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Haiyan Chen,1 Jiamin Cao,2 Feng Zhang,2 Wei Xiong2 1Wuzhou Workers Hospital, Wuzhou, Guangxi Zhuang, People’s Republic of China; 2Department of Ophthalmology, Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of ChinaCorrespondence: Wei Xiong, Department of Ophthalmology, Third Xiangya Hospital, Central South University, Yuelu District, 138 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Tel +86 13808469035, Email weixiong420@csu.edu.cnAbstract: Growing research proves gut microbiota and thyroid autoimmunity are linked. Graves’ disease (GD), as an autoimmune thyroid disease (AITD), is attributed to the production of thyroid-stimulating hormone receptor (TSHR) autoantibodies that bind to the thyroid follicular endothelial cells. It is well known that genetic factors, environmental factors, and immune disorders count for much in the development of GD. So far, the pathogenesis of GD is not elucidated. Emerging research reveals that the change in gut microbiota composition and its metabolites are related to GD. The gut microbial diversity is reduced in GDs compared with healthy controls (HCs). Firmicutes and Bacteroidetes account for a large proportion at the genus level. It is found that phyla Bacteroidetes increased while phyla Firmicutes decreased in Graves’ Disease patients (GD patients). Moreover, gut microbiota modulates the immune system to produce cytokines through bacterial metabolites. This article aims to find out the relation between gut microbiota dysbiosis and the development of GD. As more molecular pathways of bacterial metabolites are revealed, targeting microbiota is expected to the treatment of GD.Keywords: Graves’ Disease, gut microbiota, autoimmunity, dysbiosis, Firmicutes, bacteroidetes

Shipeng Chen,1– 3 Mengna Li,1– 3 Changning Xue,1– 3 Xiangting Zhou,1– 3 Jianxia Wei,1– 3 Lemei Zheng,1– 3 Yumei Duan,1– 3 Hongyu Deng,1 Faqing Tang,1 Wei Xiong,1– 3 Bo Xiang,1– 3 Ming Zhou1– 3 1NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China; 2Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China; 3The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of ChinaCorrespondence: Ming Zhou; Bo Xiang, Email zhouming2001@163.com; xiangbolin@csu.edu.cnPurpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition.Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings.Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay.Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs. Keywords: cinobufotalin injection, liver cancer, cinobufagin, network pharmacology, cell cycle, core ingredients

Jiamin Cao, Feng Zhang, Haiyan Chen, Bingxuan Wu, Jiayang Yin, Changci Chenzhao, Wei Xiong Department of Ophthalmology, Central South University, Changsha City, People’s Republic of ChinaCorrespondence: Wei Xiong, Email weixiong420@csu.edu.cnBackground: Manifestations of thyroid-associated ophthalmopathy (TAO) vary greatly. Few tools and indicators are available to assess TAO, restricting personalized diagnosis and treatment.Aim: To identify an aptamer targeting thyroid-stimulating hormone receptor (TSHR) and utilize this aptamer to evaluate clinical activity in patients with TAO.Methods: An aptamer targeting TSHR was developed by exponential enrichment and systematic evaluation of TSHR ligands. After truncation and optimization, the affinity, equilibrium dissociation constant, and serum stability of this aptamer were evaluated. The affinity of the TSHR-targeting aptamer to isolated fibrocytes was assessed, as was aptamer internalization by fibrocytes. The mechanism of binding was determined by molecular docking. The correlation between disease manifestations and the percentage of TSHR-positive cells was assessed by correlation analysis.Results: The aptamer TSHR-21-42 was developed to bind to TSHR, with the equilibrium dissociation constant being 71.46 Kd. Isolated fibrocytes were shown to bind TSHR-21-42 through TSHR, with its affinity maintained at various temperatures and ion concentrations. TSHR-21-42 could compete with anti-TSHR antibody, both for binding site to TSHR and uptake by cells after binding. In addition, TSHR-21-42 could bind to leukocytes in peripheral blood, with this binding differing in patients with TAO and healthy control subjects. The percentage of TSHR-positive monocytes, as determined by binding of TSHR-21-42, correlated positively with clinical activity score in patients with TAO, indicating that TSHR-21-42 binding could assess the severity of TAO.Conclusion: This aptamer targeting TSHR may be used to objectively assess disease activity in patients with TAO, by evaluating the percentages of TSHR positive cells in peripheral blood.Keywords: thyroid-associated ophthalmopathy, thyroid-stimulating hormone receptor, aptamer, clinical activity score, precision medicine

Jiamin Cao, Feng Zhang, Wei Xiong Department of Ophthalmology, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Feng Zhang; Wei Xiong, Department of Ophthalmology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People’s Republic of China, Email fengz2022@csu.edu.cn; weixiong420@csu.edu.cnAbstract: Aptamers are widely applied to diagnosis and therapy because of their targeting. However, the current progress of research into aptamers for the treatment of eye disorders has not been well-documented. The current literature on aptamers was reviewed in this study. Aptamer-related drugs and biochemical sensors have been evaluated for several eye disorders within the past decade; S58 targeting TGF-β receptor II and pegaptanib targeting vascular endothelial growth factor (VEGF) are used to prevent fibrosis after glaucoma filtration surgery. Anti-brain-derived neurotrophic factor aptamer has been used to diagnose glaucoma. The first approved aptamer drug (pegaptanib) has been used to inhibit angiogenesis in age-related macular degeneration (AMD) and diabetic retinopathy (DR), and its efficacy and safety have been demonstrated in clinical trials. Aptamers, including E10030, RBM-007, AS1411, and avacincaptad pegol, targeting other angiogenesis-related biomarkers have also been discovered and subjected to clinical trials. Aptamers, such as C promoter binding factor 1, CD44, and advanced end products in AMD and DR, targeting other signal pathway proteins have also been discovered for therapy, and biochemical sensors for early diagnosis have been developed based on aptamers targeting VEGF, connective tissue growth factor, and lipocalin 1. Aptamers used for early detection and treatment of ocular tumors were derived from other disease biomarkers, such as CD71, nucleolin, and high mobility group A. In this review, the development and application of aptamers in eye disorders in recent years are systematically discussed, which may inspire a new link between aptamers and eye disorders. The aptamer development trajectory also facilitates the discovery of the pathogenesis and therapeutic strategies for various eye disorders.Keywords: aptamer, ophthalmology, targeting therapy, early diagnosis

Tao Yin,1,* Yan Lu,2,* Wei Xiong,3,* Chengdong Yu,4 Delu Yin,5 Huijing He6 1Department of Technology, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 2Department of Cardiology, First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Gynecology Endocrine & Reproductive Center, National Clinical Research Center for Obstetric & Gynecologic Diseases Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College/Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Department of Growth and Development, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 5Department of Child Health Care, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 6Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huijing He, Department of Epidemiology and Statistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, 5 Dongdansantiao, Dongcheng District, Beijing, 100005, People’s Republic of China, Tel +8615010086743, Email huijing_he@ibms.pumc.edu.cn Delu Yin, Department of Child Health Care, Capital Institute of Pediatrics, 2 Yabao Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +8613810349722, Email deluyin@126.comPurpose: To understand the physical and mental health status of primary healthcare providers (PHPs) including physicians, nurses and other staff and the workplace risk factors for depression, anxiety and intention-to-leave.Patients and Methods: In December 2021, a national cross-sectional survey was conducted from 62 urban communities in China, and all PHPs were invited to complete a standardized questionnaire. Information on demographic, health-related lifestyle, cardiovascular risk factors and physical health status, occupational stress and intention-to-leave was collected. Depression and anxiety were assessed using the Zung Self-Rating Anxiety/Depression Scale (SAS/SDS).Results: A total of 4901 PHPs were included. 67.0% males currently drank alcohol vs 25.3% in females; 36.0% males currently smoked cigarettes vs 1.4% in females. Notably, more than half males were overweight or obese, but this proportion was 24.2% in females. The prevalence of chronic diseases, including hypertension, diabetes, dyslipidemia, non-alcoholic fatty liver disease, gout, and disease clustering were higher in males than in females. The prevalence of depression and anxiety were high, 50% had depression, of whom 15.6% had moderate/severe depression. Over 15% participants had varied levels of anxiety, and approximately 4% had moderate/severe anxiety. PHPs who aged 18– 29 (OR: 1.31, 95% CI: 1.05– 1.64), were males (OR: 1.34, 95% CI: 1.14– 1.57), with lower professional title (comparing with staff with senior title, the ORs of the intermedium, junior and none were 1.83, 2.18 and 2.49, respectively), took charge in nursing (OR: 1.41, 95% CI: 1.20– 1.65), with higher perceived stress level (OR: 1.82, 95% CI: 1.41– 2.34), and suffering from severe fatigue (OR: 2.55, 95% CI: 1.99– 3.27) were more likely to have depression. Likewise, PHPs who were younger, with intermedium professional title, had higher perceived pressure level, and higher fatigue levels were more likely to have anxiety.Conclusion: The mental health of PHPs is worrisome, with a high burden of chronic diseases and occupational risk factors. Younger PHPs, nurses, and those with higher levels of work pressure and fatigue are more vulnerable to psychological problems. The high prevalence of intention-to-leave calls for strategies that relieve the workplace stress and enhance the human resource capability.Keywords: depression, anxiety, stress, intention-to-leave, COVID-19, primary healthcare

Chengxuan Liu,1 Weijian Xiong,1 Jing Song,2 Xiaoqin Ouyang,1 Yang Fu3 1Department of Nephrology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 2Molecular Medicine and Cancer Research Centre, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Rehabilitation, Chongqing Traditional Chinese medicine Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Yang Fu, Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Branch Road, Jiangbei District, Chongqing, 400021, People’s Republic of China, Email fuyang@stu.cdutcm.edu.cnIntroduction: The overall survival of patients with high-stage clear cell renal carcinoma (ccRCC) is poor. However, promising molecular-level prognostic marker is still lacking to date.Methods: We systematically evaluated the prognostic potential of immune-related long non-coding RNAs (lncRNAs) in ccRCC. The expressions of lncRNAs were validated in clinical tissues of ccRCC. Functional experiments were performed to investigate the role of lncRNAs in ccRCC.Results: Eight hundred and ninety-three lncRNAs were differentially expressed in ccRCC and compared with normal controls and were screened out using three independent cohorts. Among them, 290 immune-related lncRNAs were identified. We identified a seven-lncRNA signature (LINC01270, FIRRE, RP11-37B2.1, RP11-253I19.3, RP11-438L19.1, RP11-504P24.9, and CTB-41I6.1) associated with the overall survival of late-stage ccRCC patients. Further multivariate Cox analysis using clinical factors as covariates showed that our lncRNA signature was an independent biomarker in training (P < 0.001, Log rank test) and validation cohorts (P = 0.003). The seven lncRNAs were closely related to the major targets (PD-1, PD-L1, and CTLA4) of immune checkpoint blockade drugs, implying that they may have potential value in predicting immunotherapy response. The seven lncRNAs may play an important role in tumor-infiltrating immune cells (eg, T/B cells) and tumor progression through regulating the binding of protein receptors/complexes, as revealed by functional analysis. qRT-PCR showed that LINC01270 was upregulated in ccRCC tissues (n=20) compared with paired normal samples. Functional experiments showed that LINC01270 silencing inhibited the proliferation, invasion, and migration of ccRCC cells.Discussion: In summary, the seven-lncRNA signature has great potential in prognosis for patients with late-stage ccRCC, which could be a novel clinical biomarker. LINC01270 could be a novel therapeutic target of ccRCC.Keywords: long non-coding RNA FIRRE, prognosis, renal cell carcinoma, tumor immune

Yumin Chen,1 Wei Xiong,2,3 Ying Zhang,1 Xue Bai,1 Guoliang Cheng,1 Yifan Zhang,1 Rui Chen,1 Yinghui Guo,1 Hui Kong,1 Yue Zhang,4 Huihua Qu,5 Yan Zhao1 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Institutes of Health Research, Mayinglong Pharmaceutical Group Co., Ltd, Wuhan, Hubei, People’s Republic of China; 4School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Centre of Scientific Experiment, Beijing University of Chinese Medicine, Beijing, People’s Republic of ChinaHuihua QuCentre of Scientific Experiment, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, People’s Republic of China, Email quhuihuadr@163.comCorrespondence: Yan Zhao, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 Bei San Huan Dong Lu, Chaoyang District, Beijing, People’s Republic of China, Email zhaoyandr@163.comBackground: At present, people are susceptible to developing depression and anxiety disorders in response to stress. However, there is no specific medicine for anxiety. Os Draconis (OD, named “Long gu” in Chinese) are fossilized bones that have been used in traditional Chinese medicine to treat neurological diseases for thousands of years. Thus, we conducted this study to determine the biological basis for the anxiolytic effect of OD.Methods: In this study, novel carbon dots (OD-CDs) from OD decoctions were discovered and separated. OD-CDs were anatomized using nanomaterials characterization methods to characterize the morphological structure, optical properties, and functional group properties. Four behavioural tests were conducted to observe the behavioural activities of mice, including the open field test (OFT), light/dark box test (LDT), elevated plus maze test (EPMT), and novelty-suppressed feeding test (NSFT), to determine its anxiolytic effects. Moreover, we assessed the possible mechanisms of the OD-CDs by detecting hormones associated with the hypothalamic-pituitary-adrenal (HPA) axis.Results: OD-CDs were spherical and monodispersed with a narrow size distribution between 1 and 5 nm and had a yield of 3.67%. OD-CDs increased the activity time of mice in the central zone in the OFT. The mice in the experimental group showed more frequent activity in the light compartment and the open arms, in LDT and EPMT, respectively. In addition, OD-CDs shortened the feeding latency in the NSFT. Furthermore, the results after OD-CDs intervention showed a significant increase in serum serotonin (5-HT) and norepinephrine (NE). In addition, the concentrations of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ATCH), and corticosterone (CORT) were decreased.Conclusion: These results demonstrate a definite anxiolytic effect of OD-CDs and reveal the possible mechanism of action of OD-CDs’ anxiolytic effect, which supports the research of OD for neurological disorders and a promising new trend of therapeutic approach and drug development.Graphical Abstract: Keywords: Os Draconis, carbon dots, anti-anxiety, HPA axis

Kai Dai,1,&ast; Zhibing Li,2,&ast; Yafei Luo,1,&ast; Qianhui Xiong,1,&ast; Yao Xiong,3,&ast; Zhifang Song,1,&ast; Wenjun Xiong1 1Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanchang University, Medical Department of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China; 2Department of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, Medical Department of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China; 3Department of Cardiovascular Medicine, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Medical Department of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjun XiongDepartment of Cardiovascular Medicine, The First Affiliated Hospital of Nanchang University, Medical Department of Nanchang University, No. 461 Bayi Avenue, Nanchang, 330006, Jiangxi, People’s Republic of China, Tel +8613767970074, Email xiongwenjunnc@foxmail.comBackground: Cardiac rupture (CR) is a serious complication of acute myocardial infarction (AMI). We aimed to explore the predictive value of blood cell parameters for identifying CR in patients with AMI using the introduction of propensity score matching (PSM).Methods: This retrospective study enrolled patients who were diagnosed with AMI from January 2013 to May 2020. A total of 109 patients with CR were included, and 327 hospitalized non-CR patients were randomly selected at a 1:3 ratio. Based on the 1:1 nearest neighbour matching method by using SPSS, the covariances of the two groups were balanced. After PSM, the independent risk factors for CR were selected by using multivariate logistic regression analysis, and receiver operating characteristic (ROC) curve analysis was applied to evaluate the predictive value of blood cell parameters for CR. Ninety cases were matched successfully in each of the two groups.Results: Among the 180 patients with AMI after PSM, the results of multivariate logistic regression analysis showed that the monocyte-to-lymphocyte ratio (MLR) (OR = 3.57, 95% CI: 1.28– 9.97, P = 0.015) and monocyte-to-haematocrit ratio (MHR) (OR = 1.80, 95% CI: 1.02– 3.20, P = 0.043) were independently related to the risk of CR. Additionally, the MLR (area under the curve (AUC): 0.74) and MHR (AUC: 0.73) were useful for distinguishing CR patients after PSM. To differentiate CR patients from the control subjects, the optimal cut-offs of the MLR and MHR were 0.61 (63% sensitivity and 80% specificity) and 2.06 (57% sensitivity and 81% specificity), respectively.Conclusion: The blood cell parameters MLR and MHR were independently correlated with CR. Additional, the MLR and MHR were useful to predict CR in patients with AMI.Keywords: cardiac rupture, acute myocardial infarction, blood cell parameters, monocyte-to-lymphocyte ratio, inflammatory, monocyte-to-haematocrit ratio

Weibiao Xiong,1,* Lan’e Wu,1,* Runke Tang,2 Qingqing Zhang,1 Qian Guo,1 Shuhua Song3 1Xiong Wei-Biao Workroom, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, 330003, People’s Republic of China; 2Department of Rehabilitation, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, 330003, People’s Republic of China; 3Department of Dermatology, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, 330003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lan’e WuXiong Wei-Biao Workroom, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, No. 90, Bayi Road, Nanchang, Jiangxi, 330003, People’s Republic of ChinaTel +86-0791-86292774Email wulane502@163.comBackground: Grape seed proanthocyanidins (GSPs) have been shown to inhibit the progression of many cancers, including cutaneous squamous cell carcinoma (CSCC). Circular RNA (circRNA) is a key regulator for cancer progression. However, it is unclear whether GSPs can mediate the progression of CSCC by regulating circRNA.Methods: Quantitative real-time PCR was conducted to determine the expression of hsa_circ_0070934, microRNA (miR)-136-5p and prenylated Rab acceptor family 2 (PRAF2). MTT assay and colony formation assay were used to assess cell proliferation. Cell cycle process and apoptosis were detected by flow cytometry, and cell migration and invasion were measured by transwell assay. Western blot analysis was utilized to examine protein expression. In addition, dual-luciferase reporter assay and RIP assay were used to evaluate the interaction between miR-136-5p and hsa_circ_0070934 or PRAF2. Subcutaneous xenograft models were constructed to explore the function of GSPs on CSCC tumor growth in vivo.Results: GSPs could reduce hsa_circ_0070934 expression and inhibit CSCC cell proliferation, cell cycle process, migration, invasion, while promote apoptosis. Overexpressed hsa_circ_0070934 could reverse the suppressive effect of GSPs on CSCC cell progression. MiR-136-5p could be sponged by hsa_circ_0070934, and its overexpression also abolished the positively regulation of hsa_circ_0070934 on the progression of GSPs-induced CSCC cells. PRAF2 was a target of miR-136-5p, and its expression could be decreased by GSPs and increased by hsa_circ_0070934. The inhibitory effect of miR-136-5p on CSCC cell progression could be reversed by PRAF2 overexpression. Additionally, GSPs also could inhibit CSCC tumor growth in vivo.Conclusion: Our data showed that GSPs regulated the hsa_circ_0070934/miR-136-5p/PRAF2 axis to restrain CSCC progression.Keywords: cutaneous squamous cell carcinoma, GSPs, hsa_circ_0070934, miR-136-5p, PRAF2

Weichuan Xiong,1,2 KeJian Qian2 1Department of Critical Care Medicine, The Third Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of ChinaCorrespondence: KeJian Qian Email kejianqian@sina.comObjective: To investigate the 28-day mortality, the length of ICU stay, days in the hospital, days of ventilator use, adverse events, and nosocomial infection events of low-protein, hypocaloric nutrition with glutamine in the first 7 days of the intensive care unit (ICU) patients with severe traumatic brain injury (STBI).Patients and Methods: A total of 53 patients diagnosed with STBI enrolled from the third affiliated hospital of Nanchang University (Nanchang, China), from January 2019 to July 2020, were divided into two groups. We performed a randomized prospective controlled trial. The intervention group (n=27) was nutritional supported (intestinal or parenteral) with a caloric capacity of 20– 40% of European Conference on Clinical Nutrition and Metabolism (ESPEN) recommendations; specifically, low-protein intake was 0.5– 0.7g/kg per day (containing the amount of alanyl-glutamine), glutamine was 0.3 g/kg per day, and the intervention treatment lasted for 7 days. The control group (n=26) was nutritionally supported with a caloric capacity of 70– 100% of ESPEN recommendations, and the protein intake was 1.2– 1.7 g/kg per day. The primary endpoint was 28-day mortality. Secondary endpoints were the length of ICU stay, days in the hospital, days of ventilator use, adverse events and nosocomial infection events.Results: There were no differences in baseline characteristics between groups. Survival curve analysis using the Kaplan-Meier method revealed no significant difference in 28-day mortality between the two groups (P=0.31) while adverse events (χ2= 5.853, P=0.016), nosocomial infection rate (χ2 = 4.316, P=0.038), the length of ICU stay (t=− 2.617, P=0.012), hospitalization time (t=− 2.169, P=0.036), and days of ventilator use (t=− 2.144,P=0.037) of patients in the intervention group were significantly lower than those in the control group.Conclusion: Low-protein, hypocaloric nutrition with glutamine did not show different outcomes in 28-day mortality compared to full-feeding nutritional support in the ICU patients with STBI. However, low-protein, hypocaloric nutrition with glutamine could provide a lower need for ICU time, hospitalization time, and ventilator time in the ICU patients with STBI.Keywords: acute phase, severe traumatic brain injury, nutrition, low-protein, hypocaloric, glutamine

Dizhou Zhao, Jieyu Fang, Wei Xiong, Jun Lin, Wanmei Chen, Chujun Wu Department of Anesthesia, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Jieyu FangDepartment of Anesthesia, The First Affiliated Hospital of Sun Yat-Sen University, No. 56 Zhongshan Road II, Guangzhou, People’s Republic of ChinaTel + 86-13660121136Email fangjy@mail.sysu.edu.cnBackground: Sugammadex has been a revolutionary reversal of neuromuscular blockade. It is known to be highly efficient. However, a change in the coagulation profile is one of the most dangerous potential complications which is a concern for both surgeon and anesthetist. Bleeding may cause hypovolemic shock, hematoma, and so on. To investigate the effects of sugammadex on coagulation profiles in patients with thyroidectomy, we compared patients that were treated with either sugammadex or neostigmine.Patients and Methods: Eighty patients with thyroid neoplasms undergoing thyroidectomy were randomly allocated to sugammadex group (group S) or neostigmine group (group N). Induction of anesthesia was preformed using propofol, sufentanil, and rocuronium. Group S received sugammadex 2.0mg/kg after trachea intubation, similarly Group N received neostigmine 40 μg/kg, for reversal of rocuronium-induced neuromuscular blockade. The intraoperative coagulation profiles were monitored after the rocuronium injection (T0), 10 minutes after reversal (T1) and 30 minutes after reversal (T2) by testing activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB), thrombin time (TT), and TEG-Haemonetics. Amount of bleeding was recorded during perioperative period.Results: There was no significant difference in the thromboelastogram, APTT, PT, FIB, or TT measurements at each time point in Group N. The reaction time (R time) and kinetics time (K time) of Group S in T1 were significantly longer than the corresponding times at T0 and T2, and the R times were significantly longer than those in Group N at the same time points (P< 0.05). Additionally, in Group S, the APTT was prolonged in T1 and returned to normal in T2.Conclusion: The result showed that sugammadex provided transient efficacy in prolonging the coagulation parameters, while neostigmine did not change the coagulation profile.Keywords: sugammadex, neostigmine, TEG-Haemonetics, coagulation, thyroidectomy

Jie Xia,1– 4,* Lina Sun,5,* Suqin Xu,1– 4 Qiu Xiang,1– 4 Jianping Zhao,1– 4 Weining Xiong,1– 4 Yongjian Xu,1– 4 Shuyuan Chu1– 4,6 1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 2Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 3Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 4Key Site of National Clinical Research Center for Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 6Laboratory of Respiratory Disease, Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuyuan Chu; Jie XiaDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of ChinaTel +8613978345180; +8627-83665520Email emilyyuanchu@163.com; xiajhzu1215@126.comPurpose: Patients with chronic obstructive pulmonary disease (COPD) would have a poor prognosis if they were not continuously managed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. We aim to develop a model to classify whether COPD patients have been continuously managed according to GOLD in the previous year.Methods: The Managed group were COPD patients from a prospective cohort from November 2017 to November 2019, who have been continuously managed according to GOLD for 1 year. The Control group were COPD patients who were not continuously managed according to GOLD. They were from a retrospective cohort from October 2016 to October 2017 in the same hospitals as the Managed group. A synthetic minority over-sampling technique (SMOTE) algorithm was used to up-sample the Managed group in a training dataset. Features for classification were selected using a support vector machine recursive feature elimination (SVM-RFE) algorithm. The classification model was developed using LibSVM, and its performance was assessed on the testing dataset.Results: The final analysis included 15 subjects in the Managed group and 191 in the Control group. SVM-RFE selects nine features including smoking history, post-bronchodilator (post-)FVC before management, and those after 1-year follow-up (BMI, moderate and severe AECOPD frequency in previous 12 months, mMRC score, post-FEV1, post-FEV1%pred, post-FVC, and post-FEV1/FVC). For our model, positive predictive value is 66.7%, F1 score is 0.978, and AUC is 0.987.Conclusion: SVM classifier combined with SVM-REF feature selection algorithm could achieve good classification between COPD patients who are or are not continuously managed. This model could be applied in clinical practice to help doctors make decisions and enhance COPD patients’ compliance with standard treatment.Keywords: COPD, GOLD, continuous management, support vector machine

Shuyi He,1– 3,* Jingyu Li,1– 3,* Mingjian Chen,1– 3 Liehua Deng,4 Yuxin Yang,1– 3 Zhaoyang Zeng,1– 3 Wei Xiong,1– 3 Xu Wu1– 3 1NHC Key Laboratory of Carcinogenesis and Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, People’s Republic of China; 2Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China; 4Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xu WuCentral South University, 110 Xiangya Road, Kaifu District, Changsha City, Hunan Province 410078, People’s Republic of ChinaEmail wuxu1028@csu.edu.cnIntroduction: Near-infrared (NIR) hyperthermia agents are promising in cancer photothermal therapy due to their deeper penetration ability and less side effects. Spherical gold nanoshell and graphene-based nanomaterials are two major NIR hyperthermia agents that have been reported for photothermal therapy of cancer. Herein, we constructed a two-dimensional graphene oxide-template gold nanosheet (GO@SiO2@AuNS) hybrid that could destruct cancer cells with efficient photothermal effect.Methods: Graphene oxide was coated with a layer of mesoporous silica, which provided binding sites for gold seeds. Then, seed-growth method was utilized to grow a layer of gold nanosheet to form the GO@SiO2@AuNS hybrid, which possessed great biocompatibility and high photothermal conversion efficiency.Results: With the irradiation of NIR laser (808 nm) with low power density (0.3 W/cm2), GO@SiO2@AuNS hybrid showed a photothermal conversion efficiency of 30%, leading to a temperature increase of 16.4 °C in water. Colorectal cancer cells (KM12C) were killed with the treatment of GO@SiO2@AuNS hybrid under NIR irradiation.Conclusion: The GO@SiO2@AuNS hybrid may expand the library of the 2D nanostructures based on gold for cancer photothermal therapy.Keywords: graphene oxide, gold nanosheets, photothermal therapy, near-infrared

Weixian Hu,1,* Chengbin Zheng,1,* Renjie Li,2 Xingyu Feng,1 Guoliang Zheng,3 Zhichao Zheng,3 Wenjun Xiong,4 Guosheng Lin,5 Yongjian Zhou,5 Wei Wang,4 Yan Zhao,3 Yong Li1 1Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People’s Republic of China; 2Department of Bariatric and Metabolic Surgery, Klinikum Ernst von Bergmann, Potsdam 14467, Germany; 3Department of Gastric Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of China; 4Department of Gastrointestinal Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, People’s Republic of China; 5Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People’s Republic of China*These authors contributed equally to this work.Correspondence: Yong LiDepartment of General Surgery, Guangdong Provincial People’s Hospital; Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, Guangzhou, Guangdong 510080, People’s Republic of ChinaTel +86-13822177479Fax +86-83827812Email liyong@gdph.org.cnYan ZhaoDepartment of Gastric Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of ChinaTel +86-18900918909Email zhaoyan@CancerHosp-LN-CMU.comPurpose: Gastrointestinal stromal tumors (GISTs) are commonly known to be derived from the gastrointestinal (GI) tract, but recently there have been more and more literature describing lesions with similar pathological and immunohistochemical resembling GISTs but located outside the GI tract, and they have been termed as extra-GISTs (eGISTs). However, due to the rare incidence of eGISTs, its association with survival outcomes is poorly understood, especially in the Chinese population. Here, we aimed to identify the risk factors of eGISTs and to assess their association with overall survival (OS) and disease-free survival (DFS).Patients and Methods: Data of pathologically confirmed eGISTs cases, without radiological and perioperative evidence of other primary lesions, and with no microscopically identified adhesion between the tumor and the gastrointestinal serosa, which were surgically treated between January 2006 and September 2017 were retrieved from the database of four high-volume hospitals. Immunohistochemical and genetic testing were performed on the postoperative lesions and were staged using the National Institutes of Health (NIH) criteria.Results: A total of 55 cases were retrieved. eGISTs were identified from the retroperitoneum (36.4%), mesocolon (25.5%), small bowel mesentery (12.7%), abdominopelvic cavity (12.7%), lesser omental sac (5.5%), ovary (3.6%), pancreatic capsule (1.8%), or urinary bladder (1.8%). Based on the NIH risk classification, majority of the lesion were classified as high risk (85.5%). KIT 11 was the most common mutation site (76.5%) and 25.0% of the cases were wild-type eGISTs. Multivariate analyses showed that tumor location and size were independent factors affecting prognoses. Patients with tumors in the retroperitoneum had significantly poorer OS and DFS as compared to those in the non-retroperitoneum (HR [95% CI] for OS and DFS: 2.546 [1.023– 6.337] [P = 0.037] and 2.475 [0.975– 6.273] [P = 0.049], respectively). Similar findings were found for tumors of size > 15 cm, compared to ≤ 15 cm (HR [95% CI] for OS and DFS: 5.350 [2.022– 14.156] [P < 0.001] and 3.861 [1.493– 9.988] [P = 0.003], respectively).Conclusion: eGISTs were predominantly found from the retroperitoneum and mostly classified as high risk. Those located in the retroperitoneum and of size > 15 cm had the poorer OS and DFS as compared to those in the non-retroperitoneum and of size < 15 cm.Keywords: extra gastrointestinal stromal tumors, multicenter, immunohistopathology, gene mutation, National Institutes of Health criteria, risk factor, retroperitoneum, overall survival, disease-free survival, recurrence

Lingxi Guo,1,2,* Weining Xiong,3,* Dong Liu,1,2,* Yun Feng,1,2,* Peng Wang,4,* Xuan Dong,5,* Rong Chen,1,2,* Yi Wang,6 Lei Zhang,6 Jingwen Huang,1,2 Hanssa Dwarka Summah,7 Fangying Lu,1,2 Yusang Xie,1,2 Huihuang Lin,1,2 Jiayang Yan,1,2 Hongzhou Lu,8 Min Zhou,1,2 Jieming Qu1,2 1Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Departement of Respiratory and Critical Care Medicine, Baoshan Branch of Shanghai First People’s Hospital, Shanghai, People’s Republic of China; 5Tuberculosis and Respiratory Department, Wuhan Jinyintan Hospital, Wuhan, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Key Cite of National Clinical Research Center for Respiratory Disease, Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, People’s Republic of China; 7Chest Department, Poudre D’Or Chest Hospital, Riviere du Rempart, Mauritius; 8Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jieming QuDepartment of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20025, People’s Republic of ChinaEmail jmqu0906@163.comMin ZhouDepartment of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20025, People’s Republic of ChinaEmail doctor_zhou_99@163.comPurpose: To predict the risk of developing severe pneumonia among mild novel coronavirus pneumonia (mNCP) patients on admission.Methods: A retrospective cohort study was conducted at three hospitals in Shanghai and Wuhan from January 2020 to February 2020. Real-time polymerasechain–reaction assays were used to detect COVID-19. A total of 529 patients diagnosed with NCP were recruited from three hospitals and classified by four severity types during hospitalization following the standards of the Chinese Diagnosis and Treatment of Pneumonia Caused by New Coronavirus Infection (eighth version). Patients were excluded if admitted by ICU on admission (n=92, on a general ward while meeting the condition of severe or critical type on admission (n=25), or there was insufficient clinical information (n=64). In sum, 348 patients with mNCP were finally included, and 68 developed severe pneumonia.Results: mNCP severity prognostic index values were calculated based on multivariate logistic regression: history of diabetes (OR 2.064, 95% CI 1.010– 4.683; p=0.043), time from symptom onset to admission ≥ 7 days (OR 1.945, 95% CI 1.054– 3.587; p=0.033), lymphocyte count ≤ 0.8 (OR 1.816, 95% CI 1.008– 3.274; p=0.047), myoglobin ≥ 90 mg/L (OR 2.496, 95% CI 1.235– 5.047; p=0.011), and D-dimer ≥ 0.5 mg/L (OR 2.740, 95% CI 1.395– 5.380; p=0.003). This model showed a c-statistics of 0.747, with sensitivity and specificity 0.764 and 0.644, respectively, under cutoff of 165.Conclusion: We designed a clinical predictive tool for risk of severe pneumonia among mNCP patients to provided guidance for medicines. Further studies are required for external validation.Keywords: novel coronavirus pneumonia, predicting score, severe pneumonia

Peng Wan,1– 3,* Shiyun Cui,1– 3,* Zhenbao Ma,1– 3 Lin Chen,1– 3 Xiaoshen Li,1– 3 Ruonan Zhao,1– 3 Wenguang Xiong,1– 3 Zhenling Zeng1– 3 1Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 2National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, People’s Republic of China; 3National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenguang Xiong Email xiongwg@scau.edu.cnZhenling Zeng Tel +86 20 85281204Fax +86 20 8528 4896Email zlzeng@scau.edu.cnPurpose: The plasmid-borne mobilized colistin resistance gene (mcr-1) was discovered in 2015. Subsequently, the rapid horizontal transfer of mcr-1 gene to diverse bacterial species poses a serious threat to public health, which urgently needs the introduction of novel antimicrobial strategies. Therefore, the purpose of this study is to sensitize bacteria to colistin and reduce the propagation of mcr-1 gene by curing mcr-1-harboring plasmid in Escherichia coli (E. coli) using the CRISPR-Cas9 system.Methods: Two sgRNAs specific to mcr-1 gene were designed and cloned into plasmid pCas9. The recombinant plasmid pCas9-mcr was transformed into E. coli carrying pUC19-mcr-1 or pHNSHP45, separately. The elimination efficiency in strains was evaluated by PCR and quantitative real-time PCR (qPCR). The antimicrobial susceptibility test was performed using the broth microdilution method.Results: In this study, we constructed the high copy number plasmid pUC19-mcr-1 and recombinant plasmid pCas9-m1 or pCas9-m2, which contain 20 nt or 30 nt sgRNA sequences targeted to mcr-1, respectively. PCR and qPCR results showed that mcr-1-harboring plasmids could be efficiently eliminated, and there was no significant correlation between sgRNA lengths and curing efficiency. However, when comparing restructured high copy number plasmid (pUC19-mcr-1) to natural resistance plasmid (pHNSHP45) in eliminating efficiency, we found that the content of plasmid backbone had an influence on efficiency. Furthermore, the conjugation assays verified that the engineered CRISPR-Cas9 system in bacteria or in bacteria genome can protect the recipient from plasmid-borne mcr-1 transfer via conjugation. Additionally, sequence analysis showed that three different types of defects in CRISPR-Cas9 system lead to escape mutants.Conclusion: We presented a method that only one plasmid-mediated CRISPR-Cas9 system can be used to efficiently resensitize E. coli to colistin. Moreover, this system provided a great potentiality to counteract the propagation of mcr-1 among bacterial pathogens.Keywords: sgRNA lengths, curing efficiency, backbone content, quantitative real-time PCR, conjugation assays, escape mutants

Yangmengfan Chen,1,* Ming Guan,1,* Ranyue Ren,1 Chenghao Gao,1 Hao Cheng,2 Yong Li,1 Biao Gao,3 Yong Wei,3 Jijiang Fu,3 Jun Sun,4 Wei Xiong1 1Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 2Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 3The State Key Laboratory of Refractories and Metallurgy, School of Materials and Metallurgy, Wuhan University of Science and Technology, Wuhan 430081, People’s Republic of China; 4Department of Biochemistry and Molecular Biology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun SunDepartment of Biochemistry and Molecular Biology, Basic Medical School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of ChinaTel +86 189 7128 0215Email sunjun99@hotmail.comWei XiongDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, People’s Republic of ChinaTel +86 132 1273 6006Email 1996tj0558@hust.edu.cnIntroduction: The bone regeneration of endosseous implanted biomaterials is often impaired by the host immune response, especially macrophage-related inflammation which plays an important role in the bone healing process. Thus, it is a promising strategy to design an osteo-immunomodulatory biomaterial to take advantage of the macrophage-related immune response and improve the osseointegration performance of the implant.Methods: In this study, we developed an antibacterial silver nanoparticle-loaded TiO2 nanotubes (Ag@TiO2-NTs) using an electrochemical anodization method to make the surface modification and investigated the influences of Ag@TiO2-NTs on the macrophage polarization, osteo-immune microenvironment as well as its potential molecular mechanisms in vitro and in vivo.Results: The results showed that Ag@TiO2-NTs with controlled releasing of ultra-low-dose Ag+ ions had the excellent ability to induce the macrophage polarization towards the M2 phenotype and create a suitable osteo-immune microenvironment in vitro, via inhibiting PI3K/Akt, suppressing the downstream effector GLUT1, and activating autophagy. Moreover, Ag@TiO2-NTs surface could improve bone formation, suppress inflammation, and promote osteo-immune microenvironment compared to the TiO2-NTs and polished Ti surfaces in vivo. These findings suggested that Ag@TiO2-NTs with controlled releasing of ultra-low-dose Ag+ ions could not only inhibit the inflammation process but also promote the bone healing by inducing healing-associated M2 polarization.Discussion: Using this surface modification strategy to modulate the macrophage-related immune response, rather than prevent the host response, maybe a promising strategy for implant surgeries in the future.Keywords: silver nanoparticle, TiO2 nanotubes, immune response, glucose transport, autophagy

Xueying Chen,1 Qi Wang,1 Yinan Hu,1 Lei Zhang,1 Weining Xiong,1 Yongjian Xu,1 Jun Yu,2 Yi Wang1 1Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Key Cite of National Clinical Research Center for Respiratory Disease, Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 2Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of ChinaCorrespondence: Yi WangDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hongshan District, Wuhan, Hubei Province, People’s Republic of ChinaTel +86-27-8366-5562Email wangyi@tjh.tjmu.edu.cnJun YuDepartment of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hongshan District, Wuhan, Hubei Province, People’s Republic of ChinaTel +86-27-8366-3597Email junyu2016@hotmail.comObjective: To develop a practicable nomogram aimed at predicting the risk of severe exacerbations in COPD patients at three and five years.Methods: COPD patients with prospective follow-up data were extracted from Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) obtained from National Heart, Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center. We comprehensively considered the demographic characteristics, clinical data and inflammation marker of disease severity. Cox proportional hazard regression was performed to identify the best combination of predictors on the basis of the smallest Akaike Information Criterion. A nomogram was developed and evaluated on discrimination, calibration, and clinical efficacy by the concordance index (C-index), calibration plot and decision curve analysis, respectively. Internal validation of the nomogram was assessed by the calibration plot with 1000 bootstrapped resamples.Results: Among 1711 COPD patients, 523 (30.6%) suffered from at least one severe exacerbation during follow-up. After stepwise regression analysis, six variables were determined including BMI, severe exacerbations in the prior year, comorbidity index, post-bronchodilator FEV1% predicted, and white blood cells. Nomogram to estimate patients’ likelihood of severe exacerbations at three and five years was established. The C-index of the nomogram was 0.74 (95%CI: 0.71– 0.76), outperforming ADO, BODE and DOSE risk score. Besides, the calibration plot of three and five years showed great agreement between nomogram predicted possibility and actual risk. Decision curve analysis indicated that implementation of the nomogram in clinical practice would be beneficial and better than aforementioned risk scores.Conclusion: Our new nomogram was a useful tool to assess the probability of severe exacerbations at three and five years for COPD patients and could facilitate clinicians in stratifying patients and providing optimal therapies.Keywords: severe exacerbations, COPD, nomogram, prediction model

Xiufeng Zhang,1–3 Dongdong Han,1–3 Pengfei Pei,1–3 Jie Hao,1–3 Yixing Lu,1–3 Peng Wan,1–3 Xianfeng Peng,4 Weibiao Lv,5 Wenguang Xiong,1–3 Zhenling Zeng1–3 1National Laboratory of Safety Evaluation (Environmental Assessment) of Veterinary Drugs, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Veterinary Drugs Development and Safety Evaluation, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 3National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou 510642, People’s Republic of China; 4Guangzhou Insighter Biotechnology Co., Ltd, Guangzhou 510642, People’s Republic of China; 5Department of Clinical Laboratory, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528000, People’s Republic of ChinaCorrespondence: Wenguang Xiong; Zhenling ZengSouth China Agricultural University, Wushan Road, Tianhe District, Guangzhou 510642, People’s Republic of ChinaTel +86 20-85281204Fax +86 20-85284896Email xiongwg@scau.edu.cn; zlzeng@scau.edu.cnBackground: Bacterial infections cause a serious public health crisis due to the emergence of resistance towards multiple conventional antibacterial drugs. In particular, multidrug-resistant (MDR) Enterococcus faecium which belongs to “ESKAPE” organisms is causing significant problems worldwide. Hence, there is an urgent need to find alternative therapies. Recently, substituted benzene guanidine compounds have been used as lead structures to discover new promising drugs in both synthetic and medicinal chemistry.Purpose: Here we investigated the antimicrobial activity of a new substituted benzene guanidine analog, isopropoxy benzene guanidine, against Enterococci.Material and methods: The isopropoxy benzene guanidine was synthesized by Guangzhou Insighter Biotechnology Co., Ltd and tested on both reference bacterial strain and 32 clinical MDR Enterococci strains. The in vitro antibacterial activity was evaluated by microdilution method and kill kinetic assays. The potential antibacterial mechanism was measured by fluorescence spectrometry using fluorescent membrane potential probe 3, 3-diethyloxacarbocyanine iodide (DiOC2 (3)).Results: Isopropoxy benzene guanidine exhibited potent bactericidal activity against both reference strain and MDR Enterococci isolates. The minimum inhibitory concentration (MIC) range for isopropoxy benzene guanidine was 1–4 μg/mL. Minimum bactericidal concentration (MBC) was about 2-8-fold of its MIC values. Time-kill studies showed that isopropoxy benzene guanidine provided superior bactericidal effect against reference and MDR strains within 12 hrs at 2×MIC. Furthermore, isopropoxy benzene guanidine could cause a large reduction in the magnitude of the generated membrane potential compared to that of the untreated cells.Conclusion: The present study highlights the potent bactericidal activity of isopropoxy benzene guanidine on Enterococci by disrupting the cell membrane potential. These findings demonstrate that isopropoxy benzene guanidine may be a good chemical lead for further medicinal chemistry and pharmaceutical development and could be used as a therapeutic agent for infectious diseases caused by MDR Enterococci.Keywords: isopropoxy benzene guanidine, MDR Enterococci, DiOC2, 3, cell membrane potential, bactericidal activity

Xiaoyu Yang,1,* Wenbin Kang,1,* Wei Xiong,1 Dihan Lu,1 Zhibin Zhou,1 Xi Chen,2 Xue Zhou,1,3 Xia Feng1 1Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China; 3MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA*These authors contributed equally to this workCorrespondence: Xue Zhou; Xia FengDepartment of Anesthesiology, First Affiliated Hospital of Sun Yat-Sen University, No. 58 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, People’s Republic of ChinaTel +86-20-87332200-8273Fax +86-020-873355766Email zhoux77@mail.sysu.edu.cn; fengxia@mail.sysu.edu.cnBackground: Femoral nerve block (FNB) has been considered as an excellent analgesic modality in total knee arthroplasty (TKA) pain control. However, relatively high concentration of ropivacaine could lead to quadriceps muscle weakness and increase the risk of postoperative falls.Objective: This double-blinded randomized controlled study was designed to investigate the effect of a combination of dexmedetomidine with a lower concentration of ropivacaine on quadriceps muscle strength and analgesic effect in FNB.Methods: A total of 90 patients scheduled for TKA were randomized to receive continuous FNB postoperatively using 0.2% ropivacaine (H group), 0.1% ropivacaine (L group) or 0.1% ropivacaine combined with 2 μg/kg dexmedetomidine (LD group). Meanwhile, intravenous patient-controlled analgesia with morphine was administered to patients. The primary endpoint was the strength of quadriceps muscle evaluated by manual muscle testing (MMT) and Timed Up and Go test (TUG). The secondary endpoint was the pain scores and morphine consumption among different groups.Results: For MMT, LD group showed higher quadriceps muscle strength than the other two groups (P

Qiuping Xu,1,2 Danhua Lin,1 Xu Li,3 Rendong Xiao,3 Zhiqiang Liu,4 Weimin Xiong,2 Lin Cai,2 Fei He2,51Medical Department, The Affiliated Hospital of Putian University, Putian, Fujian, People’s Republic of China; 2Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Department of Thoracic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 4The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 5Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, People’s Republic of ChinaObjective: In this study, we analyzed the association between genetic variants of genes in the NOTCH signaling pathway and the prognosis of non-small-cell lung cancer (NSCLC) in the Chinese population. We also explored the interaction between genetic and epidemiological factors for the test group.Methods: We performed genotyping of 987 NSCLC patients. Then, we used Cox proportional hazard models to analyze the associations between single-nucleotide polymorphisms (SNPs) and the prognosis of NSCLC. We employed Stata software to test the heterogeneity of associations between subgroups, and we analyzed the additive and multiplicative interactions between SNPs and epidemiologic factors.Results: This work revealed the important prognostic and predictive value of rs915894 in the NOTCH4 gene, which may be regarded as a promising prognosis biomarker of NSCLC. Cox regression analysis indicated that the C allele of rs915894 is associated with longer survival and decreased risk of death in NSCLC (codominant model: adjusted HR =0.83, 95% CI =0.70–0.99; dominant model: adjusted HR =0.83, 95% CI =0.71–0.98). Additional stepwise regression analysis suggested that this SNP is an independently favorable factor for the prognosis of NSCLC (dominant model: adjusted HR =0.85, 95% CI =0.72–0.99). This protective effect is more pronounced for patients who are not smokers, have a history of other lung diseases, or have a family history of cancer. We also detected statistically significant additive and multiplicative interactions between rs915894 and smoking, rs915894 and history of lung diseases, and rs915894 and family history of cancer, which all affect NSCLC survival.Conclusion: This study demonstrated that rs915894 in NOTCH4 may be a genetic marker for NSCLC prognosis in the Chinese population and that rs915894 may have an interactive relationship with epidemiologic factors.Keywords: NOTCH signaling pathway, single-nucleotide polymorphism, non-small-cell lung cancer, interaction, prognosis

Hui Ren,1,2,* Zhihui Chen,1,* Liang Yang,1,* Weixin Xiong,1 Hong Yang,3 Kaiwu Xu,1 Ertao Zhai,1 Li Ding,4 Yulong He,1,2 Xingming Song11Department of Gastrointestinal Surgery Centre, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Center for Digestive Disease, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of China; 3Department of Operating Room, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Department of Pathology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workAim: Identifying high-efficiency prognostic markers for colorectal cancer (CRC) is necessary for clinical practice. Increasing evidence demonstrates that apolipoprotein C1 (APOC1) promotes carcinogenesis in some human cancers. However, the expression status and biological function of APOC1 in CRC remain unclear.Materials and methods: We detected the association between APOC1 expression and clinicopathological features in 140 CRC patients by immunohistochemistry. Small interfering RNA (siRNA) technology was used to downregulate APOC1 expression in CRC cells. Cell proliferation was estimated by CCK8 and clonogenic assays. The cell cycle and apoptosis were analyzed by flow cytometry. Cell migration and invasion were examined by a transwell assay. Gene set enrichment analysis (GSEA) and protein expression of signaling pathways were used to suggest the possible APOC1-associated pathways in CRC.Results: APOC1 was highly expressed in CRC tissues. High immunohistochemistry (IHC) expression of APOC1 was correlated with the N stage, M stage and TNM stage. High IHC APOC1 expression in CRC tissues was associated with poor prognosis. Univariate and multivariate Cox regression analyses showed that APOC1 was an independent risk factor for OS. Cell proliferation of CRC cell lines was inhibited by the downregulation of APOC1. Moreover, si-APOC1 transfection induced cell cycle arrest but low apoptosis increases by regulating the expression of related proteins. Cell migration and invasion were also inhibited by the downregulation of APOC1. The Cancer Genome Atlas Colorectal Adenocarcinoma (TCGA COAD-READ) dataset analyzed by GSEA showed that APOC1 might be involved in the mitogen-activated protein kinase (MAPK) signaling pathway, which was further preliminarily confirmed by Western blotting.Conclusion: APOC1 was overexpressed in CRC tissues, and a high level of APOC1 contributed to a poor prognosis. APOC1 expression influenced the cell proliferation ability and motility capacity of CRC via the MAPK pathway. APOC1 could act as a novel prognostic biomarker in CRC.Keywords: apolipoprotein C1, APOC1, colorectal cancer, prognosis, MAPK signaling

Ming Guan,1,2 Yangmengfan Chen,1 Yong Wei,3 Hao Song,3 Chenghao Gao,1 Hao Cheng,4 Yong Li,1 Kaifu Huo,5 Jijiang Fu,3 Wei Xiong11Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 2Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI 48109-1078, USA; 3The State Key Laboratory of Refractories and Metallurgy, Wuhan University of Science and Technology, Wuhan 430081, People’s Republic of China; 4Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 5Wuhan National Lab for Optoelectronics, Huazhong University of Science and Techonology, Wuhan 430074, People’s Republic of ChinaBackground: Titanium (Ti) implant-associated infection, which is mostly caused by bacterial adhesion and biofilm formation, may result in implant failure and secondary surgery. Thus it is an urgent issue to prevent bacterial infections at the earliest step.Purpose: To develop a novel surface strategy of polydopamine (PDA) and silver (Ag) nanoparticle-loaded TiO2 nanorods (NRDs) coatings on Ti alloy.Materials and methods: Ag-TiO2@PDA NRDs was fabricated on Ti alloy by hydrothermal synthesis. The antibacterial activity of Ag-TiO2@PDA NRDs against Escherichia coli and methicillin-resistant Staphylococcus aureus were tested by FE-SEM, Live/Dead staining, zone of inhibition, bacteria counting method and protein leakage analysis in vitro. In addition, an implant infection model was conducted and the samples were tested by X-ray, Micro-CT and histological analysis in vivo. Besides, cell morphology and cytotoxicity of Mouse calvarial cells (MC3T3-E1) were characterized by FE-SEM, immunofluorescence and CCK-8 test in vitro.Results: Our study successfully developed a new surface coating of Ag-TiO2@PDA NRDs. The selective physical puncture of bacteria and controlled release of Ag+ ions of Ag-TiO2@PDA NRDs achieved a long-lasting bactericidal ability and anti-biofilm activity with satisfied biocompatibility.Conclusion: This strategy may be promising for clinical applications to reduce the occurrence of infection in the implant surgeriesKeywords: bacterial infection, polydopamine, silver nanoparticles, physical puncture, TiO2 nanorods, bactericidal activity

Lingxiao Chen,1,* Wei He,1,* Huichuan Jiang,1,* Longxiang Wu,1 Wei Xiong,1 Bolun Li,1 Zhihua Zhou,2 Yuna Qian3–5 1Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; 2School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan 411201, China; 3Wenzhou Institute of Biomaterials and Engineering, Chinese Academy of Science, Wenzhou, Zhejiang 325001, China; 4School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; 5Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, Chongqing 400045, China *These authors contributed equally to this work Purpose: PB is one of the most severe complications of late stage prostate cancer and negatively impacts patient quality of life. A major challenge for the treatment of cancer bone metastasis is the management of efficient drug delivery to metastatic bone lesion. We aimed to explore the use of aptamers as promising tools to develop a targeted drug delivery system for PBs. Materials and methods: In vivo SELEX was applied to identify bone targeting aptamer in a mouse model with PBs. Results: The aptamer (designated as “PB”) with the highest bone targeting frequency in mice bearing PC3 PB was selected for further analysis. The PB aptamer specifically targeted modulated endothelial cells in response to cancer cells in the bones of mice bearing PC3 PBs. The targeting efficiency of the PB aptamer conjugated to gold particles was verified in vivo. Conclusion: This investigation highlights the promise of in vivo SELEX for the discovery of bone targeting aptamers for use in drug delivery. Keywords: aptamer, tumor endothelial targeting, drug delivery

Wencheng Ding,1,* Teng Ji,1,* Wei Xiong,2 Tian Li,1 Demin Pu,1 Rong Liu1 1Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Department of Pharmacology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Purpose: In this study, we investigated the effect of Realgar on the apoptosis of HPV16-positive cervical cells in vitro. Methods: The effect of Realgar on the apoptosis of HPV16-positive cervical cells was investigated by annexin V-fluorescein isothiocyanate/propidium iodide staining and growth inhibition assays using HPV16-positive cervical cancer cell line SiHa and HPV16-positive immortalized cervical epithelial cell line S12. The expression of genes was measured by real-time PCR, and the expression of corresponding proteins was detected by Western blotting. The adhesion and invasion of cells were detected by adhesion assay and Transwell invasion assay, respectively. Results: The Realgar inhibited the proliferation and induced the apoptosis of SiHa and S12 cells in a dose- and time-dependent manner. The Realgar suppressed the expression of HPV16 E7 and caspase-3. The Realgar suppressed the adhesion and invasion of both cells. Conclusion: The Realgar induced apoptosis, inhibited the proliferation of HPV16-positive cell lines through a HPV16 E7-dependent pathway, and inhibited cell adhesion and invasion. Keywords: Realgar, antitumor, human papillomavirus, E7

Weigang Dai,1,2,* Jian Zhang,1,2,* Weixin Xiong,1,2 Jianbo Xu,1,2 Shirong Cai,1,2 Min Tan,1,2 Yulong He,1,2 Wu Song,1,2 Yujie Yuan1,2 1Center of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, People’s Republic of China; 2Center of Gastric Cancer, Sun Yat-sen University, Guangzhou 510080, Guangdong, People’s Republic of China *These authors contributed equally to this work Background: Laparoscopic right hemicolectomy (LRC) with a principle of D3 lymphadenectomy seems to be appropriate in treatment of right-sided colon cancer (RCC). This study aimed to evaluate clinical efficacy of superior mesenteric artery (SMA)-guided LRC (SLRC) for RCC patients.Patients and methods: Data for RCC patients with radical resection were retrieved from our database and electronic medical records (January 2010 to December 2014). Patients undergoing SLRC procedure were compared with those undergoing conventional laparoscopic right hemicolectomy (CLRC), with a match ratio of 1:2 for group balance. Perioperative and long-term outcomes were compared between two groups.Results: In sum, 102 matched patients were selected, with a median follow-up of 32 (range, 3–68) months. The mean operative time was significantly reduced in the SLRC group compared to the CLRC group (206.9 vs 240.0 minutes, P=0.007), with increased incidence of postoperative complications observed (14.7% vs 8.8%, P=0.499). Average length of stay after surgery (7.4 vs 8.0 days), estimated blood loss (85.3 vs 105.4 mL), number of harvested (28.4 vs 28.2) and positive (0.6 vs 0.9) lymph nodes, and overall costs ($4826.9 vs $4874.6) were comparable between two groups (P>0.05). The 3-year disease-free survival rate (89.4% vs 92.1%, P=0.840) and overall survival rate (93.0% vs 83.1%, P=0.273) were similar in both groups. Older age (≥65 years, P=0.049) and advanced tumor stage (≥II, P=0.009) were independent risk factors of recurrence.Conclusion: The perioperative and oncologic outcomes of SLRC were not superior, but comparable to CLRC. SMA-guided dissection was a feasible surgical approach in treatment of RCC. Keywords: right colon cancer, right hemicolectomy, laparoscopic surgery, D3 lymphadenectomy, outcomes

Zhiqiang Liu,1,2 Yong Lin,3 Shuling Kang,4 Qiuping Xu,2 Weimin Xiong,2 Lin Cai,2 Fei He2,5 1The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China; 2Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, China; 3Clinical Laboratory, Zhongshan Hospital, Medical College of Xiamen University, Xiamen, Fujian, China; 4Fuzhou Center for Disease Control and Prevention, Fuzhou, Fujian, China; 5Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, China Objective: The etiology of lung cancer has been attributed to both environmental and genetic factors. In this study, we investigated the association between five miRNA gene single-nucleotide polymorphisms (SNPs) and the risk of lung cancer, and explored the interaction between genetic and environmental factors in the Han people of China, the ethnic group that represents >90% of the population of the country.Methods: This case–control study included 1,067 cases and 1,085 controls. Epidemiological data were collected by in-person interviews using a standard questionnaire. Matrix-assisted laser desorption/ionization time of flight mass spectrometry was applied to genotype the selected miRNA gene SNPs. Unconditional logistic regression and stratified analysis were used to analyze the associations between these SNPs and lung cancer, and to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Crossover analysis, logistic regression, and the Excel table made by Andersson were used to analyze the combined and interaction effects of gene–environment.Results: The rs12894467 CC/CT genotype was associated with a significantly increased risk for lung cancer in women (adjusted OR =1.46, 95% CI=1.01–2.10). Smokers carrying the CC/CT genotype were associated with a significantly decreased risk of lung cancer, the adjusted OR was 0.75 (95% CI: 0.57–0.98). In the dominant model, rs12894467 and gender were associated with a positive multiplicative interaction; rs12894467 and smoking were associated with a negative multiplicative interaction.Conclusion: The rs12894467 polymorphism was potentially associated with primary lung cancer in the Han Chinese population and had an interactive relationship with environmental factors. Keywords: microRNAs, single-nucleotide polymorphism, lung cancer, case–control studies, susceptibility

Xiaoying Li,1,* Xin Hong,2,* Xianshu Gao,1 Xiaobin Gu,1 Wei Xiong,3 Jing Zhao,4 Hongliang Yu,5 Ming Cui,1 Mu Xie,1 Yun Bai,1 Shaoqian Sun6 1Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China; 2Department of Urology, Peking University International Hospital, Peking University, Beijing, China; 3Department of Oncology, Tangshan People’s Hospital, Hebei, China; 4Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; 5Department of Radiation Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China; 6College of Biochemical Engineering, Beijing Union University, Beijing, China *These authors contributed equally to this work Purpose: In our previous study, we found that AKR1C3 was a radioresistance gene in KY170R cells. Downregulating the expression of AKR1C3 could enhance the radiosensitivity of esophageal carcinoma cells. In this study, we investigated whether methyl jasmonate (MeJ), an inhibitor of Aldo-keto reductase family1 member C3 (AKR1C3), could overcome radiation resistance in AKR1C3 highly expressed cells.Patients and methods: We used clone formation assays to detect radiosensitivity effects. Flow cytometry assays were used to detect reactive oxygen species (ROS) accumulation and apoptosis. Enzyme linked immunosorbent assays (ELISAs) were used to detect the concentrations of prostaglandin F2 (PGF2) and prostaglandin D2 (PGD2) in the cells after incubation with MeJ. Western blotting was used to detect AKR1C3 and peroxisome proliferator-activated receptor gamma (PPARγ) expression.Results: We found that AKR1C3 was highly expressed in radioresistant esophageal carcinoma cells. MeJ inhibited the expression of AKR1C3 and enhanced the radiation sensitivity of esophageal carcinoma cells expressing high levels of AKR1C3 (P0.05).The radiation sensitivity effect of MeJ also depended upon the generation of ROS in KY170R cells; 48 h after irradiation, ROS levels in the MeJ group was twofold higher than in the untreated KY170R cells (P0.05).Conclusion: Our results indicate that MeJ can increase the radiation sensitivity of AKR1C3-overexpressing KY170R cells by inhibiting the 11-ketoprostaglandin reductase activity of AKR1C3 and increasing cellular ROS levels. Keywords: radiosensitivity, esophageal carcinoma, methyl jasmonate, AKR1C3

Wei Xiong,1 Wei Sang,1 Ke Gang Linghu,1 Zhang Feng Zhong,1 Wai San Cheang,1 Juan Li,2 Yuan Jia Hu,1 Hua Yu,1,3,4 Yi Tao Wang1 1Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao SAR, China; 2Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu, China; 3Hong Kong Baptist University Shenzhen Research Center, Shenzhen, Guangdong, China; 4School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China Introduction: Berberine (BBR) is a plant-derived benzylisoquinoline alkaloid and has been demonstrated to be a potential treatment for various chronic diseases. The poor water solubility and P-glycoprotein (Pgp)-mediated drug efflux are the main challenges for its further application in a clinical setting. Materials and methods: In this study, a Brij-S20 (BS20)-modified nanocrystal formulation (BBR-BS20-NCs) has been developed and investigated with the purpose of improving the intestinal absorption of BBR. The physicochemical properties of the developed BBR-BS20-NCs were characterized and the enhancement of the BBR-BS20-NCs on BBR absorption were investigated both in vitro and in vivo. Results: The results indicated that BS20 could significantly enhance the intracellular uptake of BBR in MDCK-MDR1 cells via a short-term and reversible modulation on the Pgp function, accompanied by a marked increase in Pgp mRNA expression but without significant influence on the Pgp protein expression. Moreover, the morphology of the prepared BBR-BS20-NCs was observed to be prism-like, with a smooth surface and an average diameter of 148.0 ± 3.2 nm. Compared to raw BBR and physical mixture, BBR-BS20-NCs facilitated the dissolution rate and extent of release of BBR in aqueous solution, and further increased the absorption of BBR in MDCK-MDR1 monolayer by overcoming the Pgp-mediated secretory transport (Papp[BL-AP] values of 2.85 ± 0.04 × 10-6 cm/s, 2.21 ± 0.14 × 10-6 cm/s, and 2.00 ± 0.07 × 10-6 cm/s for pure BBR, physical mixture, and BBR-BS20-NCs, respectively). Significant improvements in the maximum concentration observed (Cmax) and area under drug concentration-time curve (AUC0–t) of BBR-BS20-NCs were obtained in pharmacokinetic studies compared to pure BBR, and the relative bioavailability of BBR-BS20-NCs to pure BBR was 404.1%. Conclusion: The developed BBR-BS20-NCs combine the advantages of nanocrystal formulation and functional excipient. The novel pharmaceutical design provides a new strategy to improve the oral bioavailability of those drugs with both poor water solubility and Pgp-mediated efflux. Keywords: berberine, poor water solubility, Pgp-mediated drug efflux, Brij, nanocrystals

Haoyu Ren,1 Yifan Shen,2 Daixing Hu,1 Wei He,1 Jing Zhou,1 Yijia Cao,1 Yu Mao,1 Yi Dou,1 Wei Xiong,1 Qi Xiao,1 Yuhong Zhang,2 Xinliang Su1 1Department of Endocrine and Breast Surgery, 2The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China Background: Mutations of BRAFV600E and TERT promoters are associated with thyroid cancer development. This study further investigated association of these mutations with clinicopathological characteristics from patients with papillary thyroid carcinoma (PTC). Methods: Tumor tissues from 342 PTC patients were obtained for DNA extraction and polymerase chain reaction amplification to detect the BRAFV600E mutation using amplification-refractory mutation system-polymerase chain reaction. TERT promoter mutations were assessed using Sanger DNA sequencing. The association of these gene mutations with clinicopathological characteristics was then statistically analyzed. Results: Two hundred and seventy of 342 (78.9%) PTC patients harbored the BRAFV600E mutation, which was associated with older age male patients. Moreover, TERT promoter mutations occurred in 12 of 342 (3.5 %) PTC patients, all of whom also had the BRAF mutation. One hundred thirty-three patients with papillary thyroid microcarcinoma (PTMC) had no TERT mutations. Statistically, the coexistence of BRAF and TERT promoter mutations were significantly associated with older age, larger tumor size, extrathyroidal extension, and advanced tumor stage, but not with central lymph node metastasis, lateral lymph node metastasis, numbers of lymph node metastasis >5, and numbers of involved/harvested lymph nodes (No. of LNs involved or harvested). The multivariate analyses showed older age (odds ratio [OR], 2.194; 95% CI: 1.117–4.311; p=0.023), larger tumor size (OR, 4.100; 95% CI: 2.257–7.450; p

Yi Gong,1,* Jiayang Yin,2,* Boding Tong,2 Jingkun Li,3 Jiexi Zeng,2 Zhongkun Zuo,1 Fei Ye,1 Yongheng Luo,4 Jing Xiao,1 Wei Xiong2 1Department of Minimal Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, China; 2Department of Ophthalmology and Eye Research Center, The Second Xiangya Hospital, Central South University, Changsha, China; 3E.N.T Department, The Second Xiangya Hospital, Central South University, Changsha, China; 4Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China *These authors contributed equally to this work Background: Orbital decompression is an important surgical procedure for treatment of Graves’ ophthalmopathy (GO), especially in women. It is reasonable for balanced orbital decompression of the lateral and medial wall. Various surgical approaches, including endoscopic transnasal surgery for medial wall and eye-side skin incision surgery for lateral wall, are being used nowadays, but many of them lack the validity, safety, or cosmetic effect. Patients and methods: Endoscopic orbital decompression of lateral wall through hairline approach and decompression of medial wall via endoscopic transnasal surgery was done to achieve a balanced orbital decompression, aiming to improve the appearance of proptosis and create conditions for possible strabismus and eyelid surgery afterward. From January 29, 2016 to February 14, 2017, this surgery was performed on 41 orbits in 38 patients with GO, all of which were at inactive stage of disease. Just before surgery and at least 3 months after surgery, Hertel’s ophthalmostatometer and computed tomography (CT) were used to check proptosis and questionnaires of GO quality of life (QOL) were completed. Findings: The postoperative retroversion of eyeball was 4.18±1.11 mm (Hertel’s ophthalmostatometer) and 4.17±1.14 mm (CT method). The patients’ QOL was significantly improved, especially the change in appearance without facial scar. The only postoperative complication was local soft tissue depression at temporal region. Obvious depression occurred in four cases (9.76%), which can be repaired by autologous fat filling. Interpretation: This surgery is effective, safe, and cosmetic. Effective balanced orbital decompression can be achieved by using this original and innovative surgery method. The whole manipulation is safe and controllable under endoscope. The postoperative scar of endoscopic surgery through hairline approach is covered by hair and the anatomic structure of anterior orbit is not impacted. Keywords: orbital decompression, Graves’ ophthalmopathy, hairline approach, endoscopic surgery, lateral wall

Wei Xiong,1 Mei Xu,2 Yunfeng Zhao,3 Xueling Wu,4 Bigyan Pudasaini,1 Jin-ming Liu1 1Department of Cardio-Pulmonary Circulation, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 2Department of Pediatrics, Gongli Hospital, Second Military Medical University, 3Department of Respiratory Medicine, Punan Hospital, 4Department of Respiratory Medicine, Renji Hospital, Jiaotong University School of Medicine, Shanghai, People’s Republic of China Background: The major characteristic of COPD is systemic inflammation. The parameters such as neutrophil-to-lymphocyte ratio (NLR) and eosinophil-to-basophil ratio (EBR) in routine blood test (RBT) are considered to be the underlying biomarkers of inflammation. We hypothesized that the prognosis of patients with COPD can be predicted with RBT. Methods: Patients with COPD in stable stage were enrolled. The RBT, pulmonary function testing (PFT), BODE index, C-reactive protein (CRP), procalcitonin, and erythrocyte sedimentation rate (ESR) were performed at enrollment and every follow-up once in every 3 months during the 24-month follow-up period. Meanwhile, exacerbation count and mortality incidence were recorded. The correlation between the prognostic biomarkers and the prognosis of patients was analyzed. Results: The NLR and EBR in RBT have a significant correlation with the severity of patients with COPD. The NLR is an independent predictor for mortality and the EBR is an independent predictor for exacerbation. Conclusion: As an inexpensive, accessible, and convenient assay, RBT may be used as a practical means in the prediction of prognosis of patients with COPD in future clinical settings. Keywords: COPD, prognosis, inflammation, routine blood test, neutrophil-to-lymphocyte ratio, eosinophil-to-basophil ratio

Na Xu,1,2,* Hao Cheng,3,4,* Jiangwen Xu,1 Feng Li,3 Biao Gao,1 Zi Li,3 Chenghao Gao,3 Kaifu Huo,5 Jijiang Fu,1,2 Wei Xiong3 1The State Key Laboratory of Refractories and Metallurgy, School of Materials and Metallurgy, Wuhan University of Science and Technology, 2Institute of Biology and Medicine, Wuhan University of Science and Technology, 3Orthopaedic Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 5Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, People’s Republic of China *These authors contributed equally to this work Abstract: Antibiotic-resistant bacteria have become a major issue due to the long-term use and abuse of antibiotics in treatments in clinics. The combination therapy of antibiotics and silver (Ag) nanoparticles is an effective way of both enhancing the antibacterial effect and decreasing the usage of antibiotics. Although the method has been proved to be effective in vitro, no in vivo tests have been carried out at present. Herein, we described a combination therapy of local delivery of Ag and systemic antibiotics treatment in vitro in an infection model of rat. Ag nanoparticle-loaded TiO2 nanotube (NT) arrays (Ag-NTs) were fabricated on titanium implants for a customized release of Ag ion. The antibacterial properties of silver combined with antibiotics vancomycin, rifampin, gentamicin, and levofloxacin, respectively, were tested in vitro by minimum inhibitory concentration (MIC) assay, disk diffusion assay, and antibiofilm formation test. Enhanced antibacterial activity of combination therapy was observed for all the chosen bacterial strains, including gram-negative Escherichia coli (ATCC 25922), gram-positive Staphylococcus aureus (ATCC 25923), and methicillin-resistant Staphylococcus aureus (MRSA; ATCC 33591 and ATCC 43300). Moreover, after a relative short (3 weeks) combinational treatment, animal experiments in vivo further proved the synergistic antibacterial effect by X-ray and histological and immunohistochemical analyses. These results demonstrated that the combination of Ag nanoparticles and antibiotics significantly enhanced the antibacterial effect both in vitro and in vivo through the synergistic effect. The strategy is promising for clinical application to reduce the usage of antibiotics and shorten the administration time of implant-associated infection. Keywords: implant-associated infection, silver nanoparticles, TiO2 nanotube, antibiotics, synergistic bactericidal activity

Wei Xiong,1,2 Lixia Peng,1,2 Hongbo Chen,3 Qin Li1,2 1Southern Medical University, Guangzhou, 2Department of Plastic Surgery, General Hospital of Guangzhou Military Command of PLA, Guangzhou, People’s Republic of China; 3Division of Life Sciences and Health, Graduate School at Shenzhen, Tsinghua University, Shenzhen, People’s Republic of China Abstract: To enhance the therapeutic effects of chemotherapy on malignant melanoma, paclitaxel (PTX)-loaded methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles (MPEG-b-PCL NPs) that had their surfaces modified with polydopamine (PTX-loaded MPEG-b-PCL NPs@PDA) were prepared as drug vehicles. The block copolymer MPEG-b-PCL was synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance spectroscopy and gel permeation chromatography. The PTX-loaded NPs were prepared by a modified nanoprecipitation technique. The PTX-loaded NPs and PTX-loaded NPs@PDA were characterized in terms of size and size distribution, zeta potential, surface morphology, drug encapsulation efficiency, and drug release. Confocal laser scanning microscopy showed that coumarin-6-loaded NPs@PDA could be internalized by human melanoma cell line A875 cells. The cellular uptake efficiency of NPs was greatly enhanced after PDA modification. The antitumor efficacy of the PTX-loaded NPs@PDA was investigated in vitro by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and in vivo by a xenograft tumor model. The PTX-loaded NPs@PDA could significantly inhibit tumor growth compared to Taxol® and precursor PTX-loaded NPs. All the results suggested that the PTX-loaded MPEG-b-PCL NPs that had their surfaces modified with PDA are promising nanocarriers for malignant melanoma therapy. Keywords: cancer nanotechnology, drug delivery, surface modification, polydopamine, malignant melanoma

The solenoidal large intensity device (SoLID) is a new experimental apparatus planned for Hall A at the Thomas Jefferson National Accelerator Facility (JLab). SoLID will combine large angular and momentum acceptance with the capability to handle very high data rates at high luminosity. With a slate of approved high-impact physics experiments, SoLID will push JLab to a new limit at the QCD intensity frontier that will exploit the full potential of its 12 GeV electron beam. In this paper, we present an overview of the rich physics program that can be realized with SoLID, which encompasses the tomography of the nucleon in 3D momentum space from semi-inclusive deep inelastic scattering, expanding the phase space in the search for new physics and novel hadronic effects in parity-violating DIS, a precision measurement of J/ψ production at threshold that probes the gluon field and its contribution to the proton mass, tomography of the nucleon in combined coordinate and momentum space with deep exclusive reactions, and more. To meet the challenging requirements, the design of SoLID described here takes full advantage of recent progress in detector, data acquisition and computing technologies. In addition, we outline potential experiments beyond the currently approved program and discuss the physics that could be explored should upgrades of CEBAF become a reality in the future.

Xuguang Qin,1 Weiguo Xiong,1 Enben Guan,2 Chunpeng Lu1 1Department of Cardiology, First Affiliated Hospital of Tsinghua University, Beijing, People’s Republic of China; 2Department of Pediatric, The Affiliated Hospital of Qingdao Medical College, Qingdao, People’s Republic of China Abstract: Coronary artery anomalies (CAAs) are present at birth, but are usually asymptomatic and are found during coronary angiography or multi-slice computed tomography (MSCT) detection. The most common coronary anomaly is the separating origin of left anterior descending coronary artery (LAD) and left circumflex artery (LCX) from the left sinus of Valsalva, and this variant is benign. Herein, we present three extremely rare cases of anomalous right coronary artery (RCA) detected incidentally during routine coronary angiography and confirmed by multi-slice computed tomography (MSCT) technique. All the anomalous right coronary artery coursed between the pulmonary artery and aorta. We discuss how to make an accurate diagnosis for appropriate management. Keywords: coronary anomaly, anomalous right coronary artery, coronary angiography, elderly

Xuguang Qin,1 Weiguo Xiong,1 Li Wang,1 Enben Guan,2 Chunpeng Lu1 1Department of Cardiology, First Affiliated Hospital of Tsinghua University, Beijing, People's Republic of China; 2Department of Pediatric, The Affiliated Hospital of Qingdao Medical College, Shandong Province, People's Republic of China Background: Use of intensive anticoagulation and antiplatelet therapy in acute myocardial infarction (AMI) potentially increases the risk of bleeding complications during percutaneous coronary intervention via the transfemoral route. Recently, the transradial access has been intensively employed as an alternative means for diagnostic and interventional procedures. A low incidence of vascular access site bleeding complications suggests that the transradial access is a safe alternative to the transfemoral technique in patients with AMI. The safety and efficacy of transradial access for emergent percutaneous coronary intervention in patients with AMI has not been investigated in the People's Republic of China. Methods: We analyzed data from our single-center registry on 596 consecutive patients between October 2003 and October 2010. The patients were retrospectively divided into a transradial group (n = 296) and a transfemoral group (n = 300). A dedicated doctor was appointed to collect the following data: puncture time, coronary angiography time, percutaneous coronary intervention time, X-ray exposure time, duration of hospitalization, and complication rates associated with puncture, such as puncture site bleeding, hematoma, pseudoaneurysm, and major adverse cardiac events. Results: There were no significant differences in baseline characteristics and angiographic findings between the two groups. There were also no significant differences in coronary angiography time (8.2 ± 2.4 versus 7.6 ± 2.0 minutes), percutaneous coronary intervention time (30 ± 6.8 versus 29.6 ± 8.1 minutes), or X-ray exposure time (4.6 ± 1.4 versus 4.4 ± 1.3 minutes) between the groups. There were significant differences in puncture time (4.4 ± 1.6 versus 2.4 ± 0.8 minutes) and duration of hospitalization (3.2 ± 1.6 versus 5.4 ± 1.8 days) between the groups (P < 0.001). The complication rate using transradial access was 2.03% (6/296) versus 6.0% (18/300) using transfemoral access (P < 0.0001). Conclusion: Transradial access for emergent percutaneous coronary intervention is safe and effective in patients with AMI, and it is suggested that this route could be used more widely in these patients. Keywords: percutaneous coronary intervention, vascular access, radial artery, stent deployment

The Fe-Zn binary system was re−modeled using exponential equation Li=hi•exp(-T/τi) (i=0,1,2…) to describe the excess Gibbs energy of the solution phases and intermetallic compounds with large homogeneities. A self-consistent set of thermodynamic parameters is obtained and the calculated phase diagrams and thermodynamic properties using the exponential equation agree well with the experimental data. Compared with previous assessments using the linear equation to describe the interaction parameters, the artificial miscibility gap at high temperatures was removed. In addition, the calculated thermodynamic properties of the liquid phase were more reasonable than those resulting from all the previous calculations. The present calculations yield noticeable improvements to the previous calculations.

A new electron scattering experiment (E12-21-003) to verify and understandthe nature of hidden sector particles, with particular emphasis on theso-called X17 particle, has been approved at Jefferson Lab. The search forthese particles is motivated by new hidden sector models introduced to accountfor a variety of experimental and observational puzzles: excess in $e^+e^-$pairs observed in multiple nuclear transitions, the 4.2$\sigma$ disagreementbetween experiments and the standard model prediction for the muon anomalousmagnetic moment, and the small-scale structure puzzle in cosmologicalsimulations. The aforementioned X17 particle has been hypothesized to accountfor the excess in $e^+e^-$ pairs observed from the $^8$Be M1, $^4$He M0, and,most recently, $^{12}$C E1 nuclear transitions to their ground states observedby the ATOMKI group. This experiment will use a high resolution electromagneticcalorimeter to search for or set new limits on the production rate of the X17and other hidden sector particles in the $3 - 60$ MeV mass range via their$e^+e^-$ decay (or $\gamma\gamma$ decay with limited tracking). In thesemodels, the $1 - 100$ MeV mass range is particularly well-motivated and thelower part of this range still remains unexplored. Our proposed directdetection experiment will use a magnetic-spectrometer-free setup (the PRadapparatus) to detect all three final state particles in the visible decay of ahidden sector particle for an effective control of the background and willcover the proposed mass range in a single setting. The use of thewell-demonstrated PRad setup allows for an essentially ready-to-run anduniquely cost-effective search for hidden sector particles in the $3 - 60$ MeVmass range with a sensitivity of 8.9$\times$10$^{-8}$ - 5.8$\times$10$^{-9}$ to$\epsilon^2$, the square of the kinetic mixing interaction constant betweenhidden and visible sectors.