therapeutic target. Keywords: esophageal squamous cell carcinoma, RNA, untranslated RNA, small untranslated, biomarker

Jianqin Yan,1,* Hai Zhang,1,* Furong Cheng,1 Yanmei He,1 Ting Su,1 Xuequan Zhang,2 Man Zhang,2 Yutong Zhu,3 Congrui Li,3 Jun Cao,1 Bin He1 1National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China; 2College of Chemical Engineering, Sichuan University, Chengdu 610065, China; 3College of Chemistry, Sichuan University, Chengdu 610065, China *These authors contributed equally to this work Background: Stability, enhanced drug-loading efficiency (DLE), and specific accumulation of therapeutics at tumor sites remain major challenges for successful cancer therapy.Purpose: This study describes a newly developed intelligent nanosystem that integrates stealthy, active targeting, stimulus-responsiveness, and π-π interaction properties in a single carrier, based on the multifunctional star-shaped biodegradable polyester.Patients and methods: This highly stable, smart nanocarrier with spherical structures and a low critical micelle concentration (CMC) can provide spacious harbor and strong π–π interaction and hydrophobic interactions for hydrophobic doxorubicin (DOX). Its structure and morphology were characterized by proton nuclear magnetic resonance (1H-NMR) spectra, Fourier transform infrared (FTIR) spectra, Gel permeation chromatography (GPC), dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Antitumor effciency of polymeric micelles using CCK-8 assay, and the intracellular-activated delivery system was tracked by confocal laser scanning microscopy (CLSM) and flow cytometry.Results: The synthesized copolymer can be self-assembled into nanoparticles with size of 50 nm and critical micellar concentration of 2.10 µg/mL. The drug-loading content of nanoparticles can be enhanced to 17.35%. Additionally, the stimulus-responsive evaluation and drug release study showed that the nanocarrier can rapidly respond to the intracellular reductive environment and dissociate for drug release. An in vitro study demonstrated that the nanocarrier can ferry doxorubicin selectively into tumor tissue, rapidly enter cancer cells, and controllably release its payload in response to an intracellular reductive environment, resulting in excellent antitumor activity in vitro.Conclusion: This study provides a facile and versatile approach for the design of multifunctional star-shaped biodegradable polyester nanovehicles for effective cancer treatment. Keywords: intelligent, star-shaped, biodegradable multifunctional polyester, stimuli-responsiveness, intracellular drug delivery, active targeting, cancer therapy

Binchan He,1,* Shen Geng,2,* Wei Zhou,1 Yuwen Rui,1 Xianmin Mu,3 Chen Zhang,3 Qiang You,3 Xin Su1,2 1Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China; 2Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southern Medical University, Guangdong 510000, China; 3Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210002, Jiangsu, China *These authors contributed equally to this work Purpose: ICAM-1 plays a critical role in the development of acute respiratory distress syndrome (ARDS). MK2 regulates the expression of ICAM-1 in human pulmonary microvascular endothelial cells. To explore whether the inhibition of MK2 activation has the same effect in experimental animals, MMI-0100, a peptide-mediated inhibitor of MK2, was used to verify whether MMI-0100 can ameliorate lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1.Methods: In this study, C57BL/6 mice were randomly divided into three groups: a control group, an lipopolysaccharides (LPS) group, and an LPS plus MMI-0100 group. Mice were killed 24 hours after the administration of LPS and MMI-0100. The mouse lung tissue histopathology, wet/dry weight ratio (W/D), and the neutrophil count were used to measure the severity of lung inflammation in mice. The pulmonary microvascular endothelial cells (PMVECs) of the mice were isolated. The mRNA expression of ICAM-1 in mouse PMVECs was determined using RT-PCR, and the protein expression of MK2 and ICAM-1 in mouse PMVECs was analyzed using Western blotting and immunohistochemistry.Results: We found that the level of phosphorylated MK2 in the LPS plus MMI-0100 group was reduced. Compared with the LPS group, the LPS plus MMI-0100 group of mice showed less severe inflammation, including a lower W/D and neutrophil count. The mRNA and protein expression of ICAM-1 in the LPS group was significantly higher than in the control group in mouse PMVECs, and the ICAM-1 level was reduced after the administration of MMI-0100.Conclusion: These data indicate that MMI-0100 ameliorates lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1. Keywords: pulmonary microvascular endothelial cell, inflammation, acute respiratory distress syndrome

Wenyu Zhang,1,2 Wei Cai,1,2 Baochun He,2,3 Nan Xiang,1 Chihua Fang,1 Fucang Jia2,3 1Department of Hepatobiliary Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Research Lab for Medical Imaging and Digital Surgery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China; 3Shenzhen Key Laboratory of Minimally Invasive Surgical Robotics and System, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China Objective: The objective of the study was to develop and validate a radiomics-based formula for the preoperative prediction of postoperative pancreatic fistula (POPF) in patients undergoing pancreaticoduodenectomy (PD).Materials and methods: A total of 117 consecutive patients who underwent PD were enrolled in this retrospective study. Radiomics features were extracted from portal venous phase computed tomography of the above patients. The least absolute shrinkage and selection operator logistic regression was used to construct a formula of Rad-score calculation. Then the performance of the formula was assessed with standard pancreatic Fistula Risk Score.Results: The Rad-score could predict POPF with an area under the curve (AUC) of 0.8248 in the training cohort and of 0.7609 in the validation cohort. Patients who had experienced POPF generally had a statistically higher Rad-score than those who had not experienced POPF in both cohorts. The AUC of the Rad-score was statistically higher than the Fistula Risk Score for predicting POPF in both the training and validation cohort.Conclusion: A novel radiomics-based formula was developed and validated for predicting POPF in patients who underwent PD, which provides a new method for identifying POPF risks and may help to improve informed decision-making in the prevention of POPF at low cost. Keywords: pancreatoduodenectomy, postoperative pancreatic fistula, diagnostic imaging, radiomics

Background:Lung cancer is a common cancer and the leading cause of cancer-related death worldwide. SIX3 is a human homologue of the highly conserved sine oculis gene family essential during embryonic development in vertebrates, and encodes a homeo-domain c

Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properti

Shi-Ming Zhang, Qing-Ge Zhu, Xiao-Xiao Ding, Song Lin, Jing Zhao, Lei Guan, Ting Li, Bing He, Hu-Qin Zhang The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an JiaoTong University, Xi’an, 710049, China Background: The prognostic value of EGFR and KRAS mutations in resected non-small cell lung cancer (NSCLC) has been reported. However, conflicting results were reported in these studies. The effect of mutations in these two genes in resected NSCLC remains controversial.Methods: We searched Internet databases for studies reporting disease-free survival (DFS) and overall survival (OS) in resected NSCLC patients with EGFR or KRAS mutations. A meta-analysis calculating the pooled hazard ratio (HR) for DFS and OS was used to measure the association of EGFR or KRAS mutations with the prognosis of patients after surgery.Results: A total of 9,635 patients from 32 studies were included in this analysis. The combined HR for EGFR mutations on DFS was 0.77 (95% CI 0.66–0.90, p=0.001) and on OS was 0.72 (95% CI 0.66–0.80, p

Siyang Song,1,2,* Hongzhe Fu,2,* Bing He,2 Dan Wang,3 Mengmeng Qin,2 Dan Yang,1,2 Dechun Liu,2 Ge Song,2 Yujie Shi,2 Hua Zhang,2 Xueqing Wang,2 Wenbing Dai,2 Qiang Zhang1,2 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China; 2Beijing Key Laboratory of Molecular Pharmaceutics and the State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; 3Pharmaceutics Department, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China *These authors contributed equally to this work Introduction: Endocytosis of nanomaterials is the first step of nano-bio interaction and current regulation is mostly by nanomaterials but seldom by intracellular signaling proteins. Materials and methods: Herein, we synthesized tubular nanocarbon (oxMWCNT) and lamellar-like nanocarbon (oxGRAPHENE) and formulated their aqueous dispersion. A549 and Caco-2 cells were selected as the models of tumor and intestinal epithelial cells, respectively. After knocking down three members of Rho GTPases (Cdc42, Rac1, RhoA) in these two cell lines, their silencing effects on the uptake pathways of nanomaterials with different morphologies were investigated. Results: An unexpected finding was that the knock-down led to opposite uptake trends in different types of cells. The endocytosis of carbon nanomaterials increased in Caco-2 cells when Rho GTPases were inactivated, while that in A549 cells decreased. For nanomaterials with different shapes, the involved GTPase member of Rho family, or regulating protein molecule, was different. Concretely, Cdc42 and Rac1 were involved in oxMWCNT endocytosis, while all three GTPases participated in oxGRAPHENE internalization. More interestingly, such difference induced different uptake pathways, namely, the cellular uptake of oxMWCNT was clathrin-mediated and oxGRAPHENE was caveolin-modulated, both with the involvement of dynamin. Conclusion: In conclusion, this study provides new insights for the potential intervention in nano-bio interplay. Keywords: shape, cellular uptake, intracellular distribution, nanomaterials, Rho GTPases

Peiyi Shi,1,* Jian Sun,2,* Biyu He,1 Huan Song,1 Zhongqi Li,1 Weimin Kong,2 Jianping Wang,3 Jianming Wang,1 Hengchuan Xue3 1Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Thoracic Surgery, The First People’s Hospital of Yancheng City, Yancheng, People’s Republic of China; 3Department of Thoracic Surgery, People’s Hospital of Yangzhong, Yangzhong, People’s Republic of China *These authors contributed equally to this work Introduction: Circular RNAs (circRNAs) function as efficient microRNA sponges with gene-regulatory potential and are promising cancer biomarkers. In this study, we used the Arraystar Human circRNA Array to construct a genome-wide circRNA profile of esophageal squamous cell cancer (ESCC) and breast cancer (BC). Patients and methods: Expression levels between cancer lesions and adjacent normal-appearing tissues were compared. We observed 469 upregulated circRNAs and 275 downregulated circRNAs in ESCC. Hsa_circRNA_103670 was upregulated 20.3-fold, while hsa_circRNA_030162 was downregulated 12.1-fold. For BC, 715 circRNAs were upregulated, and 440 circRNAs were downregulated. Hsa_circRNA_005230 was upregulated 12.2-fold, while hsa_circRNA_406225 was downregulated 12.4-fold. Results: When we set the criteria as fold change in expression ≥2 between cancer and adjacent normal-appearing tissue with a P-value

Wenqi Diao,1,* Ning Shen,1,* Yipeng Du,1,* John R Erb-Downward,2 Xiaoyan Sun,1 Chenxia Guo,1 Qian Ke,1 Gary B Huffnagle,2,3 Margaret R Gyetko,2 Bei He1 1Department of Respiratory Medicine, Peking University Third Hospital, Beijing 100191, China; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; 3Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA *These authors contributed equally to this work Background: The role of airway microbiota in COPD is highly debated. Symptomology assessment is vital for the management of clinically stable COPD patients; however, the link between symp­toms and the airway microbiome is currently unknown. Purpose: The present study aimed to evaluate the relationship among stable COPD patients. Patients and methods: We conducted pyrosequencing of bacterial 16S rRNA using induced sputum samples in a Han Chinese cohort that included 40 clinically stable COPD patients and 19 healthy controls. Results: Alterations in community composition and core bacte­rial taxa (Neisseria subflava, etc.) were observed in patients with severe symptoms compared with controls. The co-occurrence network indicated that the key microbiota enriched in COPD patients showed higher expression in patients with severe symptoms. The association pattern of symptoms with the sputum microbiome was obviously different from that of lung function in COPD patients. Conclusion: These findings broaden our insights into the relationship between the sputum microbiota and the symptom severity in COPD patients, emphasizing the role of symptoms in the airway microbiome, independent of lung function. Keywords: chronic obstructive pulmonary disease, symptom, sputum, microbiome

Heparan sulfate (HS) proteoglycans (HSPGs) bind to multiple growth factors/morphogens and regulate their signaling. 6-O-sulfation (6S) of glucosamine within HS chains is critical for many of these ligand interactions. Sulf-1 and Sulf-2, which are extracellular neutral-pH sulfatases, provide a novel post-synthetic mechanism for regulation of HSPG function by removing 6S from intact HS chains. The Sulfs can thereby modulate several signaling pathways, including the promotion of Wnt signaling. We found induction of SULF2 transcripts and Sulf-2 protein in human lung adenocarcinoma and squamous cell carcinoma, the two major classes of non-small-cell lung carcinomas (NSCLCs). We confirmed widespread Sulf-2 protein expression in tumor cells of 10/10 surgical specimens of human lung squamous carcinomas. We studied five Sulf-2(+) NSCLC cell lines, including two, which were derived by cigarette-smoke transformation of bronchial epithelial cells. shRNA-mediated Sulf-2 knockdown in these lines caused an increase in 6S on their cell surface and in parallel reversed their transformed phenotype in vitro, eliminated autocrine Wnt signaling and strongly blunted xenograft tumor formation in nude mice. Conversely, forced Sulf-2 expression in non-malignant bronchial epithelial cells produced a partially transformed phenotype. Our findings support an essential role for Sulf-2 in lung cancer, the leading cancer killer.

Lingshuang Lv,1,* Tiecheng Li,2,* Kun Xu,1 Peiyi Shi,1 Biyu He,1 Weimin Kong,3 Jianming Wang,1 Jian Sun3 1Department of Epidemiology, Key Laboratory of Infectious Diseases, School of Public Health, Nanjing Medical University, Nanjing, China; 2Department of Tuberculosis, the Fourth People’s Hospital of Lianyungang City, Lianyungang, China; 3Department of Thoracic Surgery, the First People’s Hospital of Yancheng City, Yancheng, China *These authors contributed equally to this work Purpose: Multidrug-resistant tuberculosis (MDR-TB) requires long-term treatment, has a high fatality rate, and constitutes a global threat. Earlier detection of treatment failure is required to predict therapeutic efficacy.Patients and methods: We enrolled MDR-TB patients consecutively from January 2011 through December 2012 in Lianyungang, China. Sputum smear microscopy tests and sputum cultures were performed once a month for the first 6 months following initiation of antituberculosis treatment and once every 2 months thereafter until the end of therapy. The sensitivity, specificity and area under the receiver operating characteristic curve (AUC) were used with a 95% CI to estimate the role of sputum bacteriology conversion in predicting treatment outcomes.Results: Among the 92 MDR-TB patients enrolled in this study, 40.2% had poor treatment outcomes. The median initial sputum bacteriology conversion time was 1 month. Patients having 2-month sputum smear conversions (adjusted odds ratio [OR]: 7.19, 95% CI: 2.60–19.84) or culture conversions (adjusted OR: 2.88, 95% CI: 1.11–7.45) were more likely to experience good outcomes. The sensitivity and specificity obtained when using two-month sputum smear conversions to predict treatment outcomes were 67.6% (95% CI: 50.2–82.0) and 76.4% (95% CI: 63.0–86.8), respectively. The sensitivity and specificity obtained when using 2-month culture conversions to predict treatment outcomes were 48.6% (95% CI: 32.0–65.6) and 74.5% (95% CI: 61.0–85.3), respectively. The AUC for two-month smear conversions was 0.72 (95% CI: 0.62–0.81), significantly higher than that obtained for 2-month culture conversions (0.62, 95% CI: 0.52–0.72) (Χ2 = 4.18, P = 0.041).Conclusion: The prognoses of MDR-TB patients displaying persistent sputum positivity were inferior to those for whom sputum bacteriology conversion was observed. Thus, sputum smear conversion results obtained 2 months after treatment initiation may provide a potential means for predicting MDR-TB treatment outcomes. Keywords: multidrug-resistant tuberculosis, sputum smear conversion, sputum culture conversion, treatment outcome, prognosis

Michelle Case,1 Sina Shirinpour,1 Huishi Zhang,1 Yvonne H Datta,2 Stephen C Nelson,3 Karim T Sadak,4 Kalpna Gupta,2 Bin He1,5 1Department of Biomedical Engineering, 2Department of Medicine, University of Minnesota, 3Pediatric Hematology-Oncology, Children’s Hospitals and Clinics of Minnesota, 4Pediatric Hematology-Oncology, University of Minnesota Masonic Children’s Hospital, 5Institute for Engineering in Medicine, University of Minnesota, Minneapolis, MN, USA Objective: Pain is a major issue in the care of patients with sickle cell disease (SCD). The mechanisms behind pain and the best way to treat it are not well understood. We studied how electroencephalography (EEG) is altered in SCD patients. Methods: We recruited 20 SCD patients and compared their resting state EEG to that of 14 healthy controls. EEG power was found across frequency bands using Welch’s method. Electrophysiological source imaging was assessed for each frequency band using the eLORETA algorithm. Results: SCD patients had increased theta power and decreased beta2 power compared to controls. Source localization revealed that areas of greater theta band activity were in areas related to pain processing. Imaging parameters were significantly correlated to emergency department visits, which indicate disease severity and chronic pain intensity. Conclusion: The present results support the pain mechanism referred to as thalamocortical dysrhythmia. This mechanism causes increased theta power in patients. Significance: Our findings show that EEG can be used to quantitatively evaluate differences between controls and SCD patients. Our results show the potential of EEG to differentiate between different levels of pain in an unbiased setting, where specific frequency bands could be used as biomarkers for chronic pain. Keywords: sickle cell disease, electroencephalography, chronic pain, electrophysiological source imaging, thalamocortical dysrhythmia