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Su-Hua Yang,1,&ast; Yi-Shan He,2,&ast; Shu-Qin Zheng,3 Xiu-Jun Zhang,3 Hong Dai,1,&ast; Yuan Xue2,3,&ast; 1Department of General Surgery, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China; 2Department of Infectious Diseases, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China; 3Institute of Hepatology, Changzhou Third People’s Hospital, Changzhou, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Dai, Department of General Surgery, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China, Email daihong@njmu.edu.cn Yuan Xue, Institute of Hepatology, Changzhou Third People’s Hospital, Changzhou Medical Center, Nanjing Medical University, No. 300 Lanling North Road, Changzhou, Jiangsu, 213000, People’s Republic of China, Tel +86 519 82009059, Email xueyuan@njmu.edu.cnAim: This study aimed to explore the effects of the triglyceride-glucose (TyG) index on hepatocellular carcinoma (HCC) development in patients with hepatitis B virus (HBV)-related liver cirrhosis (LC).Methods: A total of 242 patients with HBV-related LC were enrolled and followed-up. Logistic regression analysis was performed to investigate risk factors for HCC.Results: The median follow-up time was 37 months (range: 6– 123 months). At the end of the follow-up, 11 (11.3%) patients with compensated cirrhosis (CC) and 45 (31.0%) with decompensated cirrhosis (DC) developed HCC. The TyG index was higher in the HCC group than in the non-HCC group (P=0.05). Univariate analysis showed that age (P< 0.01), DC (P< 0.01), TyG index (P=0.08), albumin (ALB) level (P=0.05), platelet (PLT) count (P< 0.01), and HBV DNA positivity (P< 0.01) were associated with HCC development. Multivariate analysis revealed that age, DC, TyG index, PLT count, and HBV DNA positivity were independent risk factors for HCC development (P=0.01, 0.01, < 0.01, 0.05, and < 0.01, respectively). For patients with DC, multivariate logistic regression analysis revealed that age, TyG index, and HBV DNA positivity were independent risk factors for HCC development (all P< 0.05). A new model encompassing age, DC, TyG, PLT, and positive HBV DNA had optimal predictive accuracy in patients with DC or CC, with a cutoff value of 0.197. The areas under the receiver operating characteristic curves (AUROCs) of the model for predicting HCC development in patients with LC, DC, and CC were 0.778, 0.721, and 0.783, respectively.Conclusion: TyG index was identified as an independent risk factor for HCC development in patients with LC.Keywords: hepatocellular carcinoma, triglyceride-glucose index, insulin resistance, liver cirrhosis, decompensated cirrhosis

Cheng-Fu Wang,1 Bao-Jun Chen,1 Bo Luan,1 Yong Wang,2 Xiao-Jiao Zhang,1 Hai-Bo Qu1 1Department of Cardiology, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang, People’s Republic of China; 2Department of Cardiology, Shenzhen Luohu Hospital Group Luohu People’s Hospital (The Third Affiliated Hospital of Shenzhen University), Shenzhen, People’s Republic of ChinaCorrespondence: Hai-Bo Qu, Email drquhaibo@163.comBackground: Retrograde guidewire (GW) tracking success via a poor septal collateral channel (CC) when an antegrade approach fails is crucial for successful revascularization of coronary chronic total occlusion (CTO) with poor septal CC. However, the incidence, predictors, and management strategies for retrograde GW tracking failure via poor septal CC remain unclear.Methods: In total, 122 CTO patients who underwent retrograde septal percutaneous coronary intervention (PCI) with poor CC between January 2017 and May 2022 were retrospectively analyzed. Patients were divided into the retrograde GW tracking success group (success group) and the retrograde GW tracking failure group (failure group). Clinical and angiographic data were compared to investigate the predictors of retrograde GW tracking failure.Results: The incidence of GW tracking failure was 22.1% (27/122). Patients in the failure group had a higher prevalence of left anterior descending artery (LAD) CTO (66.7% vs 37.9%; p = 0.009) and a higher incidence of well-developed non-septal collateral (66.7% vs 30.5%; p = 0.001). Patients with a septal CC diameter ≥ 1 mm (48.1% vs 70.5%; p = 0.040), ≥ 3 septal CCs (44.4% vs 66.3%; p = 0.046), and initial retrograde application of Guidezilla (37.0% vs 60.0%; p = 0.048) were significantly lower in the failure group than in the success group. The binary logistics regression model showed that a CC diameter < 1 mm, well-developed non-septal collateral, and LAD CTO were independent predictors for GW tracking failure in patients undergoing retrograde CTO PCI via poor septal CC.Conclusion: The success rate of retrograde GW tracking via poor septal CC was high, with a relatively high procedural success rate. A CC diameter < 1 mm, well-developed non-septal collateral, and LAD CTO were independent predictors of GW tracking failure in patients undergoing retrograde CTO PCI via poor septal CC.Keywords: coronary chronic total occlusion, retrograde, PCI, septal collateral channels

Xiao-Jie Zhang,1 Jian-Guo Zhou,1 Miao Pan,1 Wei Yuan,2 Bo Gao1 1Department of Pharmacy, General Hospital of Yangquan Coal Industry Group, Yangquan, People’s Republic of China; 2Department of Oncology and Interventional Radiology, Yangquan Hospital of Shanxi Medical University, Yangquan, People’s Republic of ChinaCorrespondence: Wei Yuan, Department of Oncology and Interventional Radiology, Yangquan Hospital of Shanxi Medical University, No. 218 of North Street, Mining District, Yangquan, 045000, People’s Republic of China, Tel/Fax +86 131 6212 9135, Email lvyingyw@126.com Bo Gao, Department of Pharmacy, General Hospital of Yangquan Coal Industry Group, Yangquan, People’s Republic of China, Tel/Fax +86 139 3539 8859, Email gaobo12@um.gt.cnObjective: Through analyzing the characteristics and influencing factors of adverse drug reactions/adverse events (ADR/ADE) in a hospital to promote rational drug use in the clinic.Methods: A total of 1221 ADR/ADE reports collected from a hospital in 2022 were retrieved through the National Adverse Drug Reaction Monitoring Center. The effective reports were screened according to the Guiding Principles for Collection and Reporting of Individual Adverse Drug Reactions, and classified the standardized drugs. The systems/organs and main clinical symptoms affected by ADR/ADE were classified according to the WHO Glossary of Adverse Drug Reaction Terms. The severity, age and gender, occupational distribution, drug category, route of administration, drug dosage form, system/organ involved, and main clinical symptoms of ADR/ADE reports were analyzed.Results: Among 1221 ADR/ADE reports, 890 cases (75.27%) reported by doctors; 144 cases (11.79%) were serious; Precisely 49.22% of ADR/ADE occurred in patients aged 51 to 70 years old; The highest incidence of adverse reactions was 636 cases (52.09%) by intravenous infusion, 406 cases (33.25%) by oral administration. The top categories of reported cases were anti-infective drugs (29.40%) and anti-tumor drugs (27.52%); Systems/organs involved in ADR/ADE were mainly the skin and its accessories (24.96%) and blood system (21.35%). 166 cases were cured, 893 cases were symptomatic, 160 cases were unknown, and 2 cases had sequelae.Conclusion: The occurrence of ADR/ADE is related to many influencing factors such as age, drug categories, and route of administration. Therefore, it is recommended that hospitals strengthen the monitoring of ADR/ADE, especially the elderly, anti-infective drugs and intravenous administration.Keywords: adverse drug reactions, adverse events, report analysis, the rational use of drugs

Xiao-Yan Wang,1 Xiao-Jing Zhang,2 Xiao Xia,3 Shu-Zhen Chang,4 An-Zhao Wu4 1Infectious Diseases Department II, Shandong Public Health Clinical Center, Jinan, 250000, People’s Republic of China; 2Public Health Department, Shandong Public Health Clinical Center, Jinan, 250000, People’s Republic of China; 3Medical Insurance Office, Shandong Public Health Clinical Center, Jinan, 250000, People’s Republic of China; 4TCM & Western Medicine Department, Shandong Public Health Clinical Center, Jinan, 250000, People’s Republic of ChinaCorrespondence: An-Zhao Wu, TCM & Western Medicine Department, Shandong Public Health Clinical Center, 2999 Gangxing West Road, High Tech District, Jinan, 250000, People’s Republic of China, Tel +86 531-86568184, Email anzhaowu564@outlook.comObjective: This study aimed to analyze the epidemiological and clinical characteristics of measles in Jinan, Shandong, China, over a 32-year stage to facilitate measles prevention in the future.Methods: Data on measles cases from 1991 to 2022 were obtained from the public health department and medical records of patients at Shandong Public Health Clinical Center. Retrospective analysis was conducted on the distribution of measles cases in different years, months, and age groups, and observation of the differences in clinical manifestations and complications among different age groups.Results: From January 1991 to December 2022, 7531 measles cases were recorded at Shandong Public Health Clinical Center. During the 32-year period, there were two outbreaks of measles in 2008 and 2016, respectively. During the COVID-19 pandemic period from 2020 to 2022, the number of cases reached the lowest point in the past 30 years. The number and percentage of cases in the 0– 1y groups was significantly higher than in other age groups, and 97.75% patients in this group did not receive measles vaccine. Complications such as pneumonia and myocarditis appeared more frequent in patients under 12 years of age, but liver function damage is more common in adult patients.Conclusion: Although the measles epidemic has been greatly controlled since the use of measles vaccine, intermittent outbreaks still exist, so there is still a long way to go to eliminate measles. The proportion of infants under the age of 1 without measles vaccine and adults over 24 years old accounts for nearly 80% of the total. This group of people should be of concern, and feasible measures should be designated to protect these susceptible populations.Keywords: measles, epidemiology, clinical characteristics, vaccination, China

Zhen-Hua Li,1,&ast; Jie Wang,1,&ast; Xin Cheng,1,&ast; Yi-Cheng Mao,1 Kang-Di Zhang,1 Wen-Jie Yu,1 Ying-Qing Li,1 Kai Huang,1,2 Kun Ding,1 Xiao-Jing Yang,1 Cheng-Yang Hu,3 Xiu-Jun Zhang1,4 1Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Hospital Infection Prevention and Control, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Humanistic Medicine, School of Humanistic Medicine, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 4Center for Evidence-Based Practice, Anhui Medical University, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cheng-Yang Hu; Xiu-Jun Zhang, Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China, Tel/Fax +86 551 65167031 ; +86 551 65169635, Email cy.hu@ahmu.edu.cn; zhangxiujun@ahmu.edu.cnBackground: There is growing evidence that the COVID-19 pandemic has had a dramatic impact on public mental health. However, less attention has been paid to left-behind experience college students (LBEs). This online study aimed to investigate the relationship between psychological capital (PsyCap) and anxiety among LBEs during COVID-19 pandemic, and further analyze the mediation role of self-esteem between them.Methods: A total of 9990 students were chosen using the stratified cluster sampling method. Three self-reported questionnaires were used to assess the PsyCap, self-esteem, and anxiety, respectively. All the statistical analyses were conducted using SPSS 23.0 and R, and to further investigate the mediation effect of self-esteem in the association of PsyCap with anxiety, AMOS 23.0 was used to build a structural equation model.Results: PsyCap, self-esteem, and anxiety were significantly correlated among LBEs during the COVID-19 pandemic. PsyCap affects anxiety directly (β = – 0.22, SE = 0.051, 95% CI: – 0.27, – 0.17, P < 0.05). In addition, self-esteem partially mediated the relationship between PsyCap and anxiety (mediating effect value = – 0.16, 95% CI: – 0.20, – 0.13, P < 0.05).Conclusion: During the pandemic of COVID-19, left-behind experience had a negative influence on the PsyCap and self-esteem of college students. In addition, for LBEs, self-esteem plays an important mediating role between PsyCap and anxiety. Therefore, from the perspective of PsyCap and self-esteem, schools should translate them into practical educational strategies to enhance the mental health and mitigate the anxiety levels of LBEs.Keywords: left-behind experience, COVID-19, psychology, mental health

Xiao-Hui Song,1,&ast; Bo Liu,2,3,&ast; Fang Lei,2,4 Ye-Mao Liu,2,5,6 Xingyuan Zhang,2,4 Ze Chen,7 Peng Zhang,2,4 Xiao-Jing Zhang,2,4 Zhi-Gang She,1,2 Jingjing Cai,2,8 Jin-Hua Wang,9 Hongliang Li1– 3,6 1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Institute of Model Animal, Wuhan University, Wuhan, People’s Republic of China; 3Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 4School of Basic Medical Science, Wuhan University, Wuhan, People’s Republic of China; 5Department of Cardiology, Huanggang Central Hospital of Yangtze University, Huanggang, People’s Republic of China; 6Huanggang Institute of Translational Medicine, Huanggang Central Hospital of Yangtze University, Huanggang, People’s Republic of China; 7Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 8Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 9Department of Neurology, Huanggang Central Hospital of Yangtze University, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongliang Li, Department of Cardiology, Renmin Hospital of Wuhan University, Luojia Mount Wuchang, Wuhan, 430072, People’s Republic of China, Tel/Fax +86-27-68759302, Email lihl@whu.edu.cn Jin-Hua Wang, Department of Neurology, Huanggang Central Hospital of Yangtze University, Hubei, 438000, People’s Republic of China, Email wangjinhua1985@qq.comPurpose: Emerging evidence suggested that metabolic dysfunction-associated fatty liver disease (MAFLD) was significantly associated with atherosclerotic diseases. Atherosclerosis in the peripheral arteries is the most common cause of peripheral arterial disease (PAD), which has not been substantially controlled in the past. We aimed to investigate the association between MAFLD and PAD in the Chinese population.Patients and Methods: This observational study covered 102,115 participants who underwent health checkups with detailed examinations for PAD and MAFLD. PAD was measured by ankle-brachial index, and MAFLD was diagnosed by abdominal ultrasound. The generalized linear mixed models and random-effects Cox proportional hazards models were used to analyze the relationship between MAFLD and PAD.Results: The baseline characteristics showed that patients with MAFLD had higher prevalence of PAD compared with those without MAFLD (2.7% vs 2.2%). Compared to non-MAFLD, the individuals with MAFLD were associated with a higher risk of the presence of PAD (adjusted odds ratio: 1.30, 95% confidence interval (CI): 1.19– 1.42, P < 0.001). In the prospective cohort study, 6833 participants underwent a follow-up of 2.76 (standard deviation: 1.36) years, and MAFLD at baseline was a higher risk of associated with incident PAD (adjusted hazards ratio: 1.67, 95% CI: 1.17– 2.38, P = 0.005). Moreover, with the accumulation of metabolic abnormalities, the risk of the PAD was increased in the individuals with MAFLD. Furthermore, MAFLD attributed risk of PAD was more evident in participants without metabolic comorbidities.Conclusion: MAFLD was associated with a significantly higher risk for the prevalence and incidence of PAD in the Chinese population. The finding suggested that individuals with MAFLD are not only have a higher risk of coronary heart diseases but also have an increased risk of atherosclerosis in peripheral arteries.Keywords: chronic liver disease, metabolic disorder, arteriosclerosis, cross-sectional study, prospective cohort study

Lijin Lin,1– 4,&ast; Ze Chen,4,5,&ast; Ting Ding,1,2,&ast; Hui Liu,4,6,&ast; Feng Zhou,4,7 Xuewei Huang,3,4 Xingyuan Zhang,4,8 Weifang Liu,4,8 Bing-Hong Zhang,9 Yufeng Yuan,10 Peng Zhang,4,8 Xiao-Jing Zhang,4,8 Zhi-Gang She,3,4 Jingjing Cai,4,11 Wenping Chen,1,2 Hongliang Li2– 4,7 1Department of Endocrinology, Huanggang Central Hospital, Huanggang, People’s Republic of China; 2Huanggang Institute of Translational Medicine, Huanggang, People’s Republic of China; 3Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 4Institute of Model Animal of Wuhan University, Wuhan, People’s Republic of China; 5Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 6Neonatology of Gastroenterology, Tongren Hospital of Wuhan University & Wuhan Third Hospital, Wuhan, People’s Republic of China; 7Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 8Basic Medical School of Wuhan University, Wuhan, People’s Republic of China; 9Neonatology Department, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 10Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 11Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongliang Li; Wenping Chen Email lihl@whu.edu.cn; chenwenping@hgyy.org.cnPurpose: To analyze the impact of hyperglycemia on the clinical outcome of COVID-19 in patients with newly diagnosed diabetes (NDD).Patients and Methods: We performed a retrospective study of 3114 cases of COVID-19 without pre-existing diabetes, 351 of which had NDD, in Hubei Province, China. The Cox regression model was used to calculate the risk of adverse clinical outcomes comparing the NDD vs non-NDD group before and after propensity score-matched (PSM) analysis. Patients with NDD were further divided into a sustained hyperglycemia group, a fluctuating group, and a remitted group based on their blood glucose levels during hospitalization as well as into hypoglycemic agent users and nonusers.Results: Compared to the non-NDD individuals, individuals with NDD had a significantly increased risk of all-cause mortality (adjusted HR after PSM, 2.65; 95% CI, 1.49– 4.72; P = 0.001) and secondary outcomes involving organ damage during the 28-day follow-up period. Subgroup analyses indicated that among individuals with NDD, the individuals with remitted hyperglycemia had the lowest 28-day mortality, whereas those with sustained hyperglycemia had the highest (IRR 24.27; 95% CI, 3.21– 183.36; P < 0.001). Moreover, individuals treated with hypoglycemic agents had significantly lower all-cause mortality than those not treated with hypoglycemic agents (IRR 0.08; 95% CI, 0.01– 0.56; P < 0.001).Conclusion: Our study reinforces the clinical message that NDD is strongly associated with poor outcomes in COVID-19 patients. Furthermore, resolved hyperglycemia in the later phase of the disease and the use of hypoglycemic agents were associated with improved prognosis in patients with NDD.Keywords: COVID-19, newly diagnosed diabetes, hyperglycemia, prognosis, blood glucose

Hong-Yan Ren,1 Xiao-Ju Zhang,1 Kun Zhang,2 Tian-Xiao Li,2 Bu-Lang Gao,2 Zheng-Xian Chen3 1Department of Respiratory and Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Interventional Therapy, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 3Department of Respiratory Medicine, Zhongshan University Sixth Affiliated Hospital, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Tian-Xiao Li Tel +8615981836911Email syylitianxiao@126.comIntroduction: This study was to develop a simple model for predicting malignancy of peripheral pulmonary lesions (PPLs) based on endobronchial ultrasonography (EBUS) and clinical findings.Methods: Patients who had EBUS for PPLs were analyzed and compared on the EBUS imaging characteristics and clinical data. The malignancy prediction model was established by the logistic equation of probability of malignant PPL based on the data of 135 patients. The model was tested on an additional 50 patients for efficiency.Results: Among 135 prospectively enrolled patients, 77 (57%) patients had malignant and 58 (43%) had benign lesions with the size of 36.5± 19.9 mm. Univariate analysis demonstrated a significant (P< 0.05) difference in the serum CEA (borderline 15 μg/mL) and smoking history between malignant and benign lesions but a non-significant (P> 0.05) difference in age (50 years as the cutoff value) and history of extra-thoracic malignancies. Logistic analysis of multiple factors showed that smoking history, serum CEA, borderline, air bronchogram, heterogeneous echo, and anechoic areas were significant (P< 0.02) risk factors for malignant lesions. The malignancy prediction model was established by the logistic equation of probability of malignant PPL (P) = l/[l+e–Z], where Z=− 2.986+1.993X1+2.293X2+l.552X3+1.616X4– 2.011X5+1.718X6, e is the base of the natural logarithm, X1 is the smoking history, X2 is the serum CEA, X3 is the borderline, X4 is the heterogenicity, X5 is the air bronchogram, and X6 is the anechoic area. The receiver operating characteristic curve had an area under the curve (AUC) of 0.926 (95% confidence interval: 0.883– 0.969). The sensitivity, specificity, and accuracy were 88.2% (30/34), 75.0% (12/16), and 92.0% (46/50), respectively, for the logistic equation to predict the malignancy.Conclusion: Endobronchial ultrasonography is a safe and practical method, and the model combining EBUS and clinical data can accurately predict the malignancy of peripheral pulmonary lesions.Keywords: endobronchial ultrasonography, peripheral pulmonary lesions, malignancy, benign, prediction model

Yong Wang, Xiao-jiao Zhang, Hong-wei Zhao, Chengfu Wang, Defeng Luo, Qingkun Meng, Yu Zhu, Jie Tao, Baojun Chen, Yi Li, Aijie Hou, Bo Luan Department of Cardiology, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, Shenyang City, Liaoning Province 110016, People’s Republic of ChinaCorrespondence: Bo Luan; Aijie HouDepartment of Cardiology, The People’s Hospital of China Medical University, The People’s Hospital of Liaoning Province, No. 33, Wenyi Road, Shenhe District, Shenyang City, Liaoning Province 110016, People’s Republic of ChinaTel +86-17702488970Email luanbo2016@163.com; 1758624242@qq.comBackground: Retrograde microcatheter collateral channel (CC) tracking after successful wiring of septal CC is crucial for retrograde revascularization of coronary chronic total occlusion (CTO). However, the incidence, predictors, and strategies for failure of retrograde microcatheter CC tracking after successful wiring of septal CC remain unclear.Methods: In total, 298 patients with CTO who underwent retrograde septal CC PCI between January 2015 and May 2019 were retrospectively analyzed. Clinical data were compared to investigate the predictors of initial microcatheter tracking failure.Results: The initial and final microcatheter tracking success rates were 79.2% (236/298) and 96.6% (288/298), respectively. The procedural success rate was 94.0% (280/298). The right coronary artery-to-left anterior descending artery septal ratio (48.4% vs 33.1%, p=0.037) and CC tortuosity (34.6% vs 20.8%, p=0.045) were significantly higher in the initial microcatheter CC tracking failure group than in the successful tracking group. Multivariate logistic regression analysis revealed that severe collateral tortuosity (odds ratio [OR]: 13.241, 95% confidence interval [CI]: 3.429– 27.057, p=0.038), CC entry angle of < 90° (OR:4.921, 95% CI: 1.128– 9.997, p=0.002), CC exit angle of < 90° (OR:5.037, 95% CI: 2.237– 11.182, p=0.004), use of Finecross MG as initial microcatheter (OR:1.826, 95% CI: 1.127– 3.067, p=0.035), and shunning initial retrograde application of Guidezilla (OR:0.321, 95% CI: 0.267– 0.915, p=0.024) were variables independently associated with initial microcatheter CC tracking failure in patients with CTO undergoing retrograde septal CC PCI.Conclusion: The overall initial microcatheter CC tracking failure was 20.8%. Severecollateral tortuosity, CC entry, and exit angle of < 90°, use of Finecross MG as initial microcatheter, and shunning initial retrograde application of Guidezilla were variables independently associated with initial microcatheter CC tracking failure in patients with CTO undergoing retrograde septal PCI.Keywords: coronary chronic total occlusion, retrograde microcatheter tracking, collateral channel, predictor

Li Yuan Wei,1,* Xiao Jun Zhang,1,* Li Wang,2 Li Na Hu,3 Xu Dong Zhang,4,5 Li Li,3 Jin Nan Gao1 1Department of Breast Surgery, Shanxi Bethune Hospital, Taiyuan, People’s Republic of China; 2School of Basic Medicine Sciences, Academy of Medical Science, Zhengzhou University, Henan 450053, People’s Republic of China; 3Department of Pathology, Shanxi Bethune Hospital, Taiyuan, People’s Republic of China; 4Translational Research Institute, Henan Provincial People’s Hospital, Academy of Medical Science, Zhengzhou University, Henan 450053, People’s Republic of China; 5School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia*These authors contributed equally to this workCorrespondence: Jin Nan GaoDepartment of Breast Surgery, Shanxi Bethune Hospital, Taiyuan 030000, People’s Republic of ChinaTel +86 0351- 8379761Email sxjinnan@aliyun.comLi LiDepartment of Pathology, Shanxi Bethune Hospital, Taiyuan 030000, People’s Republic of ChinaTel +86-13453163501Email limuzi73@163.comPurpose: Pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) is associated with favourable outcomes of patients with triple-negative breast cancer (TNBC). However, a proportion of TNBC patients with the residual disease do not relapse and achieve long-term survival. The aim of this study was to identify biomarkers that predict clinical outcomes in these patients.Patients and Methods: A retrospective series of 10 TNBC patients who displayed non-pCR to NACT were included in the discovery cohort. Total RNA from pre-NACT core biopsies and paired surgical specimens were subjected to the Affymetrix Human Transcriptome Array. Gene set enrichment analysis (GSEA) was used to identify signal pathways and gene signatures associated with metastasis. The Cox proportional hazard model and Kaplan–Meier survival curves were employed to assess the prognostic value of the identified signature in two independent TNBC datasets included in Gene Expression Omnibus (GEO).Results: The epithelial–mesenchymal transition (EMT) pathway was markedly more enriched in pre- (NES = 1.92; p.adjust = 0.019) and post-NACT samples (NES = 2.02; p.adjust = 0.010) from patients who developed metastasis after NACT. A subset of 6 EMT genes including LUM, SFRP4, COL6A3, MMP2, CXCL12, and HTRA1 were expressed constantly at higher levels in samples from patients who progressed to metastatic disease. The potential of the 6-EMT gene signature to predict TNBC metastasis after NACT was validated with a GEO dataset (HR=0.36, p=0.0008, 95% CI: 0.200– 0.658). Moreover, the signature appeared of predictive value in another GEO dataset of TNBC patients who received surgery followed by adjuvant chemotherapy (HR = 0.46, 95% CI: 0.225– 0.937).Conclusion: Expression analysis of the 6-EMT gene signature at diagnosis may be of predictive value for metastasis in TNCB patients who did not achieve pCR to NACT and for patients treated with surgery in combination with adjuvant therapy.Keywords: triple-negative breast cancer, neoadjuvant chemotherapy, epithelial–mesenchymal transition, distant metastasis

Qian-Kun Yang,1,* Yan-Na Su,2,* Wei Wang,1,* Nan Wang,3 Zhong-Xiang Yao,4,* Xiao-Jing Zhang1 1Department of Bone and Soft Tissue Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of China; 2Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110042, People’s Republic of China; 3Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of China; 4Department of Physiology, Army Medical University, Chongqing 400038, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Jing ZhangDepartment of Bone and Soft Tissue Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, People’s Republic of ChinaEmail zhangxiaojing@cancerhosp-ln-cmu.comBackground: Nutritional and immune status is paramount for the overall survival (OS) of patients with advanced osteosarcoma. Comprehensive prognostic predictors based on the two indices are scarce. This study aimed to construct and validate individualized web dynamic nomograms based on CONUT score or/and peripheral blood CD4+/CD8+ ratio for OS in patients with advanced osteosarcoma.Materials and Methods: The clinical data of 376 advanced osteosarcoma patients from January 2000 to December 2019 were retrospectively collected. Data from the 301 patients (diagnosed in the first 15 years) were used as the development set and data from the remaining 75 patients were assigned as the validation set. Multivariate Cox regression analyses were conducted and three prediction models were constructed, namely, CD4+/CD8+ ratio univariate model (model 1), CONUT score univariate model (model 2), and CD4+/CD8+ ratio plus CONUT score (model 3). These models were visualized by conventional nomograms and individualized web dynamic nomograms, and their performances were further evaluated by C-index, calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA), respectively.Results: In multivariate Cox analysis, age, metastasis, ALP, CD4+/CD8+ ratio, chemotherapy, and CONUT score were identified as independent prognostic factors for OS. The calibration curves of the three models all showed good agreement between the actual observation and nomogram prediction for 1-year overall survival. In the development set, the C-index and area under the curve (AUC) of model 3 (0.837, 0.848) were higher than that of model 1 (0.765, 0.773) and model 2 (0.712, 0.749). Similar trends were observed in the validation set. The net benefits of model 3 were better than the other two models within the threshold probability of 36– 80% in DCA.Conclusion: CONUT score and peripheral CD4+/CD8+ ratio are easily available, reliable, and economical prognostic predictors for survival prediction and stratification in patients with advanced osteosarcoma, but the two predictors combined can establish a better prognosis prediction model.Keywords: CONUT score, osteosarcoma, survival, nomogram

Yun-Qi Wang,1,2 Xian-Jie Zhang,1 Ying Wang11Department of Anesthesiology, People’s Hospital of Deyang City, Sichuan, People’s Republic of China; 2Department of Anesthesiology, The Sixth People’s Hospital of Deyang City, Sichuan, People’s Republic of ChinaCorrespondence: Ying WangDepartment of Anesthesiology, People’s Hospital of Deyang City, No. 173, Section 1, Taishan North Road, Deyang City, Sichuan Province, People’s Republic of ChinaEmail 459088699@qq.comObjective: Intrathecal dexmedetomidine has been used in spinal anesthesia during cesarean sections. The purpose of this meta-analysis was to investigate the effect of intrathecal dexmedetomidine on the adverse reactions of spinal anesthesia during cesarean section.Methods: We searched for relevant studies using PubMed, Web of Science, and the Cochrane library. After screening studies and extracting data, we performed a meta-analysis on the effect of intrathecal dexmedetomidine during cesarean section.Results: A total of 278 patients from 4 studies were included in this meta-analysis. The incidence of shivering in the dexmedetomidine groups was significantly lower than that in the placebo groups during cesarean section (RR=0.40, 95% CI [0.25, 0.65], P=0.0002). Intrathecal dexmedetomidine had no effect on nausea and vomiting (RR=1.08, 95% CI [0.68, 1.71], P=0.74), bradycardia (RR=1.33, 95% CI [0.31, 5.76], P=0.70), and hypotension during cesarean section (RR=0.78, 95% CI [0.59, 1.03], P=0.08).Conclusion: Intrathecal dexmedetomidine can effectively reduce the occurrence of shivering during cesarean section, but it does not affect the occurrence of nausea and vomiting, bradycardia or hypotension.Keywords: dexmedetomidine, cesarean section, spinal anesthesia, adverse reactions

Yong-Liang Yuan,1,* Neng Jiang,2,* Ze-Yun Li,1 Zhi-Zhen Song,1 Zhi-Heng Yang,1 Wen-Hua Xue,1 Xiao-Jian Zhang,1 Yue Du11Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Pharmacy, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaCorrespondence: Yong-Liang Yuan; Yue DuDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Jianshe East Road 1, Zhengzhou, Henan 450052, People’s Republic of ChinaTel/fax +86 03 716 629 5651Email yylcpu@126.com; fccduy@zzu.edu.cn*These authors contributed equally to this workPurpose: Polyphyllin VI, a main active saponin isolated from traditional medicinal plant Paris polyphylla, has exhibited antitumor activities in several cancer cell lines. In the present study, we investigated the antitumor effect of Polyphyllin VI against human osteosarcoma cells (U2OS) and the underlying molecular mechanisms.Methods: The U2OS cell lines were used to determine the antiproliferative effect of Polyphyllin VI by CCK8 assay. Cell cycle was analyzed by flow cytometry. The Polyphyllin VI-induced apoptosis was determined by Annexin V-APC/7-AAD apoptosis detection kit and JC-1 staining. Meanwhile, the autophagy was determined by acridine orange staining. The apoptosis and autophagy-related proteins were monitored by Western blot assay. Subsequently, intracellular hydrogen peroxide (H2O2) and the activation of ROS/JNK pathway were detected.Results: Polyphyllin VI could potently inhibit cell proliferation by causing G2/M phase arrest. Polyphyllin VI induced mitochondria-mediated apoptosis with the upregulation of proapoptotic proteins Bax and poly ADP-ribose polymerase, and downregulation of antiapoptotic protein Bcl-2 in U2OS cells. Concomitantly, Polyphyllin VI provoked autophagy with the upregulation of critical Atg proteins and accumulation of LC3B-II. Intracellular H2O2 production was triggered upon exposure to Polyphyllin VI, which could be blocked by ROS scavenger. Polyphyllin VI dramatically promoted JNK phosphorylation, whereas it decreased the levels of phospho-p38 and ERK.Conclusion: Our results reveal that Polyphyllin VI may effectively induce apoptosis and autophagy to suppress cell growth via ROS/JNK activation in U2OS cells, suggesting that Polyphyllin VI is a potential drug candidate for the treatment of osteosarcomas.Keywords: Polyphyllin VI, osteosarcoma, apoptosis, autophagy, JNK activation

Yi Pei,1 YueYan Zhang,2 Ke Zheng,1 GuanNing Shang,1 YuMing Wang,1 Wei Wang,1 EnDuo Qiu,1 ShengLong Li,1 Fei Liu,1 XiaoJing Zhang11Department of Bone and Soft Tissue Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, People’s Republic of China; 2Clinical Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, People’s Republic of ChinaBackground: Osteosarcoma (OS) is the most common primary malignant bone tumor. Hence, there is an urgent need to identify effective and safe therapeutic agents against OS. It has been reported that Ilex hainanensis Merr (IME) possesses antitumor properties. Integrin subunit alpha V (ITGAV) is important for the diagnosis, treatment, and prognosis of tumors.Purpose: The objective of this study was to whether IME can play a role in the treatment of osteosarcoma by regulating ITGAV.Methods: Western blot and real-time PCR were used to detect the expression of ITGAV in non-tumorous tissues, osteosarcoma tissues, and metastatic tumors. The expression of ITGAV in MG63, U2OS, and hFOB1. A total of 19 cells was determined through Western blotting and real-time PCR. The expression of ITGAV in OS cells treated with different concentrations of DDP was determined through Western blotting. Agter transfecting with control or si-ITGAV, and subsequently treated with control or 5 μmol/L DDP, MTT assay and transwell assay were used to detect the proliferaion and migration of cells. Western blot was used to detect the expression of ITGAV in cells treated with different concentrations of IME and MTT assay and transwell assay were used to detect the proliferaion and migration of cells. MG63 and U2OS cells were treated with control, 5 μmol/L DDP, 25 μmol/L IME, or 5 μmol/L DDP combined with 25 μmol/L IME, the expression of ITGAV was determined through Western blotting and real-time PCR. MTT assay and transwell assay were used to detect the proliferation and migration of cells. Inhibitory effect of IME on lung metastasis of osteosarcoma in vivo.Results: ITGAV was highly expressed in tumors, with the highest expression found in metastatic tumors and higher in OS cells. A low concentration of DDP (5 μmol/L) inhibited the expression of ITGAV. However, ITGAV may be related to the development of resistance to DDP. Silencing of ITGAV downregulates the proliferation and migration of OS cells as the effect of low-concentration DDP (5 μmol/L). IME inhibited the proliferation and migration of MG63 and U2OS cells in a concentration-dependent manner and decreased the expression of ITGAV. MTT and Transwell assays showed that 25 μmol/L IME and 5 μmol/L DDP exhibited similar inhibitory effects on the proliferation and migration of OS cells. The combination of IME with DDP resulted in the amplification of these inhibitory effects. Both DDP and IME downregulated the expression of ITGAV, and the inhibition of ITGAV was amplified by the combination of IME with DDP. In-vivo studies have shown that IME and DDP, independently or in combination, may significantly inhibit the metastasis of OS to the lungs.Conclusion: IME may reduce the resistance of OS cells to DDP to some extent.Keywords: Ilex hainanensis Merr, osteosarcoma, integrin subunit alpha V, cisplatin

Yong Huang,1,* Xue Shen,2,* Haixia Qiao,1 Hao Yang,3 Xuejiao Zhang,1 Yiyao Liu,2 Hejie Yang4 1College of Lab Medicine, Hebei North University, Zhangjiakou, 2School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 3Key Laboratory for Green Chemical Process of Ministry of Education, Wuhan Institute of Technology, Wuhan, 4State Key Laboratory for Mechanical Behavior of Materials, Xi’an Jiaotong University, Xi’an, China *These authors contributed equally to this work Background: Two frequent problems associated with titanium (Ti) surfaces of bone/dental implants are their corrosion and lack of native tissue integration.Methods: Here, we present an anodization-hydrothermal method for coating Ti surfaces with a layer of silicon (Si)- and strontium (Sr)-loaded titania nanotubes (TNs). The Ti surfaces coated with such a layer (Si–Sr-TNs) were characterized with different techniques.Results: The results indicate that the Si4+ and Sr2+ ions were evenly incorporated into the TNs and that the Si–Sr-TN layer provides good protection against corrosive media like simulated body fluid. The excellent cytocompatibility of the coating was confirmed in vitro by the significant growth and differentiation of MC3T3-E1 osteoblastic cells.Conclusion: Being easily and economically fabricated, the Si–Sr-TN surfaces may find their niche in clinical applications, thanks to their excellent biological activity and corrosion resistance. Keywords: TiO2 nanotube, silicon, strontium, cytocompatibility, corrosion resistance

Jie Zhang,1 Dan Liu,1 Mengjun Zhang,1 Yuqi Sun,1,2 Xiaojun Zhang,1 Guannan Guan,1 Xiuli Zhao,1 Mingxi Qiao,1 Dawei Chen,1 Haiyang Hu1 1Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 2Department of Pharmaceutics, School of Pharmacy, Liaoning Medical University, Jinzhou, Liaoning Province, People’s Republic of China Abstract: Polyamidoamine dendrimers, which can deliver drugs and genetic materials to resistant cells, are attracting increased research attention, but their transportation behavior in resistant cells remains unclear. In this paper, we performed a systematic analysis of the cellular uptake, intracellular transportation, and efflux of PAMAM-NH2 dendrimers in multidrug-resistant breast cancer cells (MCF-7/ADR cells) using sensitive breast cancer cells (MCF-7 cells) as the control. We found that the uptake rate of PAMAM-NH2 was much lower and exocytosis of PAMAM-NH2 was much greater in MCF-7/ADR cells than in MCF-7 cells due to the elimination of PAMAM-NH2 from P-glycoprotein and the multidrug resistance-associated protein in MCF-7/ADR cells. Macropinocytosis played a more important role in its uptake in MCF-7/ADR cells than in MCF-7 cells. PAMAM-NH2 aggregated and became more degraded in the lysosomal vesicles of the MCF-7/ADR cells than in those of the MCF-7 cells. The endoplasmic reticulum and Golgi complex were found to participate in the exocytosis rather than endocytosis process of PAMAM-NH2 in both types of cells. Our findings clearly showed the intracellular transportation process of PAMAM-NH2 in MCF-7/ADR cells and provided a guide of using PAMAM-NH2 as a drug and gene vector in resistant cells. Keywords: PAMAM dendrimers, multidrug resistance, endocytosis, intracellular transportation, exocytosis

Ning-Kui Niu,1–3 Juan-Juan Yin,3 Yin-Xue Yang,4 Zi-Li Wang,1 Zhi-Wei Zhou,3 Zhi-Xu He,5 Xiao-Wu Chen,6 Xueji Zhang,7 Wei Duan,8 Tianxin Yang,9 Shu-Feng Zhou3 1Department of Orthopedics, General Hospital of Tianjin Medical University, Tianjin, 2Department of Spinal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 4Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, 5Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 6Department of General Surgery, The First People’s Hospital of Shunde Affiliated to Southern Medical University, Shunde, Foshan, Guangdong, 7Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China; 8School of Medicine, Deakin University, Waurn Ponds, VIC, Australia; 9Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA Abstract: Tuberculosis (TB) is still a major public health issue in developing countries, and its chemotherapy is compromised by poor drug compliance and severe side effects. This study aimed to synthesize and characterize new multimodal PEGylated liposomes encapsulated with clinically commonly used anti-TB drugs with linkage to small interfering RNA (siRNA) against transforming growth factor-β1 (TGF-β1). The novel NP-siRNA liposomes could target THP-1-derived human macrophages that were the host cells of mycobacterium infection. The biological effects of the NP-siRNA liposomes were evaluated on cell cycle distribution, apoptosis, autophagy, and the gene silencing efficiency of TGF-β1 siRNA in human macrophages. We also explored the proteomic responses to the newly synthesized NP-siRNA liposomes using the stable isotope labeling with amino acids in cell culture approach. The results showed that the multifunctional PEGylated liposomes were successfully synthesized and chemically characterized with a mean size of 265.1 nm. The novel NP-siRNA liposomes functionalized with the anti-TB drugs and TGF-β1 siRNA were endocytosed efficiently by human macrophages as visualized by transmission electron microscopy and scanning electron microscopy. Furthermore, the liposomes showed a low cytotoxicity toward human macrophages. There was no significant effect on cell cycle distribution and apoptosis in THP-1-derived macrophages after drug exposure at concentrations ranging from 2.5 to 62.5 µg/mL. Notably, there was a 6.4-fold increase in the autophagy of human macrophages when treated with the NP-siRNA liposomes at 62.5 µg/mL. In addition, the TGF-β1 and nuclear factor-κB expression levels were downregulated by the NP-siRNA liposomes in THP-1-derived macrophages. The Ingenuity Pathway Analysis data showed that there were over 40 signaling pathways involved in the proteomic responses to NP-siRNA liposome exposure in human macrophages, with 160 proteins mapped. The top five canonical signaling pathways were eukaryotic initiation factor 2 signaling, actin cytoskeleton signaling, remodeling of epithelial adherens junctions, epithelial adherens junction signaling, and Rho GDP-dissociation inhibitor signaling pathways. Collectively, the novel synthetic targeting liposomes represent a promising delivery system for anti-TB drugs to human macrophages with good selectivity and minimal cytotoxicity. Keywords: tuberculosis, cytokine, liposome, apoptosis, autophagy, cell cycle, proteomics, SILAC, NF-κB, interleukin

Juan-Juan Yin,1,2 Stepan P Shumyak,2 Christopher Burgess,2 Zhi-Wei Zhou,2 Zhi-Xu He,3 Xue-Ji Zhang,4 Shu-Ting Pan,2,5 Tian-Xin Yang,6 Wei Duan,7 Jia-Xuan Qiu,5 Shu-Feng Zhou21Xiaolan People’s Hospital, Southern Medical University, Zhongshan, Guangdong, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA; 3Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 4Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, 5Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 6Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA; 7School of Medicine, Deakin University, Waurn Ponds, VIC, AustraliaAbstract: Breast cancer is a leading killer of women worldwide. Cyclodextrin-based estrogen receptor-targeting drug-delivery systems represent a promising direction in cancer therapy but have rarely been investigated. To seek new targeting therapies for membrane estrogen receptor-positive breast cancer, an estrogen-anchored cyclodextrin encapsulating a doxorubicin derivative Ada-DOX (CDE1-Ada-DOX) has been synthesized and evaluated in human breast cancer MCF-7 cells. First, we synthesized estrone-conjugated cyclodextrin (CDE1), which formed the complex CDE1-Ada-DOX via molecular recognition with the derivative adamantane-doxorubicin (Ada-DOX) (Kd=1,617 M-1). The structure of the targeting vector CDE1 was fully characterized using 1H- and 13C-nuclear magnetic resonance, mass spectrometry, and electron microscopy. CDE1-Ada-DOX showed two-phase drug-release kinetics with much slower release than Ada-DOX. The fluorescence polarization analysis reveals that CDE1-Ada-DOX binds to recombinant human estrogen receptor α fragments with a Kd of 0.027 µM. Competition assay of the drug complex with estrogen ligands demonstrated that estrone and tamoxifen competed with CDE1-Ada-DOX for membrane estrogen receptor binding in MCF-7 cells. Intermolecular self-assembly of CDE1 molecules were observed, showing tail-in-bucket and wire-like structures confirmed by transmission electronic microscopy. CDE1-Ada-DOX had an unexpected lower drug uptake (when the host–guest ratio was >1) than non-targeting drugs in MCF-7 cells due to ensconced ligands in cyclodextrins cavities resulting from the intermolecular self-assembly. The uptake of CDE1-Ada-DOX was significantly increased when the host–guest ratio was adjusted to be less than half at the concentration of CDE1 over 5 µM due to the release of the estrone residues. CDE1 elicited rapid activation of mitogen-activated protein kinases (p44/42 MAPK, Erk1/2) in minutes through phosphorylation of Thr202/Tyr204 in MCF-7 cells. These results demonstrate a targeted therapeutics delivery of CDE1-Ada-DOX to breast cancer cells in a controlled manner and that the drug vector CDE1 can potentially be employed as a molecular tool to differentiate nongenomic from genomic mechanism.Keywords: breast cancer, drug vector, functionalized, membrane estrogen receptor, polysaccharide, targeted drug delivery

Yong-Hui Ding,1,2 Zhi-Wei Zhou,2,3 Chun-Fang Ha,1 Xue-Yu Zhang,1 Shu-Ting Pan,4 Zhi-Xu He,3 Jeffrey L Edelman,2 Dong Wang,5 Yin-Xue Yang,6 Xueji Zhang,7 Wei Duan,8 Tianxin Yang,9 Jia-Xuan Qiu,4 Shu-Feng Zhou2,3 1Department of Gynecology, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; 3Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, 4Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 5Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, 6Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, 7Research Center for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, People’s Republic of China; 8School of Medicine, Deakin University, Waurn Ponds, Australia; 9Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA Abstract: Ovarian cancer is a leading killer of women, and no cure for advanced ovarian cancer is available. Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, has shown potent anticancer effects, and is under clinical investigation for the treatment of advanced solid tumor and hematologic malignancies. However, the role of ALS in the treatment of ovarian cancer remains unclear. This study investigated the effects of ALS on cell growth, apoptosis, autophagy, and epithelial to mesenchymal transition (EMT), and the underlying mechanisms in human epithelial ovarian cancer SKOV3 and OVCAR4 cells. Our docking study showed that ALS, MLN8054, and VX-680 preferentially bound to AURKA over AURKB via hydrogen bond formation, charge interaction, and π-π stacking. ALS had potent growth-inhibitory, proapoptotic, proautophagic, and EMT-inhibitory effects on SKOV3 and OVCAR4 cells. ALS arrested SKOV3 and OVCAR4 cells in G2/M phase and induced mitochondria-mediated apoptosis and autophagy in both SKOV3 and OVCAR4 cell lines in a concentration-dependent manner. ALS suppressed phosphatidylinositol 3-kinase/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase pathways but activated 5′-AMP-dependent kinase, as indicated by their altered phosphorylation, contributing to the proautophagic activity of ALS. Modulation of autophagy altered basal and ALS-induced apoptosis in SKOV3 and OVCAR4 cells. Further, ALS suppressed the EMT-like phenotype in both cell lines by restoring the balance between E-cadherin and N-cadherin. ALS downregulated sirtuin 1 and pre-B cell colony enhancing factor (PBEF/visfatin) expression levels and inhibited phosphorylation of AURKA in both cell lines. These findings indicate that ALS blocks the cell cycle by G2/M phase arrest and promotes cellular apoptosis and autophagy, but inhibits EMT via phosphatidylinositol 3-kinase/Akt/mTOR-mediated and sirtuin 1-mediated pathways in human epithelial ovarian cancer cells. Further studies are warranted to validate the efficacy and safety of ALS in the treatment of ovarian cancer. Keywords: alisertib, Aurora kinase A, epithelial ovarian cancer, cell cycle, apoptosis, autophagy, epithelial to mesenchymal transition, sirtuin 1

© 2016 Nature America, Inc. All rights reserved.Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a

The excitation of magnetospheric whistler-mode chorus in response to interplanetary (IP) shocks is investigated using wave data from the Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft. As an example, we show a typical chorus wave excitation following an IP shock event that was observed by THEMIS in the postnoon sector near the magnetopause on 3 August 2010. We then analyze characteristic changes during this event and perform a survey of similar events during the period 2008-2014 using the THEMIS and OMNI data set. Our statistical analysis demonstrates that the chorus wave excitation/intensification in response to IP shocks occurs only at high L shells (L > 8) on the dayside. We analyzed the variations of magnetic curvature following the arrival of the IP shock and found that IP shocks lead to more homogeneous background magnetic field configurations in the near-equatorial dayside magnetosphere; and therefore, the threshold of nonlinear chorus wave growth is likely to be reduced, favoring chorus wave generation. Our results provide the observational evidence to support the concept that the geomagnetic field line configuration plays a key role in the excitation of dayside chorus. Key Points Excitation of dayside chorus waves is observed These waves are in response to IP shocks IP shocks change the magnetic field line configuration.

© 2014. American Geophysical Union. All Rights Reserved. Due to its importance for global energy dissipation in the ionosphere, the diffuse aurora has been intensively studied in the past 40years. Its origin (precipitation of 0.5-10keV electrons from the plasma sheet without potential acceleration) has been generally attributed to whistler-mode chorus wave scattering in the inner magnetosphere (R < ~8 R E ), while the scattering mechanism beyond that distance remains unresolved. By modeling the quasi-linear diffusion of electrons with realistic parameters for the magnetic field, loss cone size, and wave intensity (obtained from Time History of Events and Macroscale Interactions during Substorms (THEMIS) observations as a function of magnetospheric location), we estimate the loss cone filling ratio and electron cyclotron harmonic (ECH) wave-induced electron precipitation systematically throughout the entire data set, from 6 R E out to 31 R E (the THEMIS apogee). By comparing the wave-induced precipitation directly with the equatorially mapped energy flux distribution of the diffuse aurora from ionospheric observations (OVATION Prime model) at low altitudes, we quantify the contribution of auroral energy flux precipitated due to ECH wave scattering. Although the wave amplitudes decrease, as expected, with distance from the Earth, due to the smaller loss cone size and stretched magnetic field topology, ECH waves are still capable of causing sufficient scattering of plasma sheet electrons to account for the observed diffuse auroral dissipation. Our results demonstrate that ECH waves are the dominant driver of the diffuse aurora in the outer magnetosphere, beyond ~8 R E .

Several variants of T4 lysozyme have been identified that sequester small organic ligands in cavities or clefts. To evaluate potential binding sites for non-polar molecules, we screened a number of hydrophobic large-to-small mutants for stabilization in the presence of benzene. In addition to Leu99-->Ala, binding was indicated for at least five other mutants. Variants Met102-->Ala and Leu133-->Gly, and a crevice mutant, Phe104-->Ala, were further characterized using X-ray crystallography and thermal denaturation. As predicted from the shape of the cavity in the benzene complex, mutant Leu133-->Gly also bound p-xylene. We attempted to enlarge the cavity of the Met102-->Ala mutant into a deep crevice through an additional substitution, but the double mutant failed to bind ligands because an adjacent helix rearranged into a non-helical structure, apparently due to the loss of packing interactions. In general, the protein structure contracted slightly to reduce the volume of the void created by truncating substitutions and expanded upon binding the non-polar ligand, with shifts similar to those resulting from the mutations.A polar molecule binding site was also created by truncating Arg95 to alanine. This creates a highly complementary buried polar environment that can be utilized as a specific "receptor" for a guanidinium ion. Our results suggest that creating a deficiency through truncating mutations of buried residues generates "binding potential" for ligands with characteristics similar to the deleted side-chain. Analysis of complex and apo crystal structures of binding and non-binding mutants suggests that ligand size and shape as well as protein flexibility and complementarity are all determinants of binding. Binding at non-polar sites is governed by hydrophobicity and steric interactions and is relatively permissive. Binding at a polar site is more restrictive and requires extensive complementarity between the ligand and the site.

Six "cavity-creating" mutants, Leu46----Ala (L46A), L99A, L118A, L121A, L133A, and Phe153----Ala (F153A), were constructed within the hydrophobic core of phage T4 lysozyme. The substitutions decreased the stability of the protein at pH 3.0 by different amounts, ranging from 2.7 kilocalories per mole (kcal mol-1) for L46A and L121A to 5.0 kcal mol-1 for L99A. The double mutant L99A/F153A was also constructed and decreased in stability by 8.3 kcal mol-1. The x-ray structures of all of the variants were determined at high resolution. In every case, removal of the wild-type side chain allowed some of the surrounding atoms to move toward the vacated space but a cavity always remained, which ranged in volume from 24 cubic angstroms (A3) for L46A to 150 A3 for L99A. No solvent molecules were observed in any of these cavities. The destabilization of the mutant Leu----Ala proteins relative to wild type can be approximated by a constant term (approximately 2.0 kcal mol-1) plus a term that increases in proportion to the size of the cavity. The constant term is approximately equal to the transfer free energy of leucine relative to alanine as determined from partitioning between aqueous and organic solvents. The energy term that increases with the size of the cavity can be expressed either in terms of the cavity volume (24 to 33 cal mol-1 A-3) or in terms of the cavity surface area (20 cal mol-1 A-2). The results suggest how to reconcile a number of conflicting reports concerning the strength of the hydrophobic effect in proteins.

The lysozyme from bacteriophage T4 is being used as a model system to determine the roles of individual amino acids in the folding and stability of a typical globular protein. One general finding is that the protein is very adaptable, being able to accommodate many potentially destabilizing replacements. In order to determine the importance of 'alpha-helix propensity' in protein stability, different replacements have been made within alpha-helical segments of T4 lysozyme. Several such substitutions of the form Xaa-->Ala increase the stability of the protein, supporting the idea that alanine is a strongly helix-favouring amino acid. It is possible to engineer a protein that has up to ten alanines in succession, yet still folds and has normal activity. This illustrates the redundancy that is present in the amino acid sequence. A number of 'cavity-creating' mutants of the form Leu-->Ala have been constructed to understand better the nature of hydrophobic stabilization. The structural consequences of these mutations differ from site to site. In some cases the protein structure hardly changes at all; in other cases removal of the wild-type side-chain allows surrounding atoms to move in and occupy the vacated space, although a cavity always remains. The destabilization of the protein associated with these cavity-creating mutations also varies from case to case. The results suggest how to reconcile recent conflicting reports concerning the strength of the hydrophobic effect in proteins.